Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.

The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.

“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.

“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”

Background immunosuppressants contribute to unprecedented placebo responses

The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.

A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.

Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.

The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.

“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.

The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.

In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.

Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.

Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
 

Changes in secondary endpoints followed same pattern as CRISS

The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.

However, the researchers again found that duration of background therapy affected FVC.

“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.

Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.

Is there a subgroup for whom lenabasum would be efficacious?

Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.

“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”

Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.

Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.

“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”

Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”

Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.

“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.

He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.

“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”

Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.

“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”

The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.

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

Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.

The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.

“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.

“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”

Background immunosuppressants contribute to unprecedented placebo responses

The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.

A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.

Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.

The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.

“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.

The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.

In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.

Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.

Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
 

Changes in secondary endpoints followed same pattern as CRISS

The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.

However, the researchers again found that duration of background therapy affected FVC.

“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.

Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.

Is there a subgroup for whom lenabasum would be efficacious?

Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.

“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”

Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.

Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.

“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”

Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”

Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.

“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.

He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.

“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”

Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.

“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”

The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.

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

Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.

The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.

“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.

“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”

Background immunosuppressants contribute to unprecedented placebo responses

The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.

A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.

Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.

The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.

“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.

The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.

In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.

Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.

Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
 

Changes in secondary endpoints followed same pattern as CRISS

The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.

However, the researchers again found that duration of background therapy affected FVC.

“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.

Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.

Is there a subgroup for whom lenabasum would be efficacious?

Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.

“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”

Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.

Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.

“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”

Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”

Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.

“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.

He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.

“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”

Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.

“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”

The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.

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

Further evidence that powerful magnets in some Apple iPhones can interfere with cardiac implantable electronic devices (CIEDs) comes from a small study that also suggests some devices are more susceptible than others.

The iPhone 12 Pro Max with MagSafe technology interfered with CIEDs implanted in three consecutive patients presenting to an electrophysiology lab and in 8 of 11 implantable cardioverter defibrillators (ICDs) and pacemakers (72.7%) still in their original packaging.

The results, published in the Journal of the American Heart Association, are consistent with a widely publicized single-patient report this February and evidence of electromagnetic interference with fitness wristbands and e-cigarettes.

The MagSafe technology supports wireless charging and is optimized by a ring-shaped array of magnets. Although magnet mode activation has been shown to occur in CIEDs with exposure to a magnetic field as low as 10 gauss, the field strength of the iPhone 12 Pro Max can be greater than 50 G when in direct contact, the researchers determined.

“If this becomes a standard in a lot of the new smartphones or companies start to use stronger magnets ... then we will see more and more of these consumer electronic and device interactions,” senior author Michael Wu, MD, Brown University, Providence, R.I., told this news organization.

In a May advisory on these device interactions, the U.S. Food and Drug Administration also cautioned that the number of consumer electronics with strong magnets is expected to increase over time.

That trend appears to be already underway, with Forbes reporting in February that the MagSafe batteries will be “getting stronger” as part of upgrades to the iPhone 13 and Bloomberg reporting in advance of Apple’s annual developers conference this week that an upgraded version of MagSafe is in the works to support wireless charging for its iPad. MagSafe has not been used previously in iPads.

Although Apple has acknowledged that the iPhone 12 contains more magnets than previous iPhone models, it says “they’re not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” The company maintains a page that specifically warns about the potential for interactions and advises that consumers keep the iPhone and MagSafe accessories more than 15 cm (6 inches) away from medical devices.

Older-generation iPhones have not shown this risk, with only one case of interference reported with the iPhone 6 and an Apple Watch in 1,352 tests among 148 patients with CIEDs and leads from four different manufacturers.

In the present study, magnet reversion mode was triggered in all three patients when the iPhone 12 Pro Max was placed on the skin over the device.

The phone inhibited tachycardia therapies in Medtronic’s Amplia MRI Quad CRT-D and Abbott’s 1231-40 Fortify VR device.

The Boston Scientific V273 Intua CRT-P device, however, “appeared to be less susceptible, as we were only able to elicit transient temporary asynchronous pacing but no sustained response by the iPhone 12 Pro Max magnet,” Dr. Wu and colleagues note.

Among the 11 ex vivo CIEDs tested, placing the iPhone 12 Pro Max directly over the packaged device inhibited tachytherapies in Medtronic’s Visia AF MRI ICD and Abbott’s Fortify Assura DR ICD and Ellipse DR ICD.

The phone also led to asynchronous pacing in Medtronic’s Azure, Advisa MRI, and Adapta pacemakers and in Abbott’s Assurity MRI pacemaker.

Boston Scientific devices again “appeared to be less susceptible, as no clear magnet interference” was noted in the Dynagen ICD, Emblem MRI S-ICD, or Accolade MRI pacemaker, Dr. Wu reported. There was temporary asynchronous pacing but no sustained response in the company’s U125 Valitude pacemaker.

Using the Medtronic Visia AF MRI ICD, the researchers found that the iPhone 12 Pro Max was able to trigger magnet reversion mode at a distance up to 1.5 cm (0.6 inch) from the anterior aspect of the device ex vivo.

The difference in magnet response to the iPhone 12 Pro Max among the different devices is likely due to different hall-sensor magnet sensitivity, as all of the devices were susceptible to a standard donut magnet, Dr. Wu noted. Boston Scientific’s Accolade MRI pacemaker, for example, requires a magnet stronger than 70 G to activate magnet mode, according to the product manual.

“Even so, sometimes with our test, we were able to trigger a brief response,” he said. “The response isn’t as lasting as some of the other companies, but with the small sample size, I can only speculate and suggest that maybe it’s possible. But we always want a formal study through the company or other agencies to really pinpoint which company has more susceptible devices.”

As to whether manufacturers should build CIEDs less susceptible to today’s stronger magnets, Dr. Wu said it’s worth exploring, but there are pros and cons.

Although magnets in consumer devices have the potential to inhibit lifesaving therapies, a magnet is also very useful in certain medical settings, such as a quick way to ensure pacing without worrying about electrocautery noise during surgery or to deactivate a defibrillator if there’s noise resulting in inappropriate shocks.

“It would require an overhaul of a lot of the devices going forward, and I think that’s something that’s worth exploring, especially now that a lot of devices are using wireless communication, Bluetooth, and other communication technology,” he said.

Even though the study is small, Dr. Wu said, it does represent many of the available devices and has clinical implications, given that people often put their smartphones in a breast pocket.

“This report highlights the importance of public awareness regarding an interaction between CIEDs and a recently released smartphone model with magnetic charging capability,” Dr. Wu and colleagues conclude.

Apple was contacted for comment but had not responded at press time.

The authors reported no study funding or relevant conflicts of interests.

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

Further evidence that powerful magnets in some Apple iPhones can interfere with cardiac implantable electronic devices (CIEDs) comes from a small study that also suggests some devices are more susceptible than others.

The iPhone 12 Pro Max with MagSafe technology interfered with CIEDs implanted in three consecutive patients presenting to an electrophysiology lab and in 8 of 11 implantable cardioverter defibrillators (ICDs) and pacemakers (72.7%) still in their original packaging.

The results, published in the Journal of the American Heart Association, are consistent with a widely publicized single-patient report this February and evidence of electromagnetic interference with fitness wristbands and e-cigarettes.

The MagSafe technology supports wireless charging and is optimized by a ring-shaped array of magnets. Although magnet mode activation has been shown to occur in CIEDs with exposure to a magnetic field as low as 10 gauss, the field strength of the iPhone 12 Pro Max can be greater than 50 G when in direct contact, the researchers determined.

“If this becomes a standard in a lot of the new smartphones or companies start to use stronger magnets ... then we will see more and more of these consumer electronic and device interactions,” senior author Michael Wu, MD, Brown University, Providence, R.I., told this news organization.

In a May advisory on these device interactions, the U.S. Food and Drug Administration also cautioned that the number of consumer electronics with strong magnets is expected to increase over time.

That trend appears to be already underway, with Forbes reporting in February that the MagSafe batteries will be “getting stronger” as part of upgrades to the iPhone 13 and Bloomberg reporting in advance of Apple’s annual developers conference this week that an upgraded version of MagSafe is in the works to support wireless charging for its iPad. MagSafe has not been used previously in iPads.

Although Apple has acknowledged that the iPhone 12 contains more magnets than previous iPhone models, it says “they’re not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” The company maintains a page that specifically warns about the potential for interactions and advises that consumers keep the iPhone and MagSafe accessories more than 15 cm (6 inches) away from medical devices.

Older-generation iPhones have not shown this risk, with only one case of interference reported with the iPhone 6 and an Apple Watch in 1,352 tests among 148 patients with CIEDs and leads from four different manufacturers.

In the present study, magnet reversion mode was triggered in all three patients when the iPhone 12 Pro Max was placed on the skin over the device.

The phone inhibited tachycardia therapies in Medtronic’s Amplia MRI Quad CRT-D and Abbott’s 1231-40 Fortify VR device.

The Boston Scientific V273 Intua CRT-P device, however, “appeared to be less susceptible, as we were only able to elicit transient temporary asynchronous pacing but no sustained response by the iPhone 12 Pro Max magnet,” Dr. Wu and colleagues note.

Among the 11 ex vivo CIEDs tested, placing the iPhone 12 Pro Max directly over the packaged device inhibited tachytherapies in Medtronic’s Visia AF MRI ICD and Abbott’s Fortify Assura DR ICD and Ellipse DR ICD.

The phone also led to asynchronous pacing in Medtronic’s Azure, Advisa MRI, and Adapta pacemakers and in Abbott’s Assurity MRI pacemaker.

Boston Scientific devices again “appeared to be less susceptible, as no clear magnet interference” was noted in the Dynagen ICD, Emblem MRI S-ICD, or Accolade MRI pacemaker, Dr. Wu reported. There was temporary asynchronous pacing but no sustained response in the company’s U125 Valitude pacemaker.

Using the Medtronic Visia AF MRI ICD, the researchers found that the iPhone 12 Pro Max was able to trigger magnet reversion mode at a distance up to 1.5 cm (0.6 inch) from the anterior aspect of the device ex vivo.

The difference in magnet response to the iPhone 12 Pro Max among the different devices is likely due to different hall-sensor magnet sensitivity, as all of the devices were susceptible to a standard donut magnet, Dr. Wu noted. Boston Scientific’s Accolade MRI pacemaker, for example, requires a magnet stronger than 70 G to activate magnet mode, according to the product manual.

“Even so, sometimes with our test, we were able to trigger a brief response,” he said. “The response isn’t as lasting as some of the other companies, but with the small sample size, I can only speculate and suggest that maybe it’s possible. But we always want a formal study through the company or other agencies to really pinpoint which company has more susceptible devices.”

As to whether manufacturers should build CIEDs less susceptible to today’s stronger magnets, Dr. Wu said it’s worth exploring, but there are pros and cons.

Although magnets in consumer devices have the potential to inhibit lifesaving therapies, a magnet is also very useful in certain medical settings, such as a quick way to ensure pacing without worrying about electrocautery noise during surgery or to deactivate a defibrillator if there’s noise resulting in inappropriate shocks.

“It would require an overhaul of a lot of the devices going forward, and I think that’s something that’s worth exploring, especially now that a lot of devices are using wireless communication, Bluetooth, and other communication technology,” he said.

Even though the study is small, Dr. Wu said, it does represent many of the available devices and has clinical implications, given that people often put their smartphones in a breast pocket.

“This report highlights the importance of public awareness regarding an interaction between CIEDs and a recently released smartphone model with magnetic charging capability,” Dr. Wu and colleagues conclude.

Apple was contacted for comment but had not responded at press time.

The authors reported no study funding or relevant conflicts of interests.

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

Further evidence that powerful magnets in some Apple iPhones can interfere with cardiac implantable electronic devices (CIEDs) comes from a small study that also suggests some devices are more susceptible than others.

The iPhone 12 Pro Max with MagSafe technology interfered with CIEDs implanted in three consecutive patients presenting to an electrophysiology lab and in 8 of 11 implantable cardioverter defibrillators (ICDs) and pacemakers (72.7%) still in their original packaging.

The results, published in the Journal of the American Heart Association, are consistent with a widely publicized single-patient report this February and evidence of electromagnetic interference with fitness wristbands and e-cigarettes.

The MagSafe technology supports wireless charging and is optimized by a ring-shaped array of magnets. Although magnet mode activation has been shown to occur in CIEDs with exposure to a magnetic field as low as 10 gauss, the field strength of the iPhone 12 Pro Max can be greater than 50 G when in direct contact, the researchers determined.

“If this becomes a standard in a lot of the new smartphones or companies start to use stronger magnets ... then we will see more and more of these consumer electronic and device interactions,” senior author Michael Wu, MD, Brown University, Providence, R.I., told this news organization.

In a May advisory on these device interactions, the U.S. Food and Drug Administration also cautioned that the number of consumer electronics with strong magnets is expected to increase over time.

That trend appears to be already underway, with Forbes reporting in February that the MagSafe batteries will be “getting stronger” as part of upgrades to the iPhone 13 and Bloomberg reporting in advance of Apple’s annual developers conference this week that an upgraded version of MagSafe is in the works to support wireless charging for its iPad. MagSafe has not been used previously in iPads.

Although Apple has acknowledged that the iPhone 12 contains more magnets than previous iPhone models, it says “they’re not expected to pose a greater risk of magnetic interference to medical devices than prior iPhone models.” The company maintains a page that specifically warns about the potential for interactions and advises that consumers keep the iPhone and MagSafe accessories more than 15 cm (6 inches) away from medical devices.

Older-generation iPhones have not shown this risk, with only one case of interference reported with the iPhone 6 and an Apple Watch in 1,352 tests among 148 patients with CIEDs and leads from four different manufacturers.

In the present study, magnet reversion mode was triggered in all three patients when the iPhone 12 Pro Max was placed on the skin over the device.

The phone inhibited tachycardia therapies in Medtronic’s Amplia MRI Quad CRT-D and Abbott’s 1231-40 Fortify VR device.

The Boston Scientific V273 Intua CRT-P device, however, “appeared to be less susceptible, as we were only able to elicit transient temporary asynchronous pacing but no sustained response by the iPhone 12 Pro Max magnet,” Dr. Wu and colleagues note.

Among the 11 ex vivo CIEDs tested, placing the iPhone 12 Pro Max directly over the packaged device inhibited tachytherapies in Medtronic’s Visia AF MRI ICD and Abbott’s Fortify Assura DR ICD and Ellipse DR ICD.

The phone also led to asynchronous pacing in Medtronic’s Azure, Advisa MRI, and Adapta pacemakers and in Abbott’s Assurity MRI pacemaker.

Boston Scientific devices again “appeared to be less susceptible, as no clear magnet interference” was noted in the Dynagen ICD, Emblem MRI S-ICD, or Accolade MRI pacemaker, Dr. Wu reported. There was temporary asynchronous pacing but no sustained response in the company’s U125 Valitude pacemaker.

Using the Medtronic Visia AF MRI ICD, the researchers found that the iPhone 12 Pro Max was able to trigger magnet reversion mode at a distance up to 1.5 cm (0.6 inch) from the anterior aspect of the device ex vivo.

The difference in magnet response to the iPhone 12 Pro Max among the different devices is likely due to different hall-sensor magnet sensitivity, as all of the devices were susceptible to a standard donut magnet, Dr. Wu noted. Boston Scientific’s Accolade MRI pacemaker, for example, requires a magnet stronger than 70 G to activate magnet mode, according to the product manual.

“Even so, sometimes with our test, we were able to trigger a brief response,” he said. “The response isn’t as lasting as some of the other companies, but with the small sample size, I can only speculate and suggest that maybe it’s possible. But we always want a formal study through the company or other agencies to really pinpoint which company has more susceptible devices.”

As to whether manufacturers should build CIEDs less susceptible to today’s stronger magnets, Dr. Wu said it’s worth exploring, but there are pros and cons.

Although magnets in consumer devices have the potential to inhibit lifesaving therapies, a magnet is also very useful in certain medical settings, such as a quick way to ensure pacing without worrying about electrocautery noise during surgery or to deactivate a defibrillator if there’s noise resulting in inappropriate shocks.

“It would require an overhaul of a lot of the devices going forward, and I think that’s something that’s worth exploring, especially now that a lot of devices are using wireless communication, Bluetooth, and other communication technology,” he said.

Even though the study is small, Dr. Wu said, it does represent many of the available devices and has clinical implications, given that people often put their smartphones in a breast pocket.

“This report highlights the importance of public awareness regarding an interaction between CIEDs and a recently released smartphone model with magnetic charging capability,” Dr. Wu and colleagues conclude.

Apple was contacted for comment but had not responded at press time.

The authors reported no study funding or relevant conflicts of interests.

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

A dermal-wounding strategy involving fractionated laser resurfacing not only treated actinic keratoses, but it prevented the development of nonmelanoma skin cancer on treated areas, according to the results of a small, randomized trial.

“Previous research suggests a new model to explain why older patients obtain nonmelanoma skin cancer in areas of ongoing sun exposure,” presenting author Jeffrey Wargo, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “Insulinlike growth factor-1 produced by dermal fibroblasts dictates how overlying skin keratinocytes respond to UVB radiation. The skin of a patient aged in their 20s produces normal levels of healthy fibroblasts, normal levels of insulinlike growth factor 1, and appropriate UVB response via activation of nucleotide excision, repair, and DNA damage checkpoint-signaling systems.”

Older patients, meanwhile, have an increase in senescent fibroblasts, decreased insulinlike growth factor-1 (IGF-1), and an inappropriate UVB response to DNA damage, continued Dr. Wargo, a dermatologist at the Ohio State University Wexner Medical Center in Columbus. Previous studies conducted by his mentor, Jeffrey B. Travers, MD, PhD, a dermatologist and pharmacologist at Wright State University, Dayton, showed that fractionated laser resurfacing (FLR) restores UVB response in older patients’ skin by resulting in new fibroblasts and increased levels of IGF 2 years post wounding.

To determine if FLR of aged skin can prevent the development of actinic keratosis (AK) and nonmelanoma skin cancer, Dr. Travers and Dr. Wargo recruited 48 patients at the Dayton VA Medical Center who were 60 years or older and had at least five AKs on each arm that were 3 mm or smaller, with nothing concerning for skin cancer at the screening visit.

Randomization of which arm was treated was based on an odd or even Social Security Number. That arm was treated with the 2,790 nm Erbium:YSSG ablative laser at 120 J/m² with one pass at 24% coverage from the elbow to hand dorsally. Previously published data reported outcomes for 30 of these patients at 3 and 6 months following treatment. Subsequent to that report, 18 additional subjects have been recruited to the study and follow-up has been extended. Of the 48 patients, 47 were male and their average age was 74, with a range between 61 and 87 years.

At 3 months following FLR, the ratio of AKs on the treated vs. untreated arms was reduced by fourfold, with a P value less than .00001^{, Dr. Wargo reported}. “Throughout the current 30-month follow-up period, this ratio has been maintained,” he said. “In fact, none of the ratios determined at 3, 6, 12, 18, 24, or 30 months post FLR are significantly different. Hence, as described in our first report on this work, these data indicate FLR is an effective treatment for existing AKs. However, our model predicts that FLR treatment will also prevent the occurrence of new AK lesions.”

Among 19 of the study participants who have been followed out to 30 months, untreated arms continued to accumulate increasing number of AKs. In contrast, AKs on treated arms are decreasing with time, indicating the lack of newly initiated lesions.

“A second analysis of the data posits that, if FLR were only removing existing lesions, one would predict the number of AKs that were present at 3 months on both the untreated and FLR-treated [arms] would accumulate at the same rate subsequent to 3 months point in time,” Dr. Wargo said.

He pointed out that 12 patients were removed from the study: two at 12 months, one at 18 months, eight at 24 months, and one at 30 months, as they were found to have 20 or more AKs on their untreated arm and required treatment.

Over the entire study period, “consistent with the notion that FLR was preventing new actinic neoplasia, we noted a dramatic difference in numbers of nonmelanoma skin cancer diagnosed in the untreated areas (22) versus FLR treated areas (2),” Dr. Wargo said. The majority of nonmelanoma skin cancers diagnosed were SCC (17) and 5 basal cell carcinomas on the untreated arms, whereas the 2 diagnosed on the treated arm were SCC. “These studies indicate that a dermal-wounding strategy involving FLR, which upregulates dermal IGF-1 levels, not only treats AKs but prevents nonmelanoma skin cancer,” he said.

The study was funded by the National Institutes of Health. Dr. Travers is the principal investigator. Dr. Wargo reported having no financial disclosures.

[email protected]

A dermal-wounding strategy involving fractionated laser resurfacing not only treated actinic keratoses, but it prevented the development of nonmelanoma skin cancer on treated areas, according to the results of a small, randomized trial.

“Previous research suggests a new model to explain why older patients obtain nonmelanoma skin cancer in areas of ongoing sun exposure,” presenting author Jeffrey Wargo, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “Insulinlike growth factor-1 produced by dermal fibroblasts dictates how overlying skin keratinocytes respond to UVB radiation. The skin of a patient aged in their 20s produces normal levels of healthy fibroblasts, normal levels of insulinlike growth factor 1, and appropriate UVB response via activation of nucleotide excision, repair, and DNA damage checkpoint-signaling systems.”

Older patients, meanwhile, have an increase in senescent fibroblasts, decreased insulinlike growth factor-1 (IGF-1), and an inappropriate UVB response to DNA damage, continued Dr. Wargo, a dermatologist at the Ohio State University Wexner Medical Center in Columbus. Previous studies conducted by his mentor, Jeffrey B. Travers, MD, PhD, a dermatologist and pharmacologist at Wright State University, Dayton, showed that fractionated laser resurfacing (FLR) restores UVB response in older patients’ skin by resulting in new fibroblasts and increased levels of IGF 2 years post wounding.

To determine if FLR of aged skin can prevent the development of actinic keratosis (AK) and nonmelanoma skin cancer, Dr. Travers and Dr. Wargo recruited 48 patients at the Dayton VA Medical Center who were 60 years or older and had at least five AKs on each arm that were 3 mm or smaller, with nothing concerning for skin cancer at the screening visit.

Randomization of which arm was treated was based on an odd or even Social Security Number. That arm was treated with the 2,790 nm Erbium:YSSG ablative laser at 120 J/m² with one pass at 24% coverage from the elbow to hand dorsally. Previously published data reported outcomes for 30 of these patients at 3 and 6 months following treatment. Subsequent to that report, 18 additional subjects have been recruited to the study and follow-up has been extended. Of the 48 patients, 47 were male and their average age was 74, with a range between 61 and 87 years.

At 3 months following FLR, the ratio of AKs on the treated vs. untreated arms was reduced by fourfold, with a P value less than .00001^{, Dr. Wargo reported}. “Throughout the current 30-month follow-up period, this ratio has been maintained,” he said. “In fact, none of the ratios determined at 3, 6, 12, 18, 24, or 30 months post FLR are significantly different. Hence, as described in our first report on this work, these data indicate FLR is an effective treatment for existing AKs. However, our model predicts that FLR treatment will also prevent the occurrence of new AK lesions.”

Among 19 of the study participants who have been followed out to 30 months, untreated arms continued to accumulate increasing number of AKs. In contrast, AKs on treated arms are decreasing with time, indicating the lack of newly initiated lesions.

“A second analysis of the data posits that, if FLR were only removing existing lesions, one would predict the number of AKs that were present at 3 months on both the untreated and FLR-treated [arms] would accumulate at the same rate subsequent to 3 months point in time,” Dr. Wargo said.

He pointed out that 12 patients were removed from the study: two at 12 months, one at 18 months, eight at 24 months, and one at 30 months, as they were found to have 20 or more AKs on their untreated arm and required treatment.

Over the entire study period, “consistent with the notion that FLR was preventing new actinic neoplasia, we noted a dramatic difference in numbers of nonmelanoma skin cancer diagnosed in the untreated areas (22) versus FLR treated areas (2),” Dr. Wargo said. The majority of nonmelanoma skin cancers diagnosed were SCC (17) and 5 basal cell carcinomas on the untreated arms, whereas the 2 diagnosed on the treated arm were SCC. “These studies indicate that a dermal-wounding strategy involving FLR, which upregulates dermal IGF-1 levels, not only treats AKs but prevents nonmelanoma skin cancer,” he said.

The study was funded by the National Institutes of Health. Dr. Travers is the principal investigator. Dr. Wargo reported having no financial disclosures.

[email protected]

A dermal-wounding strategy involving fractionated laser resurfacing not only treated actinic keratoses, but it prevented the development of nonmelanoma skin cancer on treated areas, according to the results of a small, randomized trial.

“Previous research suggests a new model to explain why older patients obtain nonmelanoma skin cancer in areas of ongoing sun exposure,” presenting author Jeffrey Wargo, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “Insulinlike growth factor-1 produced by dermal fibroblasts dictates how overlying skin keratinocytes respond to UVB radiation. The skin of a patient aged in their 20s produces normal levels of healthy fibroblasts, normal levels of insulinlike growth factor 1, and appropriate UVB response via activation of nucleotide excision, repair, and DNA damage checkpoint-signaling systems.”

Older patients, meanwhile, have an increase in senescent fibroblasts, decreased insulinlike growth factor-1 (IGF-1), and an inappropriate UVB response to DNA damage, continued Dr. Wargo, a dermatologist at the Ohio State University Wexner Medical Center in Columbus. Previous studies conducted by his mentor, Jeffrey B. Travers, MD, PhD, a dermatologist and pharmacologist at Wright State University, Dayton, showed that fractionated laser resurfacing (FLR) restores UVB response in older patients’ skin by resulting in new fibroblasts and increased levels of IGF 2 years post wounding.

To determine if FLR of aged skin can prevent the development of actinic keratosis (AK) and nonmelanoma skin cancer, Dr. Travers and Dr. Wargo recruited 48 patients at the Dayton VA Medical Center who were 60 years or older and had at least five AKs on each arm that were 3 mm or smaller, with nothing concerning for skin cancer at the screening visit.

Randomization of which arm was treated was based on an odd or even Social Security Number. That arm was treated with the 2,790 nm Erbium:YSSG ablative laser at 120 J/m² with one pass at 24% coverage from the elbow to hand dorsally. Previously published data reported outcomes for 30 of these patients at 3 and 6 months following treatment. Subsequent to that report, 18 additional subjects have been recruited to the study and follow-up has been extended. Of the 48 patients, 47 were male and their average age was 74, with a range between 61 and 87 years.

At 3 months following FLR, the ratio of AKs on the treated vs. untreated arms was reduced by fourfold, with a P value less than .00001^{, Dr. Wargo reported}. “Throughout the current 30-month follow-up period, this ratio has been maintained,” he said. “In fact, none of the ratios determined at 3, 6, 12, 18, 24, or 30 months post FLR are significantly different. Hence, as described in our first report on this work, these data indicate FLR is an effective treatment for existing AKs. However, our model predicts that FLR treatment will also prevent the occurrence of new AK lesions.”

Among 19 of the study participants who have been followed out to 30 months, untreated arms continued to accumulate increasing number of AKs. In contrast, AKs on treated arms are decreasing with time, indicating the lack of newly initiated lesions.

“A second analysis of the data posits that, if FLR were only removing existing lesions, one would predict the number of AKs that were present at 3 months on both the untreated and FLR-treated [arms] would accumulate at the same rate subsequent to 3 months point in time,” Dr. Wargo said.

He pointed out that 12 patients were removed from the study: two at 12 months, one at 18 months, eight at 24 months, and one at 30 months, as they were found to have 20 or more AKs on their untreated arm and required treatment.

Over the entire study period, “consistent with the notion that FLR was preventing new actinic neoplasia, we noted a dramatic difference in numbers of nonmelanoma skin cancer diagnosed in the untreated areas (22) versus FLR treated areas (2),” Dr. Wargo said. The majority of nonmelanoma skin cancers diagnosed were SCC (17) and 5 basal cell carcinomas on the untreated arms, whereas the 2 diagnosed on the treated arm were SCC. “These studies indicate that a dermal-wounding strategy involving FLR, which upregulates dermal IGF-1 levels, not only treats AKs but prevents nonmelanoma skin cancer,” he said.

The study was funded by the National Institutes of Health. Dr. Travers is the principal investigator. Dr. Wargo reported having no financial disclosures.

[email protected]

A HER3-targeted therapy has demonstrated clinically meaningful and durable efficacy in heavily pretreated patients with EGFR-mutant non–small cell lung cancer, according to results of a phase 1 study.

Patritumab deruxtecan, an antibody-drug conjugate targeting HER3, had an overall response rate (ORR) of 39% and median progression-free survival (PFS) of 8.2 months in a phase 1 study that included patients previously treated with tyrosine kinase inhibitors (TKIs) and chemotherapy, the results show.

The efficacy was seen across EGFR TKI resistance mechanisms in this very difficult-to-treat patient population, according to investigator Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute, Boston.

“There is not one category of individuals that are having a response, or not having a response,” Dr. Jänne said in a presentation at the annual meeting of the American Society of Clinical Oncology (Abstract 9007).

“Responses are observed in patients with identifiable resistance mechanisms, and in patients that do not have an identifiable resistance mechanism, but have progressed on prior EGFR TKI therapy,” he added.

More than 80% of non–small cell lung cancer (NSCLC) tumors express HER3, and of note, HER3 alterations do not appear to confer resistance to EGFR TKIs in patients with EGFR-mutant NSCLC, according to Dr. Jänne.
 

Study details

Also known as HER3-DXd, patritumab deruxtecan consists of a fully human anti-HER3 monoclonal antibody linked to a topoisomerase inhibitor payload by a tetrapeptide-based cleavable linker.

The antibody-drug conjugate is also being evaluated in metastatic breast cancer and colorectal cancer, Dr. Jänne said.

In the present phase 1 dose escalation and dose expansion study, a total of 57 patients were treated with patritumab deruxtecan at 5.6 mg/kg, the recommended dose for the expansion phase.

The median age of these patients was 65 years, and the majority (63%) were women, Dr. Jänne reported. About half had a history of central nervous system metastases.

The median number of prior lines of systemic therapy was four, making this a heavily pretreated patient population, Dr. Jänne said. All patients had received prior EGFR TKI therapy, and 86% specifically had prior osimertinib. Ninety-one percent had prior platinum-based chemotherapy, and 40% had received immunotherapy.
 

Spectrum of responses

The confirmed ORR of 39% included 1 complete response (2%) and 21 partial responses (37%), Dr. Jänne reported. The disease control rate was 72%, and median duration of response was 6.9 months at a median follow-up of 10.2 months.

The median PFS was 8.2 months in 57 patients overall and in a subset of 44 patients who had received prior osimertinib and platinum-based chemotherapy, according to the report.

Activity of patritumab deruxtecan was seen not only across patients with diverse mechanisms of EGFR TKI resistance, but also regardless of prior number of treatments, and regardless of history of brain metastases, the investigator said.

In addition, clinical responses were seen across a spectrum of baseline HER3 expression by immunohistochemistry, the investigator added.

Safety was assessed in 81 patients treated at a range of doses in the phase 1 trial. The most common grade 3 or greater treatment-emergent adverse events, observed in 5% or more of patients, included thrombocytopenia, neutropenia, and anemia, while other side effects such as fatigue and dyspnea were observed, Dr. Jänne said. About 9% of the adverse events led to treatment discontinuation in the safety cohort.

Interstitial lung disease was observed in four patients, or 5% of the safety cohort. Three of these were grade 1-2 and one was grade 3, according to the report.
 

Questions to explore

The efficacy of patritumab deruxtecan was “high” in this phase 1 study, based on the reported response rate and median PFS, said discussant Nicolas Girard, MD, PhD, of Institut Curie in Paris.

However, the most striking finding of the study was the efficacy of the antibody-drug conjugate across all reported resistance mechanisms, Dr. Girard said in his remarks.

Questions that remains to be explored, according to Dr. Girard, include the impact of previous treatment sequencing with TKIs and chemotherapy on patient outcomes with patritumab deruxtecan, as well as the assessment of intracranial response and PFS for patients treated with the agent.

In addition, antitumor activity was seen across a wide range of baseline HER3 expression levels in this study, suggesting that a predictive biomarker remains to be identified, according to Dr. Girard.

“HER3 immunohistochemistry does not seem to be the candidate in this setting,” he said.

The study was sponsored by Daiichi Sankyo. Dr. Jänne reported disclosures related to Daiichi Sankyo, as well as Araxes Pharma, Astellas Pharma, AstraZeneca, and multiple other pharmaceutical companies. Dr. Jänne is also coinventor on a Dana Farber Cancer Institute–owned patent on EGFR mutations licensed to Labcorp and receives postmarketing royalties from this invention.

Dr. Girard reported disclosures related to AbbVie, AstraZeneca, Boehringer Ingelheim, and multiple other pharmaceutical companies.

A HER3-targeted therapy has demonstrated clinically meaningful and durable efficacy in heavily pretreated patients with EGFR-mutant non–small cell lung cancer, according to results of a phase 1 study.

Patritumab deruxtecan, an antibody-drug conjugate targeting HER3, had an overall response rate (ORR) of 39% and median progression-free survival (PFS) of 8.2 months in a phase 1 study that included patients previously treated with tyrosine kinase inhibitors (TKIs) and chemotherapy, the results show.

The efficacy was seen across EGFR TKI resistance mechanisms in this very difficult-to-treat patient population, according to investigator Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute, Boston.

“There is not one category of individuals that are having a response, or not having a response,” Dr. Jänne said in a presentation at the annual meeting of the American Society of Clinical Oncology (Abstract 9007).

“Responses are observed in patients with identifiable resistance mechanisms, and in patients that do not have an identifiable resistance mechanism, but have progressed on prior EGFR TKI therapy,” he added.

More than 80% of non–small cell lung cancer (NSCLC) tumors express HER3, and of note, HER3 alterations do not appear to confer resistance to EGFR TKIs in patients with EGFR-mutant NSCLC, according to Dr. Jänne.
 

Study details

Also known as HER3-DXd, patritumab deruxtecan consists of a fully human anti-HER3 monoclonal antibody linked to a topoisomerase inhibitor payload by a tetrapeptide-based cleavable linker.

The antibody-drug conjugate is also being evaluated in metastatic breast cancer and colorectal cancer, Dr. Jänne said.

In the present phase 1 dose escalation and dose expansion study, a total of 57 patients were treated with patritumab deruxtecan at 5.6 mg/kg, the recommended dose for the expansion phase.

The median age of these patients was 65 years, and the majority (63%) were women, Dr. Jänne reported. About half had a history of central nervous system metastases.

The median number of prior lines of systemic therapy was four, making this a heavily pretreated patient population, Dr. Jänne said. All patients had received prior EGFR TKI therapy, and 86% specifically had prior osimertinib. Ninety-one percent had prior platinum-based chemotherapy, and 40% had received immunotherapy.
 

Spectrum of responses

The confirmed ORR of 39% included 1 complete response (2%) and 21 partial responses (37%), Dr. Jänne reported. The disease control rate was 72%, and median duration of response was 6.9 months at a median follow-up of 10.2 months.

The median PFS was 8.2 months in 57 patients overall and in a subset of 44 patients who had received prior osimertinib and platinum-based chemotherapy, according to the report.

Activity of patritumab deruxtecan was seen not only across patients with diverse mechanisms of EGFR TKI resistance, but also regardless of prior number of treatments, and regardless of history of brain metastases, the investigator said.

In addition, clinical responses were seen across a spectrum of baseline HER3 expression by immunohistochemistry, the investigator added.

Safety was assessed in 81 patients treated at a range of doses in the phase 1 trial. The most common grade 3 or greater treatment-emergent adverse events, observed in 5% or more of patients, included thrombocytopenia, neutropenia, and anemia, while other side effects such as fatigue and dyspnea were observed, Dr. Jänne said. About 9% of the adverse events led to treatment discontinuation in the safety cohort.

Interstitial lung disease was observed in four patients, or 5% of the safety cohort. Three of these were grade 1-2 and one was grade 3, according to the report.
 

Questions to explore

The efficacy of patritumab deruxtecan was “high” in this phase 1 study, based on the reported response rate and median PFS, said discussant Nicolas Girard, MD, PhD, of Institut Curie in Paris.

However, the most striking finding of the study was the efficacy of the antibody-drug conjugate across all reported resistance mechanisms, Dr. Girard said in his remarks.

Questions that remains to be explored, according to Dr. Girard, include the impact of previous treatment sequencing with TKIs and chemotherapy on patient outcomes with patritumab deruxtecan, as well as the assessment of intracranial response and PFS for patients treated with the agent.

In addition, antitumor activity was seen across a wide range of baseline HER3 expression levels in this study, suggesting that a predictive biomarker remains to be identified, according to Dr. Girard.

“HER3 immunohistochemistry does not seem to be the candidate in this setting,” he said.

The study was sponsored by Daiichi Sankyo. Dr. Jänne reported disclosures related to Daiichi Sankyo, as well as Araxes Pharma, Astellas Pharma, AstraZeneca, and multiple other pharmaceutical companies. Dr. Jänne is also coinventor on a Dana Farber Cancer Institute–owned patent on EGFR mutations licensed to Labcorp and receives postmarketing royalties from this invention.

Dr. Girard reported disclosures related to AbbVie, AstraZeneca, Boehringer Ingelheim, and multiple other pharmaceutical companies.

A HER3-targeted therapy has demonstrated clinically meaningful and durable efficacy in heavily pretreated patients with EGFR-mutant non–small cell lung cancer, according to results of a phase 1 study.

Patritumab deruxtecan, an antibody-drug conjugate targeting HER3, had an overall response rate (ORR) of 39% and median progression-free survival (PFS) of 8.2 months in a phase 1 study that included patients previously treated with tyrosine kinase inhibitors (TKIs) and chemotherapy, the results show.

The efficacy was seen across EGFR TKI resistance mechanisms in this very difficult-to-treat patient population, according to investigator Pasi A. Jänne, MD, PhD, of the Dana-Farber Cancer Institute, Boston.

“There is not one category of individuals that are having a response, or not having a response,” Dr. Jänne said in a presentation at the annual meeting of the American Society of Clinical Oncology (Abstract 9007).

“Responses are observed in patients with identifiable resistance mechanisms, and in patients that do not have an identifiable resistance mechanism, but have progressed on prior EGFR TKI therapy,” he added.

More than 80% of non–small cell lung cancer (NSCLC) tumors express HER3, and of note, HER3 alterations do not appear to confer resistance to EGFR TKIs in patients with EGFR-mutant NSCLC, according to Dr. Jänne.
 

Study details

Also known as HER3-DXd, patritumab deruxtecan consists of a fully human anti-HER3 monoclonal antibody linked to a topoisomerase inhibitor payload by a tetrapeptide-based cleavable linker.

The antibody-drug conjugate is also being evaluated in metastatic breast cancer and colorectal cancer, Dr. Jänne said.

In the present phase 1 dose escalation and dose expansion study, a total of 57 patients were treated with patritumab deruxtecan at 5.6 mg/kg, the recommended dose for the expansion phase.

The median age of these patients was 65 years, and the majority (63%) were women, Dr. Jänne reported. About half had a history of central nervous system metastases.

The median number of prior lines of systemic therapy was four, making this a heavily pretreated patient population, Dr. Jänne said. All patients had received prior EGFR TKI therapy, and 86% specifically had prior osimertinib. Ninety-one percent had prior platinum-based chemotherapy, and 40% had received immunotherapy.
 

Spectrum of responses

The confirmed ORR of 39% included 1 complete response (2%) and 21 partial responses (37%), Dr. Jänne reported. The disease control rate was 72%, and median duration of response was 6.9 months at a median follow-up of 10.2 months.

The median PFS was 8.2 months in 57 patients overall and in a subset of 44 patients who had received prior osimertinib and platinum-based chemotherapy, according to the report.

Activity of patritumab deruxtecan was seen not only across patients with diverse mechanisms of EGFR TKI resistance, but also regardless of prior number of treatments, and regardless of history of brain metastases, the investigator said.

In addition, clinical responses were seen across a spectrum of baseline HER3 expression by immunohistochemistry, the investigator added.

Safety was assessed in 81 patients treated at a range of doses in the phase 1 trial. The most common grade 3 or greater treatment-emergent adverse events, observed in 5% or more of patients, included thrombocytopenia, neutropenia, and anemia, while other side effects such as fatigue and dyspnea were observed, Dr. Jänne said. About 9% of the adverse events led to treatment discontinuation in the safety cohort.

Interstitial lung disease was observed in four patients, or 5% of the safety cohort. Three of these were grade 1-2 and one was grade 3, according to the report.
 

Questions to explore

The efficacy of patritumab deruxtecan was “high” in this phase 1 study, based on the reported response rate and median PFS, said discussant Nicolas Girard, MD, PhD, of Institut Curie in Paris.

However, the most striking finding of the study was the efficacy of the antibody-drug conjugate across all reported resistance mechanisms, Dr. Girard said in his remarks.

Questions that remains to be explored, according to Dr. Girard, include the impact of previous treatment sequencing with TKIs and chemotherapy on patient outcomes with patritumab deruxtecan, as well as the assessment of intracranial response and PFS for patients treated with the agent.

In addition, antitumor activity was seen across a wide range of baseline HER3 expression levels in this study, suggesting that a predictive biomarker remains to be identified, according to Dr. Girard.

“HER3 immunohistochemistry does not seem to be the candidate in this setting,” he said.

The study was sponsored by Daiichi Sankyo. Dr. Jänne reported disclosures related to Daiichi Sankyo, as well as Araxes Pharma, Astellas Pharma, AstraZeneca, and multiple other pharmaceutical companies. Dr. Jänne is also coinventor on a Dana Farber Cancer Institute–owned patent on EGFR mutations licensed to Labcorp and receives postmarketing royalties from this invention.

Dr. Girard reported disclosures related to AbbVie, AstraZeneca, Boehringer Ingelheim, and multiple other pharmaceutical companies.

Background: Critically ill patients are often vitamin D deficient, but no large randomized trials have investigated whether early vitamin D supplementation can affect clinical outcomes.

Study design: Multicenter, randomized, double-blind, placebo-controlled phase 3 trial.Setting: 44 U.S. hospitals, during April 2017–July 2018.

Synopsis: The study enrolled 1,078 patients with 25-hydroxyvitamin D levels < 20 ng/mL who were critically ill (defined as patients being admitted to the ICU with one or more risk factor for lung injury or death). Participants were randomized to early administration of a single dose of 540,000 IUs of enteral vitamin D₃ or placebo. The authors did not identify a statistically significant difference in the 90-day all-cause mortality between the two groups. Additionally, there were no significant differences in length of stay, ventilator-free days or serious adverse outcomes between the two groups.

Bottom line: Early administration of high-dose enteral vitamin D₃ did not decrease 90-day all-cause mortality in critically ill, vitamin D–deficient patients.

Citation: Ginde A et al. Early high-dose vitamin D₃ for critically ill, vitamin D–deficient patients. N Engl J Med. 2019 Dec 26; 281:2529-40.

Dr. Persaud is a hospitalist, Beth Israel Deaconess Medical Center, and instructor in medicine, Harvard Medical School, both in Boston.

Background: Critically ill patients are often vitamin D deficient, but no large randomized trials have investigated whether early vitamin D supplementation can affect clinical outcomes.

Study design: Multicenter, randomized, double-blind, placebo-controlled phase 3 trial.Setting: 44 U.S. hospitals, during April 2017–July 2018.

Synopsis: The study enrolled 1,078 patients with 25-hydroxyvitamin D levels < 20 ng/mL who were critically ill (defined as patients being admitted to the ICU with one or more risk factor for lung injury or death). Participants were randomized to early administration of a single dose of 540,000 IUs of enteral vitamin D₃ or placebo. The authors did not identify a statistically significant difference in the 90-day all-cause mortality between the two groups. Additionally, there were no significant differences in length of stay, ventilator-free days or serious adverse outcomes between the two groups.

Bottom line: Early administration of high-dose enteral vitamin D₃ did not decrease 90-day all-cause mortality in critically ill, vitamin D–deficient patients.

Citation: Ginde A et al. Early high-dose vitamin D₃ for critically ill, vitamin D–deficient patients. N Engl J Med. 2019 Dec 26; 281:2529-40.

Dr. Persaud is a hospitalist, Beth Israel Deaconess Medical Center, and instructor in medicine, Harvard Medical School, both in Boston.

Background: Critically ill patients are often vitamin D deficient, but no large randomized trials have investigated whether early vitamin D supplementation can affect clinical outcomes.

Study design: Multicenter, randomized, double-blind, placebo-controlled phase 3 trial.Setting: 44 U.S. hospitals, during April 2017–July 2018.

Synopsis: The study enrolled 1,078 patients with 25-hydroxyvitamin D levels < 20 ng/mL who were critically ill (defined as patients being admitted to the ICU with one or more risk factor for lung injury or death). Participants were randomized to early administration of a single dose of 540,000 IUs of enteral vitamin D₃ or placebo. The authors did not identify a statistically significant difference in the 90-day all-cause mortality between the two groups. Additionally, there were no significant differences in length of stay, ventilator-free days or serious adverse outcomes between the two groups.

Bottom line: Early administration of high-dose enteral vitamin D₃ did not decrease 90-day all-cause mortality in critically ill, vitamin D–deficient patients.

Citation: Ginde A et al. Early high-dose vitamin D₃ for critically ill, vitamin D–deficient patients. N Engl J Med. 2019 Dec 26; 281:2529-40.

Dr. Persaud is a hospitalist, Beth Israel Deaconess Medical Center, and instructor in medicine, Harvard Medical School, both in Boston.

Granularly mixed laterally spreading colorectal tumors (GM-LSTs) that are located in the rectum or are larger than 4 cm should be considered to be at high risk of developing into covert submucosal invasive cancer (SMIC), and should be treated by en bloc resection, according to a retrospective analysis of patients from seven Italian centers.

GM-LSTs are 1-cm or larger nonpolypoid lesions with lateral growth. They make up 1%-6% of colorectal lesions, and are important clinically because of the possibility that they are SMICs that aren’t visibly apparent.

On the one hand, homogeneous granular-type LSTs have been found to have a very low SMIC risk (0.5%) and are candidates for piecemeal removal, while non-granular LSTs present higher risk, suggesting that en bloc resection would be an appropriate strategy. Piecemeal attempts that discover a SMIC can lead to follow-up surgery because it may not be possible to evaluate submucosal invasion at pathology. Further surgery can be particularly onerous in rectal lesions, where it can reduce quality of life.

On the other hand, granularly mixed LSTs present a conundrum: SMIC risk falls somewhere between the granular and nongranular LSTs, and they make up about 25% of laterally spreading tumors.
 

A deeper look

To better characterize GM-LSTs and predict which might be covert SMICs, Ferdinando D’Amico at Humanitas University in Milan and colleagues analyzed data from 693 patients with colorectal GM-LSTs at seven Italian centers, between 2016 and 2019. The results appeared in Clinical Gastroenterology and Hepatology. Median age was 69 years, and 50.6% of patients were men.

Of patients in the study, 9.5% were found to have SMICs at histology. Of these, 62.1% occurred in lesions 4 cm or larger, and none in lesions smaller than 2 cm, and 63.6% occurred in the rectum. Overall, 24.2% of patients underwent en bloc resection.

A multivariate analysis found that lesion size was associated with risk of covert SMIC (odds ratio per mm, 1.02; 95% confidence interval, 1.0-1.03). A cutoff of 4.0 cm yielded the optimal discrimination for SMIC risk, with a 6.0% risk below that size and 14.8% above (OR, 2.32; P = .002). The researchers also considered GM-LST location in this multivariate analysis, and found a greater risk of SMIC in those located in the rectum than for those in other colonic segments (15.1% vs. 5.8%; OR, 3.08; P = .004). A logistic regression model combining size and location yielded a sensitivity of 47.0%, specificity 82.6%, and area under the curve of 0.69.

When lesions of 4 cm or greater in the rectal area were compared with nonrectal lesions less than 4 cm, the number needed to treat (NNT) to detect one covert SMIC dropped from 20 to 5.

“The 22% risk of covert SMIC for ≥4-cm rectal GM-LSTs equals the 21.4% previously reported as the highest risk for nongranular LSTs, justifying the need for an aggressive treatment, especially when considering that the unexpected finding of a covert SMIC after piecemeal resection of a rectal lesion may result in an unnecessary surgery, with major consequences for the patient. Thus, referral of these patients to a center with adequate competence in advanced resection, including [endoscopic submucosal dissection], should be recommended,” the authors wrote.

They noted that the NNT of 5 is low enough to compensate for the risk of conducting ESD instead of piecemeal endoscopic mucosal resection. Meanwhile, the NNT of 20 for smaller, nonrectal tumors puts them close to the risk category of homogeneous granular LSTs, which wouldn’t justify a more complex procedure and could instead be resected piecemeal.

For rectal lesions less than 4 cm or nonrectal lesions 4 cm or larger, SMIC risk is below 10%. In deciding which approach to take, endoscopists must weigh the low risk of surgery after discovery of an unexpected SMIC. The authors suggest use of dye or virtual chromoendoscopy for lesion characterization, along with optical magnification if available.

The study had some limitations. One is that the authors did not assess how frequently the SMIC was limited to the dominant nodule, which might affect resection strategies. Another is that the actual SMIC rate in GM-LSTs may have been underestimated: Not only were signs of overt invasion an exclusion criterion, but also patients with difficult-to-treat SMIC lesions might have been referred elsewhere.

The authors disclosed no funding source and declared that they had no relevant financial disclosures.

Granularly mixed laterally spreading colorectal tumors (GM-LSTs) that are located in the rectum or are larger than 4 cm should be considered to be at high risk of developing into covert submucosal invasive cancer (SMIC), and should be treated by en bloc resection, according to a retrospective analysis of patients from seven Italian centers.

GM-LSTs are 1-cm or larger nonpolypoid lesions with lateral growth. They make up 1%-6% of colorectal lesions, and are important clinically because of the possibility that they are SMICs that aren’t visibly apparent.

On the one hand, homogeneous granular-type LSTs have been found to have a very low SMIC risk (0.5%) and are candidates for piecemeal removal, while non-granular LSTs present higher risk, suggesting that en bloc resection would be an appropriate strategy. Piecemeal attempts that discover a SMIC can lead to follow-up surgery because it may not be possible to evaluate submucosal invasion at pathology. Further surgery can be particularly onerous in rectal lesions, where it can reduce quality of life.

On the other hand, granularly mixed LSTs present a conundrum: SMIC risk falls somewhere between the granular and nongranular LSTs, and they make up about 25% of laterally spreading tumors.
 

A deeper look

To better characterize GM-LSTs and predict which might be covert SMICs, Ferdinando D’Amico at Humanitas University in Milan and colleagues analyzed data from 693 patients with colorectal GM-LSTs at seven Italian centers, between 2016 and 2019. The results appeared in Clinical Gastroenterology and Hepatology. Median age was 69 years, and 50.6% of patients were men.

Of patients in the study, 9.5% were found to have SMICs at histology. Of these, 62.1% occurred in lesions 4 cm or larger, and none in lesions smaller than 2 cm, and 63.6% occurred in the rectum. Overall, 24.2% of patients underwent en bloc resection.

A multivariate analysis found that lesion size was associated with risk of covert SMIC (odds ratio per mm, 1.02; 95% confidence interval, 1.0-1.03). A cutoff of 4.0 cm yielded the optimal discrimination for SMIC risk, with a 6.0% risk below that size and 14.8% above (OR, 2.32; P = .002). The researchers also considered GM-LST location in this multivariate analysis, and found a greater risk of SMIC in those located in the rectum than for those in other colonic segments (15.1% vs. 5.8%; OR, 3.08; P = .004). A logistic regression model combining size and location yielded a sensitivity of 47.0%, specificity 82.6%, and area under the curve of 0.69.

When lesions of 4 cm or greater in the rectal area were compared with nonrectal lesions less than 4 cm, the number needed to treat (NNT) to detect one covert SMIC dropped from 20 to 5.

“The 22% risk of covert SMIC for ≥4-cm rectal GM-LSTs equals the 21.4% previously reported as the highest risk for nongranular LSTs, justifying the need for an aggressive treatment, especially when considering that the unexpected finding of a covert SMIC after piecemeal resection of a rectal lesion may result in an unnecessary surgery, with major consequences for the patient. Thus, referral of these patients to a center with adequate competence in advanced resection, including [endoscopic submucosal dissection], should be recommended,” the authors wrote.

They noted that the NNT of 5 is low enough to compensate for the risk of conducting ESD instead of piecemeal endoscopic mucosal resection. Meanwhile, the NNT of 20 for smaller, nonrectal tumors puts them close to the risk category of homogeneous granular LSTs, which wouldn’t justify a more complex procedure and could instead be resected piecemeal.

For rectal lesions less than 4 cm or nonrectal lesions 4 cm or larger, SMIC risk is below 10%. In deciding which approach to take, endoscopists must weigh the low risk of surgery after discovery of an unexpected SMIC. The authors suggest use of dye or virtual chromoendoscopy for lesion characterization, along with optical magnification if available.

The study had some limitations. One is that the authors did not assess how frequently the SMIC was limited to the dominant nodule, which might affect resection strategies. Another is that the actual SMIC rate in GM-LSTs may have been underestimated: Not only were signs of overt invasion an exclusion criterion, but also patients with difficult-to-treat SMIC lesions might have been referred elsewhere.

The authors disclosed no funding source and declared that they had no relevant financial disclosures.

Granularly mixed laterally spreading colorectal tumors (GM-LSTs) that are located in the rectum or are larger than 4 cm should be considered to be at high risk of developing into covert submucosal invasive cancer (SMIC), and should be treated by en bloc resection, according to a retrospective analysis of patients from seven Italian centers.

GM-LSTs are 1-cm or larger nonpolypoid lesions with lateral growth. They make up 1%-6% of colorectal lesions, and are important clinically because of the possibility that they are SMICs that aren’t visibly apparent.

On the one hand, homogeneous granular-type LSTs have been found to have a very low SMIC risk (0.5%) and are candidates for piecemeal removal, while non-granular LSTs present higher risk, suggesting that en bloc resection would be an appropriate strategy. Piecemeal attempts that discover a SMIC can lead to follow-up surgery because it may not be possible to evaluate submucosal invasion at pathology. Further surgery can be particularly onerous in rectal lesions, where it can reduce quality of life.

On the other hand, granularly mixed LSTs present a conundrum: SMIC risk falls somewhere between the granular and nongranular LSTs, and they make up about 25% of laterally spreading tumors.
 

A deeper look

To better characterize GM-LSTs and predict which might be covert SMICs, Ferdinando D’Amico at Humanitas University in Milan and colleagues analyzed data from 693 patients with colorectal GM-LSTs at seven Italian centers, between 2016 and 2019. The results appeared in Clinical Gastroenterology and Hepatology. Median age was 69 years, and 50.6% of patients were men.

Of patients in the study, 9.5% were found to have SMICs at histology. Of these, 62.1% occurred in lesions 4 cm or larger, and none in lesions smaller than 2 cm, and 63.6% occurred in the rectum. Overall, 24.2% of patients underwent en bloc resection.

A multivariate analysis found that lesion size was associated with risk of covert SMIC (odds ratio per mm, 1.02; 95% confidence interval, 1.0-1.03). A cutoff of 4.0 cm yielded the optimal discrimination for SMIC risk, with a 6.0% risk below that size and 14.8% above (OR, 2.32; P = .002). The researchers also considered GM-LST location in this multivariate analysis, and found a greater risk of SMIC in those located in the rectum than for those in other colonic segments (15.1% vs. 5.8%; OR, 3.08; P = .004). A logistic regression model combining size and location yielded a sensitivity of 47.0%, specificity 82.6%, and area under the curve of 0.69.

When lesions of 4 cm or greater in the rectal area were compared with nonrectal lesions less than 4 cm, the number needed to treat (NNT) to detect one covert SMIC dropped from 20 to 5.

“The 22% risk of covert SMIC for ≥4-cm rectal GM-LSTs equals the 21.4% previously reported as the highest risk for nongranular LSTs, justifying the need for an aggressive treatment, especially when considering that the unexpected finding of a covert SMIC after piecemeal resection of a rectal lesion may result in an unnecessary surgery, with major consequences for the patient. Thus, referral of these patients to a center with adequate competence in advanced resection, including [endoscopic submucosal dissection], should be recommended,” the authors wrote.

They noted that the NNT of 5 is low enough to compensate for the risk of conducting ESD instead of piecemeal endoscopic mucosal resection. Meanwhile, the NNT of 20 for smaller, nonrectal tumors puts them close to the risk category of homogeneous granular LSTs, which wouldn’t justify a more complex procedure and could instead be resected piecemeal.

For rectal lesions less than 4 cm or nonrectal lesions 4 cm or larger, SMIC risk is below 10%. In deciding which approach to take, endoscopists must weigh the low risk of surgery after discovery of an unexpected SMIC. The authors suggest use of dye or virtual chromoendoscopy for lesion characterization, along with optical magnification if available.

The study had some limitations. One is that the authors did not assess how frequently the SMIC was limited to the dominant nodule, which might affect resection strategies. Another is that the actual SMIC rate in GM-LSTs may have been underestimated: Not only were signs of overt invasion an exclusion criterion, but also patients with difficult-to-treat SMIC lesions might have been referred elsewhere.

The authors disclosed no funding source and declared that they had no relevant financial disclosures.

The gender gap in gastroenterology persists – currently, women constitute 39% of fellows, but only 22% of senior AGA members and less than 18% of all practicing gastroenterologists – and it has gained even greater significance within the “current historical moment” of the COVID pandemic and growing cognizance of systemic sexism and racism, according to experts.

During the pandemic, women have been more likely to stay home to care for ill family members and children affected by school closures, which increases their already disproportionate share of unpaid work, wrote Jessica Bernica, MD, of Baylor College of Medicine in Houston with her associates in Techniques and Innovations in Gastrointestinal Endoscopy. They noted that, according to one study, this “holds true for female physicians, who despite their more privileged positions, also experience higher demands at home, impacting their ability to contribute to teaching, service, and research.”

At the same time, the pandemic has brought into focus which jobs are “truly essential” – and that they are “overwhelmingly [held] by women and people of color, who are often underpaid and undervalued,” the experts wrote. The growing focus on systemic racism has also increased awareness of the chronic gender discrimination faced by female minorities, as well as by women in general, they added. In the field of gastroenterology, inherent gender bias – both systemic and self-directed – can bar women from advancing beginning as early as medical school.

To help address these issues, the experts outlined key opportunities for change as women navigate professional “forks in the road” throughout their careers.
 

Throughout their careers

During medical school and residency, women can specifically request gastroenterology rotations (“ideally with both inpatient and outpatient exposure”), attend society conferences, participate in research themselves, and join a research track or serve as chief medical resident. When applying for gastroenterology fellowships, they can prioritize programs with female faculty, which were recently found to be more likely to hire female fellows.

During fellowship, women can avail themselves of female mentors, who can help them strategize about ways to address gender bias, connect with GI groups and societies, and learn endoscopy techniques, including “unique approaches ... [that] overcome the challenges of standard scope sizes and accessibility.” At the institutional level, opportunities to affect positive changes for women trainees include “formal education on the benefits of hands-on learning and encouraging explicit and open communication between parties regarding invitation to, comfort with, and type of physical contact prior to a case.”

After fellowship, early-career gastroenterologists should scrutinize contracts for details on pay and research support, and they should ideally join a practice that either already has many women physicians on staff, or that ensures salary transparency and has “parental leave policies that are compatible with [applicants’] personal and professional goals.” But the experts advocated caution about part-time positions, which may purport to offer more flexibility but turn into full-time work for part-time pay and can preclude participation in practice management.

The experts recommended midcareer female gastroenterologists call out their own achievements rather than waiting for recognition, “actively seek promotion and tenure,” negotiate their salaries (as men tend to do routinely), and think twice before accepting professional roles that are uncompensated or do not clearly promote career advancement.

Senior gastroenterologists have unique opportunities to spearhead changes in institutional policies and practices, according to the experts. Specific examples include “explicitly stating [in job listings] that salary is negotiable, creating transparent written compensation plans, and conducting audits of job offers” to help mitigate any inequities in pay or hiring practices. In addition, senior women gastroenterologists can mentor individual women in the field, implement formal trainings on implicit bias, ensure that their practice or department tracks the gender of gastroenterologists who join, leave, or are promoted.

The experts did not report receiving funding for the work. They reported having no conflicts of interest.

The gender gap in gastroenterology persists – currently, women constitute 39% of fellows, but only 22% of senior AGA members and less than 18% of all practicing gastroenterologists – and it has gained even greater significance within the “current historical moment” of the COVID pandemic and growing cognizance of systemic sexism and racism, according to experts.

During the pandemic, women have been more likely to stay home to care for ill family members and children affected by school closures, which increases their already disproportionate share of unpaid work, wrote Jessica Bernica, MD, of Baylor College of Medicine in Houston with her associates in Techniques and Innovations in Gastrointestinal Endoscopy. They noted that, according to one study, this “holds true for female physicians, who despite their more privileged positions, also experience higher demands at home, impacting their ability to contribute to teaching, service, and research.”

At the same time, the pandemic has brought into focus which jobs are “truly essential” – and that they are “overwhelmingly [held] by women and people of color, who are often underpaid and undervalued,” the experts wrote. The growing focus on systemic racism has also increased awareness of the chronic gender discrimination faced by female minorities, as well as by women in general, they added. In the field of gastroenterology, inherent gender bias – both systemic and self-directed – can bar women from advancing beginning as early as medical school.

To help address these issues, the experts outlined key opportunities for change as women navigate professional “forks in the road” throughout their careers.
 

Throughout their careers

During medical school and residency, women can specifically request gastroenterology rotations (“ideally with both inpatient and outpatient exposure”), attend society conferences, participate in research themselves, and join a research track or serve as chief medical resident. When applying for gastroenterology fellowships, they can prioritize programs with female faculty, which were recently found to be more likely to hire female fellows.

During fellowship, women can avail themselves of female mentors, who can help them strategize about ways to address gender bias, connect with GI groups and societies, and learn endoscopy techniques, including “unique approaches ... [that] overcome the challenges of standard scope sizes and accessibility.” At the institutional level, opportunities to affect positive changes for women trainees include “formal education on the benefits of hands-on learning and encouraging explicit and open communication between parties regarding invitation to, comfort with, and type of physical contact prior to a case.”

After fellowship, early-career gastroenterologists should scrutinize contracts for details on pay and research support, and they should ideally join a practice that either already has many women physicians on staff, or that ensures salary transparency and has “parental leave policies that are compatible with [applicants’] personal and professional goals.” But the experts advocated caution about part-time positions, which may purport to offer more flexibility but turn into full-time work for part-time pay and can preclude participation in practice management.

The experts recommended midcareer female gastroenterologists call out their own achievements rather than waiting for recognition, “actively seek promotion and tenure,” negotiate their salaries (as men tend to do routinely), and think twice before accepting professional roles that are uncompensated or do not clearly promote career advancement.

Senior gastroenterologists have unique opportunities to spearhead changes in institutional policies and practices, according to the experts. Specific examples include “explicitly stating [in job listings] that salary is negotiable, creating transparent written compensation plans, and conducting audits of job offers” to help mitigate any inequities in pay or hiring practices. In addition, senior women gastroenterologists can mentor individual women in the field, implement formal trainings on implicit bias, ensure that their practice or department tracks the gender of gastroenterologists who join, leave, or are promoted.

The experts did not report receiving funding for the work. They reported having no conflicts of interest.

The gender gap in gastroenterology persists – currently, women constitute 39% of fellows, but only 22% of senior AGA members and less than 18% of all practicing gastroenterologists – and it has gained even greater significance within the “current historical moment” of the COVID pandemic and growing cognizance of systemic sexism and racism, according to experts.

During the pandemic, women have been more likely to stay home to care for ill family members and children affected by school closures, which increases their already disproportionate share of unpaid work, wrote Jessica Bernica, MD, of Baylor College of Medicine in Houston with her associates in Techniques and Innovations in Gastrointestinal Endoscopy. They noted that, according to one study, this “holds true for female physicians, who despite their more privileged positions, also experience higher demands at home, impacting their ability to contribute to teaching, service, and research.”

At the same time, the pandemic has brought into focus which jobs are “truly essential” – and that they are “overwhelmingly [held] by women and people of color, who are often underpaid and undervalued,” the experts wrote. The growing focus on systemic racism has also increased awareness of the chronic gender discrimination faced by female minorities, as well as by women in general, they added. In the field of gastroenterology, inherent gender bias – both systemic and self-directed – can bar women from advancing beginning as early as medical school.

To help address these issues, the experts outlined key opportunities for change as women navigate professional “forks in the road” throughout their careers.
 

Throughout their careers

During medical school and residency, women can specifically request gastroenterology rotations (“ideally with both inpatient and outpatient exposure”), attend society conferences, participate in research themselves, and join a research track or serve as chief medical resident. When applying for gastroenterology fellowships, they can prioritize programs with female faculty, which were recently found to be more likely to hire female fellows.

During fellowship, women can avail themselves of female mentors, who can help them strategize about ways to address gender bias, connect with GI groups and societies, and learn endoscopy techniques, including “unique approaches ... [that] overcome the challenges of standard scope sizes and accessibility.” At the institutional level, opportunities to affect positive changes for women trainees include “formal education on the benefits of hands-on learning and encouraging explicit and open communication between parties regarding invitation to, comfort with, and type of physical contact prior to a case.”

After fellowship, early-career gastroenterologists should scrutinize contracts for details on pay and research support, and they should ideally join a practice that either already has many women physicians on staff, or that ensures salary transparency and has “parental leave policies that are compatible with [applicants’] personal and professional goals.” But the experts advocated caution about part-time positions, which may purport to offer more flexibility but turn into full-time work for part-time pay and can preclude participation in practice management.

The experts recommended midcareer female gastroenterologists call out their own achievements rather than waiting for recognition, “actively seek promotion and tenure,” negotiate their salaries (as men tend to do routinely), and think twice before accepting professional roles that are uncompensated or do not clearly promote career advancement.

Senior gastroenterologists have unique opportunities to spearhead changes in institutional policies and practices, according to the experts. Specific examples include “explicitly stating [in job listings] that salary is negotiable, creating transparent written compensation plans, and conducting audits of job offers” to help mitigate any inequities in pay or hiring practices. In addition, senior women gastroenterologists can mentor individual women in the field, implement formal trainings on implicit bias, ensure that their practice or department tracks the gender of gastroenterologists who join, leave, or are promoted.

The experts did not report receiving funding for the work. They reported having no conflicts of interest.

Thermal ablation of the defect margin after endoscopic mucosal resection (EMR-T) is associated with reduced recurrence in the treatment of large (≥20-mm) nonpedunculated colorectal polyps (LNPCPs), according to a prospective international cohort study.

Residual or recurrent adenomas (RRAs) are found during 15%-20% of first surveillance endoscopies. EMR-T was previously shown in a randomized trial to be effective at reducing adenoma recurrence during surveillance endoscopy (relative risk, 0.3; P < .01).

The U.S. Multi-Society Task Force currently recommends EMR-T for LNPCPs, but real-world effectiveness remains unknown, wrote Mayenaaz Sidhu, MBBS, of the department of gastroenterology and hepatology at Westmead Hospital in Sydney and colleagues in Gastroenterology. Therefore, they undertook an international, multicenter, prospective trial to evaluate the technique in the real world.

The researchers analyzed data from consecutive patients who were referred for treatment of LNPCPs at six tertiary centers. Between May 2016 and August 2020, the study included 1,049 LNPCPs from 1,049 patients. The mean age was 67.3 years, and the median lesion size was 35 mm. Of LNPCPs, 58.7% were tubulovillous adenomas. EMR was technically successful in 98.9% of cases. Overall, 19.1% of cases required an auxiliary modality to completely remove polypoid tissue; most often this was cold avulsion with adjuvant snare-tip soft coagulation (44.4%).

Complete EMR-T was achieved in 95.4% cases. Reasons for failure included extensive post-EMR defect (n = 29), unstable colonoscope position or difficult access (n = 14), and intraprocedural adverse events (n = 5).

Of 803 patients eligible for surveillance colonoscopy, 94% underwent the procedure at a median interval of 6 months. Overall, RRAs were found in 3% of cases. Among lesions with complete EMR-T, 1.4% (10 of 707) had RRAs at first surveillance colonoscopy versus 27.1% (13 of 48) with incomplete EMR-T (P < .001). In cases with incomplete EMR-T, lesions were larger (median size, 42.50 mm vs. 37.60 mm; P = .03), there was longer procedure time (mean, 60.2 vs. 35.0 minutes; P = .01), and there was a greater likelihood of referral for surgery (8.3% vs. 3.0%; P = .04).

Intraprocedural bleeding occurred in 6% of cases, and endoscopic hemostasis was achieved in all. Clinically significant post-EMR bleeding occurred in 6.8% of cases, 59.2% of which were managed conservatively, and the remainder were evaluated endoscopically. Bleeding was controlled in every case.

Unlike RRA risk scores that use size, morphology, site, and access score, EMR-T can be used proactively to reduce RRA frequency. It is believed to work by thermally ablating microscopic tissue at the margin. The adverse events reported in the current study were similar to a systematic review and meta-analysis.

“These findings clearly support and exceed those of a recent randomized trial for EMR-T in the colorectum. They likely reflect refinements in the performance of EMR-T over time, due to greater technical experience and enhanced confidence in its safety. At its inception, the approach to EMR-T may have been timid, however, as experience grew and the safety of EMR-T became evident, a meticulous approach to uniform and complete thermal ablation of the defect margin became the standard of care,” the authors wrote.

They added that EMR-T has been shown to benefit in complex LNPCPs, including those that have undergone previous excision attempts and those involving the anorectal junction. The procedure has no added cost, since many endoscopists can readily use snare-tip soft coagulation to manage bleeding events.

“Thermal ablation of the defect margin should be viewed as an essential component of high-quality EMR for LNPCPs, consistent with recent recommendations by the U.S. Multi-Society Task Force on Colorectal Cancer,” the authors wrote.

The study was funded by the Cancer Institute of New South Wales, the Gallipoli Medical Research Foundation, and the University of British Columbia. One author reported research support for Olympus, Cook Medical, and Boston Scientific, but the remaining authors disclosed no conflicts.

Thermal ablation of the defect margin after endoscopic mucosal resection (EMR-T) is associated with reduced recurrence in the treatment of large (≥20-mm) nonpedunculated colorectal polyps (LNPCPs), according to a prospective international cohort study.

Residual or recurrent adenomas (RRAs) are found during 15%-20% of first surveillance endoscopies. EMR-T was previously shown in a randomized trial to be effective at reducing adenoma recurrence during surveillance endoscopy (relative risk, 0.3; P < .01).

The U.S. Multi-Society Task Force currently recommends EMR-T for LNPCPs, but real-world effectiveness remains unknown, wrote Mayenaaz Sidhu, MBBS, of the department of gastroenterology and hepatology at Westmead Hospital in Sydney and colleagues in Gastroenterology. Therefore, they undertook an international, multicenter, prospective trial to evaluate the technique in the real world.

The researchers analyzed data from consecutive patients who were referred for treatment of LNPCPs at six tertiary centers. Between May 2016 and August 2020, the study included 1,049 LNPCPs from 1,049 patients. The mean age was 67.3 years, and the median lesion size was 35 mm. Of LNPCPs, 58.7% were tubulovillous adenomas. EMR was technically successful in 98.9% of cases. Overall, 19.1% of cases required an auxiliary modality to completely remove polypoid tissue; most often this was cold avulsion with adjuvant snare-tip soft coagulation (44.4%).

Complete EMR-T was achieved in 95.4% cases. Reasons for failure included extensive post-EMR defect (n = 29), unstable colonoscope position or difficult access (n = 14), and intraprocedural adverse events (n = 5).

Of 803 patients eligible for surveillance colonoscopy, 94% underwent the procedure at a median interval of 6 months. Overall, RRAs were found in 3% of cases. Among lesions with complete EMR-T, 1.4% (10 of 707) had RRAs at first surveillance colonoscopy versus 27.1% (13 of 48) with incomplete EMR-T (P < .001). In cases with incomplete EMR-T, lesions were larger (median size, 42.50 mm vs. 37.60 mm; P = .03), there was longer procedure time (mean, 60.2 vs. 35.0 minutes; P = .01), and there was a greater likelihood of referral for surgery (8.3% vs. 3.0%; P = .04).

Intraprocedural bleeding occurred in 6% of cases, and endoscopic hemostasis was achieved in all. Clinically significant post-EMR bleeding occurred in 6.8% of cases, 59.2% of which were managed conservatively, and the remainder were evaluated endoscopically. Bleeding was controlled in every case.

Unlike RRA risk scores that use size, morphology, site, and access score, EMR-T can be used proactively to reduce RRA frequency. It is believed to work by thermally ablating microscopic tissue at the margin. The adverse events reported in the current study were similar to a systematic review and meta-analysis.

“These findings clearly support and exceed those of a recent randomized trial for EMR-T in the colorectum. They likely reflect refinements in the performance of EMR-T over time, due to greater technical experience and enhanced confidence in its safety. At its inception, the approach to EMR-T may have been timid, however, as experience grew and the safety of EMR-T became evident, a meticulous approach to uniform and complete thermal ablation of the defect margin became the standard of care,” the authors wrote.

They added that EMR-T has been shown to benefit in complex LNPCPs, including those that have undergone previous excision attempts and those involving the anorectal junction. The procedure has no added cost, since many endoscopists can readily use snare-tip soft coagulation to manage bleeding events.

“Thermal ablation of the defect margin should be viewed as an essential component of high-quality EMR for LNPCPs, consistent with recent recommendations by the U.S. Multi-Society Task Force on Colorectal Cancer,” the authors wrote.

The study was funded by the Cancer Institute of New South Wales, the Gallipoli Medical Research Foundation, and the University of British Columbia. One author reported research support for Olympus, Cook Medical, and Boston Scientific, but the remaining authors disclosed no conflicts.

Thermal ablation of the defect margin after endoscopic mucosal resection (EMR-T) is associated with reduced recurrence in the treatment of large (≥20-mm) nonpedunculated colorectal polyps (LNPCPs), according to a prospective international cohort study.

Residual or recurrent adenomas (RRAs) are found during 15%-20% of first surveillance endoscopies. EMR-T was previously shown in a randomized trial to be effective at reducing adenoma recurrence during surveillance endoscopy (relative risk, 0.3; P < .01).

The U.S. Multi-Society Task Force currently recommends EMR-T for LNPCPs, but real-world effectiveness remains unknown, wrote Mayenaaz Sidhu, MBBS, of the department of gastroenterology and hepatology at Westmead Hospital in Sydney and colleagues in Gastroenterology. Therefore, they undertook an international, multicenter, prospective trial to evaluate the technique in the real world.

The researchers analyzed data from consecutive patients who were referred for treatment of LNPCPs at six tertiary centers. Between May 2016 and August 2020, the study included 1,049 LNPCPs from 1,049 patients. The mean age was 67.3 years, and the median lesion size was 35 mm. Of LNPCPs, 58.7% were tubulovillous adenomas. EMR was technically successful in 98.9% of cases. Overall, 19.1% of cases required an auxiliary modality to completely remove polypoid tissue; most often this was cold avulsion with adjuvant snare-tip soft coagulation (44.4%).

Complete EMR-T was achieved in 95.4% cases. Reasons for failure included extensive post-EMR defect (n = 29), unstable colonoscope position or difficult access (n = 14), and intraprocedural adverse events (n = 5).

Of 803 patients eligible for surveillance colonoscopy, 94% underwent the procedure at a median interval of 6 months. Overall, RRAs were found in 3% of cases. Among lesions with complete EMR-T, 1.4% (10 of 707) had RRAs at first surveillance colonoscopy versus 27.1% (13 of 48) with incomplete EMR-T (P < .001). In cases with incomplete EMR-T, lesions were larger (median size, 42.50 mm vs. 37.60 mm; P = .03), there was longer procedure time (mean, 60.2 vs. 35.0 minutes; P = .01), and there was a greater likelihood of referral for surgery (8.3% vs. 3.0%; P = .04).

Intraprocedural bleeding occurred in 6% of cases, and endoscopic hemostasis was achieved in all. Clinically significant post-EMR bleeding occurred in 6.8% of cases, 59.2% of which were managed conservatively, and the remainder were evaluated endoscopically. Bleeding was controlled in every case.

Unlike RRA risk scores that use size, morphology, site, and access score, EMR-T can be used proactively to reduce RRA frequency. It is believed to work by thermally ablating microscopic tissue at the margin. The adverse events reported in the current study were similar to a systematic review and meta-analysis.

“These findings clearly support and exceed those of a recent randomized trial for EMR-T in the colorectum. They likely reflect refinements in the performance of EMR-T over time, due to greater technical experience and enhanced confidence in its safety. At its inception, the approach to EMR-T may have been timid, however, as experience grew and the safety of EMR-T became evident, a meticulous approach to uniform and complete thermal ablation of the defect margin became the standard of care,” the authors wrote.

They added that EMR-T has been shown to benefit in complex LNPCPs, including those that have undergone previous excision attempts and those involving the anorectal junction. The procedure has no added cost, since many endoscopists can readily use snare-tip soft coagulation to manage bleeding events.

“Thermal ablation of the defect margin should be viewed as an essential component of high-quality EMR for LNPCPs, consistent with recent recommendations by the U.S. Multi-Society Task Force on Colorectal Cancer,” the authors wrote.

The study was funded by the Cancer Institute of New South Wales, the Gallipoli Medical Research Foundation, and the University of British Columbia. One author reported research support for Olympus, Cook Medical, and Boston Scientific, but the remaining authors disclosed no conflicts.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

A novel oncogene may be a key driver in hepatoblastoma, according to a new study. Hepatoblastoma is the most common form of pediatric cancer, and many tumors harbor beta-catenin mutations and alterations to the Hippo tumor suppression pathway.

In mice, cells can be turned cancerous by coexpressing beta-catenin mutants and the Hippo effector YAP. Some hepatoblastomas have mutations in NFE2L2/NRF2 (NFE2L2), which is a transcription factor that can either promote or suppress tumorigenesis.

In a report in Cellular and Molecular Gastroenterology and Hepatology, researchers led by Huabo Wang, PhD, of the UPMC Children’s Hospital of Pittsburgh investigated the potential role of NFE2L2 by expressing all combinations of mutant beta-catenin, YAP^S127A, and two NFE2L2 mutants previously discovered in patients (L30P and R34P).

The researchers found that both the L30P and R34P mutations led to an increase in cellular growth and to both necrosis and cyst formation, which are both clinically uncommon. Any two of beta-catenin, YAP^S127A, and L30P/R34P caused tumor formation, indicating that NFE2L2 is an oncogene, according to the authors.

Among tumors with changes in all three regions, unbiased RNA sequencing across all combinations of mutations revealed 22 RNA transcripts common to all of them. These are probably the most important contributors to cell transformation and may also be related to increased growth, cystogenesis, and necrosis found in these tumors. Of those transcripts, 10 were highly correlated with survival in human hepatoblastomas, and 17 correlated with survival in more than one adult cancer.

Although hepatoblastomas have fewer mutations than most tumors, around 5%-10% have mutations in NFE2L2. About half have an increase in the copy number of NFE2L2.

The results suggest that wild-type NFE2L2 plays a role in suppressing cell proliferation in response to oxidative, metabolic, and electrophilic stresses. But the picture is more complex than that because NFE2L2’s pathway can have opposite effects, depending on the timing and context. Early in the oncogenesis pathway, it may protect against the damaging effects of reactive oxygen species (ROS). Later, it can make cells more tolerant to the effects of oncoproteins and promote tumor evolution, expansion, and even resistance to therapy.

Previous in vitro and tumor xenograft studies had suggested that NFE2L2 targets might play a role in apoptosis, metabolism, angiogenesis, and chemotherapeutic drug detoxification. The new results show that the L30P/R34P mutations can accelerate tumorigenesis caused by beta-catenin mutations and can promote transformation when co-expressed with either beta-catenin or YAP^S127A. That suggests that some hepatoblastomas may be driven at least in part by changes to NFE2L2. The researchers speculate that it may also be involved in combination with other oncoproteins in other types of tumors.

The researchers noted that the cysts seen in tumors with NFE2L2 mutations are bloodless, and resembled cysts that are sometimes seen in human hepatoblastomas. They were unrelated to tumor growth rate.

“Our findings demonstrate that NFE2L2 mutants alter redox balance in beta-catenin/YAP^S127A HBs and increase growth, cystogenesis, and necrosis. The unanticipated oncogenicity of L30P/R34P when coexpressed with beta-catenin or YAP^S127A also demonstrated their direct role in transformation in vivo and unequivocally established NFE2L2 as an oncoprotein that can be activated by mutation, overexpression, or other factors that perturb the normal NFE2L2:KEAP1 balance,” the authors wrote.

The study received funding from various nonindustry sources. The study authors disclosed no conflicts of interest.

Using low-dose computed tomography (LDCT) to screen for aortic valve calcification during a lung cancer screening could identify those at risk for aortic stenosis, says new research published in Annals of Internal Medicine.

Aortic stenosis is one of the most common valve disease problems and is characterized by the narrowing of the aortic valve opening, according to the American Heart Association. The condition impedes the delivery of blood from the heart to the body.

Researchers found that LDCT, which according to the Centers for Disease Control and Prevention is the only recommended screening test for lung cancer, also can be used to identify aortic valve calcification – a condition in which calcium deposits form on the aortic valve, narrowing it.

Since cardiovascular events and lung cancer are known to have the same modifiable risk factors, people screened for lung cancer could also be diagnosed with cardiovascular diseases, the authors noted in their paper.

Furthermore, a 2019 study published in the Journal of Thoracic Imaging found that LDCT can be useful for identifying not just lung cancer, but the early stages of chronic obstructive pulmonary disease and coronary artery disease.

“LDCT has been described as useful for identifying the early stages of chronic obstructive pulmonary disease and coronary artery disease, but it can also [screen for] calcified aortic valve [which corresponds] with the risk of severe aortic stenosis,” study author Marcin Fijalkowski, MD, PhD, of the Medical University of Gdansk, said in an interview. “This additional evaluation is not time-consuming and is easy to perform.”
 

Methods and results

For the study, Dr. Fijalkowski and his colleagues examined data from 6,631 people between the ages of 50 and 80 years of age with a smoking history of 30 or more pack-years. The group was enrolled in the MOLTEST BIS lung cancer screening program between 2016 and 2018, which assessed the usefulness of LDCT performed during lung cancer screening in determining the degree of aortic valve calcification as an additional finding. The researchers arbitrarily determined a calcium score of 900 as a cutoff point indicating a positive test result. Positive patients were sent for an echocardiogram for confirmation of diagnosis.

Aortic valve calcification was identified in 869 patients, 13.1% of the group. Sixty-eight participants, which is about 8% of this group, were identified as having a calcium score of 900 at least and were referred for echocardiography to confirm these results. Of this group, 0.5% were diagnosed with at least moderate aortic stenosis after receiving an echocardiogram. About 55% of the participants with this condition were unaware of their valvular heart disease, including 23% with a severe form of the disease.
 

Study identified patients who had not been aware of disease

Dr. Fijalkowski said while he was not surprised by the findings, he was surprised that the study may have saved some of the participants’ lives.

“We were expecting the same degree of calcification of aortic valve and correlation with aortic stenosis severity, but what surprised us was that half of diagnosed patients were not aware of disease,” he said. “This additional finding was lifesaving.”

In the paper, the authors noted that cardiology societies do not yet recognize LDCT as a diagnostic tool for aortic stenosis. Based on their findings, they propose that aortic valve calcification become a routine assessment procedure in the LDCT protocol for lung cancer screening.
 

Findings are ‘important’ but not practice changing

Salim S. Virani, MD, FACC, who was not involved in the study, said this new research is important.

The analyses were done well and push the needle further in a direction that suggests “when we are doing imaging for one reason, we should use the totality of information that we have available,” he noted.

“I mean, if you are looking at a lung nodule, if you see an aortic valve that’s very calcified, then it should prompt you to at least ask the patient about some symptoms related to that,” Dr. Virani explained.

However, he said more research is needed on a larger population before LDCT can be considered a diagnostic tool for aortic stenosis.

“I think we have to understand that this study was done in a very specific group of patients,” said Dr. Virani, professor in the sections of cardiology and cardiovascular research at Baylor College of Medicine, Houston. “If you were to do it in a population that was much younger, with much lower risk of even lung cancer, then the yield of a CT to pick up aortic stenosis would be lower.”

Before any practice changes are made regarding LDCT and the diagnosis of aortic stenosis, there needs to be more research on how many people in the general population are getting non–cardiology-related chest imaging and then come up with a population-based metric as to what calcium score cutoff could be used, he said.

Dr. Fijalkowski said he believes the results of his study will encourage physicians to focus not only on pulmonary nodules but also to look for additional things such as aortic valve calcification.

The experts did not disclose any relevant financial relationships.

Using low-dose computed tomography (LDCT) to screen for aortic valve calcification during a lung cancer screening could identify those at risk for aortic stenosis, says new research published in Annals of Internal Medicine.

Aortic stenosis is one of the most common valve disease problems and is characterized by the narrowing of the aortic valve opening, according to the American Heart Association. The condition impedes the delivery of blood from the heart to the body.

Researchers found that LDCT, which according to the Centers for Disease Control and Prevention is the only recommended screening test for lung cancer, also can be used to identify aortic valve calcification – a condition in which calcium deposits form on the aortic valve, narrowing it.

Since cardiovascular events and lung cancer are known to have the same modifiable risk factors, people screened for lung cancer could also be diagnosed with cardiovascular diseases, the authors noted in their paper.

Furthermore, a 2019 study published in the Journal of Thoracic Imaging found that LDCT can be useful for identifying not just lung cancer, but the early stages of chronic obstructive pulmonary disease and coronary artery disease.

“LDCT has been described as useful for identifying the early stages of chronic obstructive pulmonary disease and coronary artery disease, but it can also [screen for] calcified aortic valve [which corresponds] with the risk of severe aortic stenosis,” study author Marcin Fijalkowski, MD, PhD, of the Medical University of Gdansk, said in an interview. “This additional evaluation is not time-consuming and is easy to perform.”
 

Methods and results

For the study, Dr. Fijalkowski and his colleagues examined data from 6,631 people between the ages of 50 and 80 years of age with a smoking history of 30 or more pack-years. The group was enrolled in the MOLTEST BIS lung cancer screening program between 2016 and 2018, which assessed the usefulness of LDCT performed during lung cancer screening in determining the degree of aortic valve calcification as an additional finding. The researchers arbitrarily determined a calcium score of 900 as a cutoff point indicating a positive test result. Positive patients were sent for an echocardiogram for confirmation of diagnosis.

Aortic valve calcification was identified in 869 patients, 13.1% of the group. Sixty-eight participants, which is about 8% of this group, were identified as having a calcium score of 900 at least and were referred for echocardiography to confirm these results. Of this group, 0.5% were diagnosed with at least moderate aortic stenosis after receiving an echocardiogram. About 55% of the participants with this condition were unaware of their valvular heart disease, including 23% with a severe form of the disease.
 

Study identified patients who had not been aware of disease

Dr. Fijalkowski said while he was not surprised by the findings, he was surprised that the study may have saved some of the participants’ lives.

“We were expecting the same degree of calcification of aortic valve and correlation with aortic stenosis severity, but what surprised us was that half of diagnosed patients were not aware of disease,” he said. “This additional finding was lifesaving.”

In the paper, the authors noted that cardiology societies do not yet recognize LDCT as a diagnostic tool for aortic stenosis. Based on their findings, they propose that aortic valve calcification become a routine assessment procedure in the LDCT protocol for lung cancer screening.
 

Findings are ‘important’ but not practice changing

Salim S. Virani, MD, FACC, who was not involved in the study, said this new research is important.

The analyses were done well and push the needle further in a direction that suggests “when we are doing imaging for one reason, we should use the totality of information that we have available,” he noted.

“I mean, if you are looking at a lung nodule, if you see an aortic valve that’s very calcified, then it should prompt you to at least ask the patient about some symptoms related to that,” Dr. Virani explained.

However, he said more research is needed on a larger population before LDCT can be considered a diagnostic tool for aortic stenosis.

“I think we have to understand that this study was done in a very specific group of patients,” said Dr. Virani, professor in the sections of cardiology and cardiovascular research at Baylor College of Medicine, Houston. “If you were to do it in a population that was much younger, with much lower risk of even lung cancer, then the yield of a CT to pick up aortic stenosis would be lower.”

Before any practice changes are made regarding LDCT and the diagnosis of aortic stenosis, there needs to be more research on how many people in the general population are getting non–cardiology-related chest imaging and then come up with a population-based metric as to what calcium score cutoff could be used, he said.

Dr. Fijalkowski said he believes the results of his study will encourage physicians to focus not only on pulmonary nodules but also to look for additional things such as aortic valve calcification.

The experts did not disclose any relevant financial relationships.

Using low-dose computed tomography (LDCT) to screen for aortic valve calcification during a lung cancer screening could identify those at risk for aortic stenosis, says new research published in Annals of Internal Medicine.

Aortic stenosis is one of the most common valve disease problems and is characterized by the narrowing of the aortic valve opening, according to the American Heart Association. The condition impedes the delivery of blood from the heart to the body.

Researchers found that LDCT, which according to the Centers for Disease Control and Prevention is the only recommended screening test for lung cancer, also can be used to identify aortic valve calcification – a condition in which calcium deposits form on the aortic valve, narrowing it.

Since cardiovascular events and lung cancer are known to have the same modifiable risk factors, people screened for lung cancer could also be diagnosed with cardiovascular diseases, the authors noted in their paper.

Furthermore, a 2019 study published in the Journal of Thoracic Imaging found that LDCT can be useful for identifying not just lung cancer, but the early stages of chronic obstructive pulmonary disease and coronary artery disease.

“LDCT has been described as useful for identifying the early stages of chronic obstructive pulmonary disease and coronary artery disease, but it can also [screen for] calcified aortic valve [which corresponds] with the risk of severe aortic stenosis,” study author Marcin Fijalkowski, MD, PhD, of the Medical University of Gdansk, said in an interview. “This additional evaluation is not time-consuming and is easy to perform.”
 

Methods and results

For the study, Dr. Fijalkowski and his colleagues examined data from 6,631 people between the ages of 50 and 80 years of age with a smoking history of 30 or more pack-years. The group was enrolled in the MOLTEST BIS lung cancer screening program between 2016 and 2018, which assessed the usefulness of LDCT performed during lung cancer screening in determining the degree of aortic valve calcification as an additional finding. The researchers arbitrarily determined a calcium score of 900 as a cutoff point indicating a positive test result. Positive patients were sent for an echocardiogram for confirmation of diagnosis.

Aortic valve calcification was identified in 869 patients, 13.1% of the group. Sixty-eight participants, which is about 8% of this group, were identified as having a calcium score of 900 at least and were referred for echocardiography to confirm these results. Of this group, 0.5% were diagnosed with at least moderate aortic stenosis after receiving an echocardiogram. About 55% of the participants with this condition were unaware of their valvular heart disease, including 23% with a severe form of the disease.
 

Study identified patients who had not been aware of disease

Dr. Fijalkowski said while he was not surprised by the findings, he was surprised that the study may have saved some of the participants’ lives.

“We were expecting the same degree of calcification of aortic valve and correlation with aortic stenosis severity, but what surprised us was that half of diagnosed patients were not aware of disease,” he said. “This additional finding was lifesaving.”

In the paper, the authors noted that cardiology societies do not yet recognize LDCT as a diagnostic tool for aortic stenosis. Based on their findings, they propose that aortic valve calcification become a routine assessment procedure in the LDCT protocol for lung cancer screening.
 

Findings are ‘important’ but not practice changing

Salim S. Virani, MD, FACC, who was not involved in the study, said this new research is important.

The analyses were done well and push the needle further in a direction that suggests “when we are doing imaging for one reason, we should use the totality of information that we have available,” he noted.

“I mean, if you are looking at a lung nodule, if you see an aortic valve that’s very calcified, then it should prompt you to at least ask the patient about some symptoms related to that,” Dr. Virani explained.

However, he said more research is needed on a larger population before LDCT can be considered a diagnostic tool for aortic stenosis.

“I think we have to understand that this study was done in a very specific group of patients,” said Dr. Virani, professor in the sections of cardiology and cardiovascular research at Baylor College of Medicine, Houston. “If you were to do it in a population that was much younger, with much lower risk of even lung cancer, then the yield of a CT to pick up aortic stenosis would be lower.”

Before any practice changes are made regarding LDCT and the diagnosis of aortic stenosis, there needs to be more research on how many people in the general population are getting non–cardiology-related chest imaging and then come up with a population-based metric as to what calcium score cutoff could be used, he said.

Dr. Fijalkowski said he believes the results of his study will encourage physicians to focus not only on pulmonary nodules but also to look for additional things such as aortic valve calcification.

The experts did not disclose any relevant financial relationships.