Conference Coverage

Migraine can significantly influence a woman’s decision to have children, new research shows. Results from a multicenter study of more than 600 women showed that, among participants with migraine, those who were younger, had menstrual migraine, or had chronic migraine were more likely to decide to not become pregnant.

Although women with migraine who avoided pregnancy believed their migraines would worsen during pregnancy or make their pregnancy difficult, previous observational research indicates that migraine often improves during pregnancy.

“Women who avoided pregnancy due to migraine were most concerned that migraine would make raising a child difficult, that the migraine medications they take would have a negative impact on their child’s development, and that their migraine pattern would worsen during or just after pregnancy,” said study investigator Ryotaro Ishii, MD, PhD, a visiting scientist at Mayo Clinic in Phoenix, Arizona.

The findings were presented at the virtual annual meeting of the American Headache Society.
 

Plans for the future

There is a paucity of research on the effects of migraine on pregnancy planning, the researchers noted. The few studies that have investigated this issue have focused on women’s previous family planning decisions and experience rather than on plans for the future, the researchers noted.

To evaluate how migraine in women influences pregnancy planning, the investigators analyzed data from the American Registry for Migraine Research (ARMR). The registry, which was established by the American Migraine Foundation, collects clinical data about individuals with migraine and other headache disorders from multiple centers.

Participants eligible for the current analysis were women who had been diagnosed with migraine on the basis of the International Classification of Headache Disorders–3 criteria. All completed the ARMR questionnaire between February 2016 and September 2019. The investigators excluded patients with trigeminal autonomic cephalalgia, secondary headache, painful cranial neuropathies, other facial pain, and other headaches.

They identified 895 eligible women with migraine. Of these, 607 completed the pregnancy question. Among those participants, 121 women (19.9%) reported that migraine was a factor in their decision to not become pregnant. Of this group, 70 (11.5%) reported that migraine was a “significant” factor in deciding to not have children, and 8.4% said it was “somewhat” of a factor. The remainder of the cohort (479) reported that migraine had no influence on their pregnancy plans.

There were no between-group differences by race, marital status, employment, or income. This finding suggests that sociodemographic differences “have less impact on pregnancy planning than migraine-specific characteristics like headache frequency and experience with having migraine attacks triggered by menstruation,” Dr. Ishii said.
 

“Substantial burden”

Not surprisingly, women who avoided pregnancy had fewer children than the rest of the sample. About 60% of those who made the decision to not become pregnant had no children, and 72% had not been pregnant since they began experiencing migraine.

Compared with women who reported that migraine had no influence on their pregnancy plans, those who avoided pregnancy were more likely to have chronic migraine at 81.8% versus 70.2%. They were also more likely to have menstrual migraine at 4.1% versus 1%. In addition, women who decided to not have children because of migraine were significantly younger at an average age of 37.5 versus 47.2 years.

The number of days with headache per 3-month interval was 53.9 among women who avoided pregnancy versus 42.5 among the other women. The Migraine Disability Assessment score was also higher for women who avoided pregnancy (132.5) than for it was the other women (91.7), indicating more severe disability.

In addition, more of the women who avoided pregnancy had a history of depression (48.8%) compared with the other women (37.7%). The average score on the Patient Health Questionnaire–4 was higher among women who avoided pregnancy (4.0) than among other women (3.1), which indicates greater anxiety or depression. Among women who avoided pregnancy, 72.5% believed their migraine would worsen during pregnancy, and 68.3% believed that migraine would make pregnancy very difficult.

“Clinicians need to recognize that migraine often has a substantial burden on multiple aspects of life, including one’s plans for having children,” Dr. Ishii said.

“Clinicians should educate their patients who are considering pregnancy about the most likely course of migraine during pregnancy, migraine treatment during pregnancy, and the potential impacts of migraine and its treatment on pregnancy outcomes,” he added.
 

More education needed

Commenting on the study, Susan Hutchinson, MD, director of the Orange County Migraine and Headache Center, Irvine, California, said that not knowing how pregnancy is going to affect patients’ migraines can be “very scary” for women. In addition, patients often wonder what migraine treatments they can safely take once they do become pregnant, said Dr. Hutchinson, who was not involved in the research.

She noted that advantages of the ARMR data are that they are derived from a multicenter study and that migraine diagnoses were made by a headache specialist. A potential limitation of the study is that the population may not reflect outcomes of the millions of women who have migraine and become pregnant but never see a specialist.

“These findings show that more education is needed,” Dr. Hutchinson said.

Most women, especially those who have migraine without aura, note improvement with migraine during pregnancy, primarily because of the high, steady levels of estradiol, especially in the second and third trimesters, she said. In light of this, neurologists should reassure women that migraine is not a contraindication to pregnancy, she added.

There is also a need for additional research to assess how past experience with migraine and pregnancy influences a woman’s comfort level with additional pregnancies. Studies as to which treatments are safest for acute and preventive treatment of migraine during prepregnancy, pregnancy, and lactation are also needed, Dr. Hutchinson noted.

“If women knew they had treatment options that were evidence-based, they might be much more comfortable contemplating a pregnancy,” she said.

Dr. Ishii and Dr. Hutchinson have disclosed no relevant financial relationships.

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

Migraine can significantly influence a woman’s decision to have children, new research shows. Results from a multicenter study of more than 600 women showed that, among participants with migraine, those who were younger, had menstrual migraine, or had chronic migraine were more likely to decide to not become pregnant.

Although women with migraine who avoided pregnancy believed their migraines would worsen during pregnancy or make their pregnancy difficult, previous observational research indicates that migraine often improves during pregnancy.

“Women who avoided pregnancy due to migraine were most concerned that migraine would make raising a child difficult, that the migraine medications they take would have a negative impact on their child’s development, and that their migraine pattern would worsen during or just after pregnancy,” said study investigator Ryotaro Ishii, MD, PhD, a visiting scientist at Mayo Clinic in Phoenix, Arizona.

The findings were presented at the virtual annual meeting of the American Headache Society.
 

Plans for the future

There is a paucity of research on the effects of migraine on pregnancy planning, the researchers noted. The few studies that have investigated this issue have focused on women’s previous family planning decisions and experience rather than on plans for the future, the researchers noted.

To evaluate how migraine in women influences pregnancy planning, the investigators analyzed data from the American Registry for Migraine Research (ARMR). The registry, which was established by the American Migraine Foundation, collects clinical data about individuals with migraine and other headache disorders from multiple centers.

Participants eligible for the current analysis were women who had been diagnosed with migraine on the basis of the International Classification of Headache Disorders–3 criteria. All completed the ARMR questionnaire between February 2016 and September 2019. The investigators excluded patients with trigeminal autonomic cephalalgia, secondary headache, painful cranial neuropathies, other facial pain, and other headaches.

They identified 895 eligible women with migraine. Of these, 607 completed the pregnancy question. Among those participants, 121 women (19.9%) reported that migraine was a factor in their decision to not become pregnant. Of this group, 70 (11.5%) reported that migraine was a “significant” factor in deciding to not have children, and 8.4% said it was “somewhat” of a factor. The remainder of the cohort (479) reported that migraine had no influence on their pregnancy plans.

There were no between-group differences by race, marital status, employment, or income. This finding suggests that sociodemographic differences “have less impact on pregnancy planning than migraine-specific characteristics like headache frequency and experience with having migraine attacks triggered by menstruation,” Dr. Ishii said.
 

“Substantial burden”

Not surprisingly, women who avoided pregnancy had fewer children than the rest of the sample. About 60% of those who made the decision to not become pregnant had no children, and 72% had not been pregnant since they began experiencing migraine.

Compared with women who reported that migraine had no influence on their pregnancy plans, those who avoided pregnancy were more likely to have chronic migraine at 81.8% versus 70.2%. They were also more likely to have menstrual migraine at 4.1% versus 1%. In addition, women who decided to not have children because of migraine were significantly younger at an average age of 37.5 versus 47.2 years.

The number of days with headache per 3-month interval was 53.9 among women who avoided pregnancy versus 42.5 among the other women. The Migraine Disability Assessment score was also higher for women who avoided pregnancy (132.5) than for it was the other women (91.7), indicating more severe disability.

In addition, more of the women who avoided pregnancy had a history of depression (48.8%) compared with the other women (37.7%). The average score on the Patient Health Questionnaire–4 was higher among women who avoided pregnancy (4.0) than among other women (3.1), which indicates greater anxiety or depression. Among women who avoided pregnancy, 72.5% believed their migraine would worsen during pregnancy, and 68.3% believed that migraine would make pregnancy very difficult.

“Clinicians need to recognize that migraine often has a substantial burden on multiple aspects of life, including one’s plans for having children,” Dr. Ishii said.

“Clinicians should educate their patients who are considering pregnancy about the most likely course of migraine during pregnancy, migraine treatment during pregnancy, and the potential impacts of migraine and its treatment on pregnancy outcomes,” he added.
 

More education needed

Commenting on the study, Susan Hutchinson, MD, director of the Orange County Migraine and Headache Center, Irvine, California, said that not knowing how pregnancy is going to affect patients’ migraines can be “very scary” for women. In addition, patients often wonder what migraine treatments they can safely take once they do become pregnant, said Dr. Hutchinson, who was not involved in the research.

She noted that advantages of the ARMR data are that they are derived from a multicenter study and that migraine diagnoses were made by a headache specialist. A potential limitation of the study is that the population may not reflect outcomes of the millions of women who have migraine and become pregnant but never see a specialist.

“These findings show that more education is needed,” Dr. Hutchinson said.

Most women, especially those who have migraine without aura, note improvement with migraine during pregnancy, primarily because of the high, steady levels of estradiol, especially in the second and third trimesters, she said. In light of this, neurologists should reassure women that migraine is not a contraindication to pregnancy, she added.

There is also a need for additional research to assess how past experience with migraine and pregnancy influences a woman’s comfort level with additional pregnancies. Studies as to which treatments are safest for acute and preventive treatment of migraine during prepregnancy, pregnancy, and lactation are also needed, Dr. Hutchinson noted.

“If women knew they had treatment options that were evidence-based, they might be much more comfortable contemplating a pregnancy,” she said.

Dr. Ishii and Dr. Hutchinson have disclosed no relevant financial relationships.

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

Migraine can significantly influence a woman’s decision to have children, new research shows. Results from a multicenter study of more than 600 women showed that, among participants with migraine, those who were younger, had menstrual migraine, or had chronic migraine were more likely to decide to not become pregnant.

Although women with migraine who avoided pregnancy believed their migraines would worsen during pregnancy or make their pregnancy difficult, previous observational research indicates that migraine often improves during pregnancy.

“Women who avoided pregnancy due to migraine were most concerned that migraine would make raising a child difficult, that the migraine medications they take would have a negative impact on their child’s development, and that their migraine pattern would worsen during or just after pregnancy,” said study investigator Ryotaro Ishii, MD, PhD, a visiting scientist at Mayo Clinic in Phoenix, Arizona.

The findings were presented at the virtual annual meeting of the American Headache Society.
 

Plans for the future

There is a paucity of research on the effects of migraine on pregnancy planning, the researchers noted. The few studies that have investigated this issue have focused on women’s previous family planning decisions and experience rather than on plans for the future, the researchers noted.

To evaluate how migraine in women influences pregnancy planning, the investigators analyzed data from the American Registry for Migraine Research (ARMR). The registry, which was established by the American Migraine Foundation, collects clinical data about individuals with migraine and other headache disorders from multiple centers.

Participants eligible for the current analysis were women who had been diagnosed with migraine on the basis of the International Classification of Headache Disorders–3 criteria. All completed the ARMR questionnaire between February 2016 and September 2019. The investigators excluded patients with trigeminal autonomic cephalalgia, secondary headache, painful cranial neuropathies, other facial pain, and other headaches.

They identified 895 eligible women with migraine. Of these, 607 completed the pregnancy question. Among those participants, 121 women (19.9%) reported that migraine was a factor in their decision to not become pregnant. Of this group, 70 (11.5%) reported that migraine was a “significant” factor in deciding to not have children, and 8.4% said it was “somewhat” of a factor. The remainder of the cohort (479) reported that migraine had no influence on their pregnancy plans.

There were no between-group differences by race, marital status, employment, or income. This finding suggests that sociodemographic differences “have less impact on pregnancy planning than migraine-specific characteristics like headache frequency and experience with having migraine attacks triggered by menstruation,” Dr. Ishii said.
 

“Substantial burden”

Not surprisingly, women who avoided pregnancy had fewer children than the rest of the sample. About 60% of those who made the decision to not become pregnant had no children, and 72% had not been pregnant since they began experiencing migraine.

Compared with women who reported that migraine had no influence on their pregnancy plans, those who avoided pregnancy were more likely to have chronic migraine at 81.8% versus 70.2%. They were also more likely to have menstrual migraine at 4.1% versus 1%. In addition, women who decided to not have children because of migraine were significantly younger at an average age of 37.5 versus 47.2 years.

The number of days with headache per 3-month interval was 53.9 among women who avoided pregnancy versus 42.5 among the other women. The Migraine Disability Assessment score was also higher for women who avoided pregnancy (132.5) than for it was the other women (91.7), indicating more severe disability.

In addition, more of the women who avoided pregnancy had a history of depression (48.8%) compared with the other women (37.7%). The average score on the Patient Health Questionnaire–4 was higher among women who avoided pregnancy (4.0) than among other women (3.1), which indicates greater anxiety or depression. Among women who avoided pregnancy, 72.5% believed their migraine would worsen during pregnancy, and 68.3% believed that migraine would make pregnancy very difficult.

“Clinicians need to recognize that migraine often has a substantial burden on multiple aspects of life, including one’s plans for having children,” Dr. Ishii said.

“Clinicians should educate their patients who are considering pregnancy about the most likely course of migraine during pregnancy, migraine treatment during pregnancy, and the potential impacts of migraine and its treatment on pregnancy outcomes,” he added.
 

More education needed

Commenting on the study, Susan Hutchinson, MD, director of the Orange County Migraine and Headache Center, Irvine, California, said that not knowing how pregnancy is going to affect patients’ migraines can be “very scary” for women. In addition, patients often wonder what migraine treatments they can safely take once they do become pregnant, said Dr. Hutchinson, who was not involved in the research.

She noted that advantages of the ARMR data are that they are derived from a multicenter study and that migraine diagnoses were made by a headache specialist. A potential limitation of the study is that the population may not reflect outcomes of the millions of women who have migraine and become pregnant but never see a specialist.

“These findings show that more education is needed,” Dr. Hutchinson said.

Most women, especially those who have migraine without aura, note improvement with migraine during pregnancy, primarily because of the high, steady levels of estradiol, especially in the second and third trimesters, she said. In light of this, neurologists should reassure women that migraine is not a contraindication to pregnancy, she added.

There is also a need for additional research to assess how past experience with migraine and pregnancy influences a woman’s comfort level with additional pregnancies. Studies as to which treatments are safest for acute and preventive treatment of migraine during prepregnancy, pregnancy, and lactation are also needed, Dr. Hutchinson noted.

“If women knew they had treatment options that were evidence-based, they might be much more comfortable contemplating a pregnancy,” she said.

Dr. Ishii and Dr. Hutchinson have disclosed no relevant financial relationships.

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

A systematic two-stent approach to complex coronary bifurcation lesions led to significantly improved clinical outcomes at 1 year, compared with the long-popular provisional stenting technique, in the first randomized trial to prospectively validate a standardized definition of what constitutes a complex bifurcation.

Since the double-kissing (DK) crush technique was employed in 78% of the systematic two-stent procedures, and the two-stent approach provided superior outcomes, it’s reasonable to infer that the DK crush is the preferred technique in patients with truly complex coronary bifurcation lesions (CBLs), Shao-Liang Chen, MD, reported at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

He presented the results of the DEFINITION II trial, a multinational trial in which 653 patients at 49 medical centers who fulfilled the criteria for complex CBLs were randomized to a systematic two-stent approach or provisional stenting, with a second stent deployed by interventionalists as needed. Dr. Chen, director of the cardiology department and deputy president of Nanjing (China) Medical University, and coworkers had previously published their standardized criteria for CBLs (JACC Cardiovasc Interv. 2014 Nov;7[11]:1266-76), which they developed by analysis of a large bifurcation cohort; however, until the DEFINITION II trial, the criteria had never been used in a prospective randomized trial.

According to the standardized definition developed by Dr. Chen and associates, complex coronary bifurcation lesions must meet one major and two minor criteria.

Major criteria:

• A side branch lesion length of at least 10 mm with a diameter stenosis of 70% or more for distal left main bifurcation lesions.
• For non–left main bifurcation lesions, a side branch diameter stenosis of at least 90% along with a side branch lesion length of at least 10 mm.

Minor criteria:

• Moderate to severe calcification multiple lesions
• Bifurcation angle of <45 degrees or >70 degrees
• Thrombus-containing lesions
• Main vessel residual diameter <2.5 mm
• Main vessel lesion length of at least 25 mm

Interventionalists were strongly encouraged to utilize the DK crush or culotte stenting techniques in patients randomized to the systematic two-stent approach. In contrast, in the provisional stenting group, where 23% of patients received a second stent, that stent was placed using the T and small protrusion technique 64% of the time.

The primary endpoint was the target lesion failure rate at 1-year of follow-up. Target lesion failure was a composite comprising cardiac death, target vessel MI, and clinically driven target vessel revascularization. The rate was 6.1% in the systematic two-stent group and 11.4% with provisional stenting, for a highly significant 48% relative risk reduction. The difference was driven largely by the systematic two-stent group’s lower rates of target vessel MI – 3.0% versus 7.1% with provisional stenting – and target lesion revascularization, with rates of 2.4% and 5.5%, respectively.

“The underlying mechanisms for the increased target vessel MI rate after the provisional stenting technique are unclear, and further study is urgently warranted,” Dr. Chen said.

There were no significant between-group differences in all-cause mortality or cardiac death, although both endpoints were numerically less frequent in the two-stent group.

The primary safety outcome was the 12-month rate of definite or probable stent thrombosis. This occurred in 1.2% of the systematic two-stent group and 2.5% of the provisional stent patients, a nonsignificant difference.

Bruce Jancin/MDedge News

Discussant Davide Capodanno, MD, PhD, declared the DEFINITE II trial to be “another success for this DK crush technique everyone is talking about recently.”

He noted that, in a recent meta-analysis of 21 randomized, controlled trials including 5,711 patients with bifurcation lesions treated using five different percutaneous coronary intervention techniques, DK crush stood out from the pack. Particularly impressive was the finding that the target lesion revascularization rate in patients treated using the DK crush technique was 64% lower than with provisional stenting (JACC Cardiovasc Interv. 2020 Jun 22;13[12]:1432-44).

Dr. Capodanno said that, although the DEFINITE II results were strongly positive in favor of the systematic two-stent approach and DK crush technique, he’s not convinced of the generalizability of the study results.

“These investigators are very expert in this technique. They invented it. They’ve been using it for 10 years. So of course you may expect excellent results when you have masters of this technique,” observed Dr. Capodanno, a cardiologist at the University of Catania (Italy).

Independent replication of the DEFINITE II findings is needed. Fortunately, two ongoing randomized trials are addressing the issue of how to best treat bifurcation lesions. The EBC-MAIN trial is comparing the provisional approach with the systematic two-stent strategy in patients with left main bifurcation lesions; the study will include the DK crush as well as culotte and TAP PCI techniques, with a primary endpoint consisting of the 12-month rate of death, MI, and target lesion revascularization. And the BBK-3 trial will compare systematic two-stent strategies pitting the culotte against the DK crush, with the primary endpoint being the 9-month rate of angiographic restenosis by quantitative coronary angiography.

“After these trials are complete, we’ll probably know much more about the tailoring of bifurcation techniques for particular patients,” according to Dr. Capodanno.

Simultaneous with Dr. Chen’s presentation, the results of the DEFINITION II trial were published online (Eur Heart J. 2020 Jun 26.doi: 10.1093/eurheartj/ehaa543).

Dr. Chen and Dr. Capodanno reported having no financial conflicts of interest regarding the study, which was funded mainly by the National Science Foundation of China.

bjancin@mdedge.com

A systematic two-stent approach to complex coronary bifurcation lesions led to significantly improved clinical outcomes at 1 year, compared with the long-popular provisional stenting technique, in the first randomized trial to prospectively validate a standardized definition of what constitutes a complex bifurcation.

Since the double-kissing (DK) crush technique was employed in 78% of the systematic two-stent procedures, and the two-stent approach provided superior outcomes, it’s reasonable to infer that the DK crush is the preferred technique in patients with truly complex coronary bifurcation lesions (CBLs), Shao-Liang Chen, MD, reported at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

He presented the results of the DEFINITION II trial, a multinational trial in which 653 patients at 49 medical centers who fulfilled the criteria for complex CBLs were randomized to a systematic two-stent approach or provisional stenting, with a second stent deployed by interventionalists as needed. Dr. Chen, director of the cardiology department and deputy president of Nanjing (China) Medical University, and coworkers had previously published their standardized criteria for CBLs (JACC Cardiovasc Interv. 2014 Nov;7[11]:1266-76), which they developed by analysis of a large bifurcation cohort; however, until the DEFINITION II trial, the criteria had never been used in a prospective randomized trial.

According to the standardized definition developed by Dr. Chen and associates, complex coronary bifurcation lesions must meet one major and two minor criteria.

Major criteria:

• A side branch lesion length of at least 10 mm with a diameter stenosis of 70% or more for distal left main bifurcation lesions.
• For non–left main bifurcation lesions, a side branch diameter stenosis of at least 90% along with a side branch lesion length of at least 10 mm.

Minor criteria:

• Moderate to severe calcification multiple lesions
• Bifurcation angle of <45 degrees or >70 degrees
• Thrombus-containing lesions
• Main vessel residual diameter <2.5 mm
• Main vessel lesion length of at least 25 mm

Interventionalists were strongly encouraged to utilize the DK crush or culotte stenting techniques in patients randomized to the systematic two-stent approach. In contrast, in the provisional stenting group, where 23% of patients received a second stent, that stent was placed using the T and small protrusion technique 64% of the time.

The primary endpoint was the target lesion failure rate at 1-year of follow-up. Target lesion failure was a composite comprising cardiac death, target vessel MI, and clinically driven target vessel revascularization. The rate was 6.1% in the systematic two-stent group and 11.4% with provisional stenting, for a highly significant 48% relative risk reduction. The difference was driven largely by the systematic two-stent group’s lower rates of target vessel MI – 3.0% versus 7.1% with provisional stenting – and target lesion revascularization, with rates of 2.4% and 5.5%, respectively.

“The underlying mechanisms for the increased target vessel MI rate after the provisional stenting technique are unclear, and further study is urgently warranted,” Dr. Chen said.

There were no significant between-group differences in all-cause mortality or cardiac death, although both endpoints were numerically less frequent in the two-stent group.

The primary safety outcome was the 12-month rate of definite or probable stent thrombosis. This occurred in 1.2% of the systematic two-stent group and 2.5% of the provisional stent patients, a nonsignificant difference.

Bruce Jancin/MDedge News

Discussant Davide Capodanno, MD, PhD, declared the DEFINITE II trial to be “another success for this DK crush technique everyone is talking about recently.”

He noted that, in a recent meta-analysis of 21 randomized, controlled trials including 5,711 patients with bifurcation lesions treated using five different percutaneous coronary intervention techniques, DK crush stood out from the pack. Particularly impressive was the finding that the target lesion revascularization rate in patients treated using the DK crush technique was 64% lower than with provisional stenting (JACC Cardiovasc Interv. 2020 Jun 22;13[12]:1432-44).

Dr. Capodanno said that, although the DEFINITE II results were strongly positive in favor of the systematic two-stent approach and DK crush technique, he’s not convinced of the generalizability of the study results.

“These investigators are very expert in this technique. They invented it. They’ve been using it for 10 years. So of course you may expect excellent results when you have masters of this technique,” observed Dr. Capodanno, a cardiologist at the University of Catania (Italy).

Independent replication of the DEFINITE II findings is needed. Fortunately, two ongoing randomized trials are addressing the issue of how to best treat bifurcation lesions. The EBC-MAIN trial is comparing the provisional approach with the systematic two-stent strategy in patients with left main bifurcation lesions; the study will include the DK crush as well as culotte and TAP PCI techniques, with a primary endpoint consisting of the 12-month rate of death, MI, and target lesion revascularization. And the BBK-3 trial will compare systematic two-stent strategies pitting the culotte against the DK crush, with the primary endpoint being the 9-month rate of angiographic restenosis by quantitative coronary angiography.

“After these trials are complete, we’ll probably know much more about the tailoring of bifurcation techniques for particular patients,” according to Dr. Capodanno.

Simultaneous with Dr. Chen’s presentation, the results of the DEFINITION II trial were published online (Eur Heart J. 2020 Jun 26.doi: 10.1093/eurheartj/ehaa543).

Dr. Chen and Dr. Capodanno reported having no financial conflicts of interest regarding the study, which was funded mainly by the National Science Foundation of China.

bjancin@mdedge.com

A systematic two-stent approach to complex coronary bifurcation lesions led to significantly improved clinical outcomes at 1 year, compared with the long-popular provisional stenting technique, in the first randomized trial to prospectively validate a standardized definition of what constitutes a complex bifurcation.

Since the double-kissing (DK) crush technique was employed in 78% of the systematic two-stent procedures, and the two-stent approach provided superior outcomes, it’s reasonable to infer that the DK crush is the preferred technique in patients with truly complex coronary bifurcation lesions (CBLs), Shao-Liang Chen, MD, reported at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

He presented the results of the DEFINITION II trial, a multinational trial in which 653 patients at 49 medical centers who fulfilled the criteria for complex CBLs were randomized to a systematic two-stent approach or provisional stenting, with a second stent deployed by interventionalists as needed. Dr. Chen, director of the cardiology department and deputy president of Nanjing (China) Medical University, and coworkers had previously published their standardized criteria for CBLs (JACC Cardiovasc Interv. 2014 Nov;7[11]:1266-76), which they developed by analysis of a large bifurcation cohort; however, until the DEFINITION II trial, the criteria had never been used in a prospective randomized trial.

According to the standardized definition developed by Dr. Chen and associates, complex coronary bifurcation lesions must meet one major and two minor criteria.

Major criteria:

• A side branch lesion length of at least 10 mm with a diameter stenosis of 70% or more for distal left main bifurcation lesions.
• For non–left main bifurcation lesions, a side branch diameter stenosis of at least 90% along with a side branch lesion length of at least 10 mm.

Minor criteria:

• Moderate to severe calcification multiple lesions
• Bifurcation angle of <45 degrees or >70 degrees
• Thrombus-containing lesions
• Main vessel residual diameter <2.5 mm
• Main vessel lesion length of at least 25 mm

Interventionalists were strongly encouraged to utilize the DK crush or culotte stenting techniques in patients randomized to the systematic two-stent approach. In contrast, in the provisional stenting group, where 23% of patients received a second stent, that stent was placed using the T and small protrusion technique 64% of the time.

The primary endpoint was the target lesion failure rate at 1-year of follow-up. Target lesion failure was a composite comprising cardiac death, target vessel MI, and clinically driven target vessel revascularization. The rate was 6.1% in the systematic two-stent group and 11.4% with provisional stenting, for a highly significant 48% relative risk reduction. The difference was driven largely by the systematic two-stent group’s lower rates of target vessel MI – 3.0% versus 7.1% with provisional stenting – and target lesion revascularization, with rates of 2.4% and 5.5%, respectively.

“The underlying mechanisms for the increased target vessel MI rate after the provisional stenting technique are unclear, and further study is urgently warranted,” Dr. Chen said.

There were no significant between-group differences in all-cause mortality or cardiac death, although both endpoints were numerically less frequent in the two-stent group.

The primary safety outcome was the 12-month rate of definite or probable stent thrombosis. This occurred in 1.2% of the systematic two-stent group and 2.5% of the provisional stent patients, a nonsignificant difference.

Bruce Jancin/MDedge News

Discussant Davide Capodanno, MD, PhD, declared the DEFINITE II trial to be “another success for this DK crush technique everyone is talking about recently.”

He noted that, in a recent meta-analysis of 21 randomized, controlled trials including 5,711 patients with bifurcation lesions treated using five different percutaneous coronary intervention techniques, DK crush stood out from the pack. Particularly impressive was the finding that the target lesion revascularization rate in patients treated using the DK crush technique was 64% lower than with provisional stenting (JACC Cardiovasc Interv. 2020 Jun 22;13[12]:1432-44).

Dr. Capodanno said that, although the DEFINITE II results were strongly positive in favor of the systematic two-stent approach and DK crush technique, he’s not convinced of the generalizability of the study results.

“These investigators are very expert in this technique. They invented it. They’ve been using it for 10 years. So of course you may expect excellent results when you have masters of this technique,” observed Dr. Capodanno, a cardiologist at the University of Catania (Italy).

Independent replication of the DEFINITE II findings is needed. Fortunately, two ongoing randomized trials are addressing the issue of how to best treat bifurcation lesions. The EBC-MAIN trial is comparing the provisional approach with the systematic two-stent strategy in patients with left main bifurcation lesions; the study will include the DK crush as well as culotte and TAP PCI techniques, with a primary endpoint consisting of the 12-month rate of death, MI, and target lesion revascularization. And the BBK-3 trial will compare systematic two-stent strategies pitting the culotte against the DK crush, with the primary endpoint being the 9-month rate of angiographic restenosis by quantitative coronary angiography.

“After these trials are complete, we’ll probably know much more about the tailoring of bifurcation techniques for particular patients,” according to Dr. Capodanno.

Simultaneous with Dr. Chen’s presentation, the results of the DEFINITION II trial were published online (Eur Heart J. 2020 Jun 26.doi: 10.1093/eurheartj/ehaa543).

Dr. Chen and Dr. Capodanno reported having no financial conflicts of interest regarding the study, which was funded mainly by the National Science Foundation of China.

bjancin@mdedge.com

Phase 3 trial findings compared outcomes for COPD patients who had triple fixed-dose inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting beta₂ agonist with patients who received one of two dual-therapy combinations. The results were presented at the American Thoracic Society’s virtual clinical trial session.

A total of 8,509 patients were randomized on a 1:1:1:1 basis to receive twice daily:

• Single-inhaler combinations of the inhaled corticosteroid (ICS) budesonide at one of two doses, the long-acting muscarinic antagonist (LAMA) glycopyrrolate, and the long-acting beta2 agonist (LABA) formoterol.
• Dual-therapy combination glycopyrrolate and formoterol.
• Dual-therapy combination budesonide and formoterol.

The annual rate of moderate or severe COPD exacerbations was 1.08 and 1.07 for the triple combinations with 320 mcg and 180 mcg doses of budesonide, respectively, compared with 1.42 for glycopyrrolate-formoterol, and 1.24 for budesonide-formoterol.

Both triple combinations were significantly superior to the dual therapies for controlling exacerbations, reported Klaus F. Rabe, MD, PhD, from LungenClinic Grosshansdorf and Christian-Albrechts University Kiel (Germany), and colleagues in the ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial (NCT02465567).

“Our findings show the benefits of triple therapy with a budesonide-glycopyrrolate-formoterol combination over dual therapy with a LAMA-LABA or an inhaled glucocorticoid-LABA combination with respect to the annual rate of moderate or severe COPD exacerbations, symptoms, and health-related quality of life in patients with moderate to very-severe COPD who are at risk of exacerbations,” they wrote in a study published online in the New England Journal of Medicine..

The trial showed for the first time that “triple therapy that has half the dose of steroid compared to a standard ICS/LABA combination has had greater efficacy for the exacerbation endpoint,” Dr. Rabe said during his presentation.

Triple-therapy combinations with an ICS, LAMA, and LABA are recommended for patients with COPD who remain symptomatic or experience further exacerbations on dual–ICS/LABA or –LAMA/LABA combinations. The triple combinations have been shown in several studies to lower risk of exacerbations and are associated with both better lung function and health-related quality of life, compared with dual therapies, the investigators noted.

However, concerns about adverse events associated with long-term ICS use – including pneumonia, cataracts, and increased fracture risk, possibly related to treatment duration, dose level, or type of corticosteroid used – spurred the ETHOS investigators to compare triple and dual fixed-dose combinations for efficacy and safety over 1 year.
 

Large study

They enrolled 8,509 adults aged 40-80 years with symptomatic COPD (defined as score of 10 or higher on the 40-point COPD Assessment Test). All patients were receiving at least two inhaled maintenance therapies at the time of screening, and had a postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity of less than 0.7, with a postbronchodilator FEV₁ of 25%-65% of the predicted normal value. The patients all had a smoking history of at least 10 pack-years and a documented history of at least one moderate or severe COPD exacerbation in the year before screening.

The patients were randomized in equal proportions to receive triple therapy with budesonide at 320- or 160-mcg doses plus glycopyrrolate 18 mcg, and formoterol 9.6 mcg twice daily, or to dual therapy with either glycopyrrolate plus formoterol at the same doses, or 320 mcg budesonide plus 9.6 mcg formoterol.

As noted, for the primary endpoint of the estimated annual rate of moderate or severe exacerbations, the triple combinations were associated with significantly lower rates, with a 24% lower rate (rate ratio, 0.76) with 320 mcg budesonide triple therapy, compared with glycopyrrolate-formoterol, and a 13% lower rate (RR, 0.87), compared with budesonide formoterol (P < .001 and P = .003, respectively).

The triple combination with the 160-mcg budesonide dose was associated with a 25% lower annual rate of exacerbations (RR, 0.75) vs. glycopyrrolate-formoterol, and a 14% lower rate (RR, 0.86) vs. budesonide-formoterol (P < .001 and P = .002, respectively).

Secondary efficacy endpoints also favored the triple combination, including a 20% lower rate ratio of severe exacerbations over 52 weeks for the 320-mcg budesonide group, compared with the budesonide-formoterol group (P = .02).

The 320-mcg dose combination was also associated with a 46% lower risk for all-cause mortality, compared with glycopyrrolate-formoterol (hazard ratio, 0.54; P = .0111).

Confirmed pneumonia was seen in 4.2% of patients on the 320-mcg budesonide dose, 3.5% of those in the 160-mcg group, and 4.5% of patients treated with budesonide-formoterol. The incidence of any adverse effect was similar across the treatment groups, ranging from 61.7% to 64.5%.
 

Balance exacerbation, pneumonia risk

In the question-and-answer session following his online presentation, Dr. Rabe was asked how the investigators reconciled their data showing increased incidence of pneumonia in budenoside-containing formulations with claims by the maker of the budesonide-formoterol (Symbicort, AstraZeneca) that budesonide is not associated with increased risk of pneumonia.

“We have to say that there are individuals that we have to balance the benefit of [less] exacerbation against the risk of pneumonia,” he replied, but noted that the size of the effect, observed both in ETHOS and in the KRONOS trial, was relatively small.

“This definitely adds some information for us to think about when we’re trying to do risk-benefit analysis,” commented MeiLan K. Han, MD, MS, from the University of Michigan, who moderated the session but was not involved in the study.

The ETHOS trial was funded by AstraZeneca. Dr. Rabe disclosed consulting/advisory board activity with that company and others. Dr. Han has previously disclosed consulting/advising and research funding relationships with other companies.

SOURCE: Rabe KF et al. N Engl J Med. 2020 Jun 24. doi: 10.1056/NEJMoa1916046.

Phase 3 trial findings compared outcomes for COPD patients who had triple fixed-dose inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting beta₂ agonist with patients who received one of two dual-therapy combinations. The results were presented at the American Thoracic Society’s virtual clinical trial session.

A total of 8,509 patients were randomized on a 1:1:1:1 basis to receive twice daily:

• Single-inhaler combinations of the inhaled corticosteroid (ICS) budesonide at one of two doses, the long-acting muscarinic antagonist (LAMA) glycopyrrolate, and the long-acting beta2 agonist (LABA) formoterol.
• Dual-therapy combination glycopyrrolate and formoterol.
• Dual-therapy combination budesonide and formoterol.

The annual rate of moderate or severe COPD exacerbations was 1.08 and 1.07 for the triple combinations with 320 mcg and 180 mcg doses of budesonide, respectively, compared with 1.42 for glycopyrrolate-formoterol, and 1.24 for budesonide-formoterol.

Both triple combinations were significantly superior to the dual therapies for controlling exacerbations, reported Klaus F. Rabe, MD, PhD, from LungenClinic Grosshansdorf and Christian-Albrechts University Kiel (Germany), and colleagues in the ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial (NCT02465567).

“Our findings show the benefits of triple therapy with a budesonide-glycopyrrolate-formoterol combination over dual therapy with a LAMA-LABA or an inhaled glucocorticoid-LABA combination with respect to the annual rate of moderate or severe COPD exacerbations, symptoms, and health-related quality of life in patients with moderate to very-severe COPD who are at risk of exacerbations,” they wrote in a study published online in the New England Journal of Medicine..

The trial showed for the first time that “triple therapy that has half the dose of steroid compared to a standard ICS/LABA combination has had greater efficacy for the exacerbation endpoint,” Dr. Rabe said during his presentation.

Triple-therapy combinations with an ICS, LAMA, and LABA are recommended for patients with COPD who remain symptomatic or experience further exacerbations on dual–ICS/LABA or –LAMA/LABA combinations. The triple combinations have been shown in several studies to lower risk of exacerbations and are associated with both better lung function and health-related quality of life, compared with dual therapies, the investigators noted.

However, concerns about adverse events associated with long-term ICS use – including pneumonia, cataracts, and increased fracture risk, possibly related to treatment duration, dose level, or type of corticosteroid used – spurred the ETHOS investigators to compare triple and dual fixed-dose combinations for efficacy and safety over 1 year.
 

Large study

They enrolled 8,509 adults aged 40-80 years with symptomatic COPD (defined as score of 10 or higher on the 40-point COPD Assessment Test). All patients were receiving at least two inhaled maintenance therapies at the time of screening, and had a postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity of less than 0.7, with a postbronchodilator FEV₁ of 25%-65% of the predicted normal value. The patients all had a smoking history of at least 10 pack-years and a documented history of at least one moderate or severe COPD exacerbation in the year before screening.

The patients were randomized in equal proportions to receive triple therapy with budesonide at 320- or 160-mcg doses plus glycopyrrolate 18 mcg, and formoterol 9.6 mcg twice daily, or to dual therapy with either glycopyrrolate plus formoterol at the same doses, or 320 mcg budesonide plus 9.6 mcg formoterol.

As noted, for the primary endpoint of the estimated annual rate of moderate or severe exacerbations, the triple combinations were associated with significantly lower rates, with a 24% lower rate (rate ratio, 0.76) with 320 mcg budesonide triple therapy, compared with glycopyrrolate-formoterol, and a 13% lower rate (RR, 0.87), compared with budesonide formoterol (P < .001 and P = .003, respectively).

The triple combination with the 160-mcg budesonide dose was associated with a 25% lower annual rate of exacerbations (RR, 0.75) vs. glycopyrrolate-formoterol, and a 14% lower rate (RR, 0.86) vs. budesonide-formoterol (P < .001 and P = .002, respectively).

Secondary efficacy endpoints also favored the triple combination, including a 20% lower rate ratio of severe exacerbations over 52 weeks for the 320-mcg budesonide group, compared with the budesonide-formoterol group (P = .02).

The 320-mcg dose combination was also associated with a 46% lower risk for all-cause mortality, compared with glycopyrrolate-formoterol (hazard ratio, 0.54; P = .0111).

Confirmed pneumonia was seen in 4.2% of patients on the 320-mcg budesonide dose, 3.5% of those in the 160-mcg group, and 4.5% of patients treated with budesonide-formoterol. The incidence of any adverse effect was similar across the treatment groups, ranging from 61.7% to 64.5%.
 

Balance exacerbation, pneumonia risk

In the question-and-answer session following his online presentation, Dr. Rabe was asked how the investigators reconciled their data showing increased incidence of pneumonia in budenoside-containing formulations with claims by the maker of the budesonide-formoterol (Symbicort, AstraZeneca) that budesonide is not associated with increased risk of pneumonia.

“We have to say that there are individuals that we have to balance the benefit of [less] exacerbation against the risk of pneumonia,” he replied, but noted that the size of the effect, observed both in ETHOS and in the KRONOS trial, was relatively small.

“This definitely adds some information for us to think about when we’re trying to do risk-benefit analysis,” commented MeiLan K. Han, MD, MS, from the University of Michigan, who moderated the session but was not involved in the study.

The ETHOS trial was funded by AstraZeneca. Dr. Rabe disclosed consulting/advisory board activity with that company and others. Dr. Han has previously disclosed consulting/advising and research funding relationships with other companies.

SOURCE: Rabe KF et al. N Engl J Med. 2020 Jun 24. doi: 10.1056/NEJMoa1916046.

Phase 3 trial findings compared outcomes for COPD patients who had triple fixed-dose inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting beta₂ agonist with patients who received one of two dual-therapy combinations. The results were presented at the American Thoracic Society’s virtual clinical trial session.

A total of 8,509 patients were randomized on a 1:1:1:1 basis to receive twice daily:

• Single-inhaler combinations of the inhaled corticosteroid (ICS) budesonide at one of two doses, the long-acting muscarinic antagonist (LAMA) glycopyrrolate, and the long-acting beta2 agonist (LABA) formoterol.
• Dual-therapy combination glycopyrrolate and formoterol.
• Dual-therapy combination budesonide and formoterol.

The annual rate of moderate or severe COPD exacerbations was 1.08 and 1.07 for the triple combinations with 320 mcg and 180 mcg doses of budesonide, respectively, compared with 1.42 for glycopyrrolate-formoterol, and 1.24 for budesonide-formoterol.

Both triple combinations were significantly superior to the dual therapies for controlling exacerbations, reported Klaus F. Rabe, MD, PhD, from LungenClinic Grosshansdorf and Christian-Albrechts University Kiel (Germany), and colleagues in the ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial (NCT02465567).

“Our findings show the benefits of triple therapy with a budesonide-glycopyrrolate-formoterol combination over dual therapy with a LAMA-LABA or an inhaled glucocorticoid-LABA combination with respect to the annual rate of moderate or severe COPD exacerbations, symptoms, and health-related quality of life in patients with moderate to very-severe COPD who are at risk of exacerbations,” they wrote in a study published online in the New England Journal of Medicine..

The trial showed for the first time that “triple therapy that has half the dose of steroid compared to a standard ICS/LABA combination has had greater efficacy for the exacerbation endpoint,” Dr. Rabe said during his presentation.

Triple-therapy combinations with an ICS, LAMA, and LABA are recommended for patients with COPD who remain symptomatic or experience further exacerbations on dual–ICS/LABA or –LAMA/LABA combinations. The triple combinations have been shown in several studies to lower risk of exacerbations and are associated with both better lung function and health-related quality of life, compared with dual therapies, the investigators noted.

However, concerns about adverse events associated with long-term ICS use – including pneumonia, cataracts, and increased fracture risk, possibly related to treatment duration, dose level, or type of corticosteroid used – spurred the ETHOS investigators to compare triple and dual fixed-dose combinations for efficacy and safety over 1 year.
 

Large study

They enrolled 8,509 adults aged 40-80 years with symptomatic COPD (defined as score of 10 or higher on the 40-point COPD Assessment Test). All patients were receiving at least two inhaled maintenance therapies at the time of screening, and had a postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity of less than 0.7, with a postbronchodilator FEV₁ of 25%-65% of the predicted normal value. The patients all had a smoking history of at least 10 pack-years and a documented history of at least one moderate or severe COPD exacerbation in the year before screening.

The patients were randomized in equal proportions to receive triple therapy with budesonide at 320- or 160-mcg doses plus glycopyrrolate 18 mcg, and formoterol 9.6 mcg twice daily, or to dual therapy with either glycopyrrolate plus formoterol at the same doses, or 320 mcg budesonide plus 9.6 mcg formoterol.

As noted, for the primary endpoint of the estimated annual rate of moderate or severe exacerbations, the triple combinations were associated with significantly lower rates, with a 24% lower rate (rate ratio, 0.76) with 320 mcg budesonide triple therapy, compared with glycopyrrolate-formoterol, and a 13% lower rate (RR, 0.87), compared with budesonide formoterol (P < .001 and P = .003, respectively).

The triple combination with the 160-mcg budesonide dose was associated with a 25% lower annual rate of exacerbations (RR, 0.75) vs. glycopyrrolate-formoterol, and a 14% lower rate (RR, 0.86) vs. budesonide-formoterol (P < .001 and P = .002, respectively).

Secondary efficacy endpoints also favored the triple combination, including a 20% lower rate ratio of severe exacerbations over 52 weeks for the 320-mcg budesonide group, compared with the budesonide-formoterol group (P = .02).

The 320-mcg dose combination was also associated with a 46% lower risk for all-cause mortality, compared with glycopyrrolate-formoterol (hazard ratio, 0.54; P = .0111).

Confirmed pneumonia was seen in 4.2% of patients on the 320-mcg budesonide dose, 3.5% of those in the 160-mcg group, and 4.5% of patients treated with budesonide-formoterol. The incidence of any adverse effect was similar across the treatment groups, ranging from 61.7% to 64.5%.
 

Balance exacerbation, pneumonia risk

In the question-and-answer session following his online presentation, Dr. Rabe was asked how the investigators reconciled their data showing increased incidence of pneumonia in budenoside-containing formulations with claims by the maker of the budesonide-formoterol (Symbicort, AstraZeneca) that budesonide is not associated with increased risk of pneumonia.

“We have to say that there are individuals that we have to balance the benefit of [less] exacerbation against the risk of pneumonia,” he replied, but noted that the size of the effect, observed both in ETHOS and in the KRONOS trial, was relatively small.

“This definitely adds some information for us to think about when we’re trying to do risk-benefit analysis,” commented MeiLan K. Han, MD, MS, from the University of Michigan, who moderated the session but was not involved in the study.

The ETHOS trial was funded by AstraZeneca. Dr. Rabe disclosed consulting/advisory board activity with that company and others. Dr. Han has previously disclosed consulting/advising and research funding relationships with other companies.

SOURCE: Rabe KF et al. N Engl J Med. 2020 Jun 24. doi: 10.1056/NEJMoa1916046.

Immunotherapy after resection of the primary tumor improved survival in some patients with stage III melanoma in an analysis presented at the AACR virtual meeting II.

Among patients with stage IIIC disease, the 2-year survival rate was 70% in those who received immunotherapy and 59% in those who did not (P < .01). The median overall survival in this group was 32.8 months with immunotherapy and 28 months without it (P < .01).

Among patients with stage IIIA disease, the 2-year survival rate was 94% with immunotherapy and 91% without it (P = .03).

There was a trend toward a 2-year survival benefit with immunotherapy in patients with stage IIIB disease and in all 4,094 stage III patients, but the differences were not significant. The 2-year survival rate was 84% with immunotherapy and 81% without it among patients with stage IIIB disease (P = .35). The survival rates were 83% and 80%, respectively, in all stage III patients (P = .051).

This was an early analysis, noted investigator Justin Moyers, MD, of Loma Linda (Calif.) University. Ipilimumab was approved as adjuvant therapy for stage III melanoma patients in 2015, the year patients from this analysis were diagnosed.

“There’s really only 2 full years of survival data,” Dr. Moyers said. “I think given time, we will see a benefit amongst all the substages.”

In the meantime, “I would definitely not use this data to say whether or not [immunotherapy] should be given,” Dr. Moyers said.

The researchers were just using the database – which captures 52% of U.S. melanoma cases – to see if “real-world data mimics the clinical trial data,” Dr. Moyers said.

Overall, the findings support “adjuvant immunotherapy in the real-world setting,” he said.

The researchers also looked at treatment patterns in 2015-2016 across 8,160 patients with stage III melanoma, 4,094 of whom were included in the aforementioned survival analysis. There were 2,260 patients (27.7%) who received immunotherapy after surgery during that time period.

Uptake of adjuvant immunotherapy “was low to start, but those patients did better than ones who did not get” it, said AACR president Antoni Ribas, MD, PhD, of the University of California, Los Angeles, who was not involved in the study.

Immunotherapy recipients were younger, on average (54.8 years vs. 62.4 years). Patients with Charlson comorbidity scores above zero and those on Medicare were less likely to receive immunotherapy (18.4% Medicare vs. over 30% with other payers). There also were trends of decreased use with lower income and lower high school graduation rates.

The finding “highlights the negative impact of socioeconomic [factors] on access to proven therapy,” Dr. Ribas said.

As for low use among Medicare patients, uptake of new treatments, in general, “seems to be faster with private insurance,” he noted.

The study excluded patients who received systemic therapies other than immunotherapy, as well as those who received immunotherapy before surgery. Among study limitations, the specific immunotherapies patients received was unknown.

There was no external funding for this study. Dr. Moyers reported travel compensation from Astellas Pharmaceuticals in 2018. Dr. Ribas disclosed relationships with Amgen, Chugai, Merck, Sanofi, Tango, Arcus, Bioncotech, Compugen, CytomX, FLX Bio, ImaginAb, Isoplexis, Merus, Rgenix, and PACT.

aotto@mdedge.com

SOURCE: Moyers J et al. AACR 2020, Abstract 4338.

Immunotherapy after resection of the primary tumor improved survival in some patients with stage III melanoma in an analysis presented at the AACR virtual meeting II.

Among patients with stage IIIC disease, the 2-year survival rate was 70% in those who received immunotherapy and 59% in those who did not (P < .01). The median overall survival in this group was 32.8 months with immunotherapy and 28 months without it (P < .01).

Among patients with stage IIIA disease, the 2-year survival rate was 94% with immunotherapy and 91% without it (P = .03).

There was a trend toward a 2-year survival benefit with immunotherapy in patients with stage IIIB disease and in all 4,094 stage III patients, but the differences were not significant. The 2-year survival rate was 84% with immunotherapy and 81% without it among patients with stage IIIB disease (P = .35). The survival rates were 83% and 80%, respectively, in all stage III patients (P = .051).

This was an early analysis, noted investigator Justin Moyers, MD, of Loma Linda (Calif.) University. Ipilimumab was approved as adjuvant therapy for stage III melanoma patients in 2015, the year patients from this analysis were diagnosed.

“There’s really only 2 full years of survival data,” Dr. Moyers said. “I think given time, we will see a benefit amongst all the substages.”

In the meantime, “I would definitely not use this data to say whether or not [immunotherapy] should be given,” Dr. Moyers said.

The researchers were just using the database – which captures 52% of U.S. melanoma cases – to see if “real-world data mimics the clinical trial data,” Dr. Moyers said.

Overall, the findings support “adjuvant immunotherapy in the real-world setting,” he said.

The researchers also looked at treatment patterns in 2015-2016 across 8,160 patients with stage III melanoma, 4,094 of whom were included in the aforementioned survival analysis. There were 2,260 patients (27.7%) who received immunotherapy after surgery during that time period.

Uptake of adjuvant immunotherapy “was low to start, but those patients did better than ones who did not get” it, said AACR president Antoni Ribas, MD, PhD, of the University of California, Los Angeles, who was not involved in the study.

Immunotherapy recipients were younger, on average (54.8 years vs. 62.4 years). Patients with Charlson comorbidity scores above zero and those on Medicare were less likely to receive immunotherapy (18.4% Medicare vs. over 30% with other payers). There also were trends of decreased use with lower income and lower high school graduation rates.

The finding “highlights the negative impact of socioeconomic [factors] on access to proven therapy,” Dr. Ribas said.

As for low use among Medicare patients, uptake of new treatments, in general, “seems to be faster with private insurance,” he noted.

The study excluded patients who received systemic therapies other than immunotherapy, as well as those who received immunotherapy before surgery. Among study limitations, the specific immunotherapies patients received was unknown.

There was no external funding for this study. Dr. Moyers reported travel compensation from Astellas Pharmaceuticals in 2018. Dr. Ribas disclosed relationships with Amgen, Chugai, Merck, Sanofi, Tango, Arcus, Bioncotech, Compugen, CytomX, FLX Bio, ImaginAb, Isoplexis, Merus, Rgenix, and PACT.

aotto@mdedge.com

SOURCE: Moyers J et al. AACR 2020, Abstract 4338.

Immunotherapy after resection of the primary tumor improved survival in some patients with stage III melanoma in an analysis presented at the AACR virtual meeting II.

Among patients with stage IIIC disease, the 2-year survival rate was 70% in those who received immunotherapy and 59% in those who did not (P < .01). The median overall survival in this group was 32.8 months with immunotherapy and 28 months without it (P < .01).

Among patients with stage IIIA disease, the 2-year survival rate was 94% with immunotherapy and 91% without it (P = .03).

There was a trend toward a 2-year survival benefit with immunotherapy in patients with stage IIIB disease and in all 4,094 stage III patients, but the differences were not significant. The 2-year survival rate was 84% with immunotherapy and 81% without it among patients with stage IIIB disease (P = .35). The survival rates were 83% and 80%, respectively, in all stage III patients (P = .051).

This was an early analysis, noted investigator Justin Moyers, MD, of Loma Linda (Calif.) University. Ipilimumab was approved as adjuvant therapy for stage III melanoma patients in 2015, the year patients from this analysis were diagnosed.

“There’s really only 2 full years of survival data,” Dr. Moyers said. “I think given time, we will see a benefit amongst all the substages.”

In the meantime, “I would definitely not use this data to say whether or not [immunotherapy] should be given,” Dr. Moyers said.

The researchers were just using the database – which captures 52% of U.S. melanoma cases – to see if “real-world data mimics the clinical trial data,” Dr. Moyers said.

Overall, the findings support “adjuvant immunotherapy in the real-world setting,” he said.

The researchers also looked at treatment patterns in 2015-2016 across 8,160 patients with stage III melanoma, 4,094 of whom were included in the aforementioned survival analysis. There were 2,260 patients (27.7%) who received immunotherapy after surgery during that time period.

Uptake of adjuvant immunotherapy “was low to start, but those patients did better than ones who did not get” it, said AACR president Antoni Ribas, MD, PhD, of the University of California, Los Angeles, who was not involved in the study.

Immunotherapy recipients were younger, on average (54.8 years vs. 62.4 years). Patients with Charlson comorbidity scores above zero and those on Medicare were less likely to receive immunotherapy (18.4% Medicare vs. over 30% with other payers). There also were trends of decreased use with lower income and lower high school graduation rates.

The finding “highlights the negative impact of socioeconomic [factors] on access to proven therapy,” Dr. Ribas said.

As for low use among Medicare patients, uptake of new treatments, in general, “seems to be faster with private insurance,” he noted.

The study excluded patients who received systemic therapies other than immunotherapy, as well as those who received immunotherapy before surgery. Among study limitations, the specific immunotherapies patients received was unknown.

There was no external funding for this study. Dr. Moyers reported travel compensation from Astellas Pharmaceuticals in 2018. Dr. Ribas disclosed relationships with Amgen, Chugai, Merck, Sanofi, Tango, Arcus, Bioncotech, Compugen, CytomX, FLX Bio, ImaginAb, Isoplexis, Merus, Rgenix, and PACT.

aotto@mdedge.com

SOURCE: Moyers J et al. AACR 2020, Abstract 4338.

Teens and young adults with diabetes have cognitive deficits that vary by diabetes type and could negatively impact their medical literacy and self-care, an investigator reported at the virtual annual scientific sessions of the American Diabetes Association.

Individuals with youth-onset type 1 or 2 diabetes all performed below average on tests that measure flexible thinking and problem solving, according to the investigator, who reported an analysis including 1,380 individuals enrolled in the SEARCH for Diabetes in Youth study.

That finding suggests that diabetes diagnosed before age 20 contributes to poor fluid cognitive function, which consists of skills that facilitate goal-directed behaviors, according to investigator Allison Shapiro, MPH, PhD, of the University of Colorado at Denver, Aurora.

However, individuals with type 2 diabetes (T2D) performed even worse than those with type 1 diabetes (T1D) on the fluid cognitive function tests, even after adjustment for demographic factors and other confounders, Dr. Shapiro said in her presentation.

Further analysis revealed that individuals with T2D performed significantly worse on measures of crystallized cognition, a domain that includes skills such as vocabulary and language. That suggests the poor fluid cognitive abilities in youths with diabetes may in fact be a result of poor crystallized cognitive development, according to the investigator.

“Among adolescents and young adults with youth-onset type 2 diabetes specifically, intervention should focus on developing both fluid cognitive skills and crystallized cognitive skills,” Dr. Shapiro said.

Deficits in fluid cognitive function (such as reasoning or processing speed) can negatively affect diabetes self-care, thereby potentially increasing the risk of diabetes-related complications, while deficits in crystallized cognitive function (such as vocabulary and understanding of language) could impact medical literacy further compounding the self-care issues.

The study is believed to be one of the first to compare cognitive function deficits in youths with type 1 or 2 diabetes. Although studies in adults clearly show a detrimental relationship between diabetes and cognitive function, according to Dr. Shapiro, the bulk of the research in youths has focused on T1D.

“While limited work has been done in youth-onset type 2 diabetes, cognitive deficits are consistently observed, compared to youth without diabetes,” she said.

Results of this study emphasize the importance of dietary changes and other lifestyle interventions in young patients with diabetes, according to David Della-Morte, MD, PhD, associate professor of neurology at the University of Miami.

“Even the youngest patients may develop cognitive dysfunction,” Dr. Della-Morte said in an interview. “That means that lifestyle is very important, especially in obese patients that are prone to develop type 2 diabetes.”

The analysis by Dr. Shapiro and coinvestigators included 1,095 youths and young adults with T1D and 285 with T2D who had undergone a cognition assessment as part of a study visit. They were aged an average of 22 years, and had an average diabetes duration of 11 years.

The overall fluid cognition score was significantly lower in those individuals with T2D, compared with those with T1D, investigators found. Compared with the national average score of 100, the T2D group scored 84.7, or a full standard deviation below that average, said Dr. Shapiro, while those with T1D scored 95.5 (P < .001).

Participants with T2D also scored significantly lower in individual measures of fluid cognition, including processing speed, inhibitory control and attention, working memory, and episodic memory, she reported. At first glance, that suggested youth-onset T2D has a specific effect on fluid cognition; however, the story remains incomplete without looking at crystallized cognition markers such as vocabulary and language.

Toward that end, a picture vocabulary test conducted as part of the cognitive assessment showed a significant difference between those with T2D, who on average scored 91.5, and those with T1D, who scored 103.6 (P < .001). Accounting for those picture vocabulary scores attenuated the differences between groups in fluid cognitive scores, suggesting that differences in crystallized cognitive function underly the observed differences in fluid cognitive function between groups, Dr. Shapiro said.

Skills such as vocabulary and language are thought to be stable and not influenced by neurologic changes brought on by disease processes such as youth-onset diabetes, but rather, influenced by factors such as childcare and education, according to Dr. Shapiro.

“Crystallized cognition therefore provides a window into an individual’s cognitive functioning, independent of their disease or premorbid to the onset of their disease,” she said.

Dr. Shapiro said she had no conflicts of interest to disclose.

SOURCE: Shapiro A et al. ADA 2020, Abstract 279-OR.

Teens and young adults with diabetes have cognitive deficits that vary by diabetes type and could negatively impact their medical literacy and self-care, an investigator reported at the virtual annual scientific sessions of the American Diabetes Association.

Individuals with youth-onset type 1 or 2 diabetes all performed below average on tests that measure flexible thinking and problem solving, according to the investigator, who reported an analysis including 1,380 individuals enrolled in the SEARCH for Diabetes in Youth study.

That finding suggests that diabetes diagnosed before age 20 contributes to poor fluid cognitive function, which consists of skills that facilitate goal-directed behaviors, according to investigator Allison Shapiro, MPH, PhD, of the University of Colorado at Denver, Aurora.

However, individuals with type 2 diabetes (T2D) performed even worse than those with type 1 diabetes (T1D) on the fluid cognitive function tests, even after adjustment for demographic factors and other confounders, Dr. Shapiro said in her presentation.

Further analysis revealed that individuals with T2D performed significantly worse on measures of crystallized cognition, a domain that includes skills such as vocabulary and language. That suggests the poor fluid cognitive abilities in youths with diabetes may in fact be a result of poor crystallized cognitive development, according to the investigator.

“Among adolescents and young adults with youth-onset type 2 diabetes specifically, intervention should focus on developing both fluid cognitive skills and crystallized cognitive skills,” Dr. Shapiro said.

Deficits in fluid cognitive function (such as reasoning or processing speed) can negatively affect diabetes self-care, thereby potentially increasing the risk of diabetes-related complications, while deficits in crystallized cognitive function (such as vocabulary and understanding of language) could impact medical literacy further compounding the self-care issues.

The study is believed to be one of the first to compare cognitive function deficits in youths with type 1 or 2 diabetes. Although studies in adults clearly show a detrimental relationship between diabetes and cognitive function, according to Dr. Shapiro, the bulk of the research in youths has focused on T1D.

“While limited work has been done in youth-onset type 2 diabetes, cognitive deficits are consistently observed, compared to youth without diabetes,” she said.

Results of this study emphasize the importance of dietary changes and other lifestyle interventions in young patients with diabetes, according to David Della-Morte, MD, PhD, associate professor of neurology at the University of Miami.

“Even the youngest patients may develop cognitive dysfunction,” Dr. Della-Morte said in an interview. “That means that lifestyle is very important, especially in obese patients that are prone to develop type 2 diabetes.”

The analysis by Dr. Shapiro and coinvestigators included 1,095 youths and young adults with T1D and 285 with T2D who had undergone a cognition assessment as part of a study visit. They were aged an average of 22 years, and had an average diabetes duration of 11 years.

The overall fluid cognition score was significantly lower in those individuals with T2D, compared with those with T1D, investigators found. Compared with the national average score of 100, the T2D group scored 84.7, or a full standard deviation below that average, said Dr. Shapiro, while those with T1D scored 95.5 (P < .001).

Participants with T2D also scored significantly lower in individual measures of fluid cognition, including processing speed, inhibitory control and attention, working memory, and episodic memory, she reported. At first glance, that suggested youth-onset T2D has a specific effect on fluid cognition; however, the story remains incomplete without looking at crystallized cognition markers such as vocabulary and language.

Toward that end, a picture vocabulary test conducted as part of the cognitive assessment showed a significant difference between those with T2D, who on average scored 91.5, and those with T1D, who scored 103.6 (P < .001). Accounting for those picture vocabulary scores attenuated the differences between groups in fluid cognitive scores, suggesting that differences in crystallized cognitive function underly the observed differences in fluid cognitive function between groups, Dr. Shapiro said.

Skills such as vocabulary and language are thought to be stable and not influenced by neurologic changes brought on by disease processes such as youth-onset diabetes, but rather, influenced by factors such as childcare and education, according to Dr. Shapiro.

“Crystallized cognition therefore provides a window into an individual’s cognitive functioning, independent of their disease or premorbid to the onset of their disease,” she said.

Dr. Shapiro said she had no conflicts of interest to disclose.

SOURCE: Shapiro A et al. ADA 2020, Abstract 279-OR.

Teens and young adults with diabetes have cognitive deficits that vary by diabetes type and could negatively impact their medical literacy and self-care, an investigator reported at the virtual annual scientific sessions of the American Diabetes Association.

Individuals with youth-onset type 1 or 2 diabetes all performed below average on tests that measure flexible thinking and problem solving, according to the investigator, who reported an analysis including 1,380 individuals enrolled in the SEARCH for Diabetes in Youth study.

That finding suggests that diabetes diagnosed before age 20 contributes to poor fluid cognitive function, which consists of skills that facilitate goal-directed behaviors, according to investigator Allison Shapiro, MPH, PhD, of the University of Colorado at Denver, Aurora.

However, individuals with type 2 diabetes (T2D) performed even worse than those with type 1 diabetes (T1D) on the fluid cognitive function tests, even after adjustment for demographic factors and other confounders, Dr. Shapiro said in her presentation.

Further analysis revealed that individuals with T2D performed significantly worse on measures of crystallized cognition, a domain that includes skills such as vocabulary and language. That suggests the poor fluid cognitive abilities in youths with diabetes may in fact be a result of poor crystallized cognitive development, according to the investigator.

“Among adolescents and young adults with youth-onset type 2 diabetes specifically, intervention should focus on developing both fluid cognitive skills and crystallized cognitive skills,” Dr. Shapiro said.

Deficits in fluid cognitive function (such as reasoning or processing speed) can negatively affect diabetes self-care, thereby potentially increasing the risk of diabetes-related complications, while deficits in crystallized cognitive function (such as vocabulary and understanding of language) could impact medical literacy further compounding the self-care issues.

The study is believed to be one of the first to compare cognitive function deficits in youths with type 1 or 2 diabetes. Although studies in adults clearly show a detrimental relationship between diabetes and cognitive function, according to Dr. Shapiro, the bulk of the research in youths has focused on T1D.

“While limited work has been done in youth-onset type 2 diabetes, cognitive deficits are consistently observed, compared to youth without diabetes,” she said.

Results of this study emphasize the importance of dietary changes and other lifestyle interventions in young patients with diabetes, according to David Della-Morte, MD, PhD, associate professor of neurology at the University of Miami.

“Even the youngest patients may develop cognitive dysfunction,” Dr. Della-Morte said in an interview. “That means that lifestyle is very important, especially in obese patients that are prone to develop type 2 diabetes.”

The analysis by Dr. Shapiro and coinvestigators included 1,095 youths and young adults with T1D and 285 with T2D who had undergone a cognition assessment as part of a study visit. They were aged an average of 22 years, and had an average diabetes duration of 11 years.

The overall fluid cognition score was significantly lower in those individuals with T2D, compared with those with T1D, investigators found. Compared with the national average score of 100, the T2D group scored 84.7, or a full standard deviation below that average, said Dr. Shapiro, while those with T1D scored 95.5 (P < .001).

Participants with T2D also scored significantly lower in individual measures of fluid cognition, including processing speed, inhibitory control and attention, working memory, and episodic memory, she reported. At first glance, that suggested youth-onset T2D has a specific effect on fluid cognition; however, the story remains incomplete without looking at crystallized cognition markers such as vocabulary and language.

Toward that end, a picture vocabulary test conducted as part of the cognitive assessment showed a significant difference between those with T2D, who on average scored 91.5, and those with T1D, who scored 103.6 (P < .001). Accounting for those picture vocabulary scores attenuated the differences between groups in fluid cognitive scores, suggesting that differences in crystallized cognitive function underly the observed differences in fluid cognitive function between groups, Dr. Shapiro said.

Skills such as vocabulary and language are thought to be stable and not influenced by neurologic changes brought on by disease processes such as youth-onset diabetes, but rather, influenced by factors such as childcare and education, according to Dr. Shapiro.

“Crystallized cognition therefore provides a window into an individual’s cognitive functioning, independent of their disease or premorbid to the onset of their disease,” she said.

Dr. Shapiro said she had no conflicts of interest to disclose.

SOURCE: Shapiro A et al. ADA 2020, Abstract 279-OR.

Not all weight loss surgery patients “live happily ever after,” according to Daniel B. Jones, MD, of Harvard Medical School, Boston.

A 2014 study of 22 women who underwent weight loss surgery reported lower energy, worse quality of life, and persistent eating disorders, Dr. Jones said in a presentation at the virtual Annual Minimally Invasive Surgery Symposium by Global Academy for Medical Education.

However, postprocedure problems don’t always equal regrets, he said. “Although many women [in the 2014 study] reported negative thoughts and health issues after weight loss surgery, none of them said they regret undergoing the procedure,” he noted.

To further examine decision regret in patients who underwent gastric bypass and gastric banding, Dr. Jones participated in a study of patients’ attitudes 4 years after gastric bypass and gastric banding (Obes Surg. 2019;29:1624-31).

“Weight loss surgery is neither risk free nor universally effective, yet few studies have examined what proportion of patients regret having undergone weight loss surgery,” he noted.

Dr. Jones and colleagues interviewed patients at two weight loss surgery centers and used specific metrics and a multivariate analysis to examine associations among weight loss, quality of life, and decision regret.

A total of 205 Roux-en-Y gastric bypass (RYGB) patients responded at 1 year after surgery: 181, 156, and 134 patients responded at 2, 3, and 4 years, respectively.

At 1 year, 2% reported regret and that they would not choose the surgery again, and by 4 years, 5% reported regret, based on overall regret scores greater than 50. In addition, 13% of patients at 1 year and 4 years reported that weight loss surgery caused “some” or “a lot” of negative effects.

The researchers also interviewed gastric band patients: 170, 157, 146, and 123 responded at years 1,2,3, and 4.

Overall, 8% of these patients expressed regret at 1 year, and 20% expressed regret at 4 years, said Dr. Jones.

“Almost 20% did not think they made the right decision,” he said.

Weight loss was a key driver in regret among gastric banding patients, Dr. Jones noted. An average weight loss of 7.4% of excess body weight was associated with regret scores greater than 50, while an average weight loss of 21.1% was associated with regret scores less than 50, he said.

In addition, poor sexual function, but not weight loss or other quality-of-life factors was significantly associated with regret among RYGB patients.

Many surgeons are performing sleeve gastrectomies, which appear to yield greater weight loss than gastric banding and fewer complications than gastric bypass, said Dr. Jones. His study did not include sleeve gastrectomies, but “I expect a sleeve gastrectomy to do pretty well in this analysis,” and to be associated with less patient regret, he said.

Overall, better patient education is key to improving patients’ experiences and reducing feelings of regret, said Dr. Jones.

“The better patients understand the difference between band, bypass, and sleeve preoperatively, the better we can set expectations,” he said. Dr. Jones’ institution has developed an app for laparoscopic sleeve that guides patients through the process from preop through postoperative stay, he noted.

Given the association between amount of weight lost and regret, “setting expectations is very important,” and could include not only written consent but also webinars, information sessions, and apps for patients in advance to help mitigate regrets after the procedure, Dr. Jones concluded.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Dr. Jones disclosed serving on the medical advisory board for Allurion.

Not all weight loss surgery patients “live happily ever after,” according to Daniel B. Jones, MD, of Harvard Medical School, Boston.

A 2014 study of 22 women who underwent weight loss surgery reported lower energy, worse quality of life, and persistent eating disorders, Dr. Jones said in a presentation at the virtual Annual Minimally Invasive Surgery Symposium by Global Academy for Medical Education.

However, postprocedure problems don’t always equal regrets, he said. “Although many women [in the 2014 study] reported negative thoughts and health issues after weight loss surgery, none of them said they regret undergoing the procedure,” he noted.

To further examine decision regret in patients who underwent gastric bypass and gastric banding, Dr. Jones participated in a study of patients’ attitudes 4 years after gastric bypass and gastric banding (Obes Surg. 2019;29:1624-31).

“Weight loss surgery is neither risk free nor universally effective, yet few studies have examined what proportion of patients regret having undergone weight loss surgery,” he noted.

Dr. Jones and colleagues interviewed patients at two weight loss surgery centers and used specific metrics and a multivariate analysis to examine associations among weight loss, quality of life, and decision regret.

A total of 205 Roux-en-Y gastric bypass (RYGB) patients responded at 1 year after surgery: 181, 156, and 134 patients responded at 2, 3, and 4 years, respectively.

At 1 year, 2% reported regret and that they would not choose the surgery again, and by 4 years, 5% reported regret, based on overall regret scores greater than 50. In addition, 13% of patients at 1 year and 4 years reported that weight loss surgery caused “some” or “a lot” of negative effects.

The researchers also interviewed gastric band patients: 170, 157, 146, and 123 responded at years 1,2,3, and 4.

Overall, 8% of these patients expressed regret at 1 year, and 20% expressed regret at 4 years, said Dr. Jones.

“Almost 20% did not think they made the right decision,” he said.

Weight loss was a key driver in regret among gastric banding patients, Dr. Jones noted. An average weight loss of 7.4% of excess body weight was associated with regret scores greater than 50, while an average weight loss of 21.1% was associated with regret scores less than 50, he said.

In addition, poor sexual function, but not weight loss or other quality-of-life factors was significantly associated with regret among RYGB patients.

Many surgeons are performing sleeve gastrectomies, which appear to yield greater weight loss than gastric banding and fewer complications than gastric bypass, said Dr. Jones. His study did not include sleeve gastrectomies, but “I expect a sleeve gastrectomy to do pretty well in this analysis,” and to be associated with less patient regret, he said.

Overall, better patient education is key to improving patients’ experiences and reducing feelings of regret, said Dr. Jones.

“The better patients understand the difference between band, bypass, and sleeve preoperatively, the better we can set expectations,” he said. Dr. Jones’ institution has developed an app for laparoscopic sleeve that guides patients through the process from preop through postoperative stay, he noted.

Given the association between amount of weight lost and regret, “setting expectations is very important,” and could include not only written consent but also webinars, information sessions, and apps for patients in advance to help mitigate regrets after the procedure, Dr. Jones concluded.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Dr. Jones disclosed serving on the medical advisory board for Allurion.

Not all weight loss surgery patients “live happily ever after,” according to Daniel B. Jones, MD, of Harvard Medical School, Boston.

A 2014 study of 22 women who underwent weight loss surgery reported lower energy, worse quality of life, and persistent eating disorders, Dr. Jones said in a presentation at the virtual Annual Minimally Invasive Surgery Symposium by Global Academy for Medical Education.

However, postprocedure problems don’t always equal regrets, he said. “Although many women [in the 2014 study] reported negative thoughts and health issues after weight loss surgery, none of them said they regret undergoing the procedure,” he noted.

To further examine decision regret in patients who underwent gastric bypass and gastric banding, Dr. Jones participated in a study of patients’ attitudes 4 years after gastric bypass and gastric banding (Obes Surg. 2019;29:1624-31).

“Weight loss surgery is neither risk free nor universally effective, yet few studies have examined what proportion of patients regret having undergone weight loss surgery,” he noted.

Dr. Jones and colleagues interviewed patients at two weight loss surgery centers and used specific metrics and a multivariate analysis to examine associations among weight loss, quality of life, and decision regret.

A total of 205 Roux-en-Y gastric bypass (RYGB) patients responded at 1 year after surgery: 181, 156, and 134 patients responded at 2, 3, and 4 years, respectively.

At 1 year, 2% reported regret and that they would not choose the surgery again, and by 4 years, 5% reported regret, based on overall regret scores greater than 50. In addition, 13% of patients at 1 year and 4 years reported that weight loss surgery caused “some” or “a lot” of negative effects.

The researchers also interviewed gastric band patients: 170, 157, 146, and 123 responded at years 1,2,3, and 4.

Overall, 8% of these patients expressed regret at 1 year, and 20% expressed regret at 4 years, said Dr. Jones.

“Almost 20% did not think they made the right decision,” he said.

Weight loss was a key driver in regret among gastric banding patients, Dr. Jones noted. An average weight loss of 7.4% of excess body weight was associated with regret scores greater than 50, while an average weight loss of 21.1% was associated with regret scores less than 50, he said.

In addition, poor sexual function, but not weight loss or other quality-of-life factors was significantly associated with regret among RYGB patients.

Many surgeons are performing sleeve gastrectomies, which appear to yield greater weight loss than gastric banding and fewer complications than gastric bypass, said Dr. Jones. His study did not include sleeve gastrectomies, but “I expect a sleeve gastrectomy to do pretty well in this analysis,” and to be associated with less patient regret, he said.

Overall, better patient education is key to improving patients’ experiences and reducing feelings of regret, said Dr. Jones.

“The better patients understand the difference between band, bypass, and sleeve preoperatively, the better we can set expectations,” he said. Dr. Jones’ institution has developed an app for laparoscopic sleeve that guides patients through the process from preop through postoperative stay, he noted.

Given the association between amount of weight lost and regret, “setting expectations is very important,” and could include not only written consent but also webinars, information sessions, and apps for patients in advance to help mitigate regrets after the procedure, Dr. Jones concluded.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Dr. Jones disclosed serving on the medical advisory board for Allurion.

Social media might be the way to go for authors hoping to bump up the number of times their articles are cited by other articles, according to a presentation at the annual European Congress of Rheumatology that showed how Altmetric scores influence citation rates in journals.

Altmetrics are nontraditional bibliometrics designed to calculate scholarly impact based on online attention. The Altmetric Attention Score and donut provide a collated record of online attention. The colorful badge, which accompanies an increasing number of journal papers online, offers readers a full record of all original shares and mentions of an individual piece of scholarly content across a range of platforms, including Twitter, Facebook, online news media, blogs, Google+, Mendeley, and others.

Dimensions badges, also found on journal sites, count citations from any kind of scientific or mainstream publication. Journal citations remain one of the most recognized proxies for impact in medical research.

Assessing data from over 2,000 articles published in the two official journals of the European League Against Rheumatism – Annals of the Rheumatic Diseases (ARD) and RMD Open – during January 2015–November 2019, Paul Studenic, MD, PhD (@Stiddyo), of the Medical University of Vienna, and coauthor Caroline Ospelt, MD, PhD (@CarolineOspelt), of University Hospital Zürich, found that Altmetric Attention Scores are higher for articles published more recently, with Twitter showing by far the highest activity among the score’s subcategories.

“The total number of Twitter mentions increased by 2.8 per year from 2015 to 2019, indicating that more recently published articles were more often picked up on Twitter,” Dr. Studenic said in an interview. He noted that only original tweets that link to an article are given a full count of 1, while retweets or reposts have less impact on the score.

There are exceptions to this finding that newer articles have higher scores than older articles, he noted. A rheumatology article with one of the highest Altmetric Attention Scores (407) is a piece on the effect of habitual knuckle cracking that published in ARD in 1990. “It has one of the most colorful donuts with 42 news outlets, plus blogs, tweets, Facebook pages, Wikipedia mentions, and Mendeley reads,” Dr. Studenic said. But the article’s citation count is only 20.

“I would not say that the Altmetric Score has anything to do with the quality of the study, it’s just a measure of online popularity. So, you might be a brilliant research team that published a perfect study, but it is not of that much interest to editors, or it might not be tweeted by the journal itself because it was not found to be that interesting. In this case you will get your citations through your scientific community,” he said.

“Particularly if you look now at Altmetric Scores for what is being published on COVID-19, the numbers do not represent at all any profoundness of scientific quality, but there is a lot of tweeting of these articles and a lot of attention,” he said.

Overall, the odds for reaching the top 25% of citations increased with the time since publication. The time since publication accounted for 10% of the variability in the probability of reaching the top 25% of citations, whereas the Altmetric Attention Score accounted for about 5% of the variability.

Besides time since publication and Altmetric Attention Score, the type of article also influences citation count, the researchers found. The Altmetric Attention Score was more likely to boost the citation rate for original research and editorials, but it did little for correspondences.

The influence of Altmetric Attention Score on citation count of editorials added 16% to the 12% of variability explained by publication time. “We never found an effect for correspondence articles,” Dr. Studenic added.

Online popularity is something more likely to favor younger researchers, given their greater engagement online, he said. But he stressed that social media savvy is not absolutely necessary. “If you aren’t on social media and you want to build up a network, you can still do it by other means and your manuscript will still be seen, but I would say in that case that the attention kind of runs behind your back, whereas if you’re active on social media, you can steer it more effectively.”

The study had no outside funding. Both authors are social media advisers to ARD and RMD Open, and Dr. Ospelt is an associate editor of RMD Open and an editorial board member of ARD. Dr. Studenic reported receiving research or grant support from AbbVie, and Dr. Ospelt reported receiving consultancy fees from Gilead Sciences.

SOURCE: Studenic P and Ospelt C. Ann Rheum Dis. 2020 Jun;79(suppl 1):208.

Social media might be the way to go for authors hoping to bump up the number of times their articles are cited by other articles, according to a presentation at the annual European Congress of Rheumatology that showed how Altmetric scores influence citation rates in journals.

Altmetrics are nontraditional bibliometrics designed to calculate scholarly impact based on online attention. The Altmetric Attention Score and donut provide a collated record of online attention. The colorful badge, which accompanies an increasing number of journal papers online, offers readers a full record of all original shares and mentions of an individual piece of scholarly content across a range of platforms, including Twitter, Facebook, online news media, blogs, Google+, Mendeley, and others.

Dimensions badges, also found on journal sites, count citations from any kind of scientific or mainstream publication. Journal citations remain one of the most recognized proxies for impact in medical research.

Assessing data from over 2,000 articles published in the two official journals of the European League Against Rheumatism – Annals of the Rheumatic Diseases (ARD) and RMD Open – during January 2015–November 2019, Paul Studenic, MD, PhD (@Stiddyo), of the Medical University of Vienna, and coauthor Caroline Ospelt, MD, PhD (@CarolineOspelt), of University Hospital Zürich, found that Altmetric Attention Scores are higher for articles published more recently, with Twitter showing by far the highest activity among the score’s subcategories.

“The total number of Twitter mentions increased by 2.8 per year from 2015 to 2019, indicating that more recently published articles were more often picked up on Twitter,” Dr. Studenic said in an interview. He noted that only original tweets that link to an article are given a full count of 1, while retweets or reposts have less impact on the score.

There are exceptions to this finding that newer articles have higher scores than older articles, he noted. A rheumatology article with one of the highest Altmetric Attention Scores (407) is a piece on the effect of habitual knuckle cracking that published in ARD in 1990. “It has one of the most colorful donuts with 42 news outlets, plus blogs, tweets, Facebook pages, Wikipedia mentions, and Mendeley reads,” Dr. Studenic said. But the article’s citation count is only 20.

“I would not say that the Altmetric Score has anything to do with the quality of the study, it’s just a measure of online popularity. So, you might be a brilliant research team that published a perfect study, but it is not of that much interest to editors, or it might not be tweeted by the journal itself because it was not found to be that interesting. In this case you will get your citations through your scientific community,” he said.

“Particularly if you look now at Altmetric Scores for what is being published on COVID-19, the numbers do not represent at all any profoundness of scientific quality, but there is a lot of tweeting of these articles and a lot of attention,” he said.

Overall, the odds for reaching the top 25% of citations increased with the time since publication. The time since publication accounted for 10% of the variability in the probability of reaching the top 25% of citations, whereas the Altmetric Attention Score accounted for about 5% of the variability.

Besides time since publication and Altmetric Attention Score, the type of article also influences citation count, the researchers found. The Altmetric Attention Score was more likely to boost the citation rate for original research and editorials, but it did little for correspondences.

The influence of Altmetric Attention Score on citation count of editorials added 16% to the 12% of variability explained by publication time. “We never found an effect for correspondence articles,” Dr. Studenic added.

Online popularity is something more likely to favor younger researchers, given their greater engagement online, he said. But he stressed that social media savvy is not absolutely necessary. “If you aren’t on social media and you want to build up a network, you can still do it by other means and your manuscript will still be seen, but I would say in that case that the attention kind of runs behind your back, whereas if you’re active on social media, you can steer it more effectively.”

The study had no outside funding. Both authors are social media advisers to ARD and RMD Open, and Dr. Ospelt is an associate editor of RMD Open and an editorial board member of ARD. Dr. Studenic reported receiving research or grant support from AbbVie, and Dr. Ospelt reported receiving consultancy fees from Gilead Sciences.

SOURCE: Studenic P and Ospelt C. Ann Rheum Dis. 2020 Jun;79(suppl 1):208.

Social media might be the way to go for authors hoping to bump up the number of times their articles are cited by other articles, according to a presentation at the annual European Congress of Rheumatology that showed how Altmetric scores influence citation rates in journals.

Altmetrics are nontraditional bibliometrics designed to calculate scholarly impact based on online attention. The Altmetric Attention Score and donut provide a collated record of online attention. The colorful badge, which accompanies an increasing number of journal papers online, offers readers a full record of all original shares and mentions of an individual piece of scholarly content across a range of platforms, including Twitter, Facebook, online news media, blogs, Google+, Mendeley, and others.

Dimensions badges, also found on journal sites, count citations from any kind of scientific or mainstream publication. Journal citations remain one of the most recognized proxies for impact in medical research.

Assessing data from over 2,000 articles published in the two official journals of the European League Against Rheumatism – Annals of the Rheumatic Diseases (ARD) and RMD Open – during January 2015–November 2019, Paul Studenic, MD, PhD (@Stiddyo), of the Medical University of Vienna, and coauthor Caroline Ospelt, MD, PhD (@CarolineOspelt), of University Hospital Zürich, found that Altmetric Attention Scores are higher for articles published more recently, with Twitter showing by far the highest activity among the score’s subcategories.

“The total number of Twitter mentions increased by 2.8 per year from 2015 to 2019, indicating that more recently published articles were more often picked up on Twitter,” Dr. Studenic said in an interview. He noted that only original tweets that link to an article are given a full count of 1, while retweets or reposts have less impact on the score.

There are exceptions to this finding that newer articles have higher scores than older articles, he noted. A rheumatology article with one of the highest Altmetric Attention Scores (407) is a piece on the effect of habitual knuckle cracking that published in ARD in 1990. “It has one of the most colorful donuts with 42 news outlets, plus blogs, tweets, Facebook pages, Wikipedia mentions, and Mendeley reads,” Dr. Studenic said. But the article’s citation count is only 20.

“I would not say that the Altmetric Score has anything to do with the quality of the study, it’s just a measure of online popularity. So, you might be a brilliant research team that published a perfect study, but it is not of that much interest to editors, or it might not be tweeted by the journal itself because it was not found to be that interesting. In this case you will get your citations through your scientific community,” he said.

“Particularly if you look now at Altmetric Scores for what is being published on COVID-19, the numbers do not represent at all any profoundness of scientific quality, but there is a lot of tweeting of these articles and a lot of attention,” he said.

Overall, the odds for reaching the top 25% of citations increased with the time since publication. The time since publication accounted for 10% of the variability in the probability of reaching the top 25% of citations, whereas the Altmetric Attention Score accounted for about 5% of the variability.

Besides time since publication and Altmetric Attention Score, the type of article also influences citation count, the researchers found. The Altmetric Attention Score was more likely to boost the citation rate for original research and editorials, but it did little for correspondences.

The influence of Altmetric Attention Score on citation count of editorials added 16% to the 12% of variability explained by publication time. “We never found an effect for correspondence articles,” Dr. Studenic added.

Online popularity is something more likely to favor younger researchers, given their greater engagement online, he said. But he stressed that social media savvy is not absolutely necessary. “If you aren’t on social media and you want to build up a network, you can still do it by other means and your manuscript will still be seen, but I would say in that case that the attention kind of runs behind your back, whereas if you’re active on social media, you can steer it more effectively.”

The study had no outside funding. Both authors are social media advisers to ARD and RMD Open, and Dr. Ospelt is an associate editor of RMD Open and an editorial board member of ARD. Dr. Studenic reported receiving research or grant support from AbbVie, and Dr. Ospelt reported receiving consultancy fees from Gilead Sciences.

SOURCE: Studenic P and Ospelt C. Ann Rheum Dis. 2020 Jun;79(suppl 1):208.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

sworcester@mdedge.com

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

sworcester@mdedge.com

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

The oral selective estrogen receptor degrader (SERD) LSZ102 plus either ribociclib or alpelisib shows manageable safety and encouraging clinical activity in heavily pretreated estrogen receptor (ER)–positive breast cancer patients who progressed after prior endocrine therapy, according to interim results of an open-label phase 1/1b study.

The effects seen in the study, which is the first to report on an oral SERD in combination with both CDK4/6 and PI3Ka inhibitors, occurred regardless of ESR1 and PIK3CA mutations, said Komal Jhaveri, MD, of Memorial Sloan Kettering Cancer Center in New York.

Dr. Jhaveri reported the results at the European Society of Medical Oncology: Breast Cancer virtual meeting.

The overall response rate (ORR) among 78 patients enrolled in an LSZ102 monotherapy arm (arm A) was 1.3%, and the progression-free survival (PFS) was 1.8 months. The clinical benefit rate (CBR) was 9.1%.

Among 76 patients enrolled in an LSZ102+ribociclib arm (arm B), the ORR was 15.8%, the PFS was 6.2 months, and the CBR was 35.5%.

Among the 39 patients enrolled in an LSZ102+alpelisib arm (arm C), the ORR was 5.4%, the PFS was 3.5 months, and the CBR was 18.9%.

After the data cutoff, one additional partial response (PR) was reported in arm C, Dr. Jhaveri said, noting that two of three confirmed responses were in known PIKC3A-mutant patients.

Study participants were aged 18 years and older with a confirmed diagnosis of ER-positive breast cancer and good performance status, as well as evidence of progression after endocrine therapy for metastatic disease or evidence of progression while on therapy or within 12 months from the end of adjuvant therapy.

“For all arms, prior fulvestrant, CDK46 inhibitor, or chemotherapy were allowed. For arm C, patients with or without PIK3C were eligible, and no prior treatment with PIK3, mTOR, or AKT inhibitors was allowed,” Dr. Jhaveri said.

Dosing in the LSZ102 monotherapy arm ranged from 200 to 900 mg. Arm B patients received LSZ102 at doses of 200-600 mg and ribociclib at doses of 200-600 mg. Both continuous ribociclib and 3 weeks on/1 week off dosing were evaluated. Arm C patients received LSZ102 at doses of 300-450 mg and alpelisib at 200-300 mg.

The recommended expansion doses were 450 mg daily of LSZ102 for arm A and 450 mg LSZ102 with 400 mg of daily ribociclib for arm B. For arm C, they were 300 mg LSZ102 with 250 mg of alpelisib daily.

Of note, two of three patients with a PR in arm C had received 300 mg LSZ102 and 300 mg alpelisib, Dr. Jhaveri said.

Arm A and arm B results were presented at the San Antonio Breast Cancer Symposium in 2018 and 2019, respectively. The current report updates those findings and presents arm C data for the first time, Dr. Jhaveri said.

LSZ102 was relatively well-tolerated as a single agent and in combination with ribociclib and alpelisib, according to Dr. Jhaveri. The most frequent adverse events were gastrointestinal toxicities, including nausea, vomiting, diarrhea, and decreased appetite, which occurred across all arms.

Neutropenia and aspartate aminotransferase abnormalities, including grade 3 cases, were reported in arm B and were most likely driven by the ribociclib, Dr. Jhaveri said. Grade 3 hypoglycemia and skin rash commonly occurred in arm C, most likely driven by the alpelisib.

Five dose-limiting toxicities occurred in four patients in arm A, three occurred in two patients in arm B, and seven occurred in seven patients in arm C.

Paired biopsies collected at the time of screening and at day 15 of cycle 1 showed consistent down-regulation of ER protein levels across arms.

“No substantial dose-dependent down-regulation of the ER was observed with increasing doses of LSZ,” Dr. Jhaveri said.

Circulating tumor DNA (ctDNA) analysis showed that the dominant mutations across the arms were ESR1, PIK3CA, and TP53. These were not shown to correlate with response and were not enriched upon progression in patients with matched baseline and end-of-treatment samples, she noted.

An exploratory analysis, conducted in “a preliminary attempt to correlate clinical activity with specific mutations,” showed that, in arms B and C, respectively, ORR, CBR, and PFS weren’t correlated with the presence or absence of ESR1 and PIK3CA mutations, respectively, or the absence of detectable ctDNA from baseline samples, Dr. Jhaveri said.

“While numerically higher responses and better CBR were seen in patients with undetectable ctDNA at baseline, no statistically significant difference in any of these outcomes was observed in arms B and C,” she said.

In arm C, the numbers were small at the time of data cutoff, but incoming data suggest relatively enhanced activity of the LSZ102 plus alpelisib combination in PIKC3A-mutant patients, she noted.

“We know that inhibiting ER signaling is the mainstay of treatment for ER-positive breast cancer,” Dr. Jhaveri explained, adding that aromatase inhibitors, estrogen receptor modulators, and SERDs are important classes of antiestrogenic agents, but fulvestrant is the only approved SERD. These are effective, but many patients develop resistance, she said.

“Proposed mechanisms for endocrine resistance include activation of the cell-cycle and cell-survival signaling pathways, or of the PI3K-AKT-mTOR pathway,” Dr. Jhaveri said. “To that end, ribociclib, a CDK46 inhibitor plus fulvestrant improved survival compared to fulvestrant alone in patients with ER-positive metastatic breast cancer.”

More recently, the PI3K inhibitor alpelisib plus fulvestrant also nearly doubled PFS vs. fulvestrant alone in PIKC3A-mutant, ER-positive metastatic breast cancer, which led to the approval of the combination in the United States.

Another mechanism of endocrine resistance includes acquisition of activating mutations in the estrogen receptor gene itself that allow tumors to survive and proliferate without depending on estrogen.

EGFR mutations appear to predict resistance to aromatase inhibitor therapies, but not outcomes in patients treated with fulvestrant. However, fulvestrant, which is delivered by intramuscular injection, has its own limitations, Dr. Jhaveri said.

“LSZ102 is a novel SERD that could achieve higher exposure than fulvestrant, leading to enhanced efficacy,” she said, noting that it was shown in preclinical models to have activity and to be synergistic in combination with ribociclib and alpelisib, forming the basis for the current study.

Invited discussant, Saverio Cinieri, MD, of Ospedale Antonio Perrino, Brindisi, Italy, said the study “elegantly demonstrated that estrogen receptor protein is down-regulated by LSZ102; [that] the genomic landscape of heavily pretreated patients is dominated by mutations in ESR1, PIK3CA, and TP53; [that] common mutations do not correlate with response and are not enriched on progression; [and that] ctDNA analysis at baseline shows similar outcomes with LSZ plus ribociclib or alpelisib, regardless of mutational status.”

LSZ102 is one of four new-generation SERDs in early-phase studies, he said, concluding that “in the COVID-19 era, the use of oral therapies will be even more necessary to limit access to the hospital.”

Dr. Cinieri also said that overcoming the limitations “of a molecule like the intramuscularly administered fulvestrant goes in this direction,” and that “the clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs.”

This study was funded by Novartis. Dr. Jhaveri reported advisory and consultancy roles and/or research grants or other funding to her institution from Novartis, ADC Therapeutics, Pfizer, and numerous other pharmaceutical and biotechnology companies. Dr. Cinieri reported relationships with Lily Oncology, Pfizer, Roche, AstraZeneca, Amgen, Novartis, including honoraria, grant and research support to his institution, advisory board participation, and scientific meeting support.

sworcester@mdedge.com

SOURCE: Jhaveri K et al. ESMO Breast Cancer, Abstract LBA1.

Planning for reduced use of opioids in pain management involves identifying appropriate patients and managing their expectations, according to according to Timothy E. Miller, MB, ChB, FRCA, of Duke University, Durham, N.C., who is president of the American Society for Enhanced Recovery.

Multimodal analgesia plans can be a beneficial part of enhanced recovery and may reduce or eliminate the need for opioids in some patients, he said in a presentation at the virtual Annual Minimally Invasive Surgery Symposium sponsored by Global Academy for Medical Education.

Dr. Miller shared a treatment algorithm for achieving optimal analgesia in patients after colorectal surgery that combines intravenous or oral analgesia with local anesthetics and additional nonopioid options. The algorithm involves choosing NSAIDs, acetaminophen, or gabapentin for IV/oral use. In addition, options for local anesthetic include with a choice of single-shot transversus abdominis plane (TAP) block.

Careful patient selection is key to an opioid-free or opioid reduced anesthetic strategy, Dr. Miller said. The appropriate patients have “no chronic opioids, no anxiety, and the desire to avoid opioid side effects,” he said.

Opioid-free or opioid-reduced strategies include realigning patient expectations to prepare for pain at a level of 2-4 on a scale of 10 as “expected and reasonable,” he said. Patients given no opioids or reduced opioids may report cramping after laparoscopic surgery, as well as shoulder pain that is referred from the CO₂ bubble under the diaphragm, he said. However, opioids don’t treat the shoulder pain well, and “walking or changing position usually relieves this pain,” and it usually resolves within 24 hours, Dr. Miller noted. “Just letting the patient know what is expected in terms of pain relief in their recovery is hugely important,” he said.

The optimal analgesia after surgery is a plan that combines optimized patient comfort with the fastest functional recovery and the fewest side effects, he emphasized.

Optimized patient comfort includes optimal pain ratings at rest and with movement, a decreasing impact of pain on emotion, function, and sleep disruption, and an improvement in the patient experience, he said. The fastest functional recovery is defined as a return to drinking liquids, eating solid foods, performing activities of daily living, and maintaining normal bladder, bowel, and cognitive function. Side effects to be considered in analgesia included nausea, vomiting, sedation, ileus, itching, dizziness, and delirium, he said.

In an unpublished study, Dr. Miller and colleagues eliminated opioids intraoperatively in a series of 56 cases of laparoscopic cholecystectomy and found significantly less opioids needed in the postanesthesia care unit (PACU). In addition, opioid-free patients had significantly shorter length of stay in the PACU, he said. “We are writing this up for publication and looking into doing larger studies,” Dr. Miller said.

Questions include whether the opioid-free technique translates more broadly, he said.

In addition, it is important to continue to collect data and study methods to treat pain and reduce opioid use perioperatively, Dr. Miller said. Some ongoing concerns include data surrounding the use of gabapentin and possible association with respiratory depression, he noted. Several meta-analyses have suggested that “gabapentinoids (gabapentin, pregabalin) when given as a single dose preoperatively are associated with a decrease in postoperative pain and opioid consumption at 24 hours,” said Dr. Miller. “When gabapentinoids are included in multimodal analgesic regimens, intraoperative opioids must be reduced, and increased vigilance for respiratory depression may be warranted, especially in elderly patients,” he said.

Overall, opioid-free anesthesia is both feasible and appropriate in certain patient populations, Dr. Miller concluded. “Implement your pathway and measure your outcomes with timely feedback so you can revise your protocol based on data,” he emphasized.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Dr. Miller disclosed relationships with Edwards Lifesciences, and serving as a board member for the Perioperative Quality Initiative and as a founding member of the Morpheus Consortium.

Planning for reduced use of opioids in pain management involves identifying appropriate patients and managing their expectations, according to according to Timothy E. Miller, MB, ChB, FRCA, of Duke University, Durham, N.C., who is president of the American Society for Enhanced Recovery.

Multimodal analgesia plans can be a beneficial part of enhanced recovery and may reduce or eliminate the need for opioids in some patients, he said in a presentation at the virtual Annual Minimally Invasive Surgery Symposium sponsored by Global Academy for Medical Education.

Dr. Miller shared a treatment algorithm for achieving optimal analgesia in patients after colorectal surgery that combines intravenous or oral analgesia with local anesthetics and additional nonopioid options. The algorithm involves choosing NSAIDs, acetaminophen, or gabapentin for IV/oral use. In addition, options for local anesthetic include with a choice of single-shot transversus abdominis plane (TAP) block.

Careful patient selection is key to an opioid-free or opioid reduced anesthetic strategy, Dr. Miller said. The appropriate patients have “no chronic opioids, no anxiety, and the desire to avoid opioid side effects,” he said.

Opioid-free or opioid-reduced strategies include realigning patient expectations to prepare for pain at a level of 2-4 on a scale of 10 as “expected and reasonable,” he said. Patients given no opioids or reduced opioids may report cramping after laparoscopic surgery, as well as shoulder pain that is referred from the CO₂ bubble under the diaphragm, he said. However, opioids don’t treat the shoulder pain well, and “walking or changing position usually relieves this pain,” and it usually resolves within 24 hours, Dr. Miller noted. “Just letting the patient know what is expected in terms of pain relief in their recovery is hugely important,” he said.

The optimal analgesia after surgery is a plan that combines optimized patient comfort with the fastest functional recovery and the fewest side effects, he emphasized.

Optimized patient comfort includes optimal pain ratings at rest and with movement, a decreasing impact of pain on emotion, function, and sleep disruption, and an improvement in the patient experience, he said. The fastest functional recovery is defined as a return to drinking liquids, eating solid foods, performing activities of daily living, and maintaining normal bladder, bowel, and cognitive function. Side effects to be considered in analgesia included nausea, vomiting, sedation, ileus, itching, dizziness, and delirium, he said.

In an unpublished study, Dr. Miller and colleagues eliminated opioids intraoperatively in a series of 56 cases of laparoscopic cholecystectomy and found significantly less opioids needed in the postanesthesia care unit (PACU). In addition, opioid-free patients had significantly shorter length of stay in the PACU, he said. “We are writing this up for publication and looking into doing larger studies,” Dr. Miller said.

Questions include whether the opioid-free technique translates more broadly, he said.

In addition, it is important to continue to collect data and study methods to treat pain and reduce opioid use perioperatively, Dr. Miller said. Some ongoing concerns include data surrounding the use of gabapentin and possible association with respiratory depression, he noted. Several meta-analyses have suggested that “gabapentinoids (gabapentin, pregabalin) when given as a single dose preoperatively are associated with a decrease in postoperative pain and opioid consumption at 24 hours,” said Dr. Miller. “When gabapentinoids are included in multimodal analgesic regimens, intraoperative opioids must be reduced, and increased vigilance for respiratory depression may be warranted, especially in elderly patients,” he said.

Overall, opioid-free anesthesia is both feasible and appropriate in certain patient populations, Dr. Miller concluded. “Implement your pathway and measure your outcomes with timely feedback so you can revise your protocol based on data,” he emphasized.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Dr. Miller disclosed relationships with Edwards Lifesciences, and serving as a board member for the Perioperative Quality Initiative and as a founding member of the Morpheus Consortium.

Planning for reduced use of opioids in pain management involves identifying appropriate patients and managing their expectations, according to according to Timothy E. Miller, MB, ChB, FRCA, of Duke University, Durham, N.C., who is president of the American Society for Enhanced Recovery.

Multimodal analgesia plans can be a beneficial part of enhanced recovery and may reduce or eliminate the need for opioids in some patients, he said in a presentation at the virtual Annual Minimally Invasive Surgery Symposium sponsored by Global Academy for Medical Education.

Dr. Miller shared a treatment algorithm for achieving optimal analgesia in patients after colorectal surgery that combines intravenous or oral analgesia with local anesthetics and additional nonopioid options. The algorithm involves choosing NSAIDs, acetaminophen, or gabapentin for IV/oral use. In addition, options for local anesthetic include with a choice of single-shot transversus abdominis plane (TAP) block.

Careful patient selection is key to an opioid-free or opioid reduced anesthetic strategy, Dr. Miller said. The appropriate patients have “no chronic opioids, no anxiety, and the desire to avoid opioid side effects,” he said.

Opioid-free or opioid-reduced strategies include realigning patient expectations to prepare for pain at a level of 2-4 on a scale of 10 as “expected and reasonable,” he said. Patients given no opioids or reduced opioids may report cramping after laparoscopic surgery, as well as shoulder pain that is referred from the CO₂ bubble under the diaphragm, he said. However, opioids don’t treat the shoulder pain well, and “walking or changing position usually relieves this pain,” and it usually resolves within 24 hours, Dr. Miller noted. “Just letting the patient know what is expected in terms of pain relief in their recovery is hugely important,” he said.

The optimal analgesia after surgery is a plan that combines optimized patient comfort with the fastest functional recovery and the fewest side effects, he emphasized.

Optimized patient comfort includes optimal pain ratings at rest and with movement, a decreasing impact of pain on emotion, function, and sleep disruption, and an improvement in the patient experience, he said. The fastest functional recovery is defined as a return to drinking liquids, eating solid foods, performing activities of daily living, and maintaining normal bladder, bowel, and cognitive function. Side effects to be considered in analgesia included nausea, vomiting, sedation, ileus, itching, dizziness, and delirium, he said.

In an unpublished study, Dr. Miller and colleagues eliminated opioids intraoperatively in a series of 56 cases of laparoscopic cholecystectomy and found significantly less opioids needed in the postanesthesia care unit (PACU). In addition, opioid-free patients had significantly shorter length of stay in the PACU, he said. “We are writing this up for publication and looking into doing larger studies,” Dr. Miller said.

Questions include whether the opioid-free technique translates more broadly, he said.

In addition, it is important to continue to collect data and study methods to treat pain and reduce opioid use perioperatively, Dr. Miller said. Some ongoing concerns include data surrounding the use of gabapentin and possible association with respiratory depression, he noted. Several meta-analyses have suggested that “gabapentinoids (gabapentin, pregabalin) when given as a single dose preoperatively are associated with a decrease in postoperative pain and opioid consumption at 24 hours,” said Dr. Miller. “When gabapentinoids are included in multimodal analgesic regimens, intraoperative opioids must be reduced, and increased vigilance for respiratory depression may be warranted, especially in elderly patients,” he said.

Overall, opioid-free anesthesia is both feasible and appropriate in certain patient populations, Dr. Miller concluded. “Implement your pathway and measure your outcomes with timely feedback so you can revise your protocol based on data,” he emphasized.

Global Academy for Medical Education and this news organization are owned by the same parent company.

Dr. Miller disclosed relationships with Edwards Lifesciences, and serving as a board member for the Perioperative Quality Initiative and as a founding member of the Morpheus Consortium.

The race to develop a SARS-CoV-2 vaccine is unlike any other global research and development effort in modern medicine.

According to Paul A. Offit, MD, there are now 120 Investigational New Drug applications to the Food and Drug Administration for these vaccines, and researchers at more than 70 companies across the globe are interested in making a vaccine. The Biomedical Advanced Research and Development Authority (BARDA) has awarded $2.5 billion to five different pharmaceutical companies to make a vaccine.

“The good news is that the new coronavirus is relatively stable,” Dr. Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, said during the virtual Pediatric Dermatology 2020: Best Practices and Innovations Conference. “Although it is a single-stranded RNA virus, it does mutate to some extent, but it doesn’t look like it’s going to mutate away from the vaccine. So, this is not going to be like influenza virus, where you must give a vaccine every year. I think we can make a vaccine that will last for several years. And we know the protein we’re interested in. We’re interested in antibodies directed against the spike glycoprotein, which is abundantly present on the surface of the virus. We know that if we make an antibody response to that protein, we can therefore prevent infection.”

Some research groups are interested in developing a whole, killed virus like those used in the inactivated polio vaccine, and vaccines for hepatitis A virus and rabies, said Dr. Offit, who is a member of Accelerating COVID-19 Technical Innovations And Vaccines, a public-private partnership formed by the National Institutes of Health. Other groups are interested in making a live-attenuated vaccine like those for measles, mumps, and rubella. “Some are interested in using a vectored vaccine, where you take a virus that is relatively weak and doesn’t cause disease in people, like vesicular stomatitis virus, and then clone into that the gene that codes for this coronavirus spike protein, which is the way that we made the Ebola virus vaccine,” Dr. Offit said. “Those approaches have all been used before, with success.”

Novel approaches are also being employed to make this vaccine, including using a replication-defective adenovirus. “That means that the virus can’t reproduce itself, but it can make proteins,” he explained. “There are some proteins that are made, but most aren’t. Therefore, the virus can’t reproduce itself. We’ll see whether or not that [approach] works, but it’s never been used before.”

Another approach is to inject messenger RNA that codes for the coronavirus spike protein, where that genetic material is translated into the spike protein. The other platform being evaluated is a DNA vaccine, in which “you give DNA which is coded for that spike protein, which is transcribed to messenger RNA and then is translated to other proteins.”

Typical vaccine development involves animal models to prove the concept, dose-ranging studies in humans, and progressively larger safety and immunogenicity studies in hundreds of thousands of people. Next come phase 3 studies, “where the proof is in the pudding,” he said. “These are large, prospective placebo-controlled trials to prove that the vaccine is safe. This is the only way whether you can prove or not a vaccine is effective.”

According to Dr. Offit, the phase 3 COVID-19 vaccine trials supported by BARDA will launch in July 2020 and will enroll 20,000 people in the vaccine treatment arm and 10,000 in the placebo arm. “Some companies may branch out on their own and do smaller studies than that,” he said. “We’ll see how this plays out. Keep your eyes open for that, because you really want to make sure you have a fairly large phase 3 trial. That’s the best way to show whether something works and whether it’s safe.”

The tried and true vaccines that emerge from the effort will not be FDA-licensed products. Rather, they will be approved products under the Emergency Use Authorization program. “Ever since the 1950s, every vaccine that has been used in the U.S. has been under the auspices of FDA licensure,” said Dr. Offit, who is also professor of pediatrics and the Maurice R. Hilleman professor of vaccinology at the University of Pennsylvania, Philadelphia. “That’s not going to be true here. The FDA is involved every step of the way but here they have a somewhat lighter touch.”

A few candidate vaccines are being mass-produced at risk, “meaning they’re being produced not knowing whether these vaccines are safe and effective yet or not,” he said. “But when they’re shown in a phase 3 trial to be safe and effective, you will have already produced it, and then it’s much easier to roll it out to the general public the minute you’ve shown that it works. This is what we did for the polio vaccine back in the 1950s. We mass-produced that vaccine at risk.”

Dr. Offit emphasized the importance of managing expectations once a COVID-19 vaccine gets approved for use. “Regarding safety, these vaccines will be tested in tens of thousands of people, not tens of millions of people, so although you can disprove a relatively uncommon side effect preapproval, you’re not going to disprove a rare side effect preapproval. You’re only going to know that post approval. I think we need to make people aware of that and to let them know that through groups like the Vaccine Safety Datalink, we’re going to be monitoring these vaccines once they’re approved.”

Regarding efficacy, he continued, “we’re not going know about the rates of immunity initially; we’re only going to know about that after the vaccine [has been administered]. My guess is the protection is going to be short lived and incomplete. By short lived, I mean that protection would last for years but not decades. By incomplete, I mean that protection will be against moderate to severe disease, which is fine. You don’t need protection against all of the disease; it’s hard to do that with respiratory viruses. That means you can keep people out of the hospital, and you can keep them from dying. That’s the main goal.”

Dr. Offit closed his remarks by noting that much is at stake in this effort to develop a vaccine so quickly and that it “could go one of two ways. We could find that the vaccine is a lifesaver, and [that] we can finally end this awful pandemic. Or, if we cut corners and don’t prove that the vaccines are safe and effective as we should before they’re released, we could shake what is a fragile vaccine confidence in this country. Hopefully, it doesn’t play out that way.”

dbrunk@mdedge.com

The race to develop a SARS-CoV-2 vaccine is unlike any other global research and development effort in modern medicine.

According to Paul A. Offit, MD, there are now 120 Investigational New Drug applications to the Food and Drug Administration for these vaccines, and researchers at more than 70 companies across the globe are interested in making a vaccine. The Biomedical Advanced Research and Development Authority (BARDA) has awarded $2.5 billion to five different pharmaceutical companies to make a vaccine.

“The good news is that the new coronavirus is relatively stable,” Dr. Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, said during the virtual Pediatric Dermatology 2020: Best Practices and Innovations Conference. “Although it is a single-stranded RNA virus, it does mutate to some extent, but it doesn’t look like it’s going to mutate away from the vaccine. So, this is not going to be like influenza virus, where you must give a vaccine every year. I think we can make a vaccine that will last for several years. And we know the protein we’re interested in. We’re interested in antibodies directed against the spike glycoprotein, which is abundantly present on the surface of the virus. We know that if we make an antibody response to that protein, we can therefore prevent infection.”

Some research groups are interested in developing a whole, killed virus like those used in the inactivated polio vaccine, and vaccines for hepatitis A virus and rabies, said Dr. Offit, who is a member of Accelerating COVID-19 Technical Innovations And Vaccines, a public-private partnership formed by the National Institutes of Health. Other groups are interested in making a live-attenuated vaccine like those for measles, mumps, and rubella. “Some are interested in using a vectored vaccine, where you take a virus that is relatively weak and doesn’t cause disease in people, like vesicular stomatitis virus, and then clone into that the gene that codes for this coronavirus spike protein, which is the way that we made the Ebola virus vaccine,” Dr. Offit said. “Those approaches have all been used before, with success.”

Novel approaches are also being employed to make this vaccine, including using a replication-defective adenovirus. “That means that the virus can’t reproduce itself, but it can make proteins,” he explained. “There are some proteins that are made, but most aren’t. Therefore, the virus can’t reproduce itself. We’ll see whether or not that [approach] works, but it’s never been used before.”

Another approach is to inject messenger RNA that codes for the coronavirus spike protein, where that genetic material is translated into the spike protein. The other platform being evaluated is a DNA vaccine, in which “you give DNA which is coded for that spike protein, which is transcribed to messenger RNA and then is translated to other proteins.”

Typical vaccine development involves animal models to prove the concept, dose-ranging studies in humans, and progressively larger safety and immunogenicity studies in hundreds of thousands of people. Next come phase 3 studies, “where the proof is in the pudding,” he said. “These are large, prospective placebo-controlled trials to prove that the vaccine is safe. This is the only way whether you can prove or not a vaccine is effective.”

According to Dr. Offit, the phase 3 COVID-19 vaccine trials supported by BARDA will launch in July 2020 and will enroll 20,000 people in the vaccine treatment arm and 10,000 in the placebo arm. “Some companies may branch out on their own and do smaller studies than that,” he said. “We’ll see how this plays out. Keep your eyes open for that, because you really want to make sure you have a fairly large phase 3 trial. That’s the best way to show whether something works and whether it’s safe.”

The tried and true vaccines that emerge from the effort will not be FDA-licensed products. Rather, they will be approved products under the Emergency Use Authorization program. “Ever since the 1950s, every vaccine that has been used in the U.S. has been under the auspices of FDA licensure,” said Dr. Offit, who is also professor of pediatrics and the Maurice R. Hilleman professor of vaccinology at the University of Pennsylvania, Philadelphia. “That’s not going to be true here. The FDA is involved every step of the way but here they have a somewhat lighter touch.”

A few candidate vaccines are being mass-produced at risk, “meaning they’re being produced not knowing whether these vaccines are safe and effective yet or not,” he said. “But when they’re shown in a phase 3 trial to be safe and effective, you will have already produced it, and then it’s much easier to roll it out to the general public the minute you’ve shown that it works. This is what we did for the polio vaccine back in the 1950s. We mass-produced that vaccine at risk.”

Dr. Offit emphasized the importance of managing expectations once a COVID-19 vaccine gets approved for use. “Regarding safety, these vaccines will be tested in tens of thousands of people, not tens of millions of people, so although you can disprove a relatively uncommon side effect preapproval, you’re not going to disprove a rare side effect preapproval. You’re only going to know that post approval. I think we need to make people aware of that and to let them know that through groups like the Vaccine Safety Datalink, we’re going to be monitoring these vaccines once they’re approved.”

Regarding efficacy, he continued, “we’re not going know about the rates of immunity initially; we’re only going to know about that after the vaccine [has been administered]. My guess is the protection is going to be short lived and incomplete. By short lived, I mean that protection would last for years but not decades. By incomplete, I mean that protection will be against moderate to severe disease, which is fine. You don’t need protection against all of the disease; it’s hard to do that with respiratory viruses. That means you can keep people out of the hospital, and you can keep them from dying. That’s the main goal.”

Dr. Offit closed his remarks by noting that much is at stake in this effort to develop a vaccine so quickly and that it “could go one of two ways. We could find that the vaccine is a lifesaver, and [that] we can finally end this awful pandemic. Or, if we cut corners and don’t prove that the vaccines are safe and effective as we should before they’re released, we could shake what is a fragile vaccine confidence in this country. Hopefully, it doesn’t play out that way.”

dbrunk@mdedge.com

The race to develop a SARS-CoV-2 vaccine is unlike any other global research and development effort in modern medicine.

According to Paul A. Offit, MD, there are now 120 Investigational New Drug applications to the Food and Drug Administration for these vaccines, and researchers at more than 70 companies across the globe are interested in making a vaccine. The Biomedical Advanced Research and Development Authority (BARDA) has awarded $2.5 billion to five different pharmaceutical companies to make a vaccine.

“The good news is that the new coronavirus is relatively stable,” Dr. Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, said during the virtual Pediatric Dermatology 2020: Best Practices and Innovations Conference. “Although it is a single-stranded RNA virus, it does mutate to some extent, but it doesn’t look like it’s going to mutate away from the vaccine. So, this is not going to be like influenza virus, where you must give a vaccine every year. I think we can make a vaccine that will last for several years. And we know the protein we’re interested in. We’re interested in antibodies directed against the spike glycoprotein, which is abundantly present on the surface of the virus. We know that if we make an antibody response to that protein, we can therefore prevent infection.”

Some research groups are interested in developing a whole, killed virus like those used in the inactivated polio vaccine, and vaccines for hepatitis A virus and rabies, said Dr. Offit, who is a member of Accelerating COVID-19 Technical Innovations And Vaccines, a public-private partnership formed by the National Institutes of Health. Other groups are interested in making a live-attenuated vaccine like those for measles, mumps, and rubella. “Some are interested in using a vectored vaccine, where you take a virus that is relatively weak and doesn’t cause disease in people, like vesicular stomatitis virus, and then clone into that the gene that codes for this coronavirus spike protein, which is the way that we made the Ebola virus vaccine,” Dr. Offit said. “Those approaches have all been used before, with success.”

Novel approaches are also being employed to make this vaccine, including using a replication-defective adenovirus. “That means that the virus can’t reproduce itself, but it can make proteins,” he explained. “There are some proteins that are made, but most aren’t. Therefore, the virus can’t reproduce itself. We’ll see whether or not that [approach] works, but it’s never been used before.”

Another approach is to inject messenger RNA that codes for the coronavirus spike protein, where that genetic material is translated into the spike protein. The other platform being evaluated is a DNA vaccine, in which “you give DNA which is coded for that spike protein, which is transcribed to messenger RNA and then is translated to other proteins.”

Typical vaccine development involves animal models to prove the concept, dose-ranging studies in humans, and progressively larger safety and immunogenicity studies in hundreds of thousands of people. Next come phase 3 studies, “where the proof is in the pudding,” he said. “These are large, prospective placebo-controlled trials to prove that the vaccine is safe. This is the only way whether you can prove or not a vaccine is effective.”

According to Dr. Offit, the phase 3 COVID-19 vaccine trials supported by BARDA will launch in July 2020 and will enroll 20,000 people in the vaccine treatment arm and 10,000 in the placebo arm. “Some companies may branch out on their own and do smaller studies than that,” he said. “We’ll see how this plays out. Keep your eyes open for that, because you really want to make sure you have a fairly large phase 3 trial. That’s the best way to show whether something works and whether it’s safe.”

The tried and true vaccines that emerge from the effort will not be FDA-licensed products. Rather, they will be approved products under the Emergency Use Authorization program. “Ever since the 1950s, every vaccine that has been used in the U.S. has been under the auspices of FDA licensure,” said Dr. Offit, who is also professor of pediatrics and the Maurice R. Hilleman professor of vaccinology at the University of Pennsylvania, Philadelphia. “That’s not going to be true here. The FDA is involved every step of the way but here they have a somewhat lighter touch.”

A few candidate vaccines are being mass-produced at risk, “meaning they’re being produced not knowing whether these vaccines are safe and effective yet or not,” he said. “But when they’re shown in a phase 3 trial to be safe and effective, you will have already produced it, and then it’s much easier to roll it out to the general public the minute you’ve shown that it works. This is what we did for the polio vaccine back in the 1950s. We mass-produced that vaccine at risk.”

Dr. Offit emphasized the importance of managing expectations once a COVID-19 vaccine gets approved for use. “Regarding safety, these vaccines will be tested in tens of thousands of people, not tens of millions of people, so although you can disprove a relatively uncommon side effect preapproval, you’re not going to disprove a rare side effect preapproval. You’re only going to know that post approval. I think we need to make people aware of that and to let them know that through groups like the Vaccine Safety Datalink, we’re going to be monitoring these vaccines once they’re approved.”

Regarding efficacy, he continued, “we’re not going know about the rates of immunity initially; we’re only going to know about that after the vaccine [has been administered]. My guess is the protection is going to be short lived and incomplete. By short lived, I mean that protection would last for years but not decades. By incomplete, I mean that protection will be against moderate to severe disease, which is fine. You don’t need protection against all of the disease; it’s hard to do that with respiratory viruses. That means you can keep people out of the hospital, and you can keep them from dying. That’s the main goal.”

Dr. Offit closed his remarks by noting that much is at stake in this effort to develop a vaccine so quickly and that it “could go one of two ways. We could find that the vaccine is a lifesaver, and [that] we can finally end this awful pandemic. Or, if we cut corners and don’t prove that the vaccines are safe and effective as we should before they’re released, we could shake what is a fragile vaccine confidence in this country. Hopefully, it doesn’t play out that way.”

dbrunk@mdedge.com