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.

Use of enfortumab vedotin (Padcev), which was approved less than 2 years ago for the treatment of metastatic urothelial cancer, has been associated with cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some of which were fatal.

The cases came to light during routine surveillance, say staff from the division of pharmacovigilance of the Food and Drug Administration in a research letter published online Sept. 8, 2021, in JAMA Dermatology.

Eight cases of serious skin reactions characterized as SJS/TEN were identified from the FDA’s Adverse Event Reporting System (FAERS). In five of these cases, the diagnosis of SJS/TEN was confirmed by a dermatologist and/or biopsy findings.

The median time to onset of SJS/TEN was 11 days (range, 9-21 days) from the start of treatment.

In the eight cases, serious outcomes were reported. In four cases, deaths that were attributed to SJS/TEN occurred. “Other serious outcomes included admission to the burn unit in four cases,” the researchers wrote.
 

First-in-class agent

Enfortumab vedotin is a first-in-class agent directed against cell adhesion molecule nectin-4, which is located on the surface of cells and is highly expressed in bladder cancer. The product is an antibody conjugate, in which the antibody directs the product to these cells and then releases the cytoxic monomethyl auristantin E. It is administered intravenously.

The product was granted accelerated approval by the FDA in December 2019. This approval was based on response data from the EV-201 study, a phase 2 clinical trial that involved 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy.

The results were presented in June 2019 at the annual meeting of the American Society of Clinical Oncology. The overall response rate was 44%; 12% of patients achieved a complete response, and 32% had a partial response. The median duration of response was 7.6 months.

At the meeting, Daniel P. Petrylak, MD, professor of medicine (medical oncology) and urology at Yale Cancer Center, New Haven, Conn., noted that there is a “high unmet need” among patients with advanced and metastatic urothelial cancer. There has been a flurry of new drug approvals for this disease. Five immune checkpoint inhibitor drugs have been approved in recent years. Most patients (75%-80%) experience disease progression after receiving immunotherapy.

Enfortumab vedotin is the “first novel therapeutic to demonstrate substantial clinical activity” in patients whose disease has progressed after platinum chemotherapy and immunotherapies, commented Dr. Petrylak.

At the time, maculopapular rash of grade 3 or higher was reported in 4% of the cohort. That was the only serious dermatologic adverse event noted.
 

Clinically significant findings

The cases of severe skin reactions now being reported come from postmarketing surveillance, noted the authors, led by Michelle Nadeau Nguyen, PharmD, BCOP, BCPS. They reviewed data from FAERS, PubMed, and Embase from Dec. 18, 2019, the date the product was approved, to Oct. 7, 2020.

Other than the eight cases reported to FAERS, no additional cases were identified from PubMed or Embase.

The authors noted that, because cases of SJS/TEN are rare but serious, these well-documented postmarketing reports are clinically significant. “Moreover, we find the rapid accumulation of cases over an approximate 12-month marketing period a concerning observation,” they wrote.

The rate at which these reactions were reported is higher than would be expected, they commented.

The annual incidence of locally advanced urothelial cancer, the disease most likely to be treated with this drug, is around 12,494-40,000 cases per year in the United States. The expected incidence rate of SJS/TEN is about 1-7 cases per 1,000,000 patients. The team calculated from the reports that, among patients who received enfortumab vedotin, the rate was 20 cases per 1,000,000 patients.

This reporting rate is likely to be underestimated, inasmuch as underreporting is known to be a limitation of spontaneous reporting systems such as FAERS, the authors noted.

The mechanism for toxic skin effects with enfortumab vedotin is as yet unknown, but it may be related to the inhibitory effects of the drug on nectin-4 expression, they suggest. Nectin-4 is expressed by epithelial tissues, including skin.

Dr. Nguyen and colleagues noted that, on approval, the U.S. prescribing information for the drug noted that skin reactions were seen in 55% of patients in clinical trials.

The prescribing information was recently revised to include SJS/TEN and to recommend permanent discontinuance of the drug if cases of SJS/TEN are suspected.

“This revision is intended to increase clinicians’ awareness of the risk for SJS/TEN and mitigate serious outcomes by improving the likelihood of early identification and intervention,” they added.

The authors also encouraged continued reporting of adverse events with enfortumab vedotin to the FDA via the MedWatch portal.

The authors disclosed no relevant financial relationships.

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

Use of enfortumab vedotin (Padcev), which was approved less than 2 years ago for the treatment of metastatic urothelial cancer, has been associated with cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some of which were fatal.

The cases came to light during routine surveillance, say staff from the division of pharmacovigilance of the Food and Drug Administration in a research letter published online Sept. 8, 2021, in JAMA Dermatology.

Eight cases of serious skin reactions characterized as SJS/TEN were identified from the FDA’s Adverse Event Reporting System (FAERS). In five of these cases, the diagnosis of SJS/TEN was confirmed by a dermatologist and/or biopsy findings.

The median time to onset of SJS/TEN was 11 days (range, 9-21 days) from the start of treatment.

In the eight cases, serious outcomes were reported. In four cases, deaths that were attributed to SJS/TEN occurred. “Other serious outcomes included admission to the burn unit in four cases,” the researchers wrote.
 

First-in-class agent

Enfortumab vedotin is a first-in-class agent directed against cell adhesion molecule nectin-4, which is located on the surface of cells and is highly expressed in bladder cancer. The product is an antibody conjugate, in which the antibody directs the product to these cells and then releases the cytoxic monomethyl auristantin E. It is administered intravenously.

The product was granted accelerated approval by the FDA in December 2019. This approval was based on response data from the EV-201 study, a phase 2 clinical trial that involved 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy.

The results were presented in June 2019 at the annual meeting of the American Society of Clinical Oncology. The overall response rate was 44%; 12% of patients achieved a complete response, and 32% had a partial response. The median duration of response was 7.6 months.

At the meeting, Daniel P. Petrylak, MD, professor of medicine (medical oncology) and urology at Yale Cancer Center, New Haven, Conn., noted that there is a “high unmet need” among patients with advanced and metastatic urothelial cancer. There has been a flurry of new drug approvals for this disease. Five immune checkpoint inhibitor drugs have been approved in recent years. Most patients (75%-80%) experience disease progression after receiving immunotherapy.

Enfortumab vedotin is the “first novel therapeutic to demonstrate substantial clinical activity” in patients whose disease has progressed after platinum chemotherapy and immunotherapies, commented Dr. Petrylak.

At the time, maculopapular rash of grade 3 or higher was reported in 4% of the cohort. That was the only serious dermatologic adverse event noted.
 

Clinically significant findings

The cases of severe skin reactions now being reported come from postmarketing surveillance, noted the authors, led by Michelle Nadeau Nguyen, PharmD, BCOP, BCPS. They reviewed data from FAERS, PubMed, and Embase from Dec. 18, 2019, the date the product was approved, to Oct. 7, 2020.

Other than the eight cases reported to FAERS, no additional cases were identified from PubMed or Embase.

The authors noted that, because cases of SJS/TEN are rare but serious, these well-documented postmarketing reports are clinically significant. “Moreover, we find the rapid accumulation of cases over an approximate 12-month marketing period a concerning observation,” they wrote.

The rate at which these reactions were reported is higher than would be expected, they commented.

The annual incidence of locally advanced urothelial cancer, the disease most likely to be treated with this drug, is around 12,494-40,000 cases per year in the United States. The expected incidence rate of SJS/TEN is about 1-7 cases per 1,000,000 patients. The team calculated from the reports that, among patients who received enfortumab vedotin, the rate was 20 cases per 1,000,000 patients.

This reporting rate is likely to be underestimated, inasmuch as underreporting is known to be a limitation of spontaneous reporting systems such as FAERS, the authors noted.

The mechanism for toxic skin effects with enfortumab vedotin is as yet unknown, but it may be related to the inhibitory effects of the drug on nectin-4 expression, they suggest. Nectin-4 is expressed by epithelial tissues, including skin.

Dr. Nguyen and colleagues noted that, on approval, the U.S. prescribing information for the drug noted that skin reactions were seen in 55% of patients in clinical trials.

The prescribing information was recently revised to include SJS/TEN and to recommend permanent discontinuance of the drug if cases of SJS/TEN are suspected.

“This revision is intended to increase clinicians’ awareness of the risk for SJS/TEN and mitigate serious outcomes by improving the likelihood of early identification and intervention,” they added.

The authors also encouraged continued reporting of adverse events with enfortumab vedotin to the FDA via the MedWatch portal.

The authors disclosed no relevant financial relationships.

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

Use of enfortumab vedotin (Padcev), which was approved less than 2 years ago for the treatment of metastatic urothelial cancer, has been associated with cases of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), some of which were fatal.

The cases came to light during routine surveillance, say staff from the division of pharmacovigilance of the Food and Drug Administration in a research letter published online Sept. 8, 2021, in JAMA Dermatology.

Eight cases of serious skin reactions characterized as SJS/TEN were identified from the FDA’s Adverse Event Reporting System (FAERS). In five of these cases, the diagnosis of SJS/TEN was confirmed by a dermatologist and/or biopsy findings.

The median time to onset of SJS/TEN was 11 days (range, 9-21 days) from the start of treatment.

In the eight cases, serious outcomes were reported. In four cases, deaths that were attributed to SJS/TEN occurred. “Other serious outcomes included admission to the burn unit in four cases,” the researchers wrote.
 

First-in-class agent

Enfortumab vedotin is a first-in-class agent directed against cell adhesion molecule nectin-4, which is located on the surface of cells and is highly expressed in bladder cancer. The product is an antibody conjugate, in which the antibody directs the product to these cells and then releases the cytoxic monomethyl auristantin E. It is administered intravenously.

The product was granted accelerated approval by the FDA in December 2019. This approval was based on response data from the EV-201 study, a phase 2 clinical trial that involved 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy.

The results were presented in June 2019 at the annual meeting of the American Society of Clinical Oncology. The overall response rate was 44%; 12% of patients achieved a complete response, and 32% had a partial response. The median duration of response was 7.6 months.

At the meeting, Daniel P. Petrylak, MD, professor of medicine (medical oncology) and urology at Yale Cancer Center, New Haven, Conn., noted that there is a “high unmet need” among patients with advanced and metastatic urothelial cancer. There has been a flurry of new drug approvals for this disease. Five immune checkpoint inhibitor drugs have been approved in recent years. Most patients (75%-80%) experience disease progression after receiving immunotherapy.

Enfortumab vedotin is the “first novel therapeutic to demonstrate substantial clinical activity” in patients whose disease has progressed after platinum chemotherapy and immunotherapies, commented Dr. Petrylak.

At the time, maculopapular rash of grade 3 or higher was reported in 4% of the cohort. That was the only serious dermatologic adverse event noted.
 

Clinically significant findings

The cases of severe skin reactions now being reported come from postmarketing surveillance, noted the authors, led by Michelle Nadeau Nguyen, PharmD, BCOP, BCPS. They reviewed data from FAERS, PubMed, and Embase from Dec. 18, 2019, the date the product was approved, to Oct. 7, 2020.

Other than the eight cases reported to FAERS, no additional cases were identified from PubMed or Embase.

The authors noted that, because cases of SJS/TEN are rare but serious, these well-documented postmarketing reports are clinically significant. “Moreover, we find the rapid accumulation of cases over an approximate 12-month marketing period a concerning observation,” they wrote.

The rate at which these reactions were reported is higher than would be expected, they commented.

The annual incidence of locally advanced urothelial cancer, the disease most likely to be treated with this drug, is around 12,494-40,000 cases per year in the United States. The expected incidence rate of SJS/TEN is about 1-7 cases per 1,000,000 patients. The team calculated from the reports that, among patients who received enfortumab vedotin, the rate was 20 cases per 1,000,000 patients.

This reporting rate is likely to be underestimated, inasmuch as underreporting is known to be a limitation of spontaneous reporting systems such as FAERS, the authors noted.

The mechanism for toxic skin effects with enfortumab vedotin is as yet unknown, but it may be related to the inhibitory effects of the drug on nectin-4 expression, they suggest. Nectin-4 is expressed by epithelial tissues, including skin.

Dr. Nguyen and colleagues noted that, on approval, the U.S. prescribing information for the drug noted that skin reactions were seen in 55% of patients in clinical trials.

The prescribing information was recently revised to include SJS/TEN and to recommend permanent discontinuance of the drug if cases of SJS/TEN are suspected.

“This revision is intended to increase clinicians’ awareness of the risk for SJS/TEN and mitigate serious outcomes by improving the likelihood of early identification and intervention,” they added.

The authors also encouraged continued reporting of adverse events with enfortumab vedotin to the FDA via the MedWatch portal.

The authors disclosed no relevant financial relationships.

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

Treatment with acetylsalicylic acid (ASA) or heparin is associated with an increased risk for symptomatic intracranial hemorrhage (sICH) in patients with ischemic stroke who are undergoing endovascular therapy (EVT), new data show.

In this population, ASA and heparin are each associated with an approximately doubled risk for sICH when administered during EVT.

“We did not find any evidence for a beneficial effect on functional outcome,” investigator Wouter van der Steen, MD, research physician and PhD student at Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization. The possibility that a positive effect would be observed if the trial were continued was considered negligible, he added.

The researchers stopped the trial for safety reasons and recommend avoiding the evaluated dosages of both medications during EVT for ischemic stroke, said Dr. van der Steen.

He presented the findings from the MR CLEAN-MED trial at the European Stroke Organisation Conference (ESOC) 2021, which was held online.
 

Trial stopped for safety

Previous research has supported the safety and efficacy of EVT for ischemic stroke. Still, more than 30% of patients do not recover, despite fast and complete recanalization. Incomplete microvascular reperfusion (IMR) could explain this incomplete recovery, the researchers note.

Microthrombi, which occlude distal vessels, and neutrophil extracellular traps can cause IMR. This problem can be reduced through treatment with ASA, which has an antithrombotic effect, or with heparin, which dissolves neutrophil extracellular traps, they add. Although these drugs are associated with good clinical outcomes, they entail an increased risk for sICH.

The investigators conducted the multicenter, randomized controlled MR CLEAN-MED trial to evaluate the effect of intravenous (IV) ASA and heparin, alone or in combination, during EVT for acute ischemic stroke. Treatment was open label, but outcome assessment was blinded. Eligible participants were adults with a National Institutes of Health Stroke Scale (NIHSS) score of greater than or equal to 2 and an anterior circulation large-vessel occlusion for whom EVT could be initiated in fewer than 6 hours.

Investigators randomly assigned patients to receive or not to receive ASA. Within each of these two treatment groups, patients were randomly assigned to receive no heparin, low-dose heparin, or moderate-dose heparin.

ASA was given in a loading dose of 300 mg. Patients who were given low-dose heparin received a loading dose of 5,000 IU followed by 500 IU/h for 6 hours. Patients who received moderate-dose heparin were given a loading dose of 5,000 IU followed by 1,250 IU/h for 6 hours.

The study’s primary outcome was Modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were NIHSS score at 24 hours, NIHSS score at 5 to 7 days, and recanalization grade at 24 hours on CT angiography or MRI. The primary safety outcomes were sICH and death within 90 days.

An independent, unblinded data and safety monitoring board (DSMB) assessed the risk for the primary safety outcomes throughout the trial. The board performed interim analyses of safety and efficacy for every 300 patients.

After the fourth safety assessment, the DSMB recommended that enrollment in the moderate-dose heparin arm be discontinued for safety reasons. Enrollment in other arms continued.

After the second interim analysis, the DSMB advised that the trial steering committee be unblinded to decide whether to stop or continue the trial. The steering committee decided to stop the trial for reasons of safety.
 

Increased risk for sICH

In all, 628 patients were included in the study. The ASA groups included 310 patients, and the no-ASA groups included 318 patients. In all, 332 participants received heparin, and 296 received no heparin.

The demographic characteristics were well balanced between groups. The population’s median age was 73 years, and about 53% were men. The median baseline NIHSS score was approximately 15. About 74% of patients received IV thrombolysis. The median baseline Alberta Stroke Program Early CT Scan score was 9.

The investigators observed a slight shift toward worse outcome in the ASA group, compared with the no-ASA group (adjusted OR, 0.91). In addition, the ASA group had a significantly increased risk for sICH, compared with the no-ASA group (14% vs. 7.2%; aOR, 1.95).

Patients in the ASA group were less likely to have good functional outcome (mRS of 0 to 2; aOR, 0.76), and the mortality rate tended to be higher.

The researchers found a nonsignificant shift toward a worse functional outcome in the heparin group, compared with the no-heparin group (aOR, 0.81). The risk for sICH was significantly higher in the heparin group, compared with the no-heparin group (13% vs. 7.4%; aOR, 2.00).

Patients in the heparin group were also less likely to have a good functional outcome (aOR, 0.78), and there was a nonsignificant increase in risk for death among those patients.

The rate of sICH was 11% in the group that received low-dose heparin; it was 26% in the group that received moderate-dose heparin (aOR, 6.05). The mortality rate was 23% in the low-dose group and 47% in the moderate-dose group (aOR, 5.45).

There was no significant interaction between ASA and heparin on the primary outcome and on sICH occurrence.
 

‘A unique trial’

“MR CLEAN-MED is a unique trial because it investigated a widely used treatment but until now without any proof of effectiveness,” said Dr. van der Steen. The researchers expect that their findings will have a strong impact on the management of patients with acute ischemic stroke. They suggest that the administration of antithrombotic agents during EVT be avoided.

“We consider it probable that the increased risk of sICH explains at least a part of the nonsignificant shift towards a worse functional outcome,” co-investigator Bob Roozenbeek, MD, PhD, a neurologist at the Erasmus Medical Center, said in an interview. “However, to make more definite statements, we will have to do more in-depth analyses.”

It remains unclear whether the periprocedural use of lower dosages of antithrombotic agents or of a single bolus of heparin could be safe and effective, said Dr. van der Steen.

To gain insight into these questions, the investigators will evaluate the effect of the medications and dosages examined in this trial on primary hemostasis and coagulation activity in the trial population. They also plan to examine the effect of primary hemostasis and coagulation activity on risk for sICH and functional outcome.

Enhancing the effectiveness of thrombectomy for acute ischemic stroke continues to be an important goal for stroke therapy, said Mark Fisher, MD, professor of neurology and pathology and laboratory medicine at the University of California, Irvine, who commented on the findings for this news organization.

At least three strategies are available: The use of ancillary antithrombotic medications, neuroprotection, and modulation of the vasoconstrictive properties of the microcirculation.

“Results of MR CLEAN-MED argue against the antithrombotic strategy,” said Dr. Fisher. “The alternate strategies remain viable, and results of interventions using those approaches are awaited with great interest.”

The study was funded by the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative and the Brain Foundation Netherlands. Funding also was provided by Stryker, Medtronic, and Cerenovus. Dr. van der Steen and Dr. Fisher have disclosed no relevant financial relationships.

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

Treatment with acetylsalicylic acid (ASA) or heparin is associated with an increased risk for symptomatic intracranial hemorrhage (sICH) in patients with ischemic stroke who are undergoing endovascular therapy (EVT), new data show.

In this population, ASA and heparin are each associated with an approximately doubled risk for sICH when administered during EVT.

“We did not find any evidence for a beneficial effect on functional outcome,” investigator Wouter van der Steen, MD, research physician and PhD student at Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization. The possibility that a positive effect would be observed if the trial were continued was considered negligible, he added.

The researchers stopped the trial for safety reasons and recommend avoiding the evaluated dosages of both medications during EVT for ischemic stroke, said Dr. van der Steen.

He presented the findings from the MR CLEAN-MED trial at the European Stroke Organisation Conference (ESOC) 2021, which was held online.
 

Trial stopped for safety

Previous research has supported the safety and efficacy of EVT for ischemic stroke. Still, more than 30% of patients do not recover, despite fast and complete recanalization. Incomplete microvascular reperfusion (IMR) could explain this incomplete recovery, the researchers note.

Microthrombi, which occlude distal vessels, and neutrophil extracellular traps can cause IMR. This problem can be reduced through treatment with ASA, which has an antithrombotic effect, or with heparin, which dissolves neutrophil extracellular traps, they add. Although these drugs are associated with good clinical outcomes, they entail an increased risk for sICH.

The investigators conducted the multicenter, randomized controlled MR CLEAN-MED trial to evaluate the effect of intravenous (IV) ASA and heparin, alone or in combination, during EVT for acute ischemic stroke. Treatment was open label, but outcome assessment was blinded. Eligible participants were adults with a National Institutes of Health Stroke Scale (NIHSS) score of greater than or equal to 2 and an anterior circulation large-vessel occlusion for whom EVT could be initiated in fewer than 6 hours.

Investigators randomly assigned patients to receive or not to receive ASA. Within each of these two treatment groups, patients were randomly assigned to receive no heparin, low-dose heparin, or moderate-dose heparin.

ASA was given in a loading dose of 300 mg. Patients who were given low-dose heparin received a loading dose of 5,000 IU followed by 500 IU/h for 6 hours. Patients who received moderate-dose heparin were given a loading dose of 5,000 IU followed by 1,250 IU/h for 6 hours.

The study’s primary outcome was Modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were NIHSS score at 24 hours, NIHSS score at 5 to 7 days, and recanalization grade at 24 hours on CT angiography or MRI. The primary safety outcomes were sICH and death within 90 days.

An independent, unblinded data and safety monitoring board (DSMB) assessed the risk for the primary safety outcomes throughout the trial. The board performed interim analyses of safety and efficacy for every 300 patients.

After the fourth safety assessment, the DSMB recommended that enrollment in the moderate-dose heparin arm be discontinued for safety reasons. Enrollment in other arms continued.

After the second interim analysis, the DSMB advised that the trial steering committee be unblinded to decide whether to stop or continue the trial. The steering committee decided to stop the trial for reasons of safety.
 

Increased risk for sICH

In all, 628 patients were included in the study. The ASA groups included 310 patients, and the no-ASA groups included 318 patients. In all, 332 participants received heparin, and 296 received no heparin.

The demographic characteristics were well balanced between groups. The population’s median age was 73 years, and about 53% were men. The median baseline NIHSS score was approximately 15. About 74% of patients received IV thrombolysis. The median baseline Alberta Stroke Program Early CT Scan score was 9.

The investigators observed a slight shift toward worse outcome in the ASA group, compared with the no-ASA group (adjusted OR, 0.91). In addition, the ASA group had a significantly increased risk for sICH, compared with the no-ASA group (14% vs. 7.2%; aOR, 1.95).

Patients in the ASA group were less likely to have good functional outcome (mRS of 0 to 2; aOR, 0.76), and the mortality rate tended to be higher.

The researchers found a nonsignificant shift toward a worse functional outcome in the heparin group, compared with the no-heparin group (aOR, 0.81). The risk for sICH was significantly higher in the heparin group, compared with the no-heparin group (13% vs. 7.4%; aOR, 2.00).

Patients in the heparin group were also less likely to have a good functional outcome (aOR, 0.78), and there was a nonsignificant increase in risk for death among those patients.

The rate of sICH was 11% in the group that received low-dose heparin; it was 26% in the group that received moderate-dose heparin (aOR, 6.05). The mortality rate was 23% in the low-dose group and 47% in the moderate-dose group (aOR, 5.45).

There was no significant interaction between ASA and heparin on the primary outcome and on sICH occurrence.
 

‘A unique trial’

“MR CLEAN-MED is a unique trial because it investigated a widely used treatment but until now without any proof of effectiveness,” said Dr. van der Steen. The researchers expect that their findings will have a strong impact on the management of patients with acute ischemic stroke. They suggest that the administration of antithrombotic agents during EVT be avoided.

“We consider it probable that the increased risk of sICH explains at least a part of the nonsignificant shift towards a worse functional outcome,” co-investigator Bob Roozenbeek, MD, PhD, a neurologist at the Erasmus Medical Center, said in an interview. “However, to make more definite statements, we will have to do more in-depth analyses.”

It remains unclear whether the periprocedural use of lower dosages of antithrombotic agents or of a single bolus of heparin could be safe and effective, said Dr. van der Steen.

To gain insight into these questions, the investigators will evaluate the effect of the medications and dosages examined in this trial on primary hemostasis and coagulation activity in the trial population. They also plan to examine the effect of primary hemostasis and coagulation activity on risk for sICH and functional outcome.

Enhancing the effectiveness of thrombectomy for acute ischemic stroke continues to be an important goal for stroke therapy, said Mark Fisher, MD, professor of neurology and pathology and laboratory medicine at the University of California, Irvine, who commented on the findings for this news organization.

At least three strategies are available: The use of ancillary antithrombotic medications, neuroprotection, and modulation of the vasoconstrictive properties of the microcirculation.

“Results of MR CLEAN-MED argue against the antithrombotic strategy,” said Dr. Fisher. “The alternate strategies remain viable, and results of interventions using those approaches are awaited with great interest.”

The study was funded by the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative and the Brain Foundation Netherlands. Funding also was provided by Stryker, Medtronic, and Cerenovus. Dr. van der Steen and Dr. Fisher have disclosed no relevant financial relationships.

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

Treatment with acetylsalicylic acid (ASA) or heparin is associated with an increased risk for symptomatic intracranial hemorrhage (sICH) in patients with ischemic stroke who are undergoing endovascular therapy (EVT), new data show.

In this population, ASA and heparin are each associated with an approximately doubled risk for sICH when administered during EVT.

“We did not find any evidence for a beneficial effect on functional outcome,” investigator Wouter van der Steen, MD, research physician and PhD student at Erasmus University Medical Center, Rotterdam, the Netherlands, told this news organization. The possibility that a positive effect would be observed if the trial were continued was considered negligible, he added.

The researchers stopped the trial for safety reasons and recommend avoiding the evaluated dosages of both medications during EVT for ischemic stroke, said Dr. van der Steen.

He presented the findings from the MR CLEAN-MED trial at the European Stroke Organisation Conference (ESOC) 2021, which was held online.
 

Trial stopped for safety

Previous research has supported the safety and efficacy of EVT for ischemic stroke. Still, more than 30% of patients do not recover, despite fast and complete recanalization. Incomplete microvascular reperfusion (IMR) could explain this incomplete recovery, the researchers note.

Microthrombi, which occlude distal vessels, and neutrophil extracellular traps can cause IMR. This problem can be reduced through treatment with ASA, which has an antithrombotic effect, or with heparin, which dissolves neutrophil extracellular traps, they add. Although these drugs are associated with good clinical outcomes, they entail an increased risk for sICH.

The investigators conducted the multicenter, randomized controlled MR CLEAN-MED trial to evaluate the effect of intravenous (IV) ASA and heparin, alone or in combination, during EVT for acute ischemic stroke. Treatment was open label, but outcome assessment was blinded. Eligible participants were adults with a National Institutes of Health Stroke Scale (NIHSS) score of greater than or equal to 2 and an anterior circulation large-vessel occlusion for whom EVT could be initiated in fewer than 6 hours.

Investigators randomly assigned patients to receive or not to receive ASA. Within each of these two treatment groups, patients were randomly assigned to receive no heparin, low-dose heparin, or moderate-dose heparin.

ASA was given in a loading dose of 300 mg. Patients who were given low-dose heparin received a loading dose of 5,000 IU followed by 500 IU/h for 6 hours. Patients who received moderate-dose heparin were given a loading dose of 5,000 IU followed by 1,250 IU/h for 6 hours.

The study’s primary outcome was Modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were NIHSS score at 24 hours, NIHSS score at 5 to 7 days, and recanalization grade at 24 hours on CT angiography or MRI. The primary safety outcomes were sICH and death within 90 days.

An independent, unblinded data and safety monitoring board (DSMB) assessed the risk for the primary safety outcomes throughout the trial. The board performed interim analyses of safety and efficacy for every 300 patients.

After the fourth safety assessment, the DSMB recommended that enrollment in the moderate-dose heparin arm be discontinued for safety reasons. Enrollment in other arms continued.

After the second interim analysis, the DSMB advised that the trial steering committee be unblinded to decide whether to stop or continue the trial. The steering committee decided to stop the trial for reasons of safety.
 

Increased risk for sICH

In all, 628 patients were included in the study. The ASA groups included 310 patients, and the no-ASA groups included 318 patients. In all, 332 participants received heparin, and 296 received no heparin.

The demographic characteristics were well balanced between groups. The population’s median age was 73 years, and about 53% were men. The median baseline NIHSS score was approximately 15. About 74% of patients received IV thrombolysis. The median baseline Alberta Stroke Program Early CT Scan score was 9.

The investigators observed a slight shift toward worse outcome in the ASA group, compared with the no-ASA group (adjusted OR, 0.91). In addition, the ASA group had a significantly increased risk for sICH, compared with the no-ASA group (14% vs. 7.2%; aOR, 1.95).

Patients in the ASA group were less likely to have good functional outcome (mRS of 0 to 2; aOR, 0.76), and the mortality rate tended to be higher.

The researchers found a nonsignificant shift toward a worse functional outcome in the heparin group, compared with the no-heparin group (aOR, 0.81). The risk for sICH was significantly higher in the heparin group, compared with the no-heparin group (13% vs. 7.4%; aOR, 2.00).

Patients in the heparin group were also less likely to have a good functional outcome (aOR, 0.78), and there was a nonsignificant increase in risk for death among those patients.

The rate of sICH was 11% in the group that received low-dose heparin; it was 26% in the group that received moderate-dose heparin (aOR, 6.05). The mortality rate was 23% in the low-dose group and 47% in the moderate-dose group (aOR, 5.45).

There was no significant interaction between ASA and heparin on the primary outcome and on sICH occurrence.
 

‘A unique trial’

“MR CLEAN-MED is a unique trial because it investigated a widely used treatment but until now without any proof of effectiveness,” said Dr. van der Steen. The researchers expect that their findings will have a strong impact on the management of patients with acute ischemic stroke. They suggest that the administration of antithrombotic agents during EVT be avoided.

“We consider it probable that the increased risk of sICH explains at least a part of the nonsignificant shift towards a worse functional outcome,” co-investigator Bob Roozenbeek, MD, PhD, a neurologist at the Erasmus Medical Center, said in an interview. “However, to make more definite statements, we will have to do more in-depth analyses.”

It remains unclear whether the periprocedural use of lower dosages of antithrombotic agents or of a single bolus of heparin could be safe and effective, said Dr. van der Steen.

To gain insight into these questions, the investigators will evaluate the effect of the medications and dosages examined in this trial on primary hemostasis and coagulation activity in the trial population. They also plan to examine the effect of primary hemostasis and coagulation activity on risk for sICH and functional outcome.

Enhancing the effectiveness of thrombectomy for acute ischemic stroke continues to be an important goal for stroke therapy, said Mark Fisher, MD, professor of neurology and pathology and laboratory medicine at the University of California, Irvine, who commented on the findings for this news organization.

At least three strategies are available: The use of ancillary antithrombotic medications, neuroprotection, and modulation of the vasoconstrictive properties of the microcirculation.

“Results of MR CLEAN-MED argue against the antithrombotic strategy,” said Dr. Fisher. “The alternate strategies remain viable, and results of interventions using those approaches are awaited with great interest.”

The study was funded by the CONTRAST consortium, which is supported by the Netherlands Cardiovascular Research Initiative and the Brain Foundation Netherlands. Funding also was provided by Stryker, Medtronic, and Cerenovus. Dr. van der Steen and Dr. Fisher have disclosed no relevant financial relationships.

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