The use of gonadotropin-releasing hormone agonists has a negative effect on bone mass in transgender youth, according to data from 172 individuals.

The onset of puberty and pubertal hormones contributes to the development of bone mass and body composition in adolescence, wrote Behdad Navabi, MD, and colleagues at Children’s Hospital of Eastern Ontario, Canada. Although the safety and efficacy of gonadotropin-releasing hormone agonists (GnRHa) has been described in short-term studies of youth with gender dysphoria, concerns persist about suppression of bone mass accrual from extended use of GnRHas in this population, they noted.

In a study published in Pediatrics, the researchers reviewed data from 172 youth younger than 18 years of age who were treated with GNRHa and underwent at least one baseline dual-energy radiograph absorptiometry (DXA) measurement between January 2006 and April 2017 at a single center. The standard treatment protocol started with three doses of 7.5 mg leuprolide acetate, given intramuscularly every 4 weeks, followed by 11.25 mg intramuscularly every 12 weeks after puberty suppression was confirmed both clinically and biochemically. Areal bone mineral density (aBMD) measurement z scores were based on birth-assigned sex, age, and ethnicity, and assessed at baseline and every 12 months. In addition, volumetric bone mineral density was calculated as bone mineral apparent density (BMAD) at the lower spine, and the z score based on age-matched, birth-assigned gender BMAD.

Overall, 55.2% of the youth were vitamin D deficient or insufficient at baseline, but 87.3% were sufficient by the time of a third follow-up visit after treatment with 1,000-2,000 IU of vitamin D daily; no cases of vitamin D toxicity were reported.

At baseline, transgender females had lower z scores for the LS aBMD and BMAD compared to transgender males, reflecting a difference seen in previous studies of transgender youth and adult females, the researchers noted.

The researchers analyzed pre- and posttreatment DXA data in a subgroup of 36 transgender females and 80 transgender males to identify any changes associated with GnRHa. The average time between the DXA scans was 407 days. In this population, aBMD z scores at the lower lumbar spine (LS), left total hip (LTH), and total body less head (TBLH) decreased significantly from baseline in transgender males and females.

Among transgender males, LS bone mineral apparent density (BMAD) z scores also decreased significantly from baseline, but no such change occurred among transgender females. The most significant decrease in z scores occurred in the LS aBMD and BMAD of transgender males, with changes that reflect findings from previous studies and may be explained by decreased estrogen, the researchers wrote.

In terms of body composition, no significant changes occurred in body mass index z score from baseline to follow-up in transgender males or females, the researchers noted, and changes in both gynoid and android fat percentages were consistent with the individuals’ affirmed genders. No vertebral fractures were detected.

However, GnRHa was significantly associated with a decrease in total body fat percentage and a decrease in lean body mass (LBM) in transgender females.

The study findings were limited by several factors, including the lack of consistent baseline physical activity records, and limited analysis at follow-up of the possible role of physical activity in bone health and body composition, the researchers noted. However, the results were strengthened by the relatively large study population with baseline assessments, and by the pre- and posttreatment analysis, they added.

“Evidence on GnRHa-associated changes in body composition and BMD will help health care professionals involved in the care of youth with GD [gender dysphoria] to counsel appropriately and optimize their bone health,” the researchers said. “Given the absence of vertebral fractures detected in those with significant decreases in their LS z scores, the significance of BMD effects of GnRHa in transgender youth needs further study, as well as whether future spine radiographs are needed on the basis of BMD trajectory,” they concluded.
 

Balance bone health concerns with potential benefits

The effect of estrogen and testosterone on bone geometry in puberty varies, and the increase in the use of GnRHa as part of a multidisciplinary gender transition plan makes research on the skeletal impact of this therapy in transgender youth a top priority, Laura K. Bachrach, MD, of Stanford (Calif.) University, and Catherine M. Gordon of Harvard Medical School, Boston, wrote in an accompanying editorial.

The decrease in areal bone mineral density and in bone mineral apparent density (BMAD) z scores in the current study is not unexpected, but the key question is how much bone density recovers once the suppression therapy ends and transgender sex steroid use begins, they said. “Follow-up studies of young adults treated with GnRHa for precocious puberty in childhood are reassuring,” they wrote. “It is premature, however, to extrapolate from these findings to transgender youth,” because the impact of gender-affirming sex steroid therapy on the skeleton at older ages and stages of maturity are unclear, they emphasized.

In the absence of definitive answers, the editorial authors advised clinicians treating youth with gender dysphoria to provide a balanced view of the risks and benefits of hormone therapy, and encourage adequate intake of dietary vitamin D and calcium, along with weight-bearing physical activity, to promote general bone health. “Transgender teenagers and their parents should be reassured that some recovery from decreases in aBMD during pubertal suppression with GnRHa is likely,” the authors noted. Bone health should be monitored throughout all stages of treatment in transgender youth, but concerns about transient bone loss should not discourage gender transition therapy, they emphasized. “In this patient group, providing a pause in pubertal development offers a life-changing and, for some, a life-saving intervention,” they concluded.
 

Comparison to cisgender controls would add value

“This study is important because one of the major side effects of GnRH agonists is decreased bone density, especially the longer that patients are on them,” M. Brett Cooper, MD, of UT Southwestern Medical Center, said in an interview. The findings add to existing data to underscore the importance of screening for low bone density and low vitamin D levels, Dr. Cooper added.

Dr. Cooper said that he was not surprised by the study findings. “I think that this study supported what clinicians already knew, which is that GnRH agonists do potentially cause a decline in bone mineral density and thus, you need to support these patients as best you can with calcium, vitamin D, and weight-bearing exercise,” he noted.

Dr. Cooper emphasized two main take-home points from the study. “First, clinicians who prescribe GnRH agonists need to ensure that they are checking bone density and vitamin D measurements, and then optimizing these appropriately,” he said. “Second, when a bone density is found to be low or a vitamin level is low, clinicians need to ensure that they are monitored and treated appropriately.” Clinicians need to use these data when deciding when to start gender-affirming hormones so their patients have the best chance to recover bone density, he added.

“I think one confounding factor on this study is the ranges they used for vitamin D deficiency,” Dr. Cooper noted. “This study was done in Canada, and the scale used was in nmol/L, while most labs in the U.S. use ng/mL,” he said. “Most pediatric and adolescent societies in the United States use < 20 ng/mL as an indicator of vitamin D deficient and between 20 and 29 ng/mL as insufficient,” he explained, citing the position statement on recommended vitamin D intake for adolescents published by The Society for Adolescent Health and Medicine. In this study, the results converted to < 12 ng/mL as deficient and between 12 and 20 ng/mL as insufficient, respectively, on the U.S. scale, said Dr. Cooper.

“Therefore, I can see that there are cases where someone may have been labeled vitamin D insufficient in this study using their range, whereas in the U.S. these patients would be labeled as vitamin D deficient and treated with higher-dose supplementation,” he said. In addition, individuals with levels between 20 ng/mL and 29 ng/mL in the U.S. would still be treated with vitamin D supplementation, “whereas in their study those individuals would have been labeled as normal,” he noted.

As for future research, it would be useful to study whether bone mass in transgender young people differs from age- and gender-matched controls who are not gender diverse (cisgender), Dr. Cooper added. “It may be possible that the youth in this study are not different from their peers and maybe the GnRH agonist is not the culprit,” he said.

The study received no outside funding. The researchers, editorial authors, and Dr. Cooper had no financial conflicts to disclose.

The use of gonadotropin-releasing hormone agonists has a negative effect on bone mass in transgender youth, according to data from 172 individuals.

The onset of puberty and pubertal hormones contributes to the development of bone mass and body composition in adolescence, wrote Behdad Navabi, MD, and colleagues at Children’s Hospital of Eastern Ontario, Canada. Although the safety and efficacy of gonadotropin-releasing hormone agonists (GnRHa) has been described in short-term studies of youth with gender dysphoria, concerns persist about suppression of bone mass accrual from extended use of GnRHas in this population, they noted.

In a study published in Pediatrics, the researchers reviewed data from 172 youth younger than 18 years of age who were treated with GNRHa and underwent at least one baseline dual-energy radiograph absorptiometry (DXA) measurement between January 2006 and April 2017 at a single center. The standard treatment protocol started with three doses of 7.5 mg leuprolide acetate, given intramuscularly every 4 weeks, followed by 11.25 mg intramuscularly every 12 weeks after puberty suppression was confirmed both clinically and biochemically. Areal bone mineral density (aBMD) measurement z scores were based on birth-assigned sex, age, and ethnicity, and assessed at baseline and every 12 months. In addition, volumetric bone mineral density was calculated as bone mineral apparent density (BMAD) at the lower spine, and the z score based on age-matched, birth-assigned gender BMAD.

Overall, 55.2% of the youth were vitamin D deficient or insufficient at baseline, but 87.3% were sufficient by the time of a third follow-up visit after treatment with 1,000-2,000 IU of vitamin D daily; no cases of vitamin D toxicity were reported.

At baseline, transgender females had lower z scores for the LS aBMD and BMAD compared to transgender males, reflecting a difference seen in previous studies of transgender youth and adult females, the researchers noted.

The researchers analyzed pre- and posttreatment DXA data in a subgroup of 36 transgender females and 80 transgender males to identify any changes associated with GnRHa. The average time between the DXA scans was 407 days. In this population, aBMD z scores at the lower lumbar spine (LS), left total hip (LTH), and total body less head (TBLH) decreased significantly from baseline in transgender males and females.

Among transgender males, LS bone mineral apparent density (BMAD) z scores also decreased significantly from baseline, but no such change occurred among transgender females. The most significant decrease in z scores occurred in the LS aBMD and BMAD of transgender males, with changes that reflect findings from previous studies and may be explained by decreased estrogen, the researchers wrote.

In terms of body composition, no significant changes occurred in body mass index z score from baseline to follow-up in transgender males or females, the researchers noted, and changes in both gynoid and android fat percentages were consistent with the individuals’ affirmed genders. No vertebral fractures were detected.

However, GnRHa was significantly associated with a decrease in total body fat percentage and a decrease in lean body mass (LBM) in transgender females.

The study findings were limited by several factors, including the lack of consistent baseline physical activity records, and limited analysis at follow-up of the possible role of physical activity in bone health and body composition, the researchers noted. However, the results were strengthened by the relatively large study population with baseline assessments, and by the pre- and posttreatment analysis, they added.

“Evidence on GnRHa-associated changes in body composition and BMD will help health care professionals involved in the care of youth with GD [gender dysphoria] to counsel appropriately and optimize their bone health,” the researchers said. “Given the absence of vertebral fractures detected in those with significant decreases in their LS z scores, the significance of BMD effects of GnRHa in transgender youth needs further study, as well as whether future spine radiographs are needed on the basis of BMD trajectory,” they concluded.
 

Balance bone health concerns with potential benefits

The effect of estrogen and testosterone on bone geometry in puberty varies, and the increase in the use of GnRHa as part of a multidisciplinary gender transition plan makes research on the skeletal impact of this therapy in transgender youth a top priority, Laura K. Bachrach, MD, of Stanford (Calif.) University, and Catherine M. Gordon of Harvard Medical School, Boston, wrote in an accompanying editorial.

The decrease in areal bone mineral density and in bone mineral apparent density (BMAD) z scores in the current study is not unexpected, but the key question is how much bone density recovers once the suppression therapy ends and transgender sex steroid use begins, they said. “Follow-up studies of young adults treated with GnRHa for precocious puberty in childhood are reassuring,” they wrote. “It is premature, however, to extrapolate from these findings to transgender youth,” because the impact of gender-affirming sex steroid therapy on the skeleton at older ages and stages of maturity are unclear, they emphasized.

In the absence of definitive answers, the editorial authors advised clinicians treating youth with gender dysphoria to provide a balanced view of the risks and benefits of hormone therapy, and encourage adequate intake of dietary vitamin D and calcium, along with weight-bearing physical activity, to promote general bone health. “Transgender teenagers and their parents should be reassured that some recovery from decreases in aBMD during pubertal suppression with GnRHa is likely,” the authors noted. Bone health should be monitored throughout all stages of treatment in transgender youth, but concerns about transient bone loss should not discourage gender transition therapy, they emphasized. “In this patient group, providing a pause in pubertal development offers a life-changing and, for some, a life-saving intervention,” they concluded.
 

Comparison to cisgender controls would add value

“This study is important because one of the major side effects of GnRH agonists is decreased bone density, especially the longer that patients are on them,” M. Brett Cooper, MD, of UT Southwestern Medical Center, said in an interview. The findings add to existing data to underscore the importance of screening for low bone density and low vitamin D levels, Dr. Cooper added.

Dr. Cooper said that he was not surprised by the study findings. “I think that this study supported what clinicians already knew, which is that GnRH agonists do potentially cause a decline in bone mineral density and thus, you need to support these patients as best you can with calcium, vitamin D, and weight-bearing exercise,” he noted.

Dr. Cooper emphasized two main take-home points from the study. “First, clinicians who prescribe GnRH agonists need to ensure that they are checking bone density and vitamin D measurements, and then optimizing these appropriately,” he said. “Second, when a bone density is found to be low or a vitamin level is low, clinicians need to ensure that they are monitored and treated appropriately.” Clinicians need to use these data when deciding when to start gender-affirming hormones so their patients have the best chance to recover bone density, he added.

“I think one confounding factor on this study is the ranges they used for vitamin D deficiency,” Dr. Cooper noted. “This study was done in Canada, and the scale used was in nmol/L, while most labs in the U.S. use ng/mL,” he said. “Most pediatric and adolescent societies in the United States use < 20 ng/mL as an indicator of vitamin D deficient and between 20 and 29 ng/mL as insufficient,” he explained, citing the position statement on recommended vitamin D intake for adolescents published by The Society for Adolescent Health and Medicine. In this study, the results converted to < 12 ng/mL as deficient and between 12 and 20 ng/mL as insufficient, respectively, on the U.S. scale, said Dr. Cooper.

“Therefore, I can see that there are cases where someone may have been labeled vitamin D insufficient in this study using their range, whereas in the U.S. these patients would be labeled as vitamin D deficient and treated with higher-dose supplementation,” he said. In addition, individuals with levels between 20 ng/mL and 29 ng/mL in the U.S. would still be treated with vitamin D supplementation, “whereas in their study those individuals would have been labeled as normal,” he noted.

As for future research, it would be useful to study whether bone mass in transgender young people differs from age- and gender-matched controls who are not gender diverse (cisgender), Dr. Cooper added. “It may be possible that the youth in this study are not different from their peers and maybe the GnRH agonist is not the culprit,” he said.

The study received no outside funding. The researchers, editorial authors, and Dr. Cooper had no financial conflicts to disclose.

The use of gonadotropin-releasing hormone agonists has a negative effect on bone mass in transgender youth, according to data from 172 individuals.

The onset of puberty and pubertal hormones contributes to the development of bone mass and body composition in adolescence, wrote Behdad Navabi, MD, and colleagues at Children’s Hospital of Eastern Ontario, Canada. Although the safety and efficacy of gonadotropin-releasing hormone agonists (GnRHa) has been described in short-term studies of youth with gender dysphoria, concerns persist about suppression of bone mass accrual from extended use of GnRHas in this population, they noted.

In a study published in Pediatrics, the researchers reviewed data from 172 youth younger than 18 years of age who were treated with GNRHa and underwent at least one baseline dual-energy radiograph absorptiometry (DXA) measurement between January 2006 and April 2017 at a single center. The standard treatment protocol started with three doses of 7.5 mg leuprolide acetate, given intramuscularly every 4 weeks, followed by 11.25 mg intramuscularly every 12 weeks after puberty suppression was confirmed both clinically and biochemically. Areal bone mineral density (aBMD) measurement z scores were based on birth-assigned sex, age, and ethnicity, and assessed at baseline and every 12 months. In addition, volumetric bone mineral density was calculated as bone mineral apparent density (BMAD) at the lower spine, and the z score based on age-matched, birth-assigned gender BMAD.

Overall, 55.2% of the youth were vitamin D deficient or insufficient at baseline, but 87.3% were sufficient by the time of a third follow-up visit after treatment with 1,000-2,000 IU of vitamin D daily; no cases of vitamin D toxicity were reported.

At baseline, transgender females had lower z scores for the LS aBMD and BMAD compared to transgender males, reflecting a difference seen in previous studies of transgender youth and adult females, the researchers noted.

The researchers analyzed pre- and posttreatment DXA data in a subgroup of 36 transgender females and 80 transgender males to identify any changes associated with GnRHa. The average time between the DXA scans was 407 days. In this population, aBMD z scores at the lower lumbar spine (LS), left total hip (LTH), and total body less head (TBLH) decreased significantly from baseline in transgender males and females.

Among transgender males, LS bone mineral apparent density (BMAD) z scores also decreased significantly from baseline, but no such change occurred among transgender females. The most significant decrease in z scores occurred in the LS aBMD and BMAD of transgender males, with changes that reflect findings from previous studies and may be explained by decreased estrogen, the researchers wrote.

In terms of body composition, no significant changes occurred in body mass index z score from baseline to follow-up in transgender males or females, the researchers noted, and changes in both gynoid and android fat percentages were consistent with the individuals’ affirmed genders. No vertebral fractures were detected.

However, GnRHa was significantly associated with a decrease in total body fat percentage and a decrease in lean body mass (LBM) in transgender females.

The study findings were limited by several factors, including the lack of consistent baseline physical activity records, and limited analysis at follow-up of the possible role of physical activity in bone health and body composition, the researchers noted. However, the results were strengthened by the relatively large study population with baseline assessments, and by the pre- and posttreatment analysis, they added.

“Evidence on GnRHa-associated changes in body composition and BMD will help health care professionals involved in the care of youth with GD [gender dysphoria] to counsel appropriately and optimize their bone health,” the researchers said. “Given the absence of vertebral fractures detected in those with significant decreases in their LS z scores, the significance of BMD effects of GnRHa in transgender youth needs further study, as well as whether future spine radiographs are needed on the basis of BMD trajectory,” they concluded.
 

Balance bone health concerns with potential benefits

The effect of estrogen and testosterone on bone geometry in puberty varies, and the increase in the use of GnRHa as part of a multidisciplinary gender transition plan makes research on the skeletal impact of this therapy in transgender youth a top priority, Laura K. Bachrach, MD, of Stanford (Calif.) University, and Catherine M. Gordon of Harvard Medical School, Boston, wrote in an accompanying editorial.

The decrease in areal bone mineral density and in bone mineral apparent density (BMAD) z scores in the current study is not unexpected, but the key question is how much bone density recovers once the suppression therapy ends and transgender sex steroid use begins, they said. “Follow-up studies of young adults treated with GnRHa for precocious puberty in childhood are reassuring,” they wrote. “It is premature, however, to extrapolate from these findings to transgender youth,” because the impact of gender-affirming sex steroid therapy on the skeleton at older ages and stages of maturity are unclear, they emphasized.

In the absence of definitive answers, the editorial authors advised clinicians treating youth with gender dysphoria to provide a balanced view of the risks and benefits of hormone therapy, and encourage adequate intake of dietary vitamin D and calcium, along with weight-bearing physical activity, to promote general bone health. “Transgender teenagers and their parents should be reassured that some recovery from decreases in aBMD during pubertal suppression with GnRHa is likely,” the authors noted. Bone health should be monitored throughout all stages of treatment in transgender youth, but concerns about transient bone loss should not discourage gender transition therapy, they emphasized. “In this patient group, providing a pause in pubertal development offers a life-changing and, for some, a life-saving intervention,” they concluded.
 

Comparison to cisgender controls would add value

“This study is important because one of the major side effects of GnRH agonists is decreased bone density, especially the longer that patients are on them,” M. Brett Cooper, MD, of UT Southwestern Medical Center, said in an interview. The findings add to existing data to underscore the importance of screening for low bone density and low vitamin D levels, Dr. Cooper added.

Dr. Cooper said that he was not surprised by the study findings. “I think that this study supported what clinicians already knew, which is that GnRH agonists do potentially cause a decline in bone mineral density and thus, you need to support these patients as best you can with calcium, vitamin D, and weight-bearing exercise,” he noted.

Dr. Cooper emphasized two main take-home points from the study. “First, clinicians who prescribe GnRH agonists need to ensure that they are checking bone density and vitamin D measurements, and then optimizing these appropriately,” he said. “Second, when a bone density is found to be low or a vitamin level is low, clinicians need to ensure that they are monitored and treated appropriately.” Clinicians need to use these data when deciding when to start gender-affirming hormones so their patients have the best chance to recover bone density, he added.

“I think one confounding factor on this study is the ranges they used for vitamin D deficiency,” Dr. Cooper noted. “This study was done in Canada, and the scale used was in nmol/L, while most labs in the U.S. use ng/mL,” he said. “Most pediatric and adolescent societies in the United States use < 20 ng/mL as an indicator of vitamin D deficient and between 20 and 29 ng/mL as insufficient,” he explained, citing the position statement on recommended vitamin D intake for adolescents published by The Society for Adolescent Health and Medicine. In this study, the results converted to < 12 ng/mL as deficient and between 12 and 20 ng/mL as insufficient, respectively, on the U.S. scale, said Dr. Cooper.

“Therefore, I can see that there are cases where someone may have been labeled vitamin D insufficient in this study using their range, whereas in the U.S. these patients would be labeled as vitamin D deficient and treated with higher-dose supplementation,” he said. In addition, individuals with levels between 20 ng/mL and 29 ng/mL in the U.S. would still be treated with vitamin D supplementation, “whereas in their study those individuals would have been labeled as normal,” he noted.

As for future research, it would be useful to study whether bone mass in transgender young people differs from age- and gender-matched controls who are not gender diverse (cisgender), Dr. Cooper added. “It may be possible that the youth in this study are not different from their peers and maybe the GnRH agonist is not the culprit,” he said.

The study received no outside funding. The researchers, editorial authors, and Dr. Cooper had no financial conflicts to disclose.

Muscle symptoms, such as cramps, pain, and other discomfort many patients blame on their recently prescribed statin usually aren’t caused by the drug at all, but by the expectation of such adverse effects, conclude researchers behind the randomized SAMSON trial, now fully published .

It’s common for patients to stop taking their statin because of muscle pain and their belief that the drug itself is to blame. That can sometimes be true, but the SAMSON trial, owing to its unusual design, makes a strong case that such symptoms are usually a nocebo effect.

That is, most statin-related muscle symptoms are likely “driven by the act of taking tablets rather than whether the tablets contain a statin,” concludes the report, which appears in the September 21 issue of the Journal of the American College of Cardiology, with lead authors James P. Howard, PhD, and Frances A. Wood, MPhil, Imperial College London.

SAMSON had been presented at the American Heart Association Scientific Sessions 2020 virtual meeting, covered at the time by this news organization, and simultaneously published in abbreviated form as correspondence in the New England Journal of Medicine.

“SAMSON suggests that the bulk of statin-related intolerable side effects arise from the taking of a tablet, not from statin therapy per se,” agrees an editorial accompanying the new publication.

“The study also demonstrates that the informal experimentation of stopping and restarting a statin to evaluate symptom resolution and reinduction without use of a placebo leads to nocebo symptoms misattributed to the statin,” writes Peter P. Toth, MD, PhD, Johns Hopkins University, Baltimore.

Statin intolerance, he continues, “warrants considerable further investigation, because it undermines standard of care for a very large number of patients worldwide,” leaving them vulnerable to atherosclerotic cardiovascular disease events. “Aches and pains are a fact of life; just because a patient has them does not mean they should be attributed to their statin.”

SAMSON assigned 35 men and 25 women to take atorvastatin 20 mg/day, its matching placebo, or neither pill each for 1 month in randomly alternating order for 12 months, with double-blinding, such that each of the three regimens was maintained for a total of 4 months.

The patients, 77% of whom were prescribed statins for primary prevention and all of whom had a history of stopping the drugs because of adverse effects, documented the severity of any perceived adverse effects on a smartphone app, with a “symptom score” ranging from 0 to 100.

The symptom score averaged 8.0 in months when no tablet was taken, but it was much higher in other months: 15.4 in placebo-pill months and 16.3 in months when atorvastatin was taken. The no-tablet score was significantly lower (P < .001) than either of the two other scores, which themselves were not significantly different from each other.

Eleven patients were unable to complete all 12 one-month segments of the trial, including five because of severe symptoms, but discontinuation was no more likely to occur in the atorvastatin group than in the placebo group.

The authors calculated an overall 0.90 “nocebo ratio” for the study, defined as the difference between symptom intensity on placebo and on no pill, divided by the difference between symptom intensity on atorvastatin and on no pill.

That means, the authors propose, that 90% of the symptom burden felt by patients receiving atorvastatin was also felt on the placebo pill and could be attributed to the nocebo effect.

“Prompt onset and offset of symptoms after starting and stopping tablets is often interpreted by patients and clinicians as evidence of causation. Our data indicate that this is true,” the authors write, but “the causation is from taking a tablet, rather than from the tablet being a statin.”

SAMSON was funded by the British Heart Foundation and supported by the National Institute for Health Research Imperial Biomedical Research Centre and the Imperial Clinical Trials Unit. Dr. Howard is supported by the Wellcome Trust. Dr. Wood declared no conflicts. Disclosures for the other authors are in the report. Dr. Toth discloses serving as a consultant to Amarin, Amgen, AstraZeneca, nio89, Kowa, Merck, Resverlogix, and Theravance; and serving on a speaker’s bureau for Amarin, Amgen, Esperion, and NovoNordisk.

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

Muscle symptoms, such as cramps, pain, and other discomfort many patients blame on their recently prescribed statin usually aren’t caused by the drug at all, but by the expectation of such adverse effects, conclude researchers behind the randomized SAMSON trial, now fully published .

It’s common for patients to stop taking their statin because of muscle pain and their belief that the drug itself is to blame. That can sometimes be true, but the SAMSON trial, owing to its unusual design, makes a strong case that such symptoms are usually a nocebo effect.

That is, most statin-related muscle symptoms are likely “driven by the act of taking tablets rather than whether the tablets contain a statin,” concludes the report, which appears in the September 21 issue of the Journal of the American College of Cardiology, with lead authors James P. Howard, PhD, and Frances A. Wood, MPhil, Imperial College London.

SAMSON had been presented at the American Heart Association Scientific Sessions 2020 virtual meeting, covered at the time by this news organization, and simultaneously published in abbreviated form as correspondence in the New England Journal of Medicine.

“SAMSON suggests that the bulk of statin-related intolerable side effects arise from the taking of a tablet, not from statin therapy per se,” agrees an editorial accompanying the new publication.

“The study also demonstrates that the informal experimentation of stopping and restarting a statin to evaluate symptom resolution and reinduction without use of a placebo leads to nocebo symptoms misattributed to the statin,” writes Peter P. Toth, MD, PhD, Johns Hopkins University, Baltimore.

Statin intolerance, he continues, “warrants considerable further investigation, because it undermines standard of care for a very large number of patients worldwide,” leaving them vulnerable to atherosclerotic cardiovascular disease events. “Aches and pains are a fact of life; just because a patient has them does not mean they should be attributed to their statin.”

SAMSON assigned 35 men and 25 women to take atorvastatin 20 mg/day, its matching placebo, or neither pill each for 1 month in randomly alternating order for 12 months, with double-blinding, such that each of the three regimens was maintained for a total of 4 months.

The patients, 77% of whom were prescribed statins for primary prevention and all of whom had a history of stopping the drugs because of adverse effects, documented the severity of any perceived adverse effects on a smartphone app, with a “symptom score” ranging from 0 to 100.

The symptom score averaged 8.0 in months when no tablet was taken, but it was much higher in other months: 15.4 in placebo-pill months and 16.3 in months when atorvastatin was taken. The no-tablet score was significantly lower (P < .001) than either of the two other scores, which themselves were not significantly different from each other.

Eleven patients were unable to complete all 12 one-month segments of the trial, including five because of severe symptoms, but discontinuation was no more likely to occur in the atorvastatin group than in the placebo group.

The authors calculated an overall 0.90 “nocebo ratio” for the study, defined as the difference between symptom intensity on placebo and on no pill, divided by the difference between symptom intensity on atorvastatin and on no pill.

That means, the authors propose, that 90% of the symptom burden felt by patients receiving atorvastatin was also felt on the placebo pill and could be attributed to the nocebo effect.

“Prompt onset and offset of symptoms after starting and stopping tablets is often interpreted by patients and clinicians as evidence of causation. Our data indicate that this is true,” the authors write, but “the causation is from taking a tablet, rather than from the tablet being a statin.”

SAMSON was funded by the British Heart Foundation and supported by the National Institute for Health Research Imperial Biomedical Research Centre and the Imperial Clinical Trials Unit. Dr. Howard is supported by the Wellcome Trust. Dr. Wood declared no conflicts. Disclosures for the other authors are in the report. Dr. Toth discloses serving as a consultant to Amarin, Amgen, AstraZeneca, nio89, Kowa, Merck, Resverlogix, and Theravance; and serving on a speaker’s bureau for Amarin, Amgen, Esperion, and NovoNordisk.

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

Muscle symptoms, such as cramps, pain, and other discomfort many patients blame on their recently prescribed statin usually aren’t caused by the drug at all, but by the expectation of such adverse effects, conclude researchers behind the randomized SAMSON trial, now fully published .

It’s common for patients to stop taking their statin because of muscle pain and their belief that the drug itself is to blame. That can sometimes be true, but the SAMSON trial, owing to its unusual design, makes a strong case that such symptoms are usually a nocebo effect.

That is, most statin-related muscle symptoms are likely “driven by the act of taking tablets rather than whether the tablets contain a statin,” concludes the report, which appears in the September 21 issue of the Journal of the American College of Cardiology, with lead authors James P. Howard, PhD, and Frances A. Wood, MPhil, Imperial College London.

SAMSON had been presented at the American Heart Association Scientific Sessions 2020 virtual meeting, covered at the time by this news organization, and simultaneously published in abbreviated form as correspondence in the New England Journal of Medicine.

“SAMSON suggests that the bulk of statin-related intolerable side effects arise from the taking of a tablet, not from statin therapy per se,” agrees an editorial accompanying the new publication.

“The study also demonstrates that the informal experimentation of stopping and restarting a statin to evaluate symptom resolution and reinduction without use of a placebo leads to nocebo symptoms misattributed to the statin,” writes Peter P. Toth, MD, PhD, Johns Hopkins University, Baltimore.

Statin intolerance, he continues, “warrants considerable further investigation, because it undermines standard of care for a very large number of patients worldwide,” leaving them vulnerable to atherosclerotic cardiovascular disease events. “Aches and pains are a fact of life; just because a patient has them does not mean they should be attributed to their statin.”

SAMSON assigned 35 men and 25 women to take atorvastatin 20 mg/day, its matching placebo, or neither pill each for 1 month in randomly alternating order for 12 months, with double-blinding, such that each of the three regimens was maintained for a total of 4 months.

The patients, 77% of whom were prescribed statins for primary prevention and all of whom had a history of stopping the drugs because of adverse effects, documented the severity of any perceived adverse effects on a smartphone app, with a “symptom score” ranging from 0 to 100.

The symptom score averaged 8.0 in months when no tablet was taken, but it was much higher in other months: 15.4 in placebo-pill months and 16.3 in months when atorvastatin was taken. The no-tablet score was significantly lower (P < .001) than either of the two other scores, which themselves were not significantly different from each other.

Eleven patients were unable to complete all 12 one-month segments of the trial, including five because of severe symptoms, but discontinuation was no more likely to occur in the atorvastatin group than in the placebo group.

The authors calculated an overall 0.90 “nocebo ratio” for the study, defined as the difference between symptom intensity on placebo and on no pill, divided by the difference between symptom intensity on atorvastatin and on no pill.

That means, the authors propose, that 90% of the symptom burden felt by patients receiving atorvastatin was also felt on the placebo pill and could be attributed to the nocebo effect.

“Prompt onset and offset of symptoms after starting and stopping tablets is often interpreted by patients and clinicians as evidence of causation. Our data indicate that this is true,” the authors write, but “the causation is from taking a tablet, rather than from the tablet being a statin.”

SAMSON was funded by the British Heart Foundation and supported by the National Institute for Health Research Imperial Biomedical Research Centre and the Imperial Clinical Trials Unit. Dr. Howard is supported by the Wellcome Trust. Dr. Wood declared no conflicts. Disclosures for the other authors are in the report. Dr. Toth discloses serving as a consultant to Amarin, Amgen, AstraZeneca, nio89, Kowa, Merck, Resverlogix, and Theravance; and serving on a speaker’s bureau for Amarin, Amgen, Esperion, and NovoNordisk.

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

With summer coming to an end, and pumpkin spice lattes trending again, we might also expect to say hello to an old friend ... seasonal affective disorder (SAD). 

Have you ever woken up one morning during the fall or winter and felt out of it for a prolonged period, not your regular self? I’m not referring to a day here and there, but consistently experiencing this “down mood” around the same time each year? At some point in their life, it is estimated that 2-3% of Canadians will experience SAD. To add to that, 15% of individuals will experience milder (and less impairing) SAD.  

Seasonal affective disorder can be thought of as a type of depression that occurs during a specific time of the year, usually the winter or fall (with remission outside this period). It is typically characterized by symptoms of clinical depression such as low energy, difficulty with concentration, sleep problems, extreme fatigue, and agitation. While the evidence related to the risk factors for SAD are limited, it is suggested that a family history of SAD, female sex, location farther from the equator (that is, fewer days of sunlight), and being between the ages of 18-30 increase your risk for SAD.

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) does not provide a separate and distinct categorization for SAD. Rather, SAD is categorized as a subtype of depression. However, it is generally recognized that a diagnosis of SAD is accompanied with two consecutive years of mood episodes within a recurring specified timeframe. 
 

Nature versus nurture: An evolutionary perspective

The pathophysiology of SAD is not yet well understood. However, it is hypothesized that SAD is an adaptive response related to physiologic and behavioral patterns of reproduction and childrearing.

Historically, reproduction was closely linked to food and natural resource availability (for example, water, sunlight). Males primarily handled the hunting, while females were primarily responsible for agricultural work, a job closely tied to the seasons. With this in mind, it would logically follow that natural selection favored reproduction during times of food abundance and did not favor reproduction during times of food scarcity (that is, low energy).

Consequently, conception would occur when the growing season began (around the summer), giving females the chance to rest when heavily pregnant in the winter, and give birth in the spring. Accordingly, from an evolutionary perspective, greater seasonal variation in mood and behavior is a function of historic patterns of reproduction and food gathering. 

An alternative hypothesis of SAD is the dual vulnerability hypothesis. This hypothesis posits that SAD is the result of seasonality and depression (or “vulnerability traits”). Seasonality refers to external environmental factors such as light availability.

It’s quite well known, and perhaps your personal experience can speak to this topic as well, that shorter days may trigger SAD because reduced light exposure is associated with phase-delayed circadian rhythms. As a result, less dopamine is produced, and relatively higher levels of melatonin are produced, compared to individuals without SAD. “Vulnerability traits” refer to a genetic predisposition, or external effects (for example, stress). 
 

A disorder of the past?

By nature of natural selection, SAD is likely not to be considered an advantageous adaptive trait that would help with survival and reproduction. In fact, it could be considered a maladaptive trait. In that case, will SAD eventually fall to natural selection?

Leanna M.W. Lui, HBSc, completed an HBSc global health specialist degree at the University of Toronto, where she is now an MSc candidate.

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

With summer coming to an end, and pumpkin spice lattes trending again, we might also expect to say hello to an old friend ... seasonal affective disorder (SAD). 

Have you ever woken up one morning during the fall or winter and felt out of it for a prolonged period, not your regular self? I’m not referring to a day here and there, but consistently experiencing this “down mood” around the same time each year? At some point in their life, it is estimated that 2-3% of Canadians will experience SAD. To add to that, 15% of individuals will experience milder (and less impairing) SAD.  

Seasonal affective disorder can be thought of as a type of depression that occurs during a specific time of the year, usually the winter or fall (with remission outside this period). It is typically characterized by symptoms of clinical depression such as low energy, difficulty with concentration, sleep problems, extreme fatigue, and agitation. While the evidence related to the risk factors for SAD are limited, it is suggested that a family history of SAD, female sex, location farther from the equator (that is, fewer days of sunlight), and being between the ages of 18-30 increase your risk for SAD.

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) does not provide a separate and distinct categorization for SAD. Rather, SAD is categorized as a subtype of depression. However, it is generally recognized that a diagnosis of SAD is accompanied with two consecutive years of mood episodes within a recurring specified timeframe. 
 

Nature versus nurture: An evolutionary perspective

The pathophysiology of SAD is not yet well understood. However, it is hypothesized that SAD is an adaptive response related to physiologic and behavioral patterns of reproduction and childrearing.

Historically, reproduction was closely linked to food and natural resource availability (for example, water, sunlight). Males primarily handled the hunting, while females were primarily responsible for agricultural work, a job closely tied to the seasons. With this in mind, it would logically follow that natural selection favored reproduction during times of food abundance and did not favor reproduction during times of food scarcity (that is, low energy).

Consequently, conception would occur when the growing season began (around the summer), giving females the chance to rest when heavily pregnant in the winter, and give birth in the spring. Accordingly, from an evolutionary perspective, greater seasonal variation in mood and behavior is a function of historic patterns of reproduction and food gathering. 

An alternative hypothesis of SAD is the dual vulnerability hypothesis. This hypothesis posits that SAD is the result of seasonality and depression (or “vulnerability traits”). Seasonality refers to external environmental factors such as light availability.

It’s quite well known, and perhaps your personal experience can speak to this topic as well, that shorter days may trigger SAD because reduced light exposure is associated with phase-delayed circadian rhythms. As a result, less dopamine is produced, and relatively higher levels of melatonin are produced, compared to individuals without SAD. “Vulnerability traits” refer to a genetic predisposition, or external effects (for example, stress). 
 

A disorder of the past?

By nature of natural selection, SAD is likely not to be considered an advantageous adaptive trait that would help with survival and reproduction. In fact, it could be considered a maladaptive trait. In that case, will SAD eventually fall to natural selection?

Leanna M.W. Lui, HBSc, completed an HBSc global health specialist degree at the University of Toronto, where she is now an MSc candidate.

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

With summer coming to an end, and pumpkin spice lattes trending again, we might also expect to say hello to an old friend ... seasonal affective disorder (SAD). 

Have you ever woken up one morning during the fall or winter and felt out of it for a prolonged period, not your regular self? I’m not referring to a day here and there, but consistently experiencing this “down mood” around the same time each year? At some point in their life, it is estimated that 2-3% of Canadians will experience SAD. To add to that, 15% of individuals will experience milder (and less impairing) SAD.  

Seasonal affective disorder can be thought of as a type of depression that occurs during a specific time of the year, usually the winter or fall (with remission outside this period). It is typically characterized by symptoms of clinical depression such as low energy, difficulty with concentration, sleep problems, extreme fatigue, and agitation. While the evidence related to the risk factors for SAD are limited, it is suggested that a family history of SAD, female sex, location farther from the equator (that is, fewer days of sunlight), and being between the ages of 18-30 increase your risk for SAD.

The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5) does not provide a separate and distinct categorization for SAD. Rather, SAD is categorized as a subtype of depression. However, it is generally recognized that a diagnosis of SAD is accompanied with two consecutive years of mood episodes within a recurring specified timeframe. 
 

Nature versus nurture: An evolutionary perspective

The pathophysiology of SAD is not yet well understood. However, it is hypothesized that SAD is an adaptive response related to physiologic and behavioral patterns of reproduction and childrearing.

Historically, reproduction was closely linked to food and natural resource availability (for example, water, sunlight). Males primarily handled the hunting, while females were primarily responsible for agricultural work, a job closely tied to the seasons. With this in mind, it would logically follow that natural selection favored reproduction during times of food abundance and did not favor reproduction during times of food scarcity (that is, low energy).

Consequently, conception would occur when the growing season began (around the summer), giving females the chance to rest when heavily pregnant in the winter, and give birth in the spring. Accordingly, from an evolutionary perspective, greater seasonal variation in mood and behavior is a function of historic patterns of reproduction and food gathering. 

An alternative hypothesis of SAD is the dual vulnerability hypothesis. This hypothesis posits that SAD is the result of seasonality and depression (or “vulnerability traits”). Seasonality refers to external environmental factors such as light availability.

It’s quite well known, and perhaps your personal experience can speak to this topic as well, that shorter days may trigger SAD because reduced light exposure is associated with phase-delayed circadian rhythms. As a result, less dopamine is produced, and relatively higher levels of melatonin are produced, compared to individuals without SAD. “Vulnerability traits” refer to a genetic predisposition, or external effects (for example, stress). 
 

A disorder of the past?

By nature of natural selection, SAD is likely not to be considered an advantageous adaptive trait that would help with survival and reproduction. In fact, it could be considered a maladaptive trait. In that case, will SAD eventually fall to natural selection?

Leanna M.W. Lui, HBSc, completed an HBSc global health specialist degree at the University of Toronto, where she is now an MSc candidate.

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

The ever-widening role of immunotherapy for diseases not usually associated with these revolutionary drugs, such as gynecologic and gastrointestinal cancers, will be a key feature of new clinical data that will be presented at the forthcoming European Society of Medical Oncology (ESMO) 2021.

The meeting, which will be held online from September 16 to 21, will also see headlining results from immunotherapy trials in melanoma, lung cancer, and prostate cancer, as well as studies of the impact of COVID-19 vaccination in cancer patients.

“This is the second year of the virtual ESMO meeting, and this is important because the pandemic and the lockdown have impacted our clinical practice and research,” said conference press spokesman Antonio Passaro, MD, PhD, from the Division of Thoracic Oncology at the European Institute of Oncology, in Milan.

“But when you look at the submitted abstracts and the data that will be presented during ESMO, we can see that clinical research has been ‘resurrected,’“ he told this news organization.

A huge amount of “high-quality” data will be presented, said Dr. Passaro, which is “important,” inasmuch as this is the second year of the pandemic.

He underlined that it is “crucial” to remember that “the pandemic affected not only the lives and quality of life of our patients but also health care systems and the work and quality of life of health care professionals.”

A large amount of the new clinical data to be presented at the meeting will focus on the role of immune checkpoint inhibitors in various types of cancer, Dr. Passaro commented. Many of these will be featured in the three Presidential Symposia that will be held on Saturday, Sunday, and Monday.

These include KEYNOTE-716, a trial comparing the adjuvant use of pembrolizumab (Keytruda) to placebo after complete resection of high-risk stage II melanoma (abstract LBA3), and an analysis of the IMpower010 trial that will investigate the sites of relapse and subsequent therapy with atezolizumab (Tecentriq) in comparison with best supportive care after adjuvant chemotherapy in stage IB-IIIA non–small cell lung cancer (abstract LBA9).

Dr. Passaro commented that it is “interesting to note” that the immunotherapy data at ESMO 2021 will not only be in these “classical diseases in which immunotherapy improves survival” but also in different types of cancer, thus “widening the opportunity for our patients” to benefit.

There will be “important results” for immune checkpoint inhibitors for gynecologic cancers, as well as colorectal and gastric cancers, “which is a key topic for this ESMO meeting,” he said.

Other highlights from the Presidential Symposia include the following:

• Results from the phase 3 KEYNOTE-826 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer (abstract LBA2_PR)
• Results from the CheckMate 649 study, which examined nivolumab (Opdivo) plus chemotherapy or ipilimumab (Yervoy) in comparison with chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (abstract LBA7)
• Results from KRYSTAL-1, a phase 1/2 trial of the investigational agent adagrasib (MRTX849, Mirati Therapeutics) as monotherapy or combined with cetuximab for patients with colorectal cancer harboring a KRASG12C mutation (abstract LBA6)
• Data from FIRSTMAPPP, the first international randomized study of malignant progressive pheochromocytoma and paragangliomas comparing sunitinib (Sutent) with placebo (abstract 567O_PR)
• A combined analysis from the STAMPEDE protocol comparing androgen-deprivation therapy (ADT) alone to abiraterone acetate plus prednisolone, with or without enzalutamide, added to ADT for men with high-risk nonmetastatic prostate cancer (abstract LBA4_PR)
• Results from later-stage disease in men with de novo metastatic castration-sensitive prostate cancer enrolled in PEACE-1, a phase 3 trial investigating overall survival with abiraterone acetate plus prednisone (abstract LBA5_PR)

In addition, Dr. Passaro noted that data will be presented on the impact of the COVID-19 pandemic on cancer patients, as well as “interesting results” on the effect of COVID-19 vaccination on patients and their treatment, which is “crucial for all of us” to know. For example, the CAPTURE substudy of the TRACERx Renal trial will examine adaptive immunity to SARS-CoV-2 infection and vaccination in cancer patients (abstract 1557O).

Also in the same session, data will be presented from the VOICE study on vaccination against SARS-CoV-2 in patients receiving chemotherapy, immunotherapy, or chemo-immunotherapy for solid tumors (abstract LBA8).

At a press conference held ahead of the meeting, Pasi A. Jänne, MD, PhD, from the Dana Farber Cancer Center, Boston, who is the scientific co-chair of ESMO 2021, highlighted precision medicine as a key theme of the meeting.

He said that this is something the oncology community is “actively implementing worldwide to continue to make progress in cancer therapies and as such improve the outcomes of our patients.”

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

The ever-widening role of immunotherapy for diseases not usually associated with these revolutionary drugs, such as gynecologic and gastrointestinal cancers, will be a key feature of new clinical data that will be presented at the forthcoming European Society of Medical Oncology (ESMO) 2021.

The meeting, which will be held online from September 16 to 21, will also see headlining results from immunotherapy trials in melanoma, lung cancer, and prostate cancer, as well as studies of the impact of COVID-19 vaccination in cancer patients.

“This is the second year of the virtual ESMO meeting, and this is important because the pandemic and the lockdown have impacted our clinical practice and research,” said conference press spokesman Antonio Passaro, MD, PhD, from the Division of Thoracic Oncology at the European Institute of Oncology, in Milan.

“But when you look at the submitted abstracts and the data that will be presented during ESMO, we can see that clinical research has been ‘resurrected,’“ he told this news organization.

A huge amount of “high-quality” data will be presented, said Dr. Passaro, which is “important,” inasmuch as this is the second year of the pandemic.

He underlined that it is “crucial” to remember that “the pandemic affected not only the lives and quality of life of our patients but also health care systems and the work and quality of life of health care professionals.”

A large amount of the new clinical data to be presented at the meeting will focus on the role of immune checkpoint inhibitors in various types of cancer, Dr. Passaro commented. Many of these will be featured in the three Presidential Symposia that will be held on Saturday, Sunday, and Monday.

These include KEYNOTE-716, a trial comparing the adjuvant use of pembrolizumab (Keytruda) to placebo after complete resection of high-risk stage II melanoma (abstract LBA3), and an analysis of the IMpower010 trial that will investigate the sites of relapse and subsequent therapy with atezolizumab (Tecentriq) in comparison with best supportive care after adjuvant chemotherapy in stage IB-IIIA non–small cell lung cancer (abstract LBA9).

Dr. Passaro commented that it is “interesting to note” that the immunotherapy data at ESMO 2021 will not only be in these “classical diseases in which immunotherapy improves survival” but also in different types of cancer, thus “widening the opportunity for our patients” to benefit.

There will be “important results” for immune checkpoint inhibitors for gynecologic cancers, as well as colorectal and gastric cancers, “which is a key topic for this ESMO meeting,” he said.

Other highlights from the Presidential Symposia include the following:

• Results from the phase 3 KEYNOTE-826 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer (abstract LBA2_PR)
• Results from the CheckMate 649 study, which examined nivolumab (Opdivo) plus chemotherapy or ipilimumab (Yervoy) in comparison with chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (abstract LBA7)
• Results from KRYSTAL-1, a phase 1/2 trial of the investigational agent adagrasib (MRTX849, Mirati Therapeutics) as monotherapy or combined with cetuximab for patients with colorectal cancer harboring a KRASG12C mutation (abstract LBA6)
• Data from FIRSTMAPPP, the first international randomized study of malignant progressive pheochromocytoma and paragangliomas comparing sunitinib (Sutent) with placebo (abstract 567O_PR)
• A combined analysis from the STAMPEDE protocol comparing androgen-deprivation therapy (ADT) alone to abiraterone acetate plus prednisolone, with or without enzalutamide, added to ADT for men with high-risk nonmetastatic prostate cancer (abstract LBA4_PR)
• Results from later-stage disease in men with de novo metastatic castration-sensitive prostate cancer enrolled in PEACE-1, a phase 3 trial investigating overall survival with abiraterone acetate plus prednisone (abstract LBA5_PR)

In addition, Dr. Passaro noted that data will be presented on the impact of the COVID-19 pandemic on cancer patients, as well as “interesting results” on the effect of COVID-19 vaccination on patients and their treatment, which is “crucial for all of us” to know. For example, the CAPTURE substudy of the TRACERx Renal trial will examine adaptive immunity to SARS-CoV-2 infection and vaccination in cancer patients (abstract 1557O).

Also in the same session, data will be presented from the VOICE study on vaccination against SARS-CoV-2 in patients receiving chemotherapy, immunotherapy, or chemo-immunotherapy for solid tumors (abstract LBA8).

At a press conference held ahead of the meeting, Pasi A. Jänne, MD, PhD, from the Dana Farber Cancer Center, Boston, who is the scientific co-chair of ESMO 2021, highlighted precision medicine as a key theme of the meeting.

He said that this is something the oncology community is “actively implementing worldwide to continue to make progress in cancer therapies and as such improve the outcomes of our patients.”

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

The ever-widening role of immunotherapy for diseases not usually associated with these revolutionary drugs, such as gynecologic and gastrointestinal cancers, will be a key feature of new clinical data that will be presented at the forthcoming European Society of Medical Oncology (ESMO) 2021.

The meeting, which will be held online from September 16 to 21, will also see headlining results from immunotherapy trials in melanoma, lung cancer, and prostate cancer, as well as studies of the impact of COVID-19 vaccination in cancer patients.

“This is the second year of the virtual ESMO meeting, and this is important because the pandemic and the lockdown have impacted our clinical practice and research,” said conference press spokesman Antonio Passaro, MD, PhD, from the Division of Thoracic Oncology at the European Institute of Oncology, in Milan.

“But when you look at the submitted abstracts and the data that will be presented during ESMO, we can see that clinical research has been ‘resurrected,’“ he told this news organization.

A huge amount of “high-quality” data will be presented, said Dr. Passaro, which is “important,” inasmuch as this is the second year of the pandemic.

He underlined that it is “crucial” to remember that “the pandemic affected not only the lives and quality of life of our patients but also health care systems and the work and quality of life of health care professionals.”

A large amount of the new clinical data to be presented at the meeting will focus on the role of immune checkpoint inhibitors in various types of cancer, Dr. Passaro commented. Many of these will be featured in the three Presidential Symposia that will be held on Saturday, Sunday, and Monday.

These include KEYNOTE-716, a trial comparing the adjuvant use of pembrolizumab (Keytruda) to placebo after complete resection of high-risk stage II melanoma (abstract LBA3), and an analysis of the IMpower010 trial that will investigate the sites of relapse and subsequent therapy with atezolizumab (Tecentriq) in comparison with best supportive care after adjuvant chemotherapy in stage IB-IIIA non–small cell lung cancer (abstract LBA9).

Dr. Passaro commented that it is “interesting to note” that the immunotherapy data at ESMO 2021 will not only be in these “classical diseases in which immunotherapy improves survival” but also in different types of cancer, thus “widening the opportunity for our patients” to benefit.

There will be “important results” for immune checkpoint inhibitors for gynecologic cancers, as well as colorectal and gastric cancers, “which is a key topic for this ESMO meeting,” he said.

Other highlights from the Presidential Symposia include the following:

• Results from the phase 3 KEYNOTE-826 study of pembrolizumab plus chemotherapy versus placebo plus chemotherapy for persistent, recurrent, or metastatic cervical cancer (abstract LBA2_PR)
• Results from the CheckMate 649 study, which examined nivolumab (Opdivo) plus chemotherapy or ipilimumab (Yervoy) in comparison with chemotherapy as first-line treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (abstract LBA7)
• Results from KRYSTAL-1, a phase 1/2 trial of the investigational agent adagrasib (MRTX849, Mirati Therapeutics) as monotherapy or combined with cetuximab for patients with colorectal cancer harboring a KRASG12C mutation (abstract LBA6)
• Data from FIRSTMAPPP, the first international randomized study of malignant progressive pheochromocytoma and paragangliomas comparing sunitinib (Sutent) with placebo (abstract 567O_PR)
• A combined analysis from the STAMPEDE protocol comparing androgen-deprivation therapy (ADT) alone to abiraterone acetate plus prednisolone, with or without enzalutamide, added to ADT for men with high-risk nonmetastatic prostate cancer (abstract LBA4_PR)
• Results from later-stage disease in men with de novo metastatic castration-sensitive prostate cancer enrolled in PEACE-1, a phase 3 trial investigating overall survival with abiraterone acetate plus prednisone (abstract LBA5_PR)

In addition, Dr. Passaro noted that data will be presented on the impact of the COVID-19 pandemic on cancer patients, as well as “interesting results” on the effect of COVID-19 vaccination on patients and their treatment, which is “crucial for all of us” to know. For example, the CAPTURE substudy of the TRACERx Renal trial will examine adaptive immunity to SARS-CoV-2 infection and vaccination in cancer patients (abstract 1557O).

Also in the same session, data will be presented from the VOICE study on vaccination against SARS-CoV-2 in patients receiving chemotherapy, immunotherapy, or chemo-immunotherapy for solid tumors (abstract LBA8).

At a press conference held ahead of the meeting, Pasi A. Jänne, MD, PhD, from the Dana Farber Cancer Center, Boston, who is the scientific co-chair of ESMO 2021, highlighted precision medicine as a key theme of the meeting.

He said that this is something the oncology community is “actively implementing worldwide to continue to make progress in cancer therapies and as such improve the outcomes of our patients.”

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

The earliest responders to reach the site of the destroyed twin towers of the World Trade Center on Sept. 11, 2001, are at highest risk for chronic obstructive pulmonary disease and asthma/COPD overlap (ACO) among all those who worked at the site. The 9/11 attack was the deadliest terrorist attack on American soil.

The findings come from a case-control study that included nearly 18,000 emergency responders and volunteers. The investigators found that those who arrived at the site within 48 hours had an approximately 30% higher risk of developing COPD than those who arrived later, after adjustment for smoking and obesity, reported Rafael E de la Hoz, MD, a professor of environmental medicine, public health, and medicine at Mount Sinai Medical Center, New York, and colleagues.

“In this largest World Trade Center occupational cohort, spirometrically defined COPD and ACO were both modestly but significantly associated with World Trade Center exposure intensity, but the association seemed driven by the overlap,” he said in a narrated poster presentation during the European Respiratory Society 2021 International Congress.

“Around the world, we rely on our emergency workers to help when disasters occur,” commented Arzu Yorgancıoğlu, MD, professor and head of the department of pulmonology at Celal Bayar University, Manisa, Turkey, who was not involved in the study.

“This study shows how important it is to keep monitoring the health of workers, like those who attended the World Trade Center site 20 years ago, as occupational exposure to pollutants can lead to COPD. What we can learn from research like this is not only how best to care for emergency workers who operate in dangerous conditions but also how we can protect them in their work in the future,” she said.
 

Inconsistent findings

Fire and police personnel, emergency medical workers, construction workers, and others who labored amid the lingering pall of toxic dust and smoke at the World Trade Center site have developed asthma and other lower respiratory tract diseases over the ensuing decades.

“As the occupational cohorts age, there are concerns about chronic, longer latency, and disabling respiratory disease,” Dr. de la Hoz and colleagues wrote.

There have been inconsistent reports about the potential associations between COPD and ACO and the intensity of occupational exposure at the World Trade Center site. This prompted the investigators to further explore these associations using spirometry-defined disease.

They assessed data on 17,996 former World Trade Center site workers who had undergone at least two good-quality spirometric evaluations from 2002 to 2018.

To be classified as having COPD, workers had to have fixed airway obstruction. Those in the ACO subgroup were also required to have prebronchodilator obstruction with forced expiratory volume in 1 second of more than 400 mL in response to bronchodilation.

The patients were matched for sex and height within 5 cm using a 1:4 nested case-control design. Missing data were imputed.
 

Earliest arrivals paid the highest penalty

Of the total cohort, 85.4% were men, and 85.6% were overweight or obese. A total of 586 workers (3.3%) met the case definition for having COPD; 258 (1.4%) met the definition for having ACO.

The investigators found that the prevalence of self-reported ACO was six times higher than the prevalence of spirometry-confirmed disease. Among those who reported an onset date, 56.7% reported having asthma before COPD; the remainder reported having COPD first.

In analyses adjusted for age, sex, cohort entry period, smoking status, body mass index, metabolic syndrome parameters, and eosinophil levels, both COPD and ACO were significantly associated with early arrival at the World Trade Center site, with an adjusted odds ratio for COPD of 1.3 (95% confidence interval, 1.03-1.64), and an OR for ACO of 1.66 (95% CI, 1.1-2.49).

There was no significant interaction between early site arrival and smoking status.

The association between early exposure and COPD was no longer significant when those with ACO were excluded, the authors noted.

“We also observed that COPD more often followed asthma in these workers than the reverse, suggesting that asthma may have been on the path to COPD in most workers affected by the inhaled toxicants at the disaster site,” Dr. de la Hoz and colleagues wrote.

In addition, “our data suggest that self-reported physician diagnoses of COPD, asthma, and ACO are poorly correlated with objective data in this cohort,” they concluded.

The study was supported by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The authors and Dr. Yorgancıoğlu disclosed no relevant financial relationships.

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

The earliest responders to reach the site of the destroyed twin towers of the World Trade Center on Sept. 11, 2001, are at highest risk for chronic obstructive pulmonary disease and asthma/COPD overlap (ACO) among all those who worked at the site. The 9/11 attack was the deadliest terrorist attack on American soil.

The findings come from a case-control study that included nearly 18,000 emergency responders and volunteers. The investigators found that those who arrived at the site within 48 hours had an approximately 30% higher risk of developing COPD than those who arrived later, after adjustment for smoking and obesity, reported Rafael E de la Hoz, MD, a professor of environmental medicine, public health, and medicine at Mount Sinai Medical Center, New York, and colleagues.

“In this largest World Trade Center occupational cohort, spirometrically defined COPD and ACO were both modestly but significantly associated with World Trade Center exposure intensity, but the association seemed driven by the overlap,” he said in a narrated poster presentation during the European Respiratory Society 2021 International Congress.

“Around the world, we rely on our emergency workers to help when disasters occur,” commented Arzu Yorgancıoğlu, MD, professor and head of the department of pulmonology at Celal Bayar University, Manisa, Turkey, who was not involved in the study.

“This study shows how important it is to keep monitoring the health of workers, like those who attended the World Trade Center site 20 years ago, as occupational exposure to pollutants can lead to COPD. What we can learn from research like this is not only how best to care for emergency workers who operate in dangerous conditions but also how we can protect them in their work in the future,” she said.
 

Inconsistent findings

Fire and police personnel, emergency medical workers, construction workers, and others who labored amid the lingering pall of toxic dust and smoke at the World Trade Center site have developed asthma and other lower respiratory tract diseases over the ensuing decades.

“As the occupational cohorts age, there are concerns about chronic, longer latency, and disabling respiratory disease,” Dr. de la Hoz and colleagues wrote.

There have been inconsistent reports about the potential associations between COPD and ACO and the intensity of occupational exposure at the World Trade Center site. This prompted the investigators to further explore these associations using spirometry-defined disease.

They assessed data on 17,996 former World Trade Center site workers who had undergone at least two good-quality spirometric evaluations from 2002 to 2018.

To be classified as having COPD, workers had to have fixed airway obstruction. Those in the ACO subgroup were also required to have prebronchodilator obstruction with forced expiratory volume in 1 second of more than 400 mL in response to bronchodilation.

The patients were matched for sex and height within 5 cm using a 1:4 nested case-control design. Missing data were imputed.
 

Earliest arrivals paid the highest penalty

Of the total cohort, 85.4% were men, and 85.6% were overweight or obese. A total of 586 workers (3.3%) met the case definition for having COPD; 258 (1.4%) met the definition for having ACO.

The investigators found that the prevalence of self-reported ACO was six times higher than the prevalence of spirometry-confirmed disease. Among those who reported an onset date, 56.7% reported having asthma before COPD; the remainder reported having COPD first.

In analyses adjusted for age, sex, cohort entry period, smoking status, body mass index, metabolic syndrome parameters, and eosinophil levels, both COPD and ACO were significantly associated with early arrival at the World Trade Center site, with an adjusted odds ratio for COPD of 1.3 (95% confidence interval, 1.03-1.64), and an OR for ACO of 1.66 (95% CI, 1.1-2.49).

There was no significant interaction between early site arrival and smoking status.

The association between early exposure and COPD was no longer significant when those with ACO were excluded, the authors noted.

“We also observed that COPD more often followed asthma in these workers than the reverse, suggesting that asthma may have been on the path to COPD in most workers affected by the inhaled toxicants at the disaster site,” Dr. de la Hoz and colleagues wrote.

In addition, “our data suggest that self-reported physician diagnoses of COPD, asthma, and ACO are poorly correlated with objective data in this cohort,” they concluded.

The study was supported by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The authors and Dr. Yorgancıoğlu disclosed no relevant financial relationships.

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

The earliest responders to reach the site of the destroyed twin towers of the World Trade Center on Sept. 11, 2001, are at highest risk for chronic obstructive pulmonary disease and asthma/COPD overlap (ACO) among all those who worked at the site. The 9/11 attack was the deadliest terrorist attack on American soil.

The findings come from a case-control study that included nearly 18,000 emergency responders and volunteers. The investigators found that those who arrived at the site within 48 hours had an approximately 30% higher risk of developing COPD than those who arrived later, after adjustment for smoking and obesity, reported Rafael E de la Hoz, MD, a professor of environmental medicine, public health, and medicine at Mount Sinai Medical Center, New York, and colleagues.

“In this largest World Trade Center occupational cohort, spirometrically defined COPD and ACO were both modestly but significantly associated with World Trade Center exposure intensity, but the association seemed driven by the overlap,” he said in a narrated poster presentation during the European Respiratory Society 2021 International Congress.

“Around the world, we rely on our emergency workers to help when disasters occur,” commented Arzu Yorgancıoğlu, MD, professor and head of the department of pulmonology at Celal Bayar University, Manisa, Turkey, who was not involved in the study.

“This study shows how important it is to keep monitoring the health of workers, like those who attended the World Trade Center site 20 years ago, as occupational exposure to pollutants can lead to COPD. What we can learn from research like this is not only how best to care for emergency workers who operate in dangerous conditions but also how we can protect them in their work in the future,” she said.
 

Inconsistent findings

Fire and police personnel, emergency medical workers, construction workers, and others who labored amid the lingering pall of toxic dust and smoke at the World Trade Center site have developed asthma and other lower respiratory tract diseases over the ensuing decades.

“As the occupational cohorts age, there are concerns about chronic, longer latency, and disabling respiratory disease,” Dr. de la Hoz and colleagues wrote.

There have been inconsistent reports about the potential associations between COPD and ACO and the intensity of occupational exposure at the World Trade Center site. This prompted the investigators to further explore these associations using spirometry-defined disease.

They assessed data on 17,996 former World Trade Center site workers who had undergone at least two good-quality spirometric evaluations from 2002 to 2018.

To be classified as having COPD, workers had to have fixed airway obstruction. Those in the ACO subgroup were also required to have prebronchodilator obstruction with forced expiratory volume in 1 second of more than 400 mL in response to bronchodilation.

The patients were matched for sex and height within 5 cm using a 1:4 nested case-control design. Missing data were imputed.
 

Earliest arrivals paid the highest penalty

Of the total cohort, 85.4% were men, and 85.6% were overweight or obese. A total of 586 workers (3.3%) met the case definition for having COPD; 258 (1.4%) met the definition for having ACO.

The investigators found that the prevalence of self-reported ACO was six times higher than the prevalence of spirometry-confirmed disease. Among those who reported an onset date, 56.7% reported having asthma before COPD; the remainder reported having COPD first.

In analyses adjusted for age, sex, cohort entry period, smoking status, body mass index, metabolic syndrome parameters, and eosinophil levels, both COPD and ACO were significantly associated with early arrival at the World Trade Center site, with an adjusted odds ratio for COPD of 1.3 (95% confidence interval, 1.03-1.64), and an OR for ACO of 1.66 (95% CI, 1.1-2.49).

There was no significant interaction between early site arrival and smoking status.

The association between early exposure and COPD was no longer significant when those with ACO were excluded, the authors noted.

“We also observed that COPD more often followed asthma in these workers than the reverse, suggesting that asthma may have been on the path to COPD in most workers affected by the inhaled toxicants at the disaster site,” Dr. de la Hoz and colleagues wrote.

In addition, “our data suggest that self-reported physician diagnoses of COPD, asthma, and ACO are poorly correlated with objective data in this cohort,” they concluded.

The study was supported by the Centers for Disease Control and Prevention and the National Institute for Occupational Safety and Health. The authors and Dr. Yorgancıoğlu disclosed no relevant financial relationships.

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

Mistreatment in the workplace is common among residents in emergency medicine (EM), according to the results of a new study published online Aug. 19 in JAMA Network Open.

xavierarnau/Getty Images

The survey of more than 6,000 residents found that almost 1 in 2 respondents had been exposed to some form of workplace mistreatment in the previous year, including gender and racial discrimination, physical abuse, or sexual harassment.

“The last study on mistreatment in EM residency training in the United States occurred more than 25 years ago,” said Michelle D. Lall, MD, associate professor of medicine at Emory University, Atlanta. “These findings provide a current look. Mistreatment occurs frequently in EM residency training nationally, and it occurs more frequently in women, racial/ethnic minorities, and those who identify as LGBTQ+,” Dr. Lall added. “Additionally, we found an association between experiencing mistreatment at least a few times per month and having suicidal thoughts.”
 

Negative sequelae from workplace mistreatment

Dr. Lall explained that workplace mistreatment and institutional responses to such behaviors have been linked to hostile work environments for physicians. In previous research, workplace mistreatment has been found to negatively affect individuals’ sense of self, a phenomenon that not only hindered professional productivity but also increased a variety of other negative factors, such as stress, job dissatisfaction, negative workplace behaviors, and turnover. Perhaps not surprisingly, workplace discrimination has also been shown to have negative effects on physical and mental health.

Despite such findings, little is known about the current state of workplace mistreatment among EM residents. This led the investigators to examine the prevalence, types, and sources of such perceived treatment during their training. In addition, the researchers assessed the association between mistreatment and suicidal ideation. Insights into these problems, they say, may spur leaders in the field to develop and implement strategies to help new physicians maintain their well-being throughout their careers.

“A 2019 study by Yue-Yung Hu and associates looked at discrimination, abuse, harassment, and burnout in surgical residents, and they found that mistreatment occurs frequently among general surgery residents, especially women,” Dr. Lall said. “Our study group felt it was important to look at the rates of mistreatment among EM residents nationally in order to obtain baseline data and to use this data to identify and promote educational interventions to reduce workplace mistreatment.”
 

Emergency residents surveyed

To achieve these ends, Dr. Lall and colleagues sent a survey to all individuals enrolled in EM residencies accredited by the Accreditation Council for Graduate Medical Education who had participated in the 2020 American Board of Emergency Medicine in-training examination. The 35-item multiple-choice survey asked residents to self-report the frequency, sources, and types of mistreatment they had experienced during their training. Suicidal thoughts were assessed by asking residents whether they had considered taking their own life.

Respondents categorized the frequency of mistreatment as never having occurred, having occurred a few times a year, a few times a month, a few times a week, or every day. The investigators created a composite indicator for the study’s primary comparisons that represented the maximum reported frequency of any single exposure. Responses were categorized according to the frequency of mistreatment exposure as either no exposure, exposures a few times per year, or exposures a few times or more per month (including a few times per week or every day).
 

Almost half report mistreatment

The survey was sent to 8,162 eligible residents in EM. Of those, 6,503 (79.7%) completed the entire survey. Respondents were primarily male (62.1%) and non-Hispanic White (64.0%); 2,620 residents (34.1%) were from other racial/ethnic groups. Of the respondents, 483 residents (6.6%) identified as lesbian, gay, bisexual, transgender, queer, or other (LGBTQ+); 5,951 residents (77.5%) were married or in a relationship.

It was found that 3,463 (45.1%) of participants reported having been exposed to some sort of workplace mistreatment during the most recent academic year. A common source of mistreatment was patients and/or their families. These caused a total of 1,234 events.

Gender discrimination was reported by 2,104 residents (29.5%), 1,635 of whom were women. The most common source of such discrimination was patients or patients’ family members (1,027 women; 184 men). Other sources included nurses or staff (331 women; 59 men).

Racial discrimination was common. It was reported by 1,284 residents; 907 residents were from racial/ethnic groups other than White. Among non-White racial/ethnic groups, 248 residents reported being exposed to racial discrimination at least a few times per month. The most common source of racial discrimination was patients or their family members.

Discrimination based on sexual orientation or gender identity was reported by 220 residents. Once again, the majority of LGBTQ+ residents indicated that patients or their families were the primary source. More than 1,000 residents (n = 1047) reported sexual harassment; among these residents, 721 were women. Patients and/or patients’ family members were the most common source of such discrimination, followed by nurses and staff.

A total of 2,069 residents reported verbal or emotional abuse, including 806 women and 1,212 men. Patients/patients’ family members were the most common source, followed by attending physicians. Physical abuse was reported by 331 respondents. Physical abuse was primarily attributed to patients/patients’ families.

Suicidal thoughts were reported by 178 residents; the prevalence was comparable with respect to gender (2.4% men; 2.4% women) and race/ethnicity (2.4% non-Hispanic White; 2.7% other racial/ethnic groups). Adjusted models revealed that the prevalence for suicidal thoughts was greater among residents who identified as LGBTQ+ (odds ratio [OR], 2.04; 99% confidence interval, 1.04-3.99). An association was found between suicidal thoughts and having experienced mistreatment at least a few times each month (OR, 5.83; 99% CI, 3.70-9.20).
 

Identifying sources key to stemming mistreatment

These findings, the researchers say, demonstrate the alarming frequency with which workplace mistreatment occurs for EM residents. The survey also found that such mistreatment was more common among residents from racial/ethnic minority populations, women, and residents who identify as LGBTQ+. Perhaps most disturbingly, the occurrence of workplace mistreatment was found to be associated with suicidal thoughts.

The researchers say that although it is likely that residents in many medical specialties experience similar mistreatment to some degree, such treatment should never be considered acceptable. Indeed, Dr. Lall said that identifying sources of mistreatment may help both institutions and individuals determine interventions necessary for improving the well-being of EM residents.

“The first step is recognizing, based on our data, that mistreatment is experienced frequently in EM training in the United States,” she said. “Future qualitative studies of residents and program leaders may help identify which systems, programs, or cultural factors were associated with lower rates of mistreatment in some institutions and higher rates in others.

“Identifying these factors and developing and promoting best practices to minimize workplace mistreatment during residency may help optimize the professional career experience and improve the personal and professional well-being of physicians throughout their lives,” Dr. Lall added.

Commenting on the findings for this article, Karl Y. Bilimoria, MD, of Northwestern University, Chicago, noted that these surveys clearly lay out actionable opportunities to improve trainee mistreatment. “Given that much of the mistreatment of EM residents comes from patients and families, the solutions must be appropriately tailored to address those sources,” Dr. Bilimoria noted.

“Programs need to actively work even more to protect their trainees and faculty from this mistreatment, as it has severe effects and often leads to, or worsens, burnout,” he added.

Funding for statistical analysis was provided by the American Board of Emergency Medicine. Dr. Lall and Dr. Bilimoria reported no relevant financial relationships.

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

Mistreatment in the workplace is common among residents in emergency medicine (EM), according to the results of a new study published online Aug. 19 in JAMA Network Open.

xavierarnau/Getty Images

The survey of more than 6,000 residents found that almost 1 in 2 respondents had been exposed to some form of workplace mistreatment in the previous year, including gender and racial discrimination, physical abuse, or sexual harassment.

“The last study on mistreatment in EM residency training in the United States occurred more than 25 years ago,” said Michelle D. Lall, MD, associate professor of medicine at Emory University, Atlanta. “These findings provide a current look. Mistreatment occurs frequently in EM residency training nationally, and it occurs more frequently in women, racial/ethnic minorities, and those who identify as LGBTQ+,” Dr. Lall added. “Additionally, we found an association between experiencing mistreatment at least a few times per month and having suicidal thoughts.”
 

Negative sequelae from workplace mistreatment

Dr. Lall explained that workplace mistreatment and institutional responses to such behaviors have been linked to hostile work environments for physicians. In previous research, workplace mistreatment has been found to negatively affect individuals’ sense of self, a phenomenon that not only hindered professional productivity but also increased a variety of other negative factors, such as stress, job dissatisfaction, negative workplace behaviors, and turnover. Perhaps not surprisingly, workplace discrimination has also been shown to have negative effects on physical and mental health.

Despite such findings, little is known about the current state of workplace mistreatment among EM residents. This led the investigators to examine the prevalence, types, and sources of such perceived treatment during their training. In addition, the researchers assessed the association between mistreatment and suicidal ideation. Insights into these problems, they say, may spur leaders in the field to develop and implement strategies to help new physicians maintain their well-being throughout their careers.

“A 2019 study by Yue-Yung Hu and associates looked at discrimination, abuse, harassment, and burnout in surgical residents, and they found that mistreatment occurs frequently among general surgery residents, especially women,” Dr. Lall said. “Our study group felt it was important to look at the rates of mistreatment among EM residents nationally in order to obtain baseline data and to use this data to identify and promote educational interventions to reduce workplace mistreatment.”
 

Emergency residents surveyed

To achieve these ends, Dr. Lall and colleagues sent a survey to all individuals enrolled in EM residencies accredited by the Accreditation Council for Graduate Medical Education who had participated in the 2020 American Board of Emergency Medicine in-training examination. The 35-item multiple-choice survey asked residents to self-report the frequency, sources, and types of mistreatment they had experienced during their training. Suicidal thoughts were assessed by asking residents whether they had considered taking their own life.

Respondents categorized the frequency of mistreatment as never having occurred, having occurred a few times a year, a few times a month, a few times a week, or every day. The investigators created a composite indicator for the study’s primary comparisons that represented the maximum reported frequency of any single exposure. Responses were categorized according to the frequency of mistreatment exposure as either no exposure, exposures a few times per year, or exposures a few times or more per month (including a few times per week or every day).
 

Almost half report mistreatment

The survey was sent to 8,162 eligible residents in EM. Of those, 6,503 (79.7%) completed the entire survey. Respondents were primarily male (62.1%) and non-Hispanic White (64.0%); 2,620 residents (34.1%) were from other racial/ethnic groups. Of the respondents, 483 residents (6.6%) identified as lesbian, gay, bisexual, transgender, queer, or other (LGBTQ+); 5,951 residents (77.5%) were married or in a relationship.

It was found that 3,463 (45.1%) of participants reported having been exposed to some sort of workplace mistreatment during the most recent academic year. A common source of mistreatment was patients and/or their families. These caused a total of 1,234 events.

Gender discrimination was reported by 2,104 residents (29.5%), 1,635 of whom were women. The most common source of such discrimination was patients or patients’ family members (1,027 women; 184 men). Other sources included nurses or staff (331 women; 59 men).

Racial discrimination was common. It was reported by 1,284 residents; 907 residents were from racial/ethnic groups other than White. Among non-White racial/ethnic groups, 248 residents reported being exposed to racial discrimination at least a few times per month. The most common source of racial discrimination was patients or their family members.

Discrimination based on sexual orientation or gender identity was reported by 220 residents. Once again, the majority of LGBTQ+ residents indicated that patients or their families were the primary source. More than 1,000 residents (n = 1047) reported sexual harassment; among these residents, 721 were women. Patients and/or patients’ family members were the most common source of such discrimination, followed by nurses and staff.

A total of 2,069 residents reported verbal or emotional abuse, including 806 women and 1,212 men. Patients/patients’ family members were the most common source, followed by attending physicians. Physical abuse was reported by 331 respondents. Physical abuse was primarily attributed to patients/patients’ families.

Suicidal thoughts were reported by 178 residents; the prevalence was comparable with respect to gender (2.4% men; 2.4% women) and race/ethnicity (2.4% non-Hispanic White; 2.7% other racial/ethnic groups). Adjusted models revealed that the prevalence for suicidal thoughts was greater among residents who identified as LGBTQ+ (odds ratio [OR], 2.04; 99% confidence interval, 1.04-3.99). An association was found between suicidal thoughts and having experienced mistreatment at least a few times each month (OR, 5.83; 99% CI, 3.70-9.20).
 

Identifying sources key to stemming mistreatment

These findings, the researchers say, demonstrate the alarming frequency with which workplace mistreatment occurs for EM residents. The survey also found that such mistreatment was more common among residents from racial/ethnic minority populations, women, and residents who identify as LGBTQ+. Perhaps most disturbingly, the occurrence of workplace mistreatment was found to be associated with suicidal thoughts.

The researchers say that although it is likely that residents in many medical specialties experience similar mistreatment to some degree, such treatment should never be considered acceptable. Indeed, Dr. Lall said that identifying sources of mistreatment may help both institutions and individuals determine interventions necessary for improving the well-being of EM residents.

“The first step is recognizing, based on our data, that mistreatment is experienced frequently in EM training in the United States,” she said. “Future qualitative studies of residents and program leaders may help identify which systems, programs, or cultural factors were associated with lower rates of mistreatment in some institutions and higher rates in others.

“Identifying these factors and developing and promoting best practices to minimize workplace mistreatment during residency may help optimize the professional career experience and improve the personal and professional well-being of physicians throughout their lives,” Dr. Lall added.

Commenting on the findings for this article, Karl Y. Bilimoria, MD, of Northwestern University, Chicago, noted that these surveys clearly lay out actionable opportunities to improve trainee mistreatment. “Given that much of the mistreatment of EM residents comes from patients and families, the solutions must be appropriately tailored to address those sources,” Dr. Bilimoria noted.

“Programs need to actively work even more to protect their trainees and faculty from this mistreatment, as it has severe effects and often leads to, or worsens, burnout,” he added.

Funding for statistical analysis was provided by the American Board of Emergency Medicine. Dr. Lall and Dr. Bilimoria reported no relevant financial relationships.

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

Mistreatment in the workplace is common among residents in emergency medicine (EM), according to the results of a new study published online Aug. 19 in JAMA Network Open.

xavierarnau/Getty Images

The survey of more than 6,000 residents found that almost 1 in 2 respondents had been exposed to some form of workplace mistreatment in the previous year, including gender and racial discrimination, physical abuse, or sexual harassment.

“The last study on mistreatment in EM residency training in the United States occurred more than 25 years ago,” said Michelle D. Lall, MD, associate professor of medicine at Emory University, Atlanta. “These findings provide a current look. Mistreatment occurs frequently in EM residency training nationally, and it occurs more frequently in women, racial/ethnic minorities, and those who identify as LGBTQ+,” Dr. Lall added. “Additionally, we found an association between experiencing mistreatment at least a few times per month and having suicidal thoughts.”
 

Negative sequelae from workplace mistreatment

Dr. Lall explained that workplace mistreatment and institutional responses to such behaviors have been linked to hostile work environments for physicians. In previous research, workplace mistreatment has been found to negatively affect individuals’ sense of self, a phenomenon that not only hindered professional productivity but also increased a variety of other negative factors, such as stress, job dissatisfaction, negative workplace behaviors, and turnover. Perhaps not surprisingly, workplace discrimination has also been shown to have negative effects on physical and mental health.

Despite such findings, little is known about the current state of workplace mistreatment among EM residents. This led the investigators to examine the prevalence, types, and sources of such perceived treatment during their training. In addition, the researchers assessed the association between mistreatment and suicidal ideation. Insights into these problems, they say, may spur leaders in the field to develop and implement strategies to help new physicians maintain their well-being throughout their careers.

“A 2019 study by Yue-Yung Hu and associates looked at discrimination, abuse, harassment, and burnout in surgical residents, and they found that mistreatment occurs frequently among general surgery residents, especially women,” Dr. Lall said. “Our study group felt it was important to look at the rates of mistreatment among EM residents nationally in order to obtain baseline data and to use this data to identify and promote educational interventions to reduce workplace mistreatment.”
 

Emergency residents surveyed

To achieve these ends, Dr. Lall and colleagues sent a survey to all individuals enrolled in EM residencies accredited by the Accreditation Council for Graduate Medical Education who had participated in the 2020 American Board of Emergency Medicine in-training examination. The 35-item multiple-choice survey asked residents to self-report the frequency, sources, and types of mistreatment they had experienced during their training. Suicidal thoughts were assessed by asking residents whether they had considered taking their own life.

Respondents categorized the frequency of mistreatment as never having occurred, having occurred a few times a year, a few times a month, a few times a week, or every day. The investigators created a composite indicator for the study’s primary comparisons that represented the maximum reported frequency of any single exposure. Responses were categorized according to the frequency of mistreatment exposure as either no exposure, exposures a few times per year, or exposures a few times or more per month (including a few times per week or every day).
 

Almost half report mistreatment

The survey was sent to 8,162 eligible residents in EM. Of those, 6,503 (79.7%) completed the entire survey. Respondents were primarily male (62.1%) and non-Hispanic White (64.0%); 2,620 residents (34.1%) were from other racial/ethnic groups. Of the respondents, 483 residents (6.6%) identified as lesbian, gay, bisexual, transgender, queer, or other (LGBTQ+); 5,951 residents (77.5%) were married or in a relationship.

It was found that 3,463 (45.1%) of participants reported having been exposed to some sort of workplace mistreatment during the most recent academic year. A common source of mistreatment was patients and/or their families. These caused a total of 1,234 events.

Gender discrimination was reported by 2,104 residents (29.5%), 1,635 of whom were women. The most common source of such discrimination was patients or patients’ family members (1,027 women; 184 men). Other sources included nurses or staff (331 women; 59 men).

Racial discrimination was common. It was reported by 1,284 residents; 907 residents were from racial/ethnic groups other than White. Among non-White racial/ethnic groups, 248 residents reported being exposed to racial discrimination at least a few times per month. The most common source of racial discrimination was patients or their family members.

Discrimination based on sexual orientation or gender identity was reported by 220 residents. Once again, the majority of LGBTQ+ residents indicated that patients or their families were the primary source. More than 1,000 residents (n = 1047) reported sexual harassment; among these residents, 721 were women. Patients and/or patients’ family members were the most common source of such discrimination, followed by nurses and staff.

A total of 2,069 residents reported verbal or emotional abuse, including 806 women and 1,212 men. Patients/patients’ family members were the most common source, followed by attending physicians. Physical abuse was reported by 331 respondents. Physical abuse was primarily attributed to patients/patients’ families.

Suicidal thoughts were reported by 178 residents; the prevalence was comparable with respect to gender (2.4% men; 2.4% women) and race/ethnicity (2.4% non-Hispanic White; 2.7% other racial/ethnic groups). Adjusted models revealed that the prevalence for suicidal thoughts was greater among residents who identified as LGBTQ+ (odds ratio [OR], 2.04; 99% confidence interval, 1.04-3.99). An association was found between suicidal thoughts and having experienced mistreatment at least a few times each month (OR, 5.83; 99% CI, 3.70-9.20).
 

Identifying sources key to stemming mistreatment

These findings, the researchers say, demonstrate the alarming frequency with which workplace mistreatment occurs for EM residents. The survey also found that such mistreatment was more common among residents from racial/ethnic minority populations, women, and residents who identify as LGBTQ+. Perhaps most disturbingly, the occurrence of workplace mistreatment was found to be associated with suicidal thoughts.

The researchers say that although it is likely that residents in many medical specialties experience similar mistreatment to some degree, such treatment should never be considered acceptable. Indeed, Dr. Lall said that identifying sources of mistreatment may help both institutions and individuals determine interventions necessary for improving the well-being of EM residents.

“The first step is recognizing, based on our data, that mistreatment is experienced frequently in EM training in the United States,” she said. “Future qualitative studies of residents and program leaders may help identify which systems, programs, or cultural factors were associated with lower rates of mistreatment in some institutions and higher rates in others.

“Identifying these factors and developing and promoting best practices to minimize workplace mistreatment during residency may help optimize the professional career experience and improve the personal and professional well-being of physicians throughout their lives,” Dr. Lall added.

Commenting on the findings for this article, Karl Y. Bilimoria, MD, of Northwestern University, Chicago, noted that these surveys clearly lay out actionable opportunities to improve trainee mistreatment. “Given that much of the mistreatment of EM residents comes from patients and families, the solutions must be appropriately tailored to address those sources,” Dr. Bilimoria noted.

“Programs need to actively work even more to protect their trainees and faculty from this mistreatment, as it has severe effects and often leads to, or worsens, burnout,” he added.

Funding for statistical analysis was provided by the American Board of Emergency Medicine. Dr. Lall and Dr. Bilimoria reported no relevant financial relationships.

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

Poor lung function appears to be a stronger marker of risk for sudden cardiac death than for a survivable first coronary event, results of a prospective population-based study suggest.

Among 28,584 adults with no history of acute coronary events who were followed over 4 decades, every standard deviation decrease in forced expiratory volume in 1 second (FEV₁) was associated with a 23% increase in risk for sudden cardiac death, reported Suneela Zaigham, PhD, a cardiovascular epidemiology fellow at the University of Lund, Sweden, and colleagues.

“Our main findings and subsequent conclusions are that low FEV₁ is associated with both sudden cardiac death and nonfatal coronary events but is consistently more strongly associated with future sudden cardiac death,” Dr. Zaigham said in a narrated poster presented at the European Respiratory Society (ERS) 2021 International Congress, which was held online.

“We propose that measurement with spirometry in early life could aid in the risk stratification of future sudden cardiac death, and our results support the use of spirometry for cardiovascular risk assessment,” she said.

Marc Humbert, MD, PhD, professor of respiratory medicine at Université Paris–Saclay, who was not involved in the study, said that “this is something we can measure fairly easily, meaning that lung function could be used as part of a screening tool.

“We need to do more research to understand the links between lung function and sudden cardiac death and to investigate whether we can use lung function tests to help prevent deaths in the future,” he said.
 

Fatal vs. nonfatal events

It is well known that poor lung function is a strong predictor of future coronary events, but it was unknown whether patterns of lung impairment differ in their ability to predict future nonfatal coronary events or sudden cardiac death, Dr. Zaigham said.

To see whether measurable differences in lung function could predict risk for both fatal and nonfatal coronary events, the investigators studied 28,584 middle-aged residents of Malmö, Sweden. Baseline spirometry test results were available for all study participants.

The patients were followed for approximately 40 years for sudden cardiac death, defined as death on the day of a coronary event, or nonfatal events, defined as survival for at least 24 hours after an event.

Dr. Zaigham and colleagues used a modified version of Lunn McNeil’s competing risks method to create Cox regression models.

Results of an analysis that was adjusted for potential confounding factors indicated that one standard deviation reduction in FEV₁ was associated with a hazard ratio (HR) for sudden cardiac death of 1.23 (95% confidence interval, 1.15-1.31). In contrast, one standard deviation in FEV₁ was associated with a lower but still significant risk for nonfatal events, with an HR of 1.08 (95% CI, 1.04-1.13; P for equal associations = .002).

The results remained significant among participants who had never smoked, with an HR for sudden cardiac death of 1.34 (95% CI, 1.15-1.55) and for nonfatal events of 1.11 (95% CI, 1.02-1.21; P for equal associations = .038).

“This study suggests a link between lung health and sudden cardiac death. It shows a higher risk of fatal than nonfatal coronary events even in people whose lung function is moderately lower but may still be within a normal range,” Dr. Humbert said.

The study was supported by the Swedish Heart-Lung Foundation. Dr. Zaigham and Dr. Humbert reported having no relevant financial relationships.

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

Poor lung function appears to be a stronger marker of risk for sudden cardiac death than for a survivable first coronary event, results of a prospective population-based study suggest.

Among 28,584 adults with no history of acute coronary events who were followed over 4 decades, every standard deviation decrease in forced expiratory volume in 1 second (FEV₁) was associated with a 23% increase in risk for sudden cardiac death, reported Suneela Zaigham, PhD, a cardiovascular epidemiology fellow at the University of Lund, Sweden, and colleagues.

“Our main findings and subsequent conclusions are that low FEV₁ is associated with both sudden cardiac death and nonfatal coronary events but is consistently more strongly associated with future sudden cardiac death,” Dr. Zaigham said in a narrated poster presented at the European Respiratory Society (ERS) 2021 International Congress, which was held online.

“We propose that measurement with spirometry in early life could aid in the risk stratification of future sudden cardiac death, and our results support the use of spirometry for cardiovascular risk assessment,” she said.

Marc Humbert, MD, PhD, professor of respiratory medicine at Université Paris–Saclay, who was not involved in the study, said that “this is something we can measure fairly easily, meaning that lung function could be used as part of a screening tool.

“We need to do more research to understand the links between lung function and sudden cardiac death and to investigate whether we can use lung function tests to help prevent deaths in the future,” he said.
 

Fatal vs. nonfatal events

It is well known that poor lung function is a strong predictor of future coronary events, but it was unknown whether patterns of lung impairment differ in their ability to predict future nonfatal coronary events or sudden cardiac death, Dr. Zaigham said.

To see whether measurable differences in lung function could predict risk for both fatal and nonfatal coronary events, the investigators studied 28,584 middle-aged residents of Malmö, Sweden. Baseline spirometry test results were available for all study participants.

The patients were followed for approximately 40 years for sudden cardiac death, defined as death on the day of a coronary event, or nonfatal events, defined as survival for at least 24 hours after an event.

Dr. Zaigham and colleagues used a modified version of Lunn McNeil’s competing risks method to create Cox regression models.

Results of an analysis that was adjusted for potential confounding factors indicated that one standard deviation reduction in FEV₁ was associated with a hazard ratio (HR) for sudden cardiac death of 1.23 (95% confidence interval, 1.15-1.31). In contrast, one standard deviation in FEV₁ was associated with a lower but still significant risk for nonfatal events, with an HR of 1.08 (95% CI, 1.04-1.13; P for equal associations = .002).

The results remained significant among participants who had never smoked, with an HR for sudden cardiac death of 1.34 (95% CI, 1.15-1.55) and for nonfatal events of 1.11 (95% CI, 1.02-1.21; P for equal associations = .038).

“This study suggests a link between lung health and sudden cardiac death. It shows a higher risk of fatal than nonfatal coronary events even in people whose lung function is moderately lower but may still be within a normal range,” Dr. Humbert said.

The study was supported by the Swedish Heart-Lung Foundation. Dr. Zaigham and Dr. Humbert reported having no relevant financial relationships.

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

Poor lung function appears to be a stronger marker of risk for sudden cardiac death than for a survivable first coronary event, results of a prospective population-based study suggest.

Among 28,584 adults with no history of acute coronary events who were followed over 4 decades, every standard deviation decrease in forced expiratory volume in 1 second (FEV₁) was associated with a 23% increase in risk for sudden cardiac death, reported Suneela Zaigham, PhD, a cardiovascular epidemiology fellow at the University of Lund, Sweden, and colleagues.

“Our main findings and subsequent conclusions are that low FEV₁ is associated with both sudden cardiac death and nonfatal coronary events but is consistently more strongly associated with future sudden cardiac death,” Dr. Zaigham said in a narrated poster presented at the European Respiratory Society (ERS) 2021 International Congress, which was held online.

“We propose that measurement with spirometry in early life could aid in the risk stratification of future sudden cardiac death, and our results support the use of spirometry for cardiovascular risk assessment,” she said.

Marc Humbert, MD, PhD, professor of respiratory medicine at Université Paris–Saclay, who was not involved in the study, said that “this is something we can measure fairly easily, meaning that lung function could be used as part of a screening tool.

“We need to do more research to understand the links between lung function and sudden cardiac death and to investigate whether we can use lung function tests to help prevent deaths in the future,” he said.
 

Fatal vs. nonfatal events

It is well known that poor lung function is a strong predictor of future coronary events, but it was unknown whether patterns of lung impairment differ in their ability to predict future nonfatal coronary events or sudden cardiac death, Dr. Zaigham said.

To see whether measurable differences in lung function could predict risk for both fatal and nonfatal coronary events, the investigators studied 28,584 middle-aged residents of Malmö, Sweden. Baseline spirometry test results were available for all study participants.

The patients were followed for approximately 40 years for sudden cardiac death, defined as death on the day of a coronary event, or nonfatal events, defined as survival for at least 24 hours after an event.

Dr. Zaigham and colleagues used a modified version of Lunn McNeil’s competing risks method to create Cox regression models.

Results of an analysis that was adjusted for potential confounding factors indicated that one standard deviation reduction in FEV₁ was associated with a hazard ratio (HR) for sudden cardiac death of 1.23 (95% confidence interval, 1.15-1.31). In contrast, one standard deviation in FEV₁ was associated with a lower but still significant risk for nonfatal events, with an HR of 1.08 (95% CI, 1.04-1.13; P for equal associations = .002).

The results remained significant among participants who had never smoked, with an HR for sudden cardiac death of 1.34 (95% CI, 1.15-1.55) and for nonfatal events of 1.11 (95% CI, 1.02-1.21; P for equal associations = .038).

“This study suggests a link between lung health and sudden cardiac death. It shows a higher risk of fatal than nonfatal coronary events even in people whose lung function is moderately lower but may still be within a normal range,” Dr. Humbert said.

The study was supported by the Swedish Heart-Lung Foundation. Dr. Zaigham and Dr. Humbert reported having no relevant financial relationships.

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

The U.S. Food and Drug Administration has granted an accelerated approval to zanubrutinib (Brukinsa) for the treatment of adult patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who have received at least one anti-CD20–based regimen, the drug’s maker BeiGene announced in a press statement.  

The drug works as an inhibitor of Bruton’s tyrosine kinase (BTK), which plays a critical role in B-cell–receptor signaling, a driver in the development of marginal zone lymphoma, according to the company.

The new approval comes just 2 weeks after the oral drug received an accelerated approval for the treatment of adult patients with Waldenström’s macroglobulinemia, a rare non-Hodgkin lymphoma. The drug also has an accelerated approval for treating mantle cell lymphoma in patients who have received at least one prior therapy and is being studied in the treatment of chronic lymphocytic leukemia.

The latest indication is based on results from two single-arm clinical trials, with overall response rate (ORR) as the primary endpoint.

In the multicenter, phase 2 MAGNOLIA trial, zanubrutinib “demonstrated impressive overall response and complete remission rates, with responses observed in all MZL subtypes,” said Stephen Opat, MBBS, of Monash University in Melbourne, lead principal investigator of the study. “In addition, this next-generation BTK inhibitor was well-tolerated in these patients, with low rate of discontinuation due to adverse reactions.”

In the MAGNOLIA trial, 66 patients with R/R MZL who had received at least one anti-CD20–based regimen were treated with zanubrutinib. Among the patients were 26 with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype.

The ORR was 56% with a complete response rate of 20%, based on CT scan assessment.

In addition, the ORR was 67% with a complete response rate of 26%, based on PET-CT scan assessment.

The median duration of response (DoR) was not reached at the median follow-up time of 8.3 months, with 85% of responders still in remission at 12 months. Responses were observed in all MZL subtypes.

In an earlier, phase 1/2 trial of the agent, 20 patients were evaluated, including 9 with extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype. Based on CT scan assessment, the ORR was 80% with a complete remission rate of 20%. The median DoR was not reached at the median follow-up time of 31.4 months, with 72% of responders still in remission at 12 months.

The most common (≥30%) adverse reactions, including laboratory abnormalities, in the pooled safety population of 847 patients were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain, said the company.

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

The U.S. Food and Drug Administration has granted an accelerated approval to zanubrutinib (Brukinsa) for the treatment of adult patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who have received at least one anti-CD20–based regimen, the drug’s maker BeiGene announced in a press statement.  

The drug works as an inhibitor of Bruton’s tyrosine kinase (BTK), which plays a critical role in B-cell–receptor signaling, a driver in the development of marginal zone lymphoma, according to the company.

The new approval comes just 2 weeks after the oral drug received an accelerated approval for the treatment of adult patients with Waldenström’s macroglobulinemia, a rare non-Hodgkin lymphoma. The drug also has an accelerated approval for treating mantle cell lymphoma in patients who have received at least one prior therapy and is being studied in the treatment of chronic lymphocytic leukemia.

The latest indication is based on results from two single-arm clinical trials, with overall response rate (ORR) as the primary endpoint.

In the multicenter, phase 2 MAGNOLIA trial, zanubrutinib “demonstrated impressive overall response and complete remission rates, with responses observed in all MZL subtypes,” said Stephen Opat, MBBS, of Monash University in Melbourne, lead principal investigator of the study. “In addition, this next-generation BTK inhibitor was well-tolerated in these patients, with low rate of discontinuation due to adverse reactions.”

In the MAGNOLIA trial, 66 patients with R/R MZL who had received at least one anti-CD20–based regimen were treated with zanubrutinib. Among the patients were 26 with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype.

The ORR was 56% with a complete response rate of 20%, based on CT scan assessment.

In addition, the ORR was 67% with a complete response rate of 26%, based on PET-CT scan assessment.

The median duration of response (DoR) was not reached at the median follow-up time of 8.3 months, with 85% of responders still in remission at 12 months. Responses were observed in all MZL subtypes.

In an earlier, phase 1/2 trial of the agent, 20 patients were evaluated, including 9 with extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype. Based on CT scan assessment, the ORR was 80% with a complete remission rate of 20%. The median DoR was not reached at the median follow-up time of 31.4 months, with 72% of responders still in remission at 12 months.

The most common (≥30%) adverse reactions, including laboratory abnormalities, in the pooled safety population of 847 patients were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain, said the company.

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

The U.S. Food and Drug Administration has granted an accelerated approval to zanubrutinib (Brukinsa) for the treatment of adult patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who have received at least one anti-CD20–based regimen, the drug’s maker BeiGene announced in a press statement.  

The drug works as an inhibitor of Bruton’s tyrosine kinase (BTK), which plays a critical role in B-cell–receptor signaling, a driver in the development of marginal zone lymphoma, according to the company.

The new approval comes just 2 weeks after the oral drug received an accelerated approval for the treatment of adult patients with Waldenström’s macroglobulinemia, a rare non-Hodgkin lymphoma. The drug also has an accelerated approval for treating mantle cell lymphoma in patients who have received at least one prior therapy and is being studied in the treatment of chronic lymphocytic leukemia.

The latest indication is based on results from two single-arm clinical trials, with overall response rate (ORR) as the primary endpoint.

In the multicenter, phase 2 MAGNOLIA trial, zanubrutinib “demonstrated impressive overall response and complete remission rates, with responses observed in all MZL subtypes,” said Stephen Opat, MBBS, of Monash University in Melbourne, lead principal investigator of the study. “In addition, this next-generation BTK inhibitor was well-tolerated in these patients, with low rate of discontinuation due to adverse reactions.”

In the MAGNOLIA trial, 66 patients with R/R MZL who had received at least one anti-CD20–based regimen were treated with zanubrutinib. Among the patients were 26 with extranodal subtype, 26 with nodal subtype, 12 with splenic subtype, and 4 with unknown subtype.

The ORR was 56% with a complete response rate of 20%, based on CT scan assessment.

In addition, the ORR was 67% with a complete response rate of 26%, based on PET-CT scan assessment.

The median duration of response (DoR) was not reached at the median follow-up time of 8.3 months, with 85% of responders still in remission at 12 months. Responses were observed in all MZL subtypes.

In an earlier, phase 1/2 trial of the agent, 20 patients were evaluated, including 9 with extranodal subtype, 5 with nodal subtype, and 6 with splenic subtype. Based on CT scan assessment, the ORR was 80% with a complete remission rate of 20%. The median DoR was not reached at the median follow-up time of 31.4 months, with 72% of responders still in remission at 12 months.

The most common (≥30%) adverse reactions, including laboratory abnormalities, in the pooled safety population of 847 patients were decreased neutrophil count, upper respiratory tract infection, decreased platelet count, hemorrhage, decreased lymphocyte count, rash, and musculoskeletal pain, said the company.

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

Subclinical or preclinical interstitial lung disease in patients with connective tissue diseases is not a benign entity, and many patients may experience progression of lung fibrosis before a diagnosis of ILD is made, investigators caution.

Among patients with connective tissue disease assessed with baseline and follow-up high-resolution CT scans for ILD, nearly one-fourth had evidence of ILD progression over a median of 4.5 years, reported Anna-Maria Hoffmann-Vold, MD, PhD, from Oslo University Hospital.

“Subclinical ILD is frequently present across all connective tissue diseases. It progresses over time in a substantial subgroup of people comparable to patients with clinical ILD, and our findings really question the terms ‘subclinical/preclinical ILD,’ which may potentially lead to a suboptimal watchful waiting management,” she said in an oral abstract presentation during the European Respiratory Society International Congress.

Jesse Roman, MD, CEO at the Jane & Leonard Korman Respiratory Institute at Thomas Jefferson University, Philadelphia, who was not involved in the study, commented that the findings regarding subclinical disease come as no surprise.

“The connective tissue disorders are linked to interstitial lung disease, and we believe that they are the primary causes of interstitial lung diseases in most countries,” he said in an interview.

“Basically, what you’re detecting is that if you can identify these people early, then you can see that they behave like any other patients with interstitial lung disease with progression, so most experts recommend that patients with any kind of connective tissue disorder be followed with either CT scans or pulmonary function tests, or carefully interviewed every time they come to identify any kind of very early interstitial lung disease – particularly in patients with rheumatoid arthritis, in patients with systemic sclerosis, and in patients with dermatomyositis,” Dr. Roman said.

He noted that when patients present with an idiopathic or undiagnosed condition suggestive of ILD, clinicians at his center will order serology tests to detect potential cases of subclinical connective tissue disorders.

Observational study

Dr. Hoffmann-Vold and colleagues looked at 525 patients with connective tissue diseases assessed for ILD at their center, including 296 with systemic sclerosis, 94 with anti-synthetase syndrome, and 135 with mixed connective tissue disease.

­­They used semiquantitative assessment to determine the prevalence of ILD, defining subclinical disease as ILD extent of less than 5% on high-resolution CT, preserved lung function with forced vital capacity (FVC) greater than 80% of predicted, and no respiratory symptoms.

Clinical ILD was defined as either ILD extent greater than 5%, or ILD extent below 5% but with respiratory symptoms and FVC below 80% of predicted.

They found that 44% of the patients had ILD on high-resolution CT, 43% had no evidence of ILD, and 13% had subclinical ILD.

In a comparison of patients without ILD and those with either clinical or subclinical ILD, they found that, while the mean patient age was about 51 in all three groups, men were more likely than women to have clinical ILD. A higher proportion of patients with clinical ILD (39%) died during the total observation period of about 13 years, compared with 22% of patients without ILD, and 18% of those with subclinical ILD.

As noted before, of 395 patients with baseline and follow-up high-resolution CT, 95 (24%) had evidence of lung fibrosis progression, with 38% of patients with subclinical ILD and 51% of patients with clinical ILD having progression during follow-up.

“In our connective tissue disease patients with ILD, the symptoms-define-disease argument would clearly lead to [the idea] that ILD is not a disease until patients become symptomatic, which we all know is frequently appearing in advanced stages of ILD,” Dr. Hoffmann-Vold said.

The study was funded by Oslo University Hospital. Dr. Hoffmann-Vold and Dr. Roman reported no relevant conflicts of interest to disclose.

Subclinical or preclinical interstitial lung disease in patients with connective tissue diseases is not a benign entity, and many patients may experience progression of lung fibrosis before a diagnosis of ILD is made, investigators caution.

Among patients with connective tissue disease assessed with baseline and follow-up high-resolution CT scans for ILD, nearly one-fourth had evidence of ILD progression over a median of 4.5 years, reported Anna-Maria Hoffmann-Vold, MD, PhD, from Oslo University Hospital.

“Subclinical ILD is frequently present across all connective tissue diseases. It progresses over time in a substantial subgroup of people comparable to patients with clinical ILD, and our findings really question the terms ‘subclinical/preclinical ILD,’ which may potentially lead to a suboptimal watchful waiting management,” she said in an oral abstract presentation during the European Respiratory Society International Congress.

Jesse Roman, MD, CEO at the Jane & Leonard Korman Respiratory Institute at Thomas Jefferson University, Philadelphia, who was not involved in the study, commented that the findings regarding subclinical disease come as no surprise.

“The connective tissue disorders are linked to interstitial lung disease, and we believe that they are the primary causes of interstitial lung diseases in most countries,” he said in an interview.

“Basically, what you’re detecting is that if you can identify these people early, then you can see that they behave like any other patients with interstitial lung disease with progression, so most experts recommend that patients with any kind of connective tissue disorder be followed with either CT scans or pulmonary function tests, or carefully interviewed every time they come to identify any kind of very early interstitial lung disease – particularly in patients with rheumatoid arthritis, in patients with systemic sclerosis, and in patients with dermatomyositis,” Dr. Roman said.

He noted that when patients present with an idiopathic or undiagnosed condition suggestive of ILD, clinicians at his center will order serology tests to detect potential cases of subclinical connective tissue disorders.

Observational study

Dr. Hoffmann-Vold and colleagues looked at 525 patients with connective tissue diseases assessed for ILD at their center, including 296 with systemic sclerosis, 94 with anti-synthetase syndrome, and 135 with mixed connective tissue disease.

­­They used semiquantitative assessment to determine the prevalence of ILD, defining subclinical disease as ILD extent of less than 5% on high-resolution CT, preserved lung function with forced vital capacity (FVC) greater than 80% of predicted, and no respiratory symptoms.

Clinical ILD was defined as either ILD extent greater than 5%, or ILD extent below 5% but with respiratory symptoms and FVC below 80% of predicted.

They found that 44% of the patients had ILD on high-resolution CT, 43% had no evidence of ILD, and 13% had subclinical ILD.

In a comparison of patients without ILD and those with either clinical or subclinical ILD, they found that, while the mean patient age was about 51 in all three groups, men were more likely than women to have clinical ILD. A higher proportion of patients with clinical ILD (39%) died during the total observation period of about 13 years, compared with 22% of patients without ILD, and 18% of those with subclinical ILD.

As noted before, of 395 patients with baseline and follow-up high-resolution CT, 95 (24%) had evidence of lung fibrosis progression, with 38% of patients with subclinical ILD and 51% of patients with clinical ILD having progression during follow-up.

“In our connective tissue disease patients with ILD, the symptoms-define-disease argument would clearly lead to [the idea] that ILD is not a disease until patients become symptomatic, which we all know is frequently appearing in advanced stages of ILD,” Dr. Hoffmann-Vold said.

The study was funded by Oslo University Hospital. Dr. Hoffmann-Vold and Dr. Roman reported no relevant conflicts of interest to disclose.

Subclinical or preclinical interstitial lung disease in patients with connective tissue diseases is not a benign entity, and many patients may experience progression of lung fibrosis before a diagnosis of ILD is made, investigators caution.

Among patients with connective tissue disease assessed with baseline and follow-up high-resolution CT scans for ILD, nearly one-fourth had evidence of ILD progression over a median of 4.5 years, reported Anna-Maria Hoffmann-Vold, MD, PhD, from Oslo University Hospital.

“Subclinical ILD is frequently present across all connective tissue diseases. It progresses over time in a substantial subgroup of people comparable to patients with clinical ILD, and our findings really question the terms ‘subclinical/preclinical ILD,’ which may potentially lead to a suboptimal watchful waiting management,” she said in an oral abstract presentation during the European Respiratory Society International Congress.

Jesse Roman, MD, CEO at the Jane & Leonard Korman Respiratory Institute at Thomas Jefferson University, Philadelphia, who was not involved in the study, commented that the findings regarding subclinical disease come as no surprise.

“The connective tissue disorders are linked to interstitial lung disease, and we believe that they are the primary causes of interstitial lung diseases in most countries,” he said in an interview.

“Basically, what you’re detecting is that if you can identify these people early, then you can see that they behave like any other patients with interstitial lung disease with progression, so most experts recommend that patients with any kind of connective tissue disorder be followed with either CT scans or pulmonary function tests, or carefully interviewed every time they come to identify any kind of very early interstitial lung disease – particularly in patients with rheumatoid arthritis, in patients with systemic sclerosis, and in patients with dermatomyositis,” Dr. Roman said.

He noted that when patients present with an idiopathic or undiagnosed condition suggestive of ILD, clinicians at his center will order serology tests to detect potential cases of subclinical connective tissue disorders.

Observational study

Dr. Hoffmann-Vold and colleagues looked at 525 patients with connective tissue diseases assessed for ILD at their center, including 296 with systemic sclerosis, 94 with anti-synthetase syndrome, and 135 with mixed connective tissue disease.

­­They used semiquantitative assessment to determine the prevalence of ILD, defining subclinical disease as ILD extent of less than 5% on high-resolution CT, preserved lung function with forced vital capacity (FVC) greater than 80% of predicted, and no respiratory symptoms.

Clinical ILD was defined as either ILD extent greater than 5%, or ILD extent below 5% but with respiratory symptoms and FVC below 80% of predicted.

They found that 44% of the patients had ILD on high-resolution CT, 43% had no evidence of ILD, and 13% had subclinical ILD.

In a comparison of patients without ILD and those with either clinical or subclinical ILD, they found that, while the mean patient age was about 51 in all three groups, men were more likely than women to have clinical ILD. A higher proportion of patients with clinical ILD (39%) died during the total observation period of about 13 years, compared with 22% of patients without ILD, and 18% of those with subclinical ILD.

As noted before, of 395 patients with baseline and follow-up high-resolution CT, 95 (24%) had evidence of lung fibrosis progression, with 38% of patients with subclinical ILD and 51% of patients with clinical ILD having progression during follow-up.

“In our connective tissue disease patients with ILD, the symptoms-define-disease argument would clearly lead to [the idea] that ILD is not a disease until patients become symptomatic, which we all know is frequently appearing in advanced stages of ILD,” Dr. Hoffmann-Vold said.

The study was funded by Oslo University Hospital. Dr. Hoffmann-Vold and Dr. Roman reported no relevant conflicts of interest to disclose.