Liam Davenport

MUNICH – Adding carotid revascularization to optimized medical therapy (OMT) does not appear to offer a clinical benefit in patients with significant carotid stenosis and a low to intermediate 5-year risk of stroke, suggests a planned interim analysis of ECST-2.

Almost 430 patients with symptomatic and asymptomatic atherosclerotic carotid stenosis greater than or equal to 50% and a Carotid Artery Risk (CAR) score less than 20% were randomly assigned to OMT alone or OMT plus revascularization with carotid endarterectomy (CEA) or carotid artery stenting.

The study, which was presented at the annual European Stroke Organisation Conference, was stopped early because of slow recruitment.

Nevertheless, the current results showed that there was no significant difference at 2 years between the treatment groups in the rate of a composite endpoint, as well as the occurrence of any stroke, myocardial infarction, and periprocedural death.

In other words, “there was no evidence of benefit at 2 years from additional carotid revascularization” in patients with carotid stenosis who had a low to intermediate predicted stroke risk, said study presenter Paul Nederkoorn, MD, PhD, department of neurology, Amsterdam UMC, University of Amsterdam.

He added, however, that the complete 2 years will include additional analyses, including an analysis of silent infarcts on MRI, which may affect the results, and that longer clinical follow-up is required.

Future work will include the design and validation of a novel stroke risk prediction tool that will include MRI plaque imaging and will allow individualized patient selection for revascularization, as well as a cost-effectiveness analysis, he noted.
 

Conclusions ‘difficult’

Session co-chair Peter Kelly, MD, professor of neurology at Mater University Hospital/University College Dublin, and president-elect of the European Stroke Association, described the findings as “interesting” and that it was “great to see them.”

“I’m sure we’ll be discussing these results for a while,” he added.

But co-chair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the Stroke Unit, department of neurology, Oslo University Hospital, said that it’s “difficult to draw firm conclusions from the trial.”

The patients were highly selected, recruitment was “perhaps a bit too slow,” and the study was probably conducted over too many sites, she said in an interview.

Dr. Sandset also noted that the options available for OMT have changed over the course of the study, as well as the overall approach to management.

“We are more aware of how we should treat” these patients, and “we’re probably a bit more aggressive,” which will have shifted the outcomes in the comparator arm as the study progressed.

“That is the challenge of doing these trials that take many years to run – our practice changes.”
 

‘Old evidence’

In his presentation, Dr. Nederkoorn pointed out that, while the current guidelines for CEA are “robust,” they are based on “old evidence” from trials conducted 20-30 years ago.

During that time, he said, medical treatment has improved significantly, and the risk for stroke has approximately halved. Yet the decision to perform CEA is still largely based on the degree of stenosis and the patient’s symptom status.

Dr. Nederkoorn suggested, however, that factors such as plaque ulceration and patient characteristics and comorbidities might influence the risk-benefit ratio for revascularization.

The current trial was therefore established to test the hypothesis that patients with carotid stenosis greater than or equal to 50% and a low to intermediate risk of stroke will not benefit from additional carotid revascularization on top of optimized medical therapy.

The team conducted a prospective, multicenter, open clinical trial in which patients with both symptomatic and asymptomatic atherosclerotic carotid stenosis were randomly assigned to revascularization plus OMT or OMT alone.

Dr. Nederkoorn explained that a low to intermediate 5-year risk for stroke was established using the CAR score less than 20%.

This is based on a range of parameters, including the sex and age of the patient, degree of stenosis, the type of and time since the event, and the presence of comorbidities, among other factors.

He said that the data was originally derived from the NASCET trial, which was published in 1998, and the first ECST trial, published in the same year.

Since then, the risk of ipsilateral stroke has “strongly declined,” Dr. Nederkoorn said, and so the CAR score was recalibrated to reflect the likely benefit of current OMT.

For the trial, OMT included antihypertensive and cholesterol-lowering medications, and dietary changes, alongside antiplatelet agents and anticoagulation, if indicated, to achieve predefined, guideline-led lipid and blood pressure targets.

Revascularization included CEA and coronary artery stenting in selected patients and was recommended to be performed within 2 weeks of randomization in symptomatic patients and within 4 weeks in asymptomatic patients.

When the trial started in 2012, the intention was to recruit 2,000 patients, with a planned interim analysis after enrollment of 320 patients.

However, recruitment was suspended in 2019, with 429 patients having been enrolled, as it was clear that achieving a cohort of 2,000 patients was “not practical without a change in the trial design” to include MRI plaque imaging and without further funding.

Dr. Nederkoorn showed that the baseline characteristics of the OMT and revascularization plus OMT groups were comparable. The average age of the patients in the groups was 71-72 years, and 31% were female.

Symptomatic disease was present in about 40% of patients, and about 76% had hypertension. Type 2 diabetes was reported in roughly one-quarter of the patients.

There was no difference in the time from randomization to the revascularization procedure between patients with asymptomatic and symptomatic disease.

Moving to the primary outcome, which was a composite of periprocedural death within 90 days of randomization and clinically manifest stroke or myocardial infarction at 2 years, Dr. Nederkoorn showed that there was no significant difference between the treatment groups.

Despite a suggestion that patients undergoing revascularization experienced “more harm” in the initial follow-up period, particularly in patients with a CAR score greater than 10%, the event curves met at around 18 months.

Overall, the hazard ratio between revascularization plus OMT versus OMT alone was 0.96 (95% confidence interval, 0.53-1.76, P = .90).

Breaking down the composite endpoint, there was a numerically lower rate of any stroke with OMT alone, compared with revascularization plus OMT over the study period, but again the difference was not significant at 2 years, at a hazard ratio of 0.68 (95% CI, 0.32-1.42, P = .30).

There was only one case of periprocedural death, in the revascularization arm. Although myocardial infarction was numerically twice as likely with OMT alone, compared with the combined intervention arm, the difference was not significant, at a hazard ratio of 2.00 (95% CI, 0.68-5.84, P = .21).

The study was funded by the National Institute for Health and Care Research, the Swiss National Science Foundation, The Netherlands Organisation of Scientific Research, and the Leeds Neurology Foundation. No relevant financial relationships were declared.

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

MUNICH – Adding carotid revascularization to optimized medical therapy (OMT) does not appear to offer a clinical benefit in patients with significant carotid stenosis and a low to intermediate 5-year risk of stroke, suggests a planned interim analysis of ECST-2.

Almost 430 patients with symptomatic and asymptomatic atherosclerotic carotid stenosis greater than or equal to 50% and a Carotid Artery Risk (CAR) score less than 20% were randomly assigned to OMT alone or OMT plus revascularization with carotid endarterectomy (CEA) or carotid artery stenting.

The study, which was presented at the annual European Stroke Organisation Conference, was stopped early because of slow recruitment.

Nevertheless, the current results showed that there was no significant difference at 2 years between the treatment groups in the rate of a composite endpoint, as well as the occurrence of any stroke, myocardial infarction, and periprocedural death.

In other words, “there was no evidence of benefit at 2 years from additional carotid revascularization” in patients with carotid stenosis who had a low to intermediate predicted stroke risk, said study presenter Paul Nederkoorn, MD, PhD, department of neurology, Amsterdam UMC, University of Amsterdam.

He added, however, that the complete 2 years will include additional analyses, including an analysis of silent infarcts on MRI, which may affect the results, and that longer clinical follow-up is required.

Future work will include the design and validation of a novel stroke risk prediction tool that will include MRI plaque imaging and will allow individualized patient selection for revascularization, as well as a cost-effectiveness analysis, he noted.
 

Conclusions ‘difficult’

Session co-chair Peter Kelly, MD, professor of neurology at Mater University Hospital/University College Dublin, and president-elect of the European Stroke Association, described the findings as “interesting” and that it was “great to see them.”

“I’m sure we’ll be discussing these results for a while,” he added.

But co-chair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the Stroke Unit, department of neurology, Oslo University Hospital, said that it’s “difficult to draw firm conclusions from the trial.”

The patients were highly selected, recruitment was “perhaps a bit too slow,” and the study was probably conducted over too many sites, she said in an interview.

Dr. Sandset also noted that the options available for OMT have changed over the course of the study, as well as the overall approach to management.

“We are more aware of how we should treat” these patients, and “we’re probably a bit more aggressive,” which will have shifted the outcomes in the comparator arm as the study progressed.

“That is the challenge of doing these trials that take many years to run – our practice changes.”
 

‘Old evidence’

In his presentation, Dr. Nederkoorn pointed out that, while the current guidelines for CEA are “robust,” they are based on “old evidence” from trials conducted 20-30 years ago.

During that time, he said, medical treatment has improved significantly, and the risk for stroke has approximately halved. Yet the decision to perform CEA is still largely based on the degree of stenosis and the patient’s symptom status.

Dr. Nederkoorn suggested, however, that factors such as plaque ulceration and patient characteristics and comorbidities might influence the risk-benefit ratio for revascularization.

The current trial was therefore established to test the hypothesis that patients with carotid stenosis greater than or equal to 50% and a low to intermediate risk of stroke will not benefit from additional carotid revascularization on top of optimized medical therapy.

The team conducted a prospective, multicenter, open clinical trial in which patients with both symptomatic and asymptomatic atherosclerotic carotid stenosis were randomly assigned to revascularization plus OMT or OMT alone.

Dr. Nederkoorn explained that a low to intermediate 5-year risk for stroke was established using the CAR score less than 20%.

This is based on a range of parameters, including the sex and age of the patient, degree of stenosis, the type of and time since the event, and the presence of comorbidities, among other factors.

He said that the data was originally derived from the NASCET trial, which was published in 1998, and the first ECST trial, published in the same year.

Since then, the risk of ipsilateral stroke has “strongly declined,” Dr. Nederkoorn said, and so the CAR score was recalibrated to reflect the likely benefit of current OMT.

For the trial, OMT included antihypertensive and cholesterol-lowering medications, and dietary changes, alongside antiplatelet agents and anticoagulation, if indicated, to achieve predefined, guideline-led lipid and blood pressure targets.

Revascularization included CEA and coronary artery stenting in selected patients and was recommended to be performed within 2 weeks of randomization in symptomatic patients and within 4 weeks in asymptomatic patients.

When the trial started in 2012, the intention was to recruit 2,000 patients, with a planned interim analysis after enrollment of 320 patients.

However, recruitment was suspended in 2019, with 429 patients having been enrolled, as it was clear that achieving a cohort of 2,000 patients was “not practical without a change in the trial design” to include MRI plaque imaging and without further funding.

Dr. Nederkoorn showed that the baseline characteristics of the OMT and revascularization plus OMT groups were comparable. The average age of the patients in the groups was 71-72 years, and 31% were female.

Symptomatic disease was present in about 40% of patients, and about 76% had hypertension. Type 2 diabetes was reported in roughly one-quarter of the patients.

There was no difference in the time from randomization to the revascularization procedure between patients with asymptomatic and symptomatic disease.

Moving to the primary outcome, which was a composite of periprocedural death within 90 days of randomization and clinically manifest stroke or myocardial infarction at 2 years, Dr. Nederkoorn showed that there was no significant difference between the treatment groups.

Despite a suggestion that patients undergoing revascularization experienced “more harm” in the initial follow-up period, particularly in patients with a CAR score greater than 10%, the event curves met at around 18 months.

Overall, the hazard ratio between revascularization plus OMT versus OMT alone was 0.96 (95% confidence interval, 0.53-1.76, P = .90).

Breaking down the composite endpoint, there was a numerically lower rate of any stroke with OMT alone, compared with revascularization plus OMT over the study period, but again the difference was not significant at 2 years, at a hazard ratio of 0.68 (95% CI, 0.32-1.42, P = .30).

There was only one case of periprocedural death, in the revascularization arm. Although myocardial infarction was numerically twice as likely with OMT alone, compared with the combined intervention arm, the difference was not significant, at a hazard ratio of 2.00 (95% CI, 0.68-5.84, P = .21).

The study was funded by the National Institute for Health and Care Research, the Swiss National Science Foundation, The Netherlands Organisation of Scientific Research, and the Leeds Neurology Foundation. No relevant financial relationships were declared.

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

MUNICH – Adding carotid revascularization to optimized medical therapy (OMT) does not appear to offer a clinical benefit in patients with significant carotid stenosis and a low to intermediate 5-year risk of stroke, suggests a planned interim analysis of ECST-2.

Almost 430 patients with symptomatic and asymptomatic atherosclerotic carotid stenosis greater than or equal to 50% and a Carotid Artery Risk (CAR) score less than 20% were randomly assigned to OMT alone or OMT plus revascularization with carotid endarterectomy (CEA) or carotid artery stenting.

The study, which was presented at the annual European Stroke Organisation Conference, was stopped early because of slow recruitment.

Nevertheless, the current results showed that there was no significant difference at 2 years between the treatment groups in the rate of a composite endpoint, as well as the occurrence of any stroke, myocardial infarction, and periprocedural death.

In other words, “there was no evidence of benefit at 2 years from additional carotid revascularization” in patients with carotid stenosis who had a low to intermediate predicted stroke risk, said study presenter Paul Nederkoorn, MD, PhD, department of neurology, Amsterdam UMC, University of Amsterdam.

He added, however, that the complete 2 years will include additional analyses, including an analysis of silent infarcts on MRI, which may affect the results, and that longer clinical follow-up is required.

Future work will include the design and validation of a novel stroke risk prediction tool that will include MRI plaque imaging and will allow individualized patient selection for revascularization, as well as a cost-effectiveness analysis, he noted.
 

Conclusions ‘difficult’

Session co-chair Peter Kelly, MD, professor of neurology at Mater University Hospital/University College Dublin, and president-elect of the European Stroke Association, described the findings as “interesting” and that it was “great to see them.”

“I’m sure we’ll be discussing these results for a while,” he added.

But co-chair Else Charlotte Sandset, MD, PhD, a consultant neurologist in the Stroke Unit, department of neurology, Oslo University Hospital, said that it’s “difficult to draw firm conclusions from the trial.”

The patients were highly selected, recruitment was “perhaps a bit too slow,” and the study was probably conducted over too many sites, she said in an interview.

Dr. Sandset also noted that the options available for OMT have changed over the course of the study, as well as the overall approach to management.

“We are more aware of how we should treat” these patients, and “we’re probably a bit more aggressive,” which will have shifted the outcomes in the comparator arm as the study progressed.

“That is the challenge of doing these trials that take many years to run – our practice changes.”
 

‘Old evidence’

In his presentation, Dr. Nederkoorn pointed out that, while the current guidelines for CEA are “robust,” they are based on “old evidence” from trials conducted 20-30 years ago.

During that time, he said, medical treatment has improved significantly, and the risk for stroke has approximately halved. Yet the decision to perform CEA is still largely based on the degree of stenosis and the patient’s symptom status.

Dr. Nederkoorn suggested, however, that factors such as plaque ulceration and patient characteristics and comorbidities might influence the risk-benefit ratio for revascularization.

The current trial was therefore established to test the hypothesis that patients with carotid stenosis greater than or equal to 50% and a low to intermediate risk of stroke will not benefit from additional carotid revascularization on top of optimized medical therapy.

The team conducted a prospective, multicenter, open clinical trial in which patients with both symptomatic and asymptomatic atherosclerotic carotid stenosis were randomly assigned to revascularization plus OMT or OMT alone.

Dr. Nederkoorn explained that a low to intermediate 5-year risk for stroke was established using the CAR score less than 20%.

This is based on a range of parameters, including the sex and age of the patient, degree of stenosis, the type of and time since the event, and the presence of comorbidities, among other factors.

He said that the data was originally derived from the NASCET trial, which was published in 1998, and the first ECST trial, published in the same year.

Since then, the risk of ipsilateral stroke has “strongly declined,” Dr. Nederkoorn said, and so the CAR score was recalibrated to reflect the likely benefit of current OMT.

For the trial, OMT included antihypertensive and cholesterol-lowering medications, and dietary changes, alongside antiplatelet agents and anticoagulation, if indicated, to achieve predefined, guideline-led lipid and blood pressure targets.

Revascularization included CEA and coronary artery stenting in selected patients and was recommended to be performed within 2 weeks of randomization in symptomatic patients and within 4 weeks in asymptomatic patients.

When the trial started in 2012, the intention was to recruit 2,000 patients, with a planned interim analysis after enrollment of 320 patients.

However, recruitment was suspended in 2019, with 429 patients having been enrolled, as it was clear that achieving a cohort of 2,000 patients was “not practical without a change in the trial design” to include MRI plaque imaging and without further funding.

Dr. Nederkoorn showed that the baseline characteristics of the OMT and revascularization plus OMT groups were comparable. The average age of the patients in the groups was 71-72 years, and 31% were female.

Symptomatic disease was present in about 40% of patients, and about 76% had hypertension. Type 2 diabetes was reported in roughly one-quarter of the patients.

There was no difference in the time from randomization to the revascularization procedure between patients with asymptomatic and symptomatic disease.

Moving to the primary outcome, which was a composite of periprocedural death within 90 days of randomization and clinically manifest stroke or myocardial infarction at 2 years, Dr. Nederkoorn showed that there was no significant difference between the treatment groups.

Despite a suggestion that patients undergoing revascularization experienced “more harm” in the initial follow-up period, particularly in patients with a CAR score greater than 10%, the event curves met at around 18 months.

Overall, the hazard ratio between revascularization plus OMT versus OMT alone was 0.96 (95% confidence interval, 0.53-1.76, P = .90).

Breaking down the composite endpoint, there was a numerically lower rate of any stroke with OMT alone, compared with revascularization plus OMT over the study period, but again the difference was not significant at 2 years, at a hazard ratio of 0.68 (95% CI, 0.32-1.42, P = .30).

There was only one case of periprocedural death, in the revascularization arm. Although myocardial infarction was numerically twice as likely with OMT alone, compared with the combined intervention arm, the difference was not significant, at a hazard ratio of 2.00 (95% CI, 0.68-5.84, P = .21).

The study was funded by the National Institute for Health and Care Research, the Swiss National Science Foundation, The Netherlands Organisation of Scientific Research, and the Leeds Neurology Foundation. No relevant financial relationships were declared.

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

MANNHEIM, GERMANY – Half of patients who die from homozygous familial hypercholesterolemia (HoFH) do so by age 32 years, new registry data show.

The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.

Even those who received treatment had high LDL cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.

Worryingly, the results showed that the median age at death was 32 years. Results were presented at the annual congress of the European Atherosclerosis Society.

Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the department of internal medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
 

Call to action

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, and Secretary of the EAS, described the results as “terrifying.”

He said in an interview that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”

Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a proprotein convertase subtilisin/kexin type 9 inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.

“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.

“This is something that we should focus on for these patients from the beginning,” said Dr. Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”

He emphasized that clinicians have everything at hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”

“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Dr. Banach added.
 

Rare genetic condition

Presenting her findings, Ms. Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”

This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.

Ms. Mulder pointed out that, although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.

To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Ms. Mulder said.

It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.

Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.

The median age at diagnosis was 12 years, Ms. Mulder said, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.

Ms. Mulder also noted that, at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.

In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.

Ms. Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly ... 26% of the deceased patients had only one or no treatment.”

Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L versus 15.6 mmol/L among those who were untreated.

There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.

The median age of onset for ASCVD was 28 years. Ms. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” About 70% of patients experienced recurrent ASCVD.

There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Ms. Mulder said. Death was confirmed as stemming from cardiovascular causes in 76% of cases.

During the postpresentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville (Spain), highlighted that, if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.

“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Dr. Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration.

Ms. Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”

She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.

Ms. Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.

No funding or relevant financial relationships were declared.

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

MANNHEIM, GERMANY – Half of patients who die from homozygous familial hypercholesterolemia (HoFH) do so by age 32 years, new registry data show.

The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.

Even those who received treatment had high LDL cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.

Worryingly, the results showed that the median age at death was 32 years. Results were presented at the annual congress of the European Atherosclerosis Society.

Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the department of internal medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
 

Call to action

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, and Secretary of the EAS, described the results as “terrifying.”

He said in an interview that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”

Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a proprotein convertase subtilisin/kexin type 9 inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.

“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.

“This is something that we should focus on for these patients from the beginning,” said Dr. Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”

He emphasized that clinicians have everything at hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”

“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Dr. Banach added.
 

Rare genetic condition

Presenting her findings, Ms. Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”

This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.

Ms. Mulder pointed out that, although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.

To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Ms. Mulder said.

It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.

Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.

The median age at diagnosis was 12 years, Ms. Mulder said, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.

Ms. Mulder also noted that, at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.

In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.

Ms. Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly ... 26% of the deceased patients had only one or no treatment.”

Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L versus 15.6 mmol/L among those who were untreated.

There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.

The median age of onset for ASCVD was 28 years. Ms. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” About 70% of patients experienced recurrent ASCVD.

There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Ms. Mulder said. Death was confirmed as stemming from cardiovascular causes in 76% of cases.

During the postpresentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville (Spain), highlighted that, if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.

“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Dr. Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration.

Ms. Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”

She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.

Ms. Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.

No funding or relevant financial relationships were declared.

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

MANNHEIM, GERMANY – Half of patients who die from homozygous familial hypercholesterolemia (HoFH) do so by age 32 years, new registry data show.

The researchers looked at almost 40 patients from the HoFH International Clinical Collaborators (HICC) registry who had died before data entry, finding that they had a mean age of diagnosis of 12 years.

Even those who received treatment had high LDL cholesterol levels, and 70% developed atherosclerotic cardiovascular disease (ASCVD) at a median age of 28 years.

Worryingly, the results showed that the median age at death was 32 years. Results were presented at the annual congress of the European Atherosclerosis Society.

Patients with HoFH “have severe atherosclerotic cardiovascular disease risk,” said study presenter Janneke Mulder, a PhD candidate at the department of internal medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.

“Therefore, early diagnosis and initiation of treatments, and also a combination of treatments, is really crucial,” she added.
 

Call to action

Approached for comment, Maciej Banach, MD, PhD, full professor of cardiology, Polish Mother’s Memorial Hospital Research Institute, Lodz, and Secretary of the EAS, described the results as “terrifying.”

He said in an interview that they are a “call to action,” especially given that so few patients in the study received intensive combination lipid-lowering therapy despite having a baseline LDL cholesterol level that was “very, very high.”

Banach underlined that patients who receive triple lipid-lowering therapy with a high-intensity statin, ezetimibe (Nustendi), and a proprotein convertase subtilisin/kexin type 9 inhibitor, could expect, based on current evidence, to see their LDL cholesterol levels reduced by 85% and be on target.

“Obviously, this is kind of academic,” because in the real-world “this 85% is not observed very often,” but it offers a target for steep reductions in cholesterol levels.

“This is something that we should focus on for these patients from the beginning,” said Dr. Banach, either with a stepwise approach “or for experts in pediatric HoFH, “maybe immediately.”

He emphasized that clinicians have everything at hand to “be both effective in the early diagnosis of HoFH, the earlier the better, and obviously to be effective with its treatment.”

“We should do something to prolong the lives of those people,” because the current results are “terrifying,” Dr. Banach added.
 

Rare genetic condition

Presenting her findings, Ms. Mulder began by highlighting that HoFH is a “rare genetic condition that occurs due to mutations in cholesterol metabolism.”

This, she continued, leads to “severely increased LDL cholesterol levels, and consequently to very premature cardiovascular disease,” with patients potentially experiencing their first cardiovascular event before age 20 years.

Ms. Mulder pointed out that, although there have been case series in the literature on HoFH, they have had “limited numbers” and patients have typically spent decades being treated at the same lipid management clinic.

To broaden the understanding of the clinical characteristics and management of patients dying with HoFH, the team examined data from the HICC registry, which is “the largest contemporary database of homozygous FH patients,” Ms. Mulder said.

It includes 751 patients with HoFH from 88 centers in 38 countries who were alive in 2010 or later. Data entry was between 2016 and 2020. The current analysis focused on 37 patients who had already died by the time they were included on the registry.

Of those, 49% were women, 38% were of White ethnicity, and 43% were from high-income countries.

The median age at diagnosis was 12 years, Ms. Mulder said, explaining that this is similar to that seen in other studies. The majority (86%) underwent genetic testing, and 92% presented with xanthomas.

Ms. Mulder also noted that, at their final clinical evaluation, which was conducted a median age of 18 years after their initial diagnosis, 43% of patients were recorded as current or former smokers.

In terms of their lipid-lowering therapy, 94% were taking a statin, whereas 68% were on ezetimibe, and 23% were undergoing apheresis.

Ms. Mulder said that the median number of lipid-lowering therapies per patient was two, and that “sadly ... 26% of the deceased patients had only one or no treatment.”

Therefore, perhaps unsurprisingly even those patients who were receiving treatment had LDL cholesterol levels that were “too high,” at 9.4 mmol/L versus 15.6 mmol/L among those who were untreated.

There was a high prevalence of ASCVD, at 70% overall, or 41% for aortic stenosis, 30% for myocardial infarction, 30% for angina pectoris, and 22% each for aortic valve replacement and coronary artery bypass grafting. In addition, 19% underwent percutaneous coronary intervention.

The median age of onset for ASCVD was 28 years. Ms. Mulder pointed out, however, that, as data were not available for all patients, “this might be an underestimation.” About 70% of patients experienced recurrent ASCVD.

There was a wide range in the age at which patients with HoFH died, although the median was, “strikingly,” 32 years, Ms. Mulder said. Death was confirmed as stemming from cardiovascular causes in 76% of cases.

During the postpresentation discussion, session chair Antonio J. Vallejo-Vaz, PhD, from the Research Group of Clinical Epidemiology and Vascular Risk, Institute of Biomedicine of Seville (Spain), highlighted that, if 38% of the patients were of White ethnicity, then the remainder must therefore be from other ethnic groups.

“There could be potential issues with accessibility to lipid centers” for these patients, which could affect the findings, noted Dr. Vallejo-Vaz, who is also chief scientist of the EAS Familial Hypercholesterolaemia Studies Collaboration.

Ms. Mulder agreed, replying that their results, though already striking, may be an underestimation because the patients were all from either high or middle-income countries, “so it would be good to have some data on low-income countries.”

She was also asked about two patients who died at a much older age than did the others, at ages 70 years and 86 years, respectively, and whether they had, for example, a protective genetic mutation.

Ms. Mulder said that they do not yet know, but they are planning an extended case series on these and other long-lived patients so that they can be investigated further.

No funding or relevant financial relationships were declared.

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

Twice-daily esmolol hydrochloride gel (Galnobax, NovaLead) appears to significantly improve closure of diabetic foot ulcers, particularly in patients with risk factors for impeded wound healing, say Indian researchers.
 

Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.

As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.

The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.

The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m² and in those who weighed more than 80 kg (176 lb).

“The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers,” wrote Ashu Rastogi, MD, DM, department of endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.

Dr. Rastogi first presented the findings at the 2022 annual meeting of the European Association for the Study of Diabetes. The results were well received, with one clinician describing them as “astounding.”

However, Andrew Boulton, MD, PhD, said in an interview that, although the final published data are “interesting,” they “need further confirmation” because “there are one or two unusual features” about the study. Dr. Boulton is a professor of medicine, division of diabetes, endocrinology & gastroenterology, at the University of Manchester (England).

He highlighted that the study was of “basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy.”

In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Dr. Boulton explained is “very unusual and would therefore include some atypical and not truly diabetic ‘foot’ ulcers.”

And Frances Game, MBBCh, department of diabetes and endocrinology, University Hospitals of Derby (England) and Burton NHS Foundation Trust, added that there are questions about the study methodology.

She said in an interview that although it is a “fascinating study,” the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. “How were they blinded [to treatment]?”

The “biggest problem” with the study, however, is that the primary outcome was reported as a per-protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.

“That kind of makes [esmolol gel] look better than it is because they’ve taken out the ones who got worse,” Dr. Game noted. However, the findings, while not conclusive, do warrant further study of esmolol gel.

The authors noted that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.

Moreover, “even with the best therapy,” such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative-pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.

Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.

The current phase 3, randomized, controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.

Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups: esmolol 14% gel plus standard of care, standard of care only, or vehicle plus standard of care.

The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.

Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.

In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average hemoglobin A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm² and the average ulcer duration was 49.8 weeks.

The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.

Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group (odds ratio, 2.13; P = .03).

The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.

In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone (OR, 1.72; P = .01).

Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 (OR, 2.72; P = .03).

Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious. “However, none of the serious adverse events were considered as drug-related by the investigators,” concluded the researchers.

The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Dr. Rastogi reported no relevant financial relationships.

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

Twice-daily esmolol hydrochloride gel (Galnobax, NovaLead) appears to significantly improve closure of diabetic foot ulcers, particularly in patients with risk factors for impeded wound healing, say Indian researchers.
 

Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.

As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.

The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.

The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m² and in those who weighed more than 80 kg (176 lb).

“The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers,” wrote Ashu Rastogi, MD, DM, department of endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.

Dr. Rastogi first presented the findings at the 2022 annual meeting of the European Association for the Study of Diabetes. The results were well received, with one clinician describing them as “astounding.”

However, Andrew Boulton, MD, PhD, said in an interview that, although the final published data are “interesting,” they “need further confirmation” because “there are one or two unusual features” about the study. Dr. Boulton is a professor of medicine, division of diabetes, endocrinology & gastroenterology, at the University of Manchester (England).

He highlighted that the study was of “basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy.”

In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Dr. Boulton explained is “very unusual and would therefore include some atypical and not truly diabetic ‘foot’ ulcers.”

And Frances Game, MBBCh, department of diabetes and endocrinology, University Hospitals of Derby (England) and Burton NHS Foundation Trust, added that there are questions about the study methodology.

She said in an interview that although it is a “fascinating study,” the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. “How were they blinded [to treatment]?”

The “biggest problem” with the study, however, is that the primary outcome was reported as a per-protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.

“That kind of makes [esmolol gel] look better than it is because they’ve taken out the ones who got worse,” Dr. Game noted. However, the findings, while not conclusive, do warrant further study of esmolol gel.

The authors noted that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.

Moreover, “even with the best therapy,” such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative-pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.

Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.

The current phase 3, randomized, controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.

Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups: esmolol 14% gel plus standard of care, standard of care only, or vehicle plus standard of care.

The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.

Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.

In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average hemoglobin A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm² and the average ulcer duration was 49.8 weeks.

The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.

Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group (odds ratio, 2.13; P = .03).

The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.

In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone (OR, 1.72; P = .01).

Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 (OR, 2.72; P = .03).

Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious. “However, none of the serious adverse events were considered as drug-related by the investigators,” concluded the researchers.

The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Dr. Rastogi reported no relevant financial relationships.

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

Twice-daily esmolol hydrochloride gel (Galnobax, NovaLead) appears to significantly improve closure of diabetic foot ulcers, particularly in patients with risk factors for impeded wound healing, say Indian researchers.
 

Esmolol is a short-acting beta-adrenergic receptor blocker that is currently approved by the Food and Drug Administration for cardiac indications such as short-term use for supraventricular tachycardia.

As a gel, esmolol hydrochloride is administered topically to stimulate wound healing via mechanisms such as the migration of keratinocytes, fibroblasts, and endothelial cells into wound tissue.

The current trial enrolled patients with type 1 or 2 diabetes, finding that, among 140 assessed, target ulcer closure within 12 weeks was more than twice as likely in those assigned esmolol gel plus standard of care than those given standard of care alone.

The impact of adding esmolol gel to standard of care was even greater in patients with a body mass index (BMI) over 25 kg/m² and in those who weighed more than 80 kg (176 lb).

“The use of esmolol in the treatment of diabetic foot ulcers in addition to standard of care may be an important addition to the endeavor of healing diabetic foot ulcers,” wrote Ashu Rastogi, MD, DM, department of endocrinology, Post Graduate Institute of Medical Education and Research, Chandigarh, India, and colleagues, in their article recently published in JAMA Network Open.

Dr. Rastogi first presented the findings at the 2022 annual meeting of the European Association for the Study of Diabetes. The results were well received, with one clinician describing them as “astounding.”

However, Andrew Boulton, MD, PhD, said in an interview that, although the final published data are “interesting,” they “need further confirmation” because “there are one or two unusual features” about the study. Dr. Boulton is a professor of medicine, division of diabetes, endocrinology & gastroenterology, at the University of Manchester (England).

He highlighted that the study was of “basically neuropathic ulcers, many of which were plantar and should be able to heal without any specific additional therapy.”

In addition, the inclusion criteria state that the ulcers could be below the malleoli or 5 cm above them, which Dr. Boulton explained is “very unusual and would therefore include some atypical and not truly diabetic ‘foot’ ulcers.”

And Frances Game, MBBCh, department of diabetes and endocrinology, University Hospitals of Derby (England) and Burton NHS Foundation Trust, added that there are questions about the study methodology.

She said in an interview that although it is a “fascinating study,” the main comparison group did not receive vehicle, or placebo, gel in addition to standard of care. “How were they blinded [to treatment]?”

The “biggest problem” with the study, however, is that the primary outcome was reported as a per-protocol endpoint, not as a standard intention-to-treat analysis, which allowed the researchers to exclude patients whose ulcers increased in size by over 30% on two consecutive visits.

“That kind of makes [esmolol gel] look better than it is because they’ve taken out the ones who got worse,” Dr. Game noted. However, the findings, while not conclusive, do warrant further study of esmolol gel.

The authors noted that diabetic foot ulcers are a severe complication of diabetes, with a prevalence of 1.3%-12.0% across various countries, And the complication contributes to patient morbidity and mortality, with a 5-year mortality that is substantially higher than that of many cancers.

Moreover, “even with the best therapy,” such as advanced moist wound therapy, bioengineered tissue or skin substitutes, peptides, growth factors, electric stimulation, and negative-pressure wound therapy, just 30% of wounds linked to diabetes heal and recurrence is as high as 70%.

Against this backdrop, topical esmolol 14% gel was shown in a phase 1/2 study to be associated with ulcer area reduction and earlier wound closure versus standard of care plus a control vehicle gel.

The current phase 3, randomized, controlled trial involved individuals aged 18-75 years with type 1 or type 2 diabetes and noninfected diabetic foot ulcers classified as grade 1A and 1C on the University of Texas Wound Classification System, which had been open for at least 6 weeks and had an area of 2-25 cm2.

Patients from 27 tertiary care centers across India were enrolled in 2018-2020. They were randomized in a 3:3:1 ratio to one of three groups: esmolol 14% gel plus standard of care, standard of care only, or vehicle plus standard of care.

The study lasted 25 weeks and included a 1-week screening phase, during which all patients received standard of care, a 12-week treatment phase, and a 12-week follow-up phase. The latter included a closure confirmation period of 4 weeks and an observation period of 8 weeks.

Patients were assessed once a week during the treatment phase, and then at weeks 14, 16, 20, and 24.

In all, 176 patients were enrolled. Participants were a mean age of 56.4 years and 69.3% were men. Average hemoglobin A1c was 8.6%. Mean diabetic foot ulcer area was 4.7 cm² and the average ulcer duration was 49.8 weeks.

The primary outcome was the proportion of patients who achieved target ulcer closure during the 12-week treatment phase and was assessed in 140 patients.

Overall, 60.3% of patients treated with esmolol gel plus standard of care achieved target ulcer closure versus 41.7% of those in the standard of care alone group (odds ratio, 2.13; P = .03).

The secondary outcome was the proportion of patients with target ulcer closure by the study end and was assessed in 120 patients.

In total, 77.2% of patients in the esmolol gel plus standard of care group met the secondary endpoint, compared with 55.6% of those receiving standard of care alone (OR, 1.72; P = .01).

Further analysis suggested the benefit seen with esmolol gel plus standard of care was greater in patients with a weight greater than 80 kg versus standard of care alone (OR, 4.04; P = .04), and in those with a BMI greater than 25 (OR, 2.72; P = .03).

Treatment-emergent adverse events were reported by 33 (18.8%) participants, with 12 events deemed serious. “However, none of the serious adverse events were considered as drug-related by the investigators,” concluded the researchers.

The study was partly funded by NovaLead Pharma and the Biotechnology Industry Research Assistance Council, New Delhi, set up by the Department of Biotechnology, Government of India. Dr. Rastogi reported no relevant financial relationships.

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

Certain relatives of women with early onset breast cancer appear to face an increased risk of other early-onset cancers, a Finnish population-based study suggests.

The researchers found, for instance, that children of breast cancer patients had a 27% higher risk of any discordant early-onset cancer, and patients’ siblings had a 7.6-fold higher risk of early pancreatic cancer. The analysis also indicated that children of patients’ siblings had a significantly increased risk of testicular and ovarian cancers.

“The findings suggest that the familial risk extends to discordant early-onset cancers, including ovarian, testicular, and pancreatic cancers, as well as beyond first-degree relatives,” the researchers, led by Janne M. Pitkäniemi, PhD, Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, say. “Our findings are interesting but raise some questions about unknown [genetic] and environmental mechanisms that need to be further studied.”

Erin F. Cobain, MD, who was not involved in the research, said the findings are “not very surprising to me.”

Dr. Cobain said that at her institution, she has seen “many, many cases” of family members of early-onset breast cancer patients with discordant cancers “where we are unable to find a clear genetic cause.”

Not being able to find an identifiable cause for the clustering of early-onset cancers can be “very frustrating” for patients and their families, said Dr. Cobain, a medical oncologist at the University of Michigan Health, Ann Arbor.

The study was published online in the International Journal of Cancer.

Family members of patients with early-onset breast cancer are at elevated risk for early-onset breast cancer. However, it is “unclear whether the familial risk is limited to early-onset cancer of the same site,” the authors explained.

To investigate, the researchers studied data from the Finnish Cancer Registry and the Finnish Population System, which included 54,753 relatives from 5,562 families of females diagnosed with early-onset breast cancer, defined as probands. A proband was the first member of the family diagnosed with female breast cancer at age 40 years or younger in Finland between January 1970 and December 31, 2012. Cancers were considered familial if they occurred in a family with a previously diagnosed proband and were deemed early onset if diagnosed before age 41.

The researchers found that only 5.5% of probands’ families had a family member with a discordant early-onset cancer. The most common diagnoses were testicular cancer (0.6% of families) and cancer of the thyroid gland (also 0.6%), followed by melanoma (0.5%).

Overall, the risk of any nonbreast early-onset cancer among first-degree relatives of probands was comparable with the risk in the general population (standardized incidence ratio, 0.99; 95% confidence interval, 0.84-1.16).

However, the risk was elevated for certain family members and certain cancers.

Specifically, the children of probands had an increased risk for any discordant cancer (SIR, 1.27; 95% CI, 1.05-1.55).

The siblings of probands had an elevated risk for early-onset pancreatic cancer (SIR, 7.61) but not overall for any discordant cancer (SIR, 0.93; 95% CI, 0.68-1.25).

And siblings’ children faced an elevated risk for testicular (SIR, 1.74) and ovarian (SIR, 2.69) cancer, though not of any discordant cancer (SIR, 1.16; 95% CI, 0.97-1.37).

The researchers also found that the fathers (SIR, 0.43), mothers (SIR, 0.48), and spouses (SIR, 0.58) of probands appeared to have a decreased risk of any discordant early-onset cancer.

A potential limitation to the study was that the authors could not identify individuals with hereditary cancer syndromes or concerning gene mutations, such as BRCA carriers, because “registry data do not include comprehensive information on the gene mutation carriage status.” But the authors note that the number of BRCA carriers is likely low because of the low number of ovarian cancers observed in first-degree relatives of probands.

Dr. Cobain noted as well that the current study is potentially limited by its “very homogeneous” cohort.

But, overall, the findings indicate that familial risk is often “a much more complicated problem, mathematically and statistically,” than were there a single genetic culprit, Dr. Cobain said. One possibility is that some shared environmental exposure may be increasing the cancer risk among members of the same family.

“Genetic diversity is so vast and understanding how the interplay of multiple genes can influence an individual’s cancer risk is so much more complicated than a single BRCA1 mutation that clearly influences your breast cancer risk,” she added. However, “we’re starting to get there.”

The study was funded by the Cancer Foundation Finland and Academy of Finland. The authors and Dr. Cobain had no relevant financial relationships to declare.

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

Certain relatives of women with early onset breast cancer appear to face an increased risk of other early-onset cancers, a Finnish population-based study suggests.

The researchers found, for instance, that children of breast cancer patients had a 27% higher risk of any discordant early-onset cancer, and patients’ siblings had a 7.6-fold higher risk of early pancreatic cancer. The analysis also indicated that children of patients’ siblings had a significantly increased risk of testicular and ovarian cancers.

“The findings suggest that the familial risk extends to discordant early-onset cancers, including ovarian, testicular, and pancreatic cancers, as well as beyond first-degree relatives,” the researchers, led by Janne M. Pitkäniemi, PhD, Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, say. “Our findings are interesting but raise some questions about unknown [genetic] and environmental mechanisms that need to be further studied.”

Erin F. Cobain, MD, who was not involved in the research, said the findings are “not very surprising to me.”

Dr. Cobain said that at her institution, she has seen “many, many cases” of family members of early-onset breast cancer patients with discordant cancers “where we are unable to find a clear genetic cause.”

Not being able to find an identifiable cause for the clustering of early-onset cancers can be “very frustrating” for patients and their families, said Dr. Cobain, a medical oncologist at the University of Michigan Health, Ann Arbor.

The study was published online in the International Journal of Cancer.

Family members of patients with early-onset breast cancer are at elevated risk for early-onset breast cancer. However, it is “unclear whether the familial risk is limited to early-onset cancer of the same site,” the authors explained.

To investigate, the researchers studied data from the Finnish Cancer Registry and the Finnish Population System, which included 54,753 relatives from 5,562 families of females diagnosed with early-onset breast cancer, defined as probands. A proband was the first member of the family diagnosed with female breast cancer at age 40 years or younger in Finland between January 1970 and December 31, 2012. Cancers were considered familial if they occurred in a family with a previously diagnosed proband and were deemed early onset if diagnosed before age 41.

The researchers found that only 5.5% of probands’ families had a family member with a discordant early-onset cancer. The most common diagnoses were testicular cancer (0.6% of families) and cancer of the thyroid gland (also 0.6%), followed by melanoma (0.5%).

Overall, the risk of any nonbreast early-onset cancer among first-degree relatives of probands was comparable with the risk in the general population (standardized incidence ratio, 0.99; 95% confidence interval, 0.84-1.16).

However, the risk was elevated for certain family members and certain cancers.

Specifically, the children of probands had an increased risk for any discordant cancer (SIR, 1.27; 95% CI, 1.05-1.55).

The siblings of probands had an elevated risk for early-onset pancreatic cancer (SIR, 7.61) but not overall for any discordant cancer (SIR, 0.93; 95% CI, 0.68-1.25).

And siblings’ children faced an elevated risk for testicular (SIR, 1.74) and ovarian (SIR, 2.69) cancer, though not of any discordant cancer (SIR, 1.16; 95% CI, 0.97-1.37).

The researchers also found that the fathers (SIR, 0.43), mothers (SIR, 0.48), and spouses (SIR, 0.58) of probands appeared to have a decreased risk of any discordant early-onset cancer.

A potential limitation to the study was that the authors could not identify individuals with hereditary cancer syndromes or concerning gene mutations, such as BRCA carriers, because “registry data do not include comprehensive information on the gene mutation carriage status.” But the authors note that the number of BRCA carriers is likely low because of the low number of ovarian cancers observed in first-degree relatives of probands.

Dr. Cobain noted as well that the current study is potentially limited by its “very homogeneous” cohort.

But, overall, the findings indicate that familial risk is often “a much more complicated problem, mathematically and statistically,” than were there a single genetic culprit, Dr. Cobain said. One possibility is that some shared environmental exposure may be increasing the cancer risk among members of the same family.

“Genetic diversity is so vast and understanding how the interplay of multiple genes can influence an individual’s cancer risk is so much more complicated than a single BRCA1 mutation that clearly influences your breast cancer risk,” she added. However, “we’re starting to get there.”

The study was funded by the Cancer Foundation Finland and Academy of Finland. The authors and Dr. Cobain had no relevant financial relationships to declare.

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

Certain relatives of women with early onset breast cancer appear to face an increased risk of other early-onset cancers, a Finnish population-based study suggests.

The researchers found, for instance, that children of breast cancer patients had a 27% higher risk of any discordant early-onset cancer, and patients’ siblings had a 7.6-fold higher risk of early pancreatic cancer. The analysis also indicated that children of patients’ siblings had a significantly increased risk of testicular and ovarian cancers.

“The findings suggest that the familial risk extends to discordant early-onset cancers, including ovarian, testicular, and pancreatic cancers, as well as beyond first-degree relatives,” the researchers, led by Janne M. Pitkäniemi, PhD, Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, say. “Our findings are interesting but raise some questions about unknown [genetic] and environmental mechanisms that need to be further studied.”

Erin F. Cobain, MD, who was not involved in the research, said the findings are “not very surprising to me.”

Dr. Cobain said that at her institution, she has seen “many, many cases” of family members of early-onset breast cancer patients with discordant cancers “where we are unable to find a clear genetic cause.”

Not being able to find an identifiable cause for the clustering of early-onset cancers can be “very frustrating” for patients and their families, said Dr. Cobain, a medical oncologist at the University of Michigan Health, Ann Arbor.

The study was published online in the International Journal of Cancer.

Family members of patients with early-onset breast cancer are at elevated risk for early-onset breast cancer. However, it is “unclear whether the familial risk is limited to early-onset cancer of the same site,” the authors explained.

To investigate, the researchers studied data from the Finnish Cancer Registry and the Finnish Population System, which included 54,753 relatives from 5,562 families of females diagnosed with early-onset breast cancer, defined as probands. A proband was the first member of the family diagnosed with female breast cancer at age 40 years or younger in Finland between January 1970 and December 31, 2012. Cancers were considered familial if they occurred in a family with a previously diagnosed proband and were deemed early onset if diagnosed before age 41.

The researchers found that only 5.5% of probands’ families had a family member with a discordant early-onset cancer. The most common diagnoses were testicular cancer (0.6% of families) and cancer of the thyroid gland (also 0.6%), followed by melanoma (0.5%).

Overall, the risk of any nonbreast early-onset cancer among first-degree relatives of probands was comparable with the risk in the general population (standardized incidence ratio, 0.99; 95% confidence interval, 0.84-1.16).

However, the risk was elevated for certain family members and certain cancers.

Specifically, the children of probands had an increased risk for any discordant cancer (SIR, 1.27; 95% CI, 1.05-1.55).

The siblings of probands had an elevated risk for early-onset pancreatic cancer (SIR, 7.61) but not overall for any discordant cancer (SIR, 0.93; 95% CI, 0.68-1.25).

And siblings’ children faced an elevated risk for testicular (SIR, 1.74) and ovarian (SIR, 2.69) cancer, though not of any discordant cancer (SIR, 1.16; 95% CI, 0.97-1.37).

The researchers also found that the fathers (SIR, 0.43), mothers (SIR, 0.48), and spouses (SIR, 0.58) of probands appeared to have a decreased risk of any discordant early-onset cancer.

A potential limitation to the study was that the authors could not identify individuals with hereditary cancer syndromes or concerning gene mutations, such as BRCA carriers, because “registry data do not include comprehensive information on the gene mutation carriage status.” But the authors note that the number of BRCA carriers is likely low because of the low number of ovarian cancers observed in first-degree relatives of probands.

Dr. Cobain noted as well that the current study is potentially limited by its “very homogeneous” cohort.

But, overall, the findings indicate that familial risk is often “a much more complicated problem, mathematically and statistically,” than were there a single genetic culprit, Dr. Cobain said. One possibility is that some shared environmental exposure may be increasing the cancer risk among members of the same family.

“Genetic diversity is so vast and understanding how the interplay of multiple genes can influence an individual’s cancer risk is so much more complicated than a single BRCA1 mutation that clearly influences your breast cancer risk,” she added. However, “we’re starting to get there.”

The study was funded by the Cancer Foundation Finland and Academy of Finland. The authors and Dr. Cobain had no relevant financial relationships to declare.

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

BOSTON – Having a preoperative MRI scan does not help surgeons to reduce the likelihood of positive surgical margins when they are performing lumpectomy for early stage breast cancer, a new study concludes.

The current results suggest that MRI is “not useful to achieve this goal and not a productive use of health care resources,” said senior author Marissa Howard-McNatt, MD, director of the Breast Care Center, Wake Forest University, Winston-Salem, N.C.

“Researchers continue to look for better ways to assess margin status while the patient is still on the operating table,” she said, as a re-operation “can be traumatic.”

The study was presented at the annual meeting of the American Society of Breast Surgeons and was highlighted in a press briefing.

In the study, more than 630 patients with early stage breast cancer were randomly assigned to partial mastectomy with or without cavity shaving of the tumor margins, of whom 193 underwent MRI before their operation.

Although there was a difference in the rate of positive surgical margins before cavity shaving between patients who did and did not undergo MRI, the difference did not reach statistical significance.

“MRI exams are costly and potentially stressful for patients,” Dr. Howard-McNatt commented in a press statement. “The thought is that they will help physicians achieve negative margins during the initial surgery. However, our study shows this is simply not the case.”

Approached for comment, Mediget Teshome, MD, MPH, said, “In my practice, I primarily utilize MRI preoperatively to evaluate the extent of disease in cases where the information is not clear from mammogram and ultrasound.”

This may be when there is “discordance between the size of the malignancy or concern for chest wall or muscle involvement,” Dr. Teshome said in an interview.

MRI is also useful when there may be occult disease, such as in patients “with high suspicion for extensive intraductal component not evident on mammography and those who present with axillary metastasis and unknown breast primary,” as well as in high-risk patients with a genetic predisposition for breast cancer, she explained.

However, Dr. Teshome, an associate professor in the department of breast surgical oncology at the University of Texas MD Anderson Cancer Center, Houston, stressed that, “as with any test, it is important that preoperative MRI is performed with the specific intent to inform clinical decision-making in a meaningful way.”

“While it can provide a benefit in selected cases given its high sensitivity, MRI is associated with false positives and can also contribute to increased patient anxiety and additional procedures,” she cautioned.
 

Study details

Lumpectomy has become “a mainstay of breast cancer management, with safe and reliable outcomes as compared to mastectomy,” said Dr. Howard-McNatt, but it is associated with a higher rate of positive margins, of up to 27%.

She underlined that “re-excision surgery can contribute to greater morbidity, patient anxiety, poor cosmetic outcomes, and health care system overload,” and the desire to reduce re-operations has led to “much attention” being paid to preoperative imaging.

Their study set out to investigate the value of preoperative MRI in this regard, and for this they analyzed data on 631 women who had participated in two prior randomized trials (SHAVE1 and SHAVE2).

These women were randomly assigned to standard partial mastectomy with or without resection of cavity shave margins, with preoperative MRI performed prior to randomization in both trials at the surgeon’s discretion.

The median tumor size was 1.3 cm. An extensive intraductal component was identified in 32.8% of patients, 26.1% had palpable tumors, and 7% had invasive lobular histology. Neoadjuvant chemotherapy was administered in 6.5% of patients.

In all, 193 individuals underwent MRI. These women were less likely to have a positive surgical margin before resection of cavity shave margins, at 31.1% vs. 38.8% in those who did not have MRI, although the difference was not statistically significant (P = .073).

Multivariate analysis taking into account patient age, race, receipt of neoadjuvant chemotherapy, the presence of an extensive intraductal component, as well as histologic subtype and tumor size, revealed that MRI was not associated with a higher rate of negative surgical margins (P = .110).

However, it was shown that both tumor size (P = .040) and age (P = .032) were predictive of margin status.

It was notable that MRI use was associated with younger patient age, at a median of 63 years vs. 66 years, and smaller tumor size, at a median of 2.0 cm vs. 2.1 cm.

This latter finding “may be attributable to an inaccurate initial assessment of the extent of the actual tumor size for a variety of reasons,” Dr. Howard-McNatt commented. “For example, tumors may be discontinuous or have satellite lesions which may touch the edge of a specimen.”

The study was funded in part by the David and Katie Burke Fund for Breast Cancer Research, the Connecticut Breast Health Initiative, the Troy Cancer Program, Cleveland Clinic Akron General Operations, the Cleveland Clinic Akron General Foundation, the Lineberger Comprehensive Cancer Center, the Watson Clinic Center for Research, and LifeCycle. The study authors report no relevant financial relationships.

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

BOSTON – Having a preoperative MRI scan does not help surgeons to reduce the likelihood of positive surgical margins when they are performing lumpectomy for early stage breast cancer, a new study concludes.

The current results suggest that MRI is “not useful to achieve this goal and not a productive use of health care resources,” said senior author Marissa Howard-McNatt, MD, director of the Breast Care Center, Wake Forest University, Winston-Salem, N.C.

“Researchers continue to look for better ways to assess margin status while the patient is still on the operating table,” she said, as a re-operation “can be traumatic.”

The study was presented at the annual meeting of the American Society of Breast Surgeons and was highlighted in a press briefing.

In the study, more than 630 patients with early stage breast cancer were randomly assigned to partial mastectomy with or without cavity shaving of the tumor margins, of whom 193 underwent MRI before their operation.

Although there was a difference in the rate of positive surgical margins before cavity shaving between patients who did and did not undergo MRI, the difference did not reach statistical significance.

“MRI exams are costly and potentially stressful for patients,” Dr. Howard-McNatt commented in a press statement. “The thought is that they will help physicians achieve negative margins during the initial surgery. However, our study shows this is simply not the case.”

Approached for comment, Mediget Teshome, MD, MPH, said, “In my practice, I primarily utilize MRI preoperatively to evaluate the extent of disease in cases where the information is not clear from mammogram and ultrasound.”

This may be when there is “discordance between the size of the malignancy or concern for chest wall or muscle involvement,” Dr. Teshome said in an interview.

MRI is also useful when there may be occult disease, such as in patients “with high suspicion for extensive intraductal component not evident on mammography and those who present with axillary metastasis and unknown breast primary,” as well as in high-risk patients with a genetic predisposition for breast cancer, she explained.

However, Dr. Teshome, an associate professor in the department of breast surgical oncology at the University of Texas MD Anderson Cancer Center, Houston, stressed that, “as with any test, it is important that preoperative MRI is performed with the specific intent to inform clinical decision-making in a meaningful way.”

“While it can provide a benefit in selected cases given its high sensitivity, MRI is associated with false positives and can also contribute to increased patient anxiety and additional procedures,” she cautioned.
 

Study details

Lumpectomy has become “a mainstay of breast cancer management, with safe and reliable outcomes as compared to mastectomy,” said Dr. Howard-McNatt, but it is associated with a higher rate of positive margins, of up to 27%.

She underlined that “re-excision surgery can contribute to greater morbidity, patient anxiety, poor cosmetic outcomes, and health care system overload,” and the desire to reduce re-operations has led to “much attention” being paid to preoperative imaging.

Their study set out to investigate the value of preoperative MRI in this regard, and for this they analyzed data on 631 women who had participated in two prior randomized trials (SHAVE1 and SHAVE2).

These women were randomly assigned to standard partial mastectomy with or without resection of cavity shave margins, with preoperative MRI performed prior to randomization in both trials at the surgeon’s discretion.

The median tumor size was 1.3 cm. An extensive intraductal component was identified in 32.8% of patients, 26.1% had palpable tumors, and 7% had invasive lobular histology. Neoadjuvant chemotherapy was administered in 6.5% of patients.

In all, 193 individuals underwent MRI. These women were less likely to have a positive surgical margin before resection of cavity shave margins, at 31.1% vs. 38.8% in those who did not have MRI, although the difference was not statistically significant (P = .073).

Multivariate analysis taking into account patient age, race, receipt of neoadjuvant chemotherapy, the presence of an extensive intraductal component, as well as histologic subtype and tumor size, revealed that MRI was not associated with a higher rate of negative surgical margins (P = .110).

However, it was shown that both tumor size (P = .040) and age (P = .032) were predictive of margin status.

It was notable that MRI use was associated with younger patient age, at a median of 63 years vs. 66 years, and smaller tumor size, at a median of 2.0 cm vs. 2.1 cm.

This latter finding “may be attributable to an inaccurate initial assessment of the extent of the actual tumor size for a variety of reasons,” Dr. Howard-McNatt commented. “For example, tumors may be discontinuous or have satellite lesions which may touch the edge of a specimen.”

The study was funded in part by the David and Katie Burke Fund for Breast Cancer Research, the Connecticut Breast Health Initiative, the Troy Cancer Program, Cleveland Clinic Akron General Operations, the Cleveland Clinic Akron General Foundation, the Lineberger Comprehensive Cancer Center, the Watson Clinic Center for Research, and LifeCycle. The study authors report no relevant financial relationships.

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

BOSTON – Having a preoperative MRI scan does not help surgeons to reduce the likelihood of positive surgical margins when they are performing lumpectomy for early stage breast cancer, a new study concludes.

The current results suggest that MRI is “not useful to achieve this goal and not a productive use of health care resources,” said senior author Marissa Howard-McNatt, MD, director of the Breast Care Center, Wake Forest University, Winston-Salem, N.C.

“Researchers continue to look for better ways to assess margin status while the patient is still on the operating table,” she said, as a re-operation “can be traumatic.”

The study was presented at the annual meeting of the American Society of Breast Surgeons and was highlighted in a press briefing.

In the study, more than 630 patients with early stage breast cancer were randomly assigned to partial mastectomy with or without cavity shaving of the tumor margins, of whom 193 underwent MRI before their operation.

Although there was a difference in the rate of positive surgical margins before cavity shaving between patients who did and did not undergo MRI, the difference did not reach statistical significance.

“MRI exams are costly and potentially stressful for patients,” Dr. Howard-McNatt commented in a press statement. “The thought is that they will help physicians achieve negative margins during the initial surgery. However, our study shows this is simply not the case.”

Approached for comment, Mediget Teshome, MD, MPH, said, “In my practice, I primarily utilize MRI preoperatively to evaluate the extent of disease in cases where the information is not clear from mammogram and ultrasound.”

This may be when there is “discordance between the size of the malignancy or concern for chest wall or muscle involvement,” Dr. Teshome said in an interview.

MRI is also useful when there may be occult disease, such as in patients “with high suspicion for extensive intraductal component not evident on mammography and those who present with axillary metastasis and unknown breast primary,” as well as in high-risk patients with a genetic predisposition for breast cancer, she explained.

However, Dr. Teshome, an associate professor in the department of breast surgical oncology at the University of Texas MD Anderson Cancer Center, Houston, stressed that, “as with any test, it is important that preoperative MRI is performed with the specific intent to inform clinical decision-making in a meaningful way.”

“While it can provide a benefit in selected cases given its high sensitivity, MRI is associated with false positives and can also contribute to increased patient anxiety and additional procedures,” she cautioned.
 

Study details

Lumpectomy has become “a mainstay of breast cancer management, with safe and reliable outcomes as compared to mastectomy,” said Dr. Howard-McNatt, but it is associated with a higher rate of positive margins, of up to 27%.

She underlined that “re-excision surgery can contribute to greater morbidity, patient anxiety, poor cosmetic outcomes, and health care system overload,” and the desire to reduce re-operations has led to “much attention” being paid to preoperative imaging.

Their study set out to investigate the value of preoperative MRI in this regard, and for this they analyzed data on 631 women who had participated in two prior randomized trials (SHAVE1 and SHAVE2).

These women were randomly assigned to standard partial mastectomy with or without resection of cavity shave margins, with preoperative MRI performed prior to randomization in both trials at the surgeon’s discretion.

The median tumor size was 1.3 cm. An extensive intraductal component was identified in 32.8% of patients, 26.1% had palpable tumors, and 7% had invasive lobular histology. Neoadjuvant chemotherapy was administered in 6.5% of patients.

In all, 193 individuals underwent MRI. These women were less likely to have a positive surgical margin before resection of cavity shave margins, at 31.1% vs. 38.8% in those who did not have MRI, although the difference was not statistically significant (P = .073).

Multivariate analysis taking into account patient age, race, receipt of neoadjuvant chemotherapy, the presence of an extensive intraductal component, as well as histologic subtype and tumor size, revealed that MRI was not associated with a higher rate of negative surgical margins (P = .110).

However, it was shown that both tumor size (P = .040) and age (P = .032) were predictive of margin status.

It was notable that MRI use was associated with younger patient age, at a median of 63 years vs. 66 years, and smaller tumor size, at a median of 2.0 cm vs. 2.1 cm.

This latter finding “may be attributable to an inaccurate initial assessment of the extent of the actual tumor size for a variety of reasons,” Dr. Howard-McNatt commented. “For example, tumors may be discontinuous or have satellite lesions which may touch the edge of a specimen.”

The study was funded in part by the David and Katie Burke Fund for Breast Cancer Research, the Connecticut Breast Health Initiative, the Troy Cancer Program, Cleveland Clinic Akron General Operations, the Cleveland Clinic Akron General Foundation, the Lineberger Comprehensive Cancer Center, the Watson Clinic Center for Research, and LifeCycle. The study authors report no relevant financial relationships.

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

BOSTON – Older women who have had breast cancer frequently undergo annual surveillance mammography, even if there is only a small risk of their developing a second cancer or if they have other mortality risks associated with age and comorbidities. This ongoing annual surveillance with mammography may be doing more harm than good, warn researchers.

In a study that included almost 45,000 women who were aged 67 years or older when they were diagnosed with breast cancer, investigators found that patients commonly underwent annual mammographies.

“Even 10 years after their initial diagnosis ... about 40% of them were still getting surveillance mammography well into their 80s and 90s,” noted lead investigator Elizabeth Berger, MD, assistant professor of breast surgical oncology, Yale University, New Haven, Conn.

“Ongoing surveillance mammography in these patients may lead to overdiagnosis and overtreatment of cancers that potentially would not harm patients if left untreated,” Dr. Berger said.

“A positive or false positive finding may unnecessarily erode patient quality of life and incur costs to the patient and health care system without benefit,” she said. She added: “If an elderly woman is in poor health and has significant competing mortality risks compared to breast cancer, annual mammography may not be necessary.”

The research was presented at the annual meeting of the American Society of Breast Surgeons (ASBrS). The study was highlighted in a preview press briefing.

Speaking at the press briefing, Dr. Berger said that the “risks and benefits of surveillance mammography, including its downstream effects, should be considered by both patients and their doctors together to create a shared decision plan.” She acknowledged that the idea of skipping mammograms may be a sensitive one for patients.

She also shared what she described as “exciting news”: “We have just recently received funding from our geriatric group here at Yale to start to evaluate the potential benefits and harms of these surveillance mammographies.”

The aim is to evaluate false positive rates and the potential for overdiagnosis and overtreatment, “so stay tuned,” she added.

Approached for comment, Mediget Teshome, MD, MPH, said it was “not surprising to see the high rates of surveillance mammography, especially in the short term after treatment.”

She said in an interview that the results suggest that it “may be being overused,” given the low rates of second primary breast cancer and the “competing health concerns” of these women.

Overuse can, on the other hand, “definitely be a complex issue,” said Dr. Teshome, associate professor, department of breast surgical oncology, University of Texas MD Anderson Cancer Center, Houston.

“The goal of mammography screening is to identify breast cancer at an early stage,” she explained. She noted that because of the “competing mortality risk from other challenging and life-threatening health problems,” early-stage breast cancer “may not contribute significantly” to the overall mortality risk.

“In general, in this patient population, consideration should be given to stratifying based on an individual patient’s risk of breast cancer recurrence or new breast cancer, estimated life expectancy, as well as shared decision-making with the patient based on their goals of care.”
 

Study details

To examine the use of surveillance mammography and the risk of subsequent cancers among older women, Dr. Berger and her team used data from the Surveillance, Epidemiology, and End Results (SEER) registry to identify women aged 67 years or older who were diagnosed with a first nonmetastatic beast cancer between 2003 and 2007.

The patients were followed beginning 1 year after diagnosis until the occurrence of a second primary breast cancer, death, or the end of follow-up in 2017.

Data on 44,475 women were analyzed. Of those patients, 30% were older than 80 years. The majority (74%) of breast cancers were of stage I or II, and 72% were hormone receptor–positive (HR+).

Comorbid conditions were common; 55% of women had at least one, and 16% had three or more.

Life expectancy, determined on the basis of age, sex, and comorbidities, was estimated at less than 5 years for 26% of women. For 36% of patients, life expectancy was 6-10 years, and for 38%, it was longer than 10 years.

The cumulative incidence of developing a second primary breast cancer varied by life expectancy and the tumor’s molecular subtype.

The incidence was 3.7% among women with a life expectancy of less than 5 years, 4.9% among those expected to live 6-10 years, and 7.6% among those predicted to live more than 10 years.

Among women with a life expectancy of less than 5 years, the cumulative incidence of a second primary tumor was 4.0% among those with triple-negative breast cancer, vs. 3.0% among those with HR+ breast cancer.

Among patients whose life expectancy was more than 10 years, the cumulative incidence of a second primary tumor was 9.2% among women with triple-negative disease, vs. 7.0% among those with HR+ cancers.

The team found that it was common for women across all the groups to undergo mammography.

Among women with a life expectancy of 6-10 years, 82% underwent at least one mammogram, and 65% underwent five mammograms. Even among women with a life expectancy of less than 1 year, 51% underwent at least one mammogram within 12 months of death.

Among women with a life expectancy of less than 5 years, 68% of women had received a mammogram 1 year after treatment; 53% underwent three mammograms within 3 years after treatment.

No funding for the study was declared. The investigators have disclosed no relevant financial relationships.

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

BOSTON – Older women who have had breast cancer frequently undergo annual surveillance mammography, even if there is only a small risk of their developing a second cancer or if they have other mortality risks associated with age and comorbidities. This ongoing annual surveillance with mammography may be doing more harm than good, warn researchers.

In a study that included almost 45,000 women who were aged 67 years or older when they were diagnosed with breast cancer, investigators found that patients commonly underwent annual mammographies.

“Even 10 years after their initial diagnosis ... about 40% of them were still getting surveillance mammography well into their 80s and 90s,” noted lead investigator Elizabeth Berger, MD, assistant professor of breast surgical oncology, Yale University, New Haven, Conn.

“Ongoing surveillance mammography in these patients may lead to overdiagnosis and overtreatment of cancers that potentially would not harm patients if left untreated,” Dr. Berger said.

“A positive or false positive finding may unnecessarily erode patient quality of life and incur costs to the patient and health care system without benefit,” she said. She added: “If an elderly woman is in poor health and has significant competing mortality risks compared to breast cancer, annual mammography may not be necessary.”

The research was presented at the annual meeting of the American Society of Breast Surgeons (ASBrS). The study was highlighted in a preview press briefing.

Speaking at the press briefing, Dr. Berger said that the “risks and benefits of surveillance mammography, including its downstream effects, should be considered by both patients and their doctors together to create a shared decision plan.” She acknowledged that the idea of skipping mammograms may be a sensitive one for patients.

She also shared what she described as “exciting news”: “We have just recently received funding from our geriatric group here at Yale to start to evaluate the potential benefits and harms of these surveillance mammographies.”

The aim is to evaluate false positive rates and the potential for overdiagnosis and overtreatment, “so stay tuned,” she added.

Approached for comment, Mediget Teshome, MD, MPH, said it was “not surprising to see the high rates of surveillance mammography, especially in the short term after treatment.”

She said in an interview that the results suggest that it “may be being overused,” given the low rates of second primary breast cancer and the “competing health concerns” of these women.

Overuse can, on the other hand, “definitely be a complex issue,” said Dr. Teshome, associate professor, department of breast surgical oncology, University of Texas MD Anderson Cancer Center, Houston.

“The goal of mammography screening is to identify breast cancer at an early stage,” she explained. She noted that because of the “competing mortality risk from other challenging and life-threatening health problems,” early-stage breast cancer “may not contribute significantly” to the overall mortality risk.

“In general, in this patient population, consideration should be given to stratifying based on an individual patient’s risk of breast cancer recurrence or new breast cancer, estimated life expectancy, as well as shared decision-making with the patient based on their goals of care.”
 

Study details

To examine the use of surveillance mammography and the risk of subsequent cancers among older women, Dr. Berger and her team used data from the Surveillance, Epidemiology, and End Results (SEER) registry to identify women aged 67 years or older who were diagnosed with a first nonmetastatic beast cancer between 2003 and 2007.

The patients were followed beginning 1 year after diagnosis until the occurrence of a second primary breast cancer, death, or the end of follow-up in 2017.

Data on 44,475 women were analyzed. Of those patients, 30% were older than 80 years. The majority (74%) of breast cancers were of stage I or II, and 72% were hormone receptor–positive (HR+).

Comorbid conditions were common; 55% of women had at least one, and 16% had three or more.

Life expectancy, determined on the basis of age, sex, and comorbidities, was estimated at less than 5 years for 26% of women. For 36% of patients, life expectancy was 6-10 years, and for 38%, it was longer than 10 years.

The cumulative incidence of developing a second primary breast cancer varied by life expectancy and the tumor’s molecular subtype.

The incidence was 3.7% among women with a life expectancy of less than 5 years, 4.9% among those expected to live 6-10 years, and 7.6% among those predicted to live more than 10 years.

Among women with a life expectancy of less than 5 years, the cumulative incidence of a second primary tumor was 4.0% among those with triple-negative breast cancer, vs. 3.0% among those with HR+ breast cancer.

Among patients whose life expectancy was more than 10 years, the cumulative incidence of a second primary tumor was 9.2% among women with triple-negative disease, vs. 7.0% among those with HR+ cancers.

The team found that it was common for women across all the groups to undergo mammography.

Among women with a life expectancy of 6-10 years, 82% underwent at least one mammogram, and 65% underwent five mammograms. Even among women with a life expectancy of less than 1 year, 51% underwent at least one mammogram within 12 months of death.

Among women with a life expectancy of less than 5 years, 68% of women had received a mammogram 1 year after treatment; 53% underwent three mammograms within 3 years after treatment.

No funding for the study was declared. The investigators have disclosed no relevant financial relationships.

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

BOSTON – Older women who have had breast cancer frequently undergo annual surveillance mammography, even if there is only a small risk of their developing a second cancer or if they have other mortality risks associated with age and comorbidities. This ongoing annual surveillance with mammography may be doing more harm than good, warn researchers.

In a study that included almost 45,000 women who were aged 67 years or older when they were diagnosed with breast cancer, investigators found that patients commonly underwent annual mammographies.

“Even 10 years after their initial diagnosis ... about 40% of them were still getting surveillance mammography well into their 80s and 90s,” noted lead investigator Elizabeth Berger, MD, assistant professor of breast surgical oncology, Yale University, New Haven, Conn.

“Ongoing surveillance mammography in these patients may lead to overdiagnosis and overtreatment of cancers that potentially would not harm patients if left untreated,” Dr. Berger said.

“A positive or false positive finding may unnecessarily erode patient quality of life and incur costs to the patient and health care system without benefit,” she said. She added: “If an elderly woman is in poor health and has significant competing mortality risks compared to breast cancer, annual mammography may not be necessary.”

The research was presented at the annual meeting of the American Society of Breast Surgeons (ASBrS). The study was highlighted in a preview press briefing.

Speaking at the press briefing, Dr. Berger said that the “risks and benefits of surveillance mammography, including its downstream effects, should be considered by both patients and their doctors together to create a shared decision plan.” She acknowledged that the idea of skipping mammograms may be a sensitive one for patients.

She also shared what she described as “exciting news”: “We have just recently received funding from our geriatric group here at Yale to start to evaluate the potential benefits and harms of these surveillance mammographies.”

The aim is to evaluate false positive rates and the potential for overdiagnosis and overtreatment, “so stay tuned,” she added.

Approached for comment, Mediget Teshome, MD, MPH, said it was “not surprising to see the high rates of surveillance mammography, especially in the short term after treatment.”

She said in an interview that the results suggest that it “may be being overused,” given the low rates of second primary breast cancer and the “competing health concerns” of these women.

Overuse can, on the other hand, “definitely be a complex issue,” said Dr. Teshome, associate professor, department of breast surgical oncology, University of Texas MD Anderson Cancer Center, Houston.

“The goal of mammography screening is to identify breast cancer at an early stage,” she explained. She noted that because of the “competing mortality risk from other challenging and life-threatening health problems,” early-stage breast cancer “may not contribute significantly” to the overall mortality risk.

“In general, in this patient population, consideration should be given to stratifying based on an individual patient’s risk of breast cancer recurrence or new breast cancer, estimated life expectancy, as well as shared decision-making with the patient based on their goals of care.”
 

Study details

To examine the use of surveillance mammography and the risk of subsequent cancers among older women, Dr. Berger and her team used data from the Surveillance, Epidemiology, and End Results (SEER) registry to identify women aged 67 years or older who were diagnosed with a first nonmetastatic beast cancer between 2003 and 2007.

The patients were followed beginning 1 year after diagnosis until the occurrence of a second primary breast cancer, death, or the end of follow-up in 2017.

Data on 44,475 women were analyzed. Of those patients, 30% were older than 80 years. The majority (74%) of breast cancers were of stage I or II, and 72% were hormone receptor–positive (HR+).

Comorbid conditions were common; 55% of women had at least one, and 16% had three or more.

Life expectancy, determined on the basis of age, sex, and comorbidities, was estimated at less than 5 years for 26% of women. For 36% of patients, life expectancy was 6-10 years, and for 38%, it was longer than 10 years.

The cumulative incidence of developing a second primary breast cancer varied by life expectancy and the tumor’s molecular subtype.

The incidence was 3.7% among women with a life expectancy of less than 5 years, 4.9% among those expected to live 6-10 years, and 7.6% among those predicted to live more than 10 years.

Among women with a life expectancy of less than 5 years, the cumulative incidence of a second primary tumor was 4.0% among those with triple-negative breast cancer, vs. 3.0% among those with HR+ breast cancer.

Among patients whose life expectancy was more than 10 years, the cumulative incidence of a second primary tumor was 9.2% among women with triple-negative disease, vs. 7.0% among those with HR+ cancers.

The team found that it was common for women across all the groups to undergo mammography.

Among women with a life expectancy of 6-10 years, 82% underwent at least one mammogram, and 65% underwent five mammograms. Even among women with a life expectancy of less than 1 year, 51% underwent at least one mammogram within 12 months of death.

Among women with a life expectancy of less than 5 years, 68% of women had received a mammogram 1 year after treatment; 53% underwent three mammograms within 3 years after treatment.

No funding for the study was declared. The investigators have disclosed no relevant financial relationships.

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

Early-stage breast cancer patients who undergo a mastectomy and have a pathological analysis of their sentinel lymph nodes (SLN) performed during surgery are more likely to be overtreated with both axillary lymph node dissection (ALND) and axillary radiation (AxRT), warned U.S. investigators.

The team studied data on more than 40,000 clinically node-negative women who underwent upfront mastectomy. Just over 8,000 patients were found to have one to two SLN, with intraoperative pathology performed in approximately one-third.

Intraoperative pathology was associated with a more than eightfold increase in the likelihood of performing both ALND and AxRT, far more than any other factor.

These results provide “evidence that a significant percentage of the mastectomy patients with limited disease in up to two SLNs may be overtreated. … simply because their pathology results are read and acted on while they are on the operating table,” said senior author Olga Kantor, MD, MS, associate program director, Breast Surgical Oncology Fellowship Program, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston.

“Notably, postsurgical decisions typically involve a multidisciplinary team, including radiation oncologists, which will likely result in a more integrated overall treatment plan,” she commented in a statement.

“This study suggests that surgeons should delay ALND decision-making until a later time to avoid overtreating patients,” Dr. Kantor emphasized.

The research was presented at the annual meeting of the American Society of Breast Surgeons, and was highlighted in a premeeting press briefing.

Approached for comment on the new findings, Sarah L. Blair, MD, professor and vice chair, department of surgery, University of California San Diego Health, noted that “there is a great deal of data on deescalation in axillary surgery in patients undergoing breast conservation with radiation.”

Dr. Blair, who was not involved in the study, noted that, while there are some studies in mastectomy patients with equal oncologic results, “the topic remains more controversial.”

“This study highlights that surgeons strongly consider deescalating axillary surgery in mastectomy patients to reduce long-term complications,” she said in an interview.

“If possible, these patients should be discussed in a multidisciplinary fashion ahead of time,” she emphasized.

“If surgeons send the lymph nodes for frozen section then, as this paper demonstrates, they will act on the information and perform axillary dissection for early-stage disease.”
 

Study details

At the press briefing for the study, Dr. Kantor explained that several clinical trials, including AMAROS, have already “established the safety of axillary observation or AxRT as an alternative to ALND” in clinically node-negative breast cancer patients found to have one to two positive SLN.

She noted that “mastectomy patients were included in these trials, but they made up a minority” of the populations, ranging from 9% to 18%, “and so controversy remains over the optimal axillary management” in this patient population.

Dr. Kantor said that intraoperative pathology assessment “can help avoid the need to return to the operating room for additional axillary surgery” by checking the SLN at the time.

However, acting on the results during the procedure “does not allow for multidisciplinary discussion” and can mean that patients end up having both ALND and postoperative AxRT.

“This dual approach may result in axillary overtreatment in patients who may otherwise have been eligible for axillary radiation alone,” she underlined.

Moreover, a recent survey of 680 surgeons by the ASBrS found that 52% were performing routine intraoperative pathology assessment of SLN, and 78% of those said they would perform ALND if the results came back positive.

To investigate the impact of intraoperative pathology assessment on axillary management in mastectomy patients who would have been eligible for the AMAROS trial, the team examined data from the U.S. National Cancer Database.

They included cT1-2N0 breast cancer patients who had upfront mastectomy in 2018-2019 and were found to have one to two positive SLN.

They defined intraoperative pathology assessment as:

• “Not done/not acted on” if ALND was either not performed or performed at a later date than the pathology assessment.
• “Done/acted on” if both ALND and the pathology assessment were carried out on the same day.

In addition, AxRT was defined as postmastectomy radiation to the chest wall that included radiation to the draining lymph nodes.

The researchers identified 40,467 patients, of whom 20.3% had one to two positive SLN. Among those, axillary management consisted of observation in 33.2%, ALND in 26.6%, AxRT in 22.2%, and ALND plus AxRT in 18.0%.

Overall, 37.2% of the patients underwent intraoperative pathology and 62.8% did not, 11.8% of whom later returned to the operating room for ALND.

Patients who underwent intraoperative pathology were more likely than those who did not to have cT2 disease (48.0% vs. 44.1%), lympho-vascular invasion (43.4% vs. 37.1%), two positive SLN (26.5% vs. 19.2%), and macrometastasis (87.6% vs. 64.2%, P < .001 for all).

Rates of ALND plus AxRT were significantly higher in patients who had intraoperative pathology done/acted on than in those whom intraoperative pathology was not done/not acted on, at 41.0% vs. 4.9% (P < .001).

Adjusted multivariate analysis indicated that receipt of ALND plus AxRT was significantly associated with intraoperative pathology being done/acted on vs. being not done/acted on, at an odds ratio of 8.99 (P < .001).

There were also significant associations between having both procedures and macrometastasis in the SLN, at an odds ratio vs. micrometastasis of 3.38 (P < .001), and the number of total positive SLN, at odds ratio vs. 1 of 2.14 for two nodes, 3.92 for three nodes, and 5.32 for > three nodes (P < .001 for all).

The researchers also found that lobular tumors on histologic analysis were associated with having ALND plus AxRT, at an odds ratio vs. ductal histology of 1.40 (P < .001).

No funding was declared. Dr. Kantor and Dr. Blair report no relevant financial relationships.

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

Early-stage breast cancer patients who undergo a mastectomy and have a pathological analysis of their sentinel lymph nodes (SLN) performed during surgery are more likely to be overtreated with both axillary lymph node dissection (ALND) and axillary radiation (AxRT), warned U.S. investigators.

The team studied data on more than 40,000 clinically node-negative women who underwent upfront mastectomy. Just over 8,000 patients were found to have one to two SLN, with intraoperative pathology performed in approximately one-third.

Intraoperative pathology was associated with a more than eightfold increase in the likelihood of performing both ALND and AxRT, far more than any other factor.

These results provide “evidence that a significant percentage of the mastectomy patients with limited disease in up to two SLNs may be overtreated. … simply because their pathology results are read and acted on while they are on the operating table,” said senior author Olga Kantor, MD, MS, associate program director, Breast Surgical Oncology Fellowship Program, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston.

“Notably, postsurgical decisions typically involve a multidisciplinary team, including radiation oncologists, which will likely result in a more integrated overall treatment plan,” she commented in a statement.

“This study suggests that surgeons should delay ALND decision-making until a later time to avoid overtreating patients,” Dr. Kantor emphasized.

The research was presented at the annual meeting of the American Society of Breast Surgeons, and was highlighted in a premeeting press briefing.

Approached for comment on the new findings, Sarah L. Blair, MD, professor and vice chair, department of surgery, University of California San Diego Health, noted that “there is a great deal of data on deescalation in axillary surgery in patients undergoing breast conservation with radiation.”

Dr. Blair, who was not involved in the study, noted that, while there are some studies in mastectomy patients with equal oncologic results, “the topic remains more controversial.”

“This study highlights that surgeons strongly consider deescalating axillary surgery in mastectomy patients to reduce long-term complications,” she said in an interview.

“If possible, these patients should be discussed in a multidisciplinary fashion ahead of time,” she emphasized.

“If surgeons send the lymph nodes for frozen section then, as this paper demonstrates, they will act on the information and perform axillary dissection for early-stage disease.”
 

Study details

At the press briefing for the study, Dr. Kantor explained that several clinical trials, including AMAROS, have already “established the safety of axillary observation or AxRT as an alternative to ALND” in clinically node-negative breast cancer patients found to have one to two positive SLN.

She noted that “mastectomy patients were included in these trials, but they made up a minority” of the populations, ranging from 9% to 18%, “and so controversy remains over the optimal axillary management” in this patient population.

Dr. Kantor said that intraoperative pathology assessment “can help avoid the need to return to the operating room for additional axillary surgery” by checking the SLN at the time.

However, acting on the results during the procedure “does not allow for multidisciplinary discussion” and can mean that patients end up having both ALND and postoperative AxRT.

“This dual approach may result in axillary overtreatment in patients who may otherwise have been eligible for axillary radiation alone,” she underlined.

Moreover, a recent survey of 680 surgeons by the ASBrS found that 52% were performing routine intraoperative pathology assessment of SLN, and 78% of those said they would perform ALND if the results came back positive.

To investigate the impact of intraoperative pathology assessment on axillary management in mastectomy patients who would have been eligible for the AMAROS trial, the team examined data from the U.S. National Cancer Database.

They included cT1-2N0 breast cancer patients who had upfront mastectomy in 2018-2019 and were found to have one to two positive SLN.

They defined intraoperative pathology assessment as:

• “Not done/not acted on” if ALND was either not performed or performed at a later date than the pathology assessment.
• “Done/acted on” if both ALND and the pathology assessment were carried out on the same day.

In addition, AxRT was defined as postmastectomy radiation to the chest wall that included radiation to the draining lymph nodes.

The researchers identified 40,467 patients, of whom 20.3% had one to two positive SLN. Among those, axillary management consisted of observation in 33.2%, ALND in 26.6%, AxRT in 22.2%, and ALND plus AxRT in 18.0%.

Overall, 37.2% of the patients underwent intraoperative pathology and 62.8% did not, 11.8% of whom later returned to the operating room for ALND.

Patients who underwent intraoperative pathology were more likely than those who did not to have cT2 disease (48.0% vs. 44.1%), lympho-vascular invasion (43.4% vs. 37.1%), two positive SLN (26.5% vs. 19.2%), and macrometastasis (87.6% vs. 64.2%, P < .001 for all).

Rates of ALND plus AxRT were significantly higher in patients who had intraoperative pathology done/acted on than in those whom intraoperative pathology was not done/not acted on, at 41.0% vs. 4.9% (P < .001).

Adjusted multivariate analysis indicated that receipt of ALND plus AxRT was significantly associated with intraoperative pathology being done/acted on vs. being not done/acted on, at an odds ratio of 8.99 (P < .001).

There were also significant associations between having both procedures and macrometastasis in the SLN, at an odds ratio vs. micrometastasis of 3.38 (P < .001), and the number of total positive SLN, at odds ratio vs. 1 of 2.14 for two nodes, 3.92 for three nodes, and 5.32 for > three nodes (P < .001 for all).

The researchers also found that lobular tumors on histologic analysis were associated with having ALND plus AxRT, at an odds ratio vs. ductal histology of 1.40 (P < .001).

No funding was declared. Dr. Kantor and Dr. Blair report no relevant financial relationships.

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

Early-stage breast cancer patients who undergo a mastectomy and have a pathological analysis of their sentinel lymph nodes (SLN) performed during surgery are more likely to be overtreated with both axillary lymph node dissection (ALND) and axillary radiation (AxRT), warned U.S. investigators.

The team studied data on more than 40,000 clinically node-negative women who underwent upfront mastectomy. Just over 8,000 patients were found to have one to two SLN, with intraoperative pathology performed in approximately one-third.

Intraoperative pathology was associated with a more than eightfold increase in the likelihood of performing both ALND and AxRT, far more than any other factor.

These results provide “evidence that a significant percentage of the mastectomy patients with limited disease in up to two SLNs may be overtreated. … simply because their pathology results are read and acted on while they are on the operating table,” said senior author Olga Kantor, MD, MS, associate program director, Breast Surgical Oncology Fellowship Program, Brigham and Women’s Hospital and Dana-Farber Cancer Institute, Boston.

“Notably, postsurgical decisions typically involve a multidisciplinary team, including radiation oncologists, which will likely result in a more integrated overall treatment plan,” she commented in a statement.

“This study suggests that surgeons should delay ALND decision-making until a later time to avoid overtreating patients,” Dr. Kantor emphasized.

The research was presented at the annual meeting of the American Society of Breast Surgeons, and was highlighted in a premeeting press briefing.

Approached for comment on the new findings, Sarah L. Blair, MD, professor and vice chair, department of surgery, University of California San Diego Health, noted that “there is a great deal of data on deescalation in axillary surgery in patients undergoing breast conservation with radiation.”

Dr. Blair, who was not involved in the study, noted that, while there are some studies in mastectomy patients with equal oncologic results, “the topic remains more controversial.”

“This study highlights that surgeons strongly consider deescalating axillary surgery in mastectomy patients to reduce long-term complications,” she said in an interview.

“If possible, these patients should be discussed in a multidisciplinary fashion ahead of time,” she emphasized.

“If surgeons send the lymph nodes for frozen section then, as this paper demonstrates, they will act on the information and perform axillary dissection for early-stage disease.”
 

Study details

At the press briefing for the study, Dr. Kantor explained that several clinical trials, including AMAROS, have already “established the safety of axillary observation or AxRT as an alternative to ALND” in clinically node-negative breast cancer patients found to have one to two positive SLN.

She noted that “mastectomy patients were included in these trials, but they made up a minority” of the populations, ranging from 9% to 18%, “and so controversy remains over the optimal axillary management” in this patient population.

Dr. Kantor said that intraoperative pathology assessment “can help avoid the need to return to the operating room for additional axillary surgery” by checking the SLN at the time.

However, acting on the results during the procedure “does not allow for multidisciplinary discussion” and can mean that patients end up having both ALND and postoperative AxRT.

“This dual approach may result in axillary overtreatment in patients who may otherwise have been eligible for axillary radiation alone,” she underlined.

Moreover, a recent survey of 680 surgeons by the ASBrS found that 52% were performing routine intraoperative pathology assessment of SLN, and 78% of those said they would perform ALND if the results came back positive.

To investigate the impact of intraoperative pathology assessment on axillary management in mastectomy patients who would have been eligible for the AMAROS trial, the team examined data from the U.S. National Cancer Database.

They included cT1-2N0 breast cancer patients who had upfront mastectomy in 2018-2019 and were found to have one to two positive SLN.

They defined intraoperative pathology assessment as:

• “Not done/not acted on” if ALND was either not performed or performed at a later date than the pathology assessment.
• “Done/acted on” if both ALND and the pathology assessment were carried out on the same day.

In addition, AxRT was defined as postmastectomy radiation to the chest wall that included radiation to the draining lymph nodes.

The researchers identified 40,467 patients, of whom 20.3% had one to two positive SLN. Among those, axillary management consisted of observation in 33.2%, ALND in 26.6%, AxRT in 22.2%, and ALND plus AxRT in 18.0%.

Overall, 37.2% of the patients underwent intraoperative pathology and 62.8% did not, 11.8% of whom later returned to the operating room for ALND.

Patients who underwent intraoperative pathology were more likely than those who did not to have cT2 disease (48.0% vs. 44.1%), lympho-vascular invasion (43.4% vs. 37.1%), two positive SLN (26.5% vs. 19.2%), and macrometastasis (87.6% vs. 64.2%, P < .001 for all).

Rates of ALND plus AxRT were significantly higher in patients who had intraoperative pathology done/acted on than in those whom intraoperative pathology was not done/not acted on, at 41.0% vs. 4.9% (P < .001).

Adjusted multivariate analysis indicated that receipt of ALND plus AxRT was significantly associated with intraoperative pathology being done/acted on vs. being not done/acted on, at an odds ratio of 8.99 (P < .001).

There were also significant associations between having both procedures and macrometastasis in the SLN, at an odds ratio vs. micrometastasis of 3.38 (P < .001), and the number of total positive SLN, at odds ratio vs. 1 of 2.14 for two nodes, 3.92 for three nodes, and 5.32 for > three nodes (P < .001 for all).

The researchers also found that lobular tumors on histologic analysis were associated with having ALND plus AxRT, at an odds ratio vs. ductal histology of 1.40 (P < .001).

No funding was declared. Dr. Kantor and Dr. Blair report no relevant financial relationships.

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

The association between colorectal cancer (CRC) and overweight and obesity may be underestimated because body mass index (BMI) is typically measured too near the time of CRC diagnosis and so would not reflect prediagnostic weight loss linked to the condition, a new analysis suggests.

Obesity, assessed using BMI, was associated with a twofold higher risk of CRC 8-10 years prior to diagnosis, while weight loss of 2 kg or more within 2 years of diagnosis was associated with a “dramatic” 7.52-fold increased risk of CRC, the researchers said.

The results “illustrate the dramatic change of BMI as a risk factor associated with CRC, depending on whether the period of potential prediagnostic weight loss is accounted for or not,” Hermann Brenner, MD, MPH, of the German Cancer Research Center, Heidelberg, and colleagues conclude.

The study was published online in JAMA Network Open.

Recent evidence suggests that obesity is associated with an estimated 30% greater risk of CRC. But the extent to which excess body weight influences CRC risk may be underestimated because prediagnostic weight loss has historically been overlooked.

To understand how prediagnostic weight loss could affect the associations found between excess weight and CRC risk, the researchers examined weight data on almost 6,500 patients newly diagnosed with CRC and more than 5,400 control persons who were matched for age, sex, and country of residence. The median age of the cohort was 69 years, and 60.3% were men.

At the time of recruitment, 62% of case patients and 66% of control patients were overweight or obese. No association was found between current BMI and CRC risk.

However, when using patients’ weight from 8-10 years before CRC diagnosis, the researchers found a significant positive association between overweight or obesity and CRC risk (adjusted odds ratio, 1.27 for overweight and 2.09 for obesity). The risk for CRC increased significantly for every 5-unit increase in BMI (aOR, 1.35). These results were similar when the patients were stratified by sex and CRC subsites.

The researchers also found that weight loss of 2 kg or more within 2 years of CRC diagnosis or interview was associated with a 7.52-fold increased risk for CRC.

“While we demonstrated that prediagnostic weight loss is a major concern for CRC,” such prediagnostic weight loss “may play a similarly important role for other cancers and noncancer diseases associated with overweight and obesity,” the authors note.

“Most importantly, however, our results emphasize the importance of interventions aimed at preventing and managing overweight and obesity ... and which may factor more substantially into CRC risk and other obesity-related diseases than suggested by existing epidemiological evidence,” they write.

The study was supported in part by grants from the German Research Council and the German Federal Ministry of Education and Research. The authors have disclosed no relevant financial relationships.

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

The association between colorectal cancer (CRC) and overweight and obesity may be underestimated because body mass index (BMI) is typically measured too near the time of CRC diagnosis and so would not reflect prediagnostic weight loss linked to the condition, a new analysis suggests.

Obesity, assessed using BMI, was associated with a twofold higher risk of CRC 8-10 years prior to diagnosis, while weight loss of 2 kg or more within 2 years of diagnosis was associated with a “dramatic” 7.52-fold increased risk of CRC, the researchers said.

The results “illustrate the dramatic change of BMI as a risk factor associated with CRC, depending on whether the period of potential prediagnostic weight loss is accounted for or not,” Hermann Brenner, MD, MPH, of the German Cancer Research Center, Heidelberg, and colleagues conclude.

The study was published online in JAMA Network Open.

Recent evidence suggests that obesity is associated with an estimated 30% greater risk of CRC. But the extent to which excess body weight influences CRC risk may be underestimated because prediagnostic weight loss has historically been overlooked.

To understand how prediagnostic weight loss could affect the associations found between excess weight and CRC risk, the researchers examined weight data on almost 6,500 patients newly diagnosed with CRC and more than 5,400 control persons who were matched for age, sex, and country of residence. The median age of the cohort was 69 years, and 60.3% were men.

At the time of recruitment, 62% of case patients and 66% of control patients were overweight or obese. No association was found between current BMI and CRC risk.

However, when using patients’ weight from 8-10 years before CRC diagnosis, the researchers found a significant positive association between overweight or obesity and CRC risk (adjusted odds ratio, 1.27 for overweight and 2.09 for obesity). The risk for CRC increased significantly for every 5-unit increase in BMI (aOR, 1.35). These results were similar when the patients were stratified by sex and CRC subsites.

The researchers also found that weight loss of 2 kg or more within 2 years of CRC diagnosis or interview was associated with a 7.52-fold increased risk for CRC.

“While we demonstrated that prediagnostic weight loss is a major concern for CRC,” such prediagnostic weight loss “may play a similarly important role for other cancers and noncancer diseases associated with overweight and obesity,” the authors note.

“Most importantly, however, our results emphasize the importance of interventions aimed at preventing and managing overweight and obesity ... and which may factor more substantially into CRC risk and other obesity-related diseases than suggested by existing epidemiological evidence,” they write.

The study was supported in part by grants from the German Research Council and the German Federal Ministry of Education and Research. The authors have disclosed no relevant financial relationships.

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

The association between colorectal cancer (CRC) and overweight and obesity may be underestimated because body mass index (BMI) is typically measured too near the time of CRC diagnosis and so would not reflect prediagnostic weight loss linked to the condition, a new analysis suggests.

Obesity, assessed using BMI, was associated with a twofold higher risk of CRC 8-10 years prior to diagnosis, while weight loss of 2 kg or more within 2 years of diagnosis was associated with a “dramatic” 7.52-fold increased risk of CRC, the researchers said.

The results “illustrate the dramatic change of BMI as a risk factor associated with CRC, depending on whether the period of potential prediagnostic weight loss is accounted for or not,” Hermann Brenner, MD, MPH, of the German Cancer Research Center, Heidelberg, and colleagues conclude.

The study was published online in JAMA Network Open.

Recent evidence suggests that obesity is associated with an estimated 30% greater risk of CRC. But the extent to which excess body weight influences CRC risk may be underestimated because prediagnostic weight loss has historically been overlooked.

To understand how prediagnostic weight loss could affect the associations found between excess weight and CRC risk, the researchers examined weight data on almost 6,500 patients newly diagnosed with CRC and more than 5,400 control persons who were matched for age, sex, and country of residence. The median age of the cohort was 69 years, and 60.3% were men.

At the time of recruitment, 62% of case patients and 66% of control patients were overweight or obese. No association was found between current BMI and CRC risk.

However, when using patients’ weight from 8-10 years before CRC diagnosis, the researchers found a significant positive association between overweight or obesity and CRC risk (adjusted odds ratio, 1.27 for overweight and 2.09 for obesity). The risk for CRC increased significantly for every 5-unit increase in BMI (aOR, 1.35). These results were similar when the patients were stratified by sex and CRC subsites.

The researchers also found that weight loss of 2 kg or more within 2 years of CRC diagnosis or interview was associated with a 7.52-fold increased risk for CRC.

“While we demonstrated that prediagnostic weight loss is a major concern for CRC,” such prediagnostic weight loss “may play a similarly important role for other cancers and noncancer diseases associated with overweight and obesity,” the authors note.

“Most importantly, however, our results emphasize the importance of interventions aimed at preventing and managing overweight and obesity ... and which may factor more substantially into CRC risk and other obesity-related diseases than suggested by existing epidemiological evidence,” they write.

The study was supported in part by grants from the German Research Council and the German Federal Ministry of Education and Research. The authors have disclosed no relevant financial relationships.

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

Drinking sugar-sweetened beverages (SSBs) increases the risk of cardiovascular disease and all-cause death in people with type 2 diabetes, reveals a U.S. study that also suggests switching to coffee, tea, or low-fat milk may diminish these risks.

The researchers examined data on almost 15,500 participants with type 2 diabetes from two major studies, finding that the highest level of consumption of SSBs was associated with a 20% increased risk of all-cause mortality and a 25% raised risk of cardiovascular disease, compared with consumption of the least amounts of these products.

The research, published in BMJ, also showed that drinking coffee, tea, plain water, and low-fat milk reduced the risk of all-cause death and that switching from SSBs to the other beverages was linked to lower mortality.

“Overall, these results provide additional evidence that emphasizes the importance of beverage choices in maintaining overall health among adults with diabetes,” say senior author Le Ma, PhD, department of nutrition, Harvard School of Public Health, Boston, and colleagues.

“Collectively, these findings all point in the same direction. Lower consumption of SSBs and higher consumption of coffee, tea, plain water, or low-fat milk are optimal for better health outcomes in adults with type 2 diabetes,” Nita G. Forouhi, MD, PhD, emphasizes in an accompanying editorial.


 

Choice of drink matters

Dr. Forouhi, from the University of Cambridge (England), warned, however, that the findings “cannot be considered cause and effect,” despite the large-scale analysis.

Moreover, “questions remain,” such as the impact of beverage consumption on coronary heart disease and stroke risk, and cancer mortality, with the current study providing “inconclusive” data on the latter.

There was also no data on the addition of sugar to tea or coffee, “so the comparative health effects of unsweetened and sweetened hot beverages remain unclear,” Dr. Forouhi points out. Also unknown is whether the type of tea consumed has a differential effect.

Despite these and other reservations, she says that overall, “Choice of beverage clearly matters.”

“The case for avoiding sugar-sweetened beverages is compelling, and it is supported by various fiscal measures in more than 45 countries. It is reasonable to shift the focus to drinks that are most likely to have positive health impacts: coffee, tea, plain water, and low-fat milk,” she notes.

Dr. Forouhi ends by underlining that the current findings tally with those seen in the general population, so “one important message is that having diabetes does not have to be especially restrictive.”
 

Expanding the evidence

It was estimated that 537 million adults worldwide had type 2 diabetes in 2021, a figure set to increase to 783 million by 2045, say the authors.

Individuals with type 2 diabetes have an increased risk of cardiovascular disease, among many other comorbidities, as well as premature death. Dietary interventions can play an important role in managing these risks.

Recommendations on the healthiest beverages to drink are largely based on evidence from the general population, and data are limited on the best options for adults with type 2 diabetes, who have altered metabolism, the researchers note.

To expand on this, they examined data from the Nurses’ Health Study, which enrolled female registered nurses aged 30-55 years and was initiated in 1976, and the Health Professionals Follow-Up Study, which included male health professionals aged 40-75 years and was initiated in 1996.

For the current analysis, 11,399 women and 4,087 men with type 2 diabetes were included from the two studies, of whom 2,715 were diagnosed before study entry.

Participants’ average daily beverage intake was assessed using a validated food frequency questionnaire administered every 2-4 years. SSBs included caffeinated and caffeine-free colas, other carbonated SSBs, and noncarbonated SSBs, such as fruit punches, lemonades, or other fruit drinks.

During 285,967 person-years of follow-up, there were 7,638 (49.3%) deaths, and 3,447 (22.3%) cases of incident cardiovascular disease were documented during 248,447 person-years of follow-up.

Fully adjusted multivariate analysis comparing the lowest and highest beverage intake indicated that SSBs were associated with a significant increase in all-cause mortality, at a pooled hazard ratio of 1.20, or 1.08 for each additional serving per day (P = .01).

In contrast, the associations between all-cause mortality and consumption of artificially sweetened beverages, fruit juice, and full-fat milk were not significant, whereas coffee (HR, 0.74), tea (HR, 0.79), plain water (HR, 0.77), and low-fat milk (HR, 0.88) were linked to a reduced risk.

The team reported that there were similar associations between beverage intake and cardiovascular disease incidence, at an HR of 1.25 for SSBs, as well as for cardiovascular disease mortality, at an HR of 1.29.

Participants who increased their tea, coffee, and low-fat milk consumption during the course of the study had lower all-cause mortality than those who did not. Switching from SSBs to other beverages was also associated with lower mortality.

The researchers note, however, that there are “several potential limitations” to their study, including that “individual beverage consumption may be correlated with other dietary and lifestyle risk factors for cardiovascular disease incidence and mortality among adults with [type 2] diabetes.”

The study was sponsored by the National Institutes of Health. Dr. Ma has reported no relevant financial relationships. Disclosures for the other authors are listed with the article. Dr. Forouhi has declared receiving support from the U.K. Medical Research Council Epidemiology Unit and U.K. National Institute for Health and Care Research Biomedical Research Centre Cambridge.

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

Drinking sugar-sweetened beverages (SSBs) increases the risk of cardiovascular disease and all-cause death in people with type 2 diabetes, reveals a U.S. study that also suggests switching to coffee, tea, or low-fat milk may diminish these risks.

The researchers examined data on almost 15,500 participants with type 2 diabetes from two major studies, finding that the highest level of consumption of SSBs was associated with a 20% increased risk of all-cause mortality and a 25% raised risk of cardiovascular disease, compared with consumption of the least amounts of these products.

The research, published in BMJ, also showed that drinking coffee, tea, plain water, and low-fat milk reduced the risk of all-cause death and that switching from SSBs to the other beverages was linked to lower mortality.

“Overall, these results provide additional evidence that emphasizes the importance of beverage choices in maintaining overall health among adults with diabetes,” say senior author Le Ma, PhD, department of nutrition, Harvard School of Public Health, Boston, and colleagues.

“Collectively, these findings all point in the same direction. Lower consumption of SSBs and higher consumption of coffee, tea, plain water, or low-fat milk are optimal for better health outcomes in adults with type 2 diabetes,” Nita G. Forouhi, MD, PhD, emphasizes in an accompanying editorial.


 

Choice of drink matters

Dr. Forouhi, from the University of Cambridge (England), warned, however, that the findings “cannot be considered cause and effect,” despite the large-scale analysis.

Moreover, “questions remain,” such as the impact of beverage consumption on coronary heart disease and stroke risk, and cancer mortality, with the current study providing “inconclusive” data on the latter.

There was also no data on the addition of sugar to tea or coffee, “so the comparative health effects of unsweetened and sweetened hot beverages remain unclear,” Dr. Forouhi points out. Also unknown is whether the type of tea consumed has a differential effect.

Despite these and other reservations, she says that overall, “Choice of beverage clearly matters.”

“The case for avoiding sugar-sweetened beverages is compelling, and it is supported by various fiscal measures in more than 45 countries. It is reasonable to shift the focus to drinks that are most likely to have positive health impacts: coffee, tea, plain water, and low-fat milk,” she notes.

Dr. Forouhi ends by underlining that the current findings tally with those seen in the general population, so “one important message is that having diabetes does not have to be especially restrictive.”
 

Expanding the evidence

It was estimated that 537 million adults worldwide had type 2 diabetes in 2021, a figure set to increase to 783 million by 2045, say the authors.

Individuals with type 2 diabetes have an increased risk of cardiovascular disease, among many other comorbidities, as well as premature death. Dietary interventions can play an important role in managing these risks.

Recommendations on the healthiest beverages to drink are largely based on evidence from the general population, and data are limited on the best options for adults with type 2 diabetes, who have altered metabolism, the researchers note.

To expand on this, they examined data from the Nurses’ Health Study, which enrolled female registered nurses aged 30-55 years and was initiated in 1976, and the Health Professionals Follow-Up Study, which included male health professionals aged 40-75 years and was initiated in 1996.

For the current analysis, 11,399 women and 4,087 men with type 2 diabetes were included from the two studies, of whom 2,715 were diagnosed before study entry.

Participants’ average daily beverage intake was assessed using a validated food frequency questionnaire administered every 2-4 years. SSBs included caffeinated and caffeine-free colas, other carbonated SSBs, and noncarbonated SSBs, such as fruit punches, lemonades, or other fruit drinks.

During 285,967 person-years of follow-up, there were 7,638 (49.3%) deaths, and 3,447 (22.3%) cases of incident cardiovascular disease were documented during 248,447 person-years of follow-up.

Fully adjusted multivariate analysis comparing the lowest and highest beverage intake indicated that SSBs were associated with a significant increase in all-cause mortality, at a pooled hazard ratio of 1.20, or 1.08 for each additional serving per day (P = .01).

In contrast, the associations between all-cause mortality and consumption of artificially sweetened beverages, fruit juice, and full-fat milk were not significant, whereas coffee (HR, 0.74), tea (HR, 0.79), plain water (HR, 0.77), and low-fat milk (HR, 0.88) were linked to a reduced risk.

The team reported that there were similar associations between beverage intake and cardiovascular disease incidence, at an HR of 1.25 for SSBs, as well as for cardiovascular disease mortality, at an HR of 1.29.

Participants who increased their tea, coffee, and low-fat milk consumption during the course of the study had lower all-cause mortality than those who did not. Switching from SSBs to other beverages was also associated with lower mortality.

The researchers note, however, that there are “several potential limitations” to their study, including that “individual beverage consumption may be correlated with other dietary and lifestyle risk factors for cardiovascular disease incidence and mortality among adults with [type 2] diabetes.”

The study was sponsored by the National Institutes of Health. Dr. Ma has reported no relevant financial relationships. Disclosures for the other authors are listed with the article. Dr. Forouhi has declared receiving support from the U.K. Medical Research Council Epidemiology Unit and U.K. National Institute for Health and Care Research Biomedical Research Centre Cambridge.

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

Drinking sugar-sweetened beverages (SSBs) increases the risk of cardiovascular disease and all-cause death in people with type 2 diabetes, reveals a U.S. study that also suggests switching to coffee, tea, or low-fat milk may diminish these risks.

The researchers examined data on almost 15,500 participants with type 2 diabetes from two major studies, finding that the highest level of consumption of SSBs was associated with a 20% increased risk of all-cause mortality and a 25% raised risk of cardiovascular disease, compared with consumption of the least amounts of these products.

The research, published in BMJ, also showed that drinking coffee, tea, plain water, and low-fat milk reduced the risk of all-cause death and that switching from SSBs to the other beverages was linked to lower mortality.

“Overall, these results provide additional evidence that emphasizes the importance of beverage choices in maintaining overall health among adults with diabetes,” say senior author Le Ma, PhD, department of nutrition, Harvard School of Public Health, Boston, and colleagues.

“Collectively, these findings all point in the same direction. Lower consumption of SSBs and higher consumption of coffee, tea, plain water, or low-fat milk are optimal for better health outcomes in adults with type 2 diabetes,” Nita G. Forouhi, MD, PhD, emphasizes in an accompanying editorial.


 

Choice of drink matters

Dr. Forouhi, from the University of Cambridge (England), warned, however, that the findings “cannot be considered cause and effect,” despite the large-scale analysis.

Moreover, “questions remain,” such as the impact of beverage consumption on coronary heart disease and stroke risk, and cancer mortality, with the current study providing “inconclusive” data on the latter.

There was also no data on the addition of sugar to tea or coffee, “so the comparative health effects of unsweetened and sweetened hot beverages remain unclear,” Dr. Forouhi points out. Also unknown is whether the type of tea consumed has a differential effect.

Despite these and other reservations, she says that overall, “Choice of beverage clearly matters.”

“The case for avoiding sugar-sweetened beverages is compelling, and it is supported by various fiscal measures in more than 45 countries. It is reasonable to shift the focus to drinks that are most likely to have positive health impacts: coffee, tea, plain water, and low-fat milk,” she notes.

Dr. Forouhi ends by underlining that the current findings tally with those seen in the general population, so “one important message is that having diabetes does not have to be especially restrictive.”
 

Expanding the evidence

It was estimated that 537 million adults worldwide had type 2 diabetes in 2021, a figure set to increase to 783 million by 2045, say the authors.

Individuals with type 2 diabetes have an increased risk of cardiovascular disease, among many other comorbidities, as well as premature death. Dietary interventions can play an important role in managing these risks.

Recommendations on the healthiest beverages to drink are largely based on evidence from the general population, and data are limited on the best options for adults with type 2 diabetes, who have altered metabolism, the researchers note.

To expand on this, they examined data from the Nurses’ Health Study, which enrolled female registered nurses aged 30-55 years and was initiated in 1976, and the Health Professionals Follow-Up Study, which included male health professionals aged 40-75 years and was initiated in 1996.

For the current analysis, 11,399 women and 4,087 men with type 2 diabetes were included from the two studies, of whom 2,715 were diagnosed before study entry.

Participants’ average daily beverage intake was assessed using a validated food frequency questionnaire administered every 2-4 years. SSBs included caffeinated and caffeine-free colas, other carbonated SSBs, and noncarbonated SSBs, such as fruit punches, lemonades, or other fruit drinks.

During 285,967 person-years of follow-up, there were 7,638 (49.3%) deaths, and 3,447 (22.3%) cases of incident cardiovascular disease were documented during 248,447 person-years of follow-up.

Fully adjusted multivariate analysis comparing the lowest and highest beverage intake indicated that SSBs were associated with a significant increase in all-cause mortality, at a pooled hazard ratio of 1.20, or 1.08 for each additional serving per day (P = .01).

In contrast, the associations between all-cause mortality and consumption of artificially sweetened beverages, fruit juice, and full-fat milk were not significant, whereas coffee (HR, 0.74), tea (HR, 0.79), plain water (HR, 0.77), and low-fat milk (HR, 0.88) were linked to a reduced risk.

The team reported that there were similar associations between beverage intake and cardiovascular disease incidence, at an HR of 1.25 for SSBs, as well as for cardiovascular disease mortality, at an HR of 1.29.

Participants who increased their tea, coffee, and low-fat milk consumption during the course of the study had lower all-cause mortality than those who did not. Switching from SSBs to other beverages was also associated with lower mortality.

The researchers note, however, that there are “several potential limitations” to their study, including that “individual beverage consumption may be correlated with other dietary and lifestyle risk factors for cardiovascular disease incidence and mortality among adults with [type 2] diabetes.”

The study was sponsored by the National Institutes of Health. Dr. Ma has reported no relevant financial relationships. Disclosures for the other authors are listed with the article. Dr. Forouhi has declared receiving support from the U.K. Medical Research Council Epidemiology Unit and U.K. National Institute for Health and Care Research Biomedical Research Centre Cambridge.

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

Individuals at increased risk of type 2 diabetes may be able to reduce their risk via a novel intervention combining intermittent fasting (IF) with early time-restricted eating, indicate the results of a randomized controlled trial.

The study involved more than 200 individuals randomized to one of three groups: eat only in the morning (from 8:00 a.m. to noon) followed by 20 hours of fasting 3 days per week and eat as desired on the other days; daily calorie restriction to 70% of requirements; or standard weight loss advice.

The IF plus early time-restricted eating intervention was associated with a significant improvement in a key measure of glucose control versus calorie restriction at 6 months, while both interventions were linked to benefits in terms of cardiovascular risk markers and body composition, compared with the standard weight loss advice.

However, the research, published in Nature Medicine, showed that the additional benefit of IF plus early time-restricted eating did not persist, and less than half of participants were still following the plan at 18 months, compared with almost 80% of those in the calorie-restriction group.

“Following a time-restricted, IF diet could help lower the chances of developing type 2 diabetes,” senior author Leonie K. Heilbronn, PhD, University of Adelaide, South Australia, said in a press release.

This is “the largest study in the world to date, and the first powered to assess how the body processes and uses glucose after eating a meal,” with the latter being a better indicator of diabetes risk than a fasting glucose test, added first author Xiao Tong Teong, a PhD student, also at the University of Adelaide.

“The results of this study add to the growing body of evidence to indicate that meal timing and fasting advice extends the health benefits of a restricted-calorie diet, independently from weight loss, and this may be influential in clinical practice,” Ms. Teong added.
 

Adherence difficult to IF plus early time-restricted eating

Asked to comment, Krista Varady, PhD, said that the study design “would have been stronger if the time-restricted eating and IF interventions were separated” and compared.

“Time-restricted eating has been shown to naturally reduce calorie intake by 300-500 kcal/day,” she said in an interview, “so I’m not sure why the investigators chose to combine [it] with IF. It ... defeats the point of time-restricted eating.”

Dr. Varady, who recently coauthored a review of the clinical application of IF for weight loss, also doubted whether individuals would adhere to combined early time-restricted eating and IF. “In all honesty, I don’t think anyone would follow this diet for very long,” she said.

She added that the feasibility of this particular approach is “very questionable. In general, people don’t like diets that require them to skip dinner with family/friends on multiple days of the week,” explained Dr. Varady, professor of nutrition at the University of Illinois, Chicago.  “These regimens make social eating very difficult, which results in high attrition.

“Indeed, evidence from a recent large-scale observational study of nearly 800,000 adults shows that Americans who engage in time-restricted eating placed their eating window in the afternoon or evening,” she noted.

Dr. Varady therefore suggested that future trials should test “more feasible time-restricted eating approaches,” such as those with later eating windows and without “vigilant calorie monitoring.”

“These types of diets are much easier to follow and are more likely to produce lasting weight and glycemic control in people with obesity and prediabetes,” she observed.
 

A novel way to cut calories?

The Australian authors say there is growing interest in extending the established health benefits of calorie restriction through new approaches such as timing of meals and prolonged fasting, with IF – defined as fasting interspersed with days of ad libitum eating – gaining in popularity as an alternative to simple calorie restriction.

Time-restricted eating, which emphasizes shorter daily eating windows in alignment with circadian rhythms, has also become popular in recent years, although the authors acknowledge that current evidence suggests any benefits over calorie restriction alone in terms of body composition, blood lipids, or glucose parameters are small.

To examine the combination of IF plus early time-restricted eating, in the DIRECT trial, the team recruited individuals aged 35-75 years who had a score of at least 12 on the Australian Type 2 Diabetes Risk Assessment Tool but did not have a diagnosis of diabetes and had stable weight for more than 6 months prior to study entry.

The participants were randomized to one of three groups:

• IF plus early time-restricted eating, which allowed consumption of 30% of calculated baseline energy requirements between 8:00 a.m. and midday, followed by a 20-hour fast from midday on 3 nonconsecutive days per week. They consumed their regular diet on nonfasting days.
• Calorie restriction, where they consumed 70% of daily calculated baseline energy requirements each day and were given rotating menu plans, but no specific mealtimes.
• Standard care, where they were given a booklet on current guidelines, with no counseling or meal replacement.

There were clinic visits every 2 weeks for the first 6 months of follow-up, and then monthly visits for 12 months. The two intervention groups had one-on-one diet counseling for the first 6 months. All groups were instructed to maintain their usual physical activity levels.

A total of 209 individuals were enrolled between Sept. 26, 2018, and May 4, 2020. Their mean age was 58 years, and 57% were women. Mean body mass index was 34.8 kg/m².

In all, 40.7% of participants were allocated to IF plus early time-restricted eating, 39.7% to calorie restriction, and the remaining 19.6% to standard care.

The results showed that IF plus early time-restricted eating was associated with a significantly greater improvement in the primary outcome of postprandial glucose area under the curve (AUC) at month 6 compared with calorie restriction, at –10.1 mg/dL/min versus –3.6 mg/dL/min (P = .03).

“To our knowledge, no [prior] studies have been powered for postprandial assessments of glycemia, which are better indicators of diabetes risk than fasting assessment,” the authors underlined.

IF plus early time-restricted eating was also associated with greater reductions in postprandial insulin AUC versus calorie restriction at 6 months (P = .04). However, the differences between the IF plus early time-restricted eating and calorie restriction groups for postmeal insulin did not remain significant at 18 months of follow-up.

Both IF plus early time-restricted eating and calorie restriction were associated with greater reductions in A1c levels at 6 months versus standard care, but there was no significant difference between the two active interventions (P = .46).

Both interventions were also associated with improvements in markers of cardiovascular risk versus standard care, such as systolic blood pressure at 2 months, diastolic blood pressure at 6 months, and fasting triglycerides at both time points, with no significant differences between the two intervention groups.

IF plus early time-restricted eating and calorie restriction were also both associated with greater reductions in BMI and fat mass in the first 6 months, as well as in waist circumference.
 

Calorie restriction easier to stick to, less likely to cause fatigue

When offered the chance to modify their diet plan at 6 months, 46% of participants in the IF plus early time-restricted eating group said they would maintain 3 days of restrictions per week, while 51% chose to reduce the restrictions to 2 days per week.

In contrast, 97% of those who completed the calorie-restriction plan indicated they would continue with their current diet plan.

At 18 months, 42% of participants in the IF plus early time-restricted eating group said they still undertook 2-3 days of restrictions per week, while 78% of those assigned to calorie restriction reported that they followed a calorie-restricted diet.

Fatigue was more common with IF plus early time-restricted eating, reported by 56% of participants versus 37% of those following calorie restriction, and 35% of those in the standard care group at 6 months. Headaches and constipation were more common in the intervention groups than with standard care.

The study was supported by a National Health and Medical Research Council Project Grant, an Australian Government Research Training Program Scholarship from the University of Adelaide, and a Diabetes Australia Research Program Grant.

No relevant financial relationships were declared.
 

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

Individuals at increased risk of type 2 diabetes may be able to reduce their risk via a novel intervention combining intermittent fasting (IF) with early time-restricted eating, indicate the results of a randomized controlled trial.

The study involved more than 200 individuals randomized to one of three groups: eat only in the morning (from 8:00 a.m. to noon) followed by 20 hours of fasting 3 days per week and eat as desired on the other days; daily calorie restriction to 70% of requirements; or standard weight loss advice.

The IF plus early time-restricted eating intervention was associated with a significant improvement in a key measure of glucose control versus calorie restriction at 6 months, while both interventions were linked to benefits in terms of cardiovascular risk markers and body composition, compared with the standard weight loss advice.

However, the research, published in Nature Medicine, showed that the additional benefit of IF plus early time-restricted eating did not persist, and less than half of participants were still following the plan at 18 months, compared with almost 80% of those in the calorie-restriction group.

“Following a time-restricted, IF diet could help lower the chances of developing type 2 diabetes,” senior author Leonie K. Heilbronn, PhD, University of Adelaide, South Australia, said in a press release.

This is “the largest study in the world to date, and the first powered to assess how the body processes and uses glucose after eating a meal,” with the latter being a better indicator of diabetes risk than a fasting glucose test, added first author Xiao Tong Teong, a PhD student, also at the University of Adelaide.

“The results of this study add to the growing body of evidence to indicate that meal timing and fasting advice extends the health benefits of a restricted-calorie diet, independently from weight loss, and this may be influential in clinical practice,” Ms. Teong added.
 

Adherence difficult to IF plus early time-restricted eating

Asked to comment, Krista Varady, PhD, said that the study design “would have been stronger if the time-restricted eating and IF interventions were separated” and compared.

“Time-restricted eating has been shown to naturally reduce calorie intake by 300-500 kcal/day,” she said in an interview, “so I’m not sure why the investigators chose to combine [it] with IF. It ... defeats the point of time-restricted eating.”

Dr. Varady, who recently coauthored a review of the clinical application of IF for weight loss, also doubted whether individuals would adhere to combined early time-restricted eating and IF. “In all honesty, I don’t think anyone would follow this diet for very long,” she said.

She added that the feasibility of this particular approach is “very questionable. In general, people don’t like diets that require them to skip dinner with family/friends on multiple days of the week,” explained Dr. Varady, professor of nutrition at the University of Illinois, Chicago.  “These regimens make social eating very difficult, which results in high attrition.

“Indeed, evidence from a recent large-scale observational study of nearly 800,000 adults shows that Americans who engage in time-restricted eating placed their eating window in the afternoon or evening,” she noted.

Dr. Varady therefore suggested that future trials should test “more feasible time-restricted eating approaches,” such as those with later eating windows and without “vigilant calorie monitoring.”

“These types of diets are much easier to follow and are more likely to produce lasting weight and glycemic control in people with obesity and prediabetes,” she observed.
 

A novel way to cut calories?

The Australian authors say there is growing interest in extending the established health benefits of calorie restriction through new approaches such as timing of meals and prolonged fasting, with IF – defined as fasting interspersed with days of ad libitum eating – gaining in popularity as an alternative to simple calorie restriction.

Time-restricted eating, which emphasizes shorter daily eating windows in alignment with circadian rhythms, has also become popular in recent years, although the authors acknowledge that current evidence suggests any benefits over calorie restriction alone in terms of body composition, blood lipids, or glucose parameters are small.

To examine the combination of IF plus early time-restricted eating, in the DIRECT trial, the team recruited individuals aged 35-75 years who had a score of at least 12 on the Australian Type 2 Diabetes Risk Assessment Tool but did not have a diagnosis of diabetes and had stable weight for more than 6 months prior to study entry.

The participants were randomized to one of three groups:

• IF plus early time-restricted eating, which allowed consumption of 30% of calculated baseline energy requirements between 8:00 a.m. and midday, followed by a 20-hour fast from midday on 3 nonconsecutive days per week. They consumed their regular diet on nonfasting days.
• Calorie restriction, where they consumed 70% of daily calculated baseline energy requirements each day and were given rotating menu plans, but no specific mealtimes.
• Standard care, where they were given a booklet on current guidelines, with no counseling or meal replacement.

There were clinic visits every 2 weeks for the first 6 months of follow-up, and then monthly visits for 12 months. The two intervention groups had one-on-one diet counseling for the first 6 months. All groups were instructed to maintain their usual physical activity levels.

A total of 209 individuals were enrolled between Sept. 26, 2018, and May 4, 2020. Their mean age was 58 years, and 57% were women. Mean body mass index was 34.8 kg/m².

In all, 40.7% of participants were allocated to IF plus early time-restricted eating, 39.7% to calorie restriction, and the remaining 19.6% to standard care.

The results showed that IF plus early time-restricted eating was associated with a significantly greater improvement in the primary outcome of postprandial glucose area under the curve (AUC) at month 6 compared with calorie restriction, at –10.1 mg/dL/min versus –3.6 mg/dL/min (P = .03).

“To our knowledge, no [prior] studies have been powered for postprandial assessments of glycemia, which are better indicators of diabetes risk than fasting assessment,” the authors underlined.

IF plus early time-restricted eating was also associated with greater reductions in postprandial insulin AUC versus calorie restriction at 6 months (P = .04). However, the differences between the IF plus early time-restricted eating and calorie restriction groups for postmeal insulin did not remain significant at 18 months of follow-up.

Both IF plus early time-restricted eating and calorie restriction were associated with greater reductions in A1c levels at 6 months versus standard care, but there was no significant difference between the two active interventions (P = .46).

Both interventions were also associated with improvements in markers of cardiovascular risk versus standard care, such as systolic blood pressure at 2 months, diastolic blood pressure at 6 months, and fasting triglycerides at both time points, with no significant differences between the two intervention groups.

IF plus early time-restricted eating and calorie restriction were also both associated with greater reductions in BMI and fat mass in the first 6 months, as well as in waist circumference.
 

Calorie restriction easier to stick to, less likely to cause fatigue

When offered the chance to modify their diet plan at 6 months, 46% of participants in the IF plus early time-restricted eating group said they would maintain 3 days of restrictions per week, while 51% chose to reduce the restrictions to 2 days per week.

In contrast, 97% of those who completed the calorie-restriction plan indicated they would continue with their current diet plan.

At 18 months, 42% of participants in the IF plus early time-restricted eating group said they still undertook 2-3 days of restrictions per week, while 78% of those assigned to calorie restriction reported that they followed a calorie-restricted diet.

Fatigue was more common with IF plus early time-restricted eating, reported by 56% of participants versus 37% of those following calorie restriction, and 35% of those in the standard care group at 6 months. Headaches and constipation were more common in the intervention groups than with standard care.

The study was supported by a National Health and Medical Research Council Project Grant, an Australian Government Research Training Program Scholarship from the University of Adelaide, and a Diabetes Australia Research Program Grant.

No relevant financial relationships were declared.
 

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

Individuals at increased risk of type 2 diabetes may be able to reduce their risk via a novel intervention combining intermittent fasting (IF) with early time-restricted eating, indicate the results of a randomized controlled trial.

The study involved more than 200 individuals randomized to one of three groups: eat only in the morning (from 8:00 a.m. to noon) followed by 20 hours of fasting 3 days per week and eat as desired on the other days; daily calorie restriction to 70% of requirements; or standard weight loss advice.

The IF plus early time-restricted eating intervention was associated with a significant improvement in a key measure of glucose control versus calorie restriction at 6 months, while both interventions were linked to benefits in terms of cardiovascular risk markers and body composition, compared with the standard weight loss advice.

However, the research, published in Nature Medicine, showed that the additional benefit of IF plus early time-restricted eating did not persist, and less than half of participants were still following the plan at 18 months, compared with almost 80% of those in the calorie-restriction group.

“Following a time-restricted, IF diet could help lower the chances of developing type 2 diabetes,” senior author Leonie K. Heilbronn, PhD, University of Adelaide, South Australia, said in a press release.

This is “the largest study in the world to date, and the first powered to assess how the body processes and uses glucose after eating a meal,” with the latter being a better indicator of diabetes risk than a fasting glucose test, added first author Xiao Tong Teong, a PhD student, also at the University of Adelaide.

“The results of this study add to the growing body of evidence to indicate that meal timing and fasting advice extends the health benefits of a restricted-calorie diet, independently from weight loss, and this may be influential in clinical practice,” Ms. Teong added.
 

Adherence difficult to IF plus early time-restricted eating

Asked to comment, Krista Varady, PhD, said that the study design “would have been stronger if the time-restricted eating and IF interventions were separated” and compared.

“Time-restricted eating has been shown to naturally reduce calorie intake by 300-500 kcal/day,” she said in an interview, “so I’m not sure why the investigators chose to combine [it] with IF. It ... defeats the point of time-restricted eating.”

Dr. Varady, who recently coauthored a review of the clinical application of IF for weight loss, also doubted whether individuals would adhere to combined early time-restricted eating and IF. “In all honesty, I don’t think anyone would follow this diet for very long,” she said.

She added that the feasibility of this particular approach is “very questionable. In general, people don’t like diets that require them to skip dinner with family/friends on multiple days of the week,” explained Dr. Varady, professor of nutrition at the University of Illinois, Chicago.  “These regimens make social eating very difficult, which results in high attrition.

“Indeed, evidence from a recent large-scale observational study of nearly 800,000 adults shows that Americans who engage in time-restricted eating placed their eating window in the afternoon or evening,” she noted.

Dr. Varady therefore suggested that future trials should test “more feasible time-restricted eating approaches,” such as those with later eating windows and without “vigilant calorie monitoring.”

“These types of diets are much easier to follow and are more likely to produce lasting weight and glycemic control in people with obesity and prediabetes,” she observed.
 

A novel way to cut calories?

The Australian authors say there is growing interest in extending the established health benefits of calorie restriction through new approaches such as timing of meals and prolonged fasting, with IF – defined as fasting interspersed with days of ad libitum eating – gaining in popularity as an alternative to simple calorie restriction.

Time-restricted eating, which emphasizes shorter daily eating windows in alignment with circadian rhythms, has also become popular in recent years, although the authors acknowledge that current evidence suggests any benefits over calorie restriction alone in terms of body composition, blood lipids, or glucose parameters are small.

To examine the combination of IF plus early time-restricted eating, in the DIRECT trial, the team recruited individuals aged 35-75 years who had a score of at least 12 on the Australian Type 2 Diabetes Risk Assessment Tool but did not have a diagnosis of diabetes and had stable weight for more than 6 months prior to study entry.

The participants were randomized to one of three groups:

• IF plus early time-restricted eating, which allowed consumption of 30% of calculated baseline energy requirements between 8:00 a.m. and midday, followed by a 20-hour fast from midday on 3 nonconsecutive days per week. They consumed their regular diet on nonfasting days.
• Calorie restriction, where they consumed 70% of daily calculated baseline energy requirements each day and were given rotating menu plans, but no specific mealtimes.
• Standard care, where they were given a booklet on current guidelines, with no counseling or meal replacement.

There were clinic visits every 2 weeks for the first 6 months of follow-up, and then monthly visits for 12 months. The two intervention groups had one-on-one diet counseling for the first 6 months. All groups were instructed to maintain their usual physical activity levels.

A total of 209 individuals were enrolled between Sept. 26, 2018, and May 4, 2020. Their mean age was 58 years, and 57% were women. Mean body mass index was 34.8 kg/m².

In all, 40.7% of participants were allocated to IF plus early time-restricted eating, 39.7% to calorie restriction, and the remaining 19.6% to standard care.

The results showed that IF plus early time-restricted eating was associated with a significantly greater improvement in the primary outcome of postprandial glucose area under the curve (AUC) at month 6 compared with calorie restriction, at –10.1 mg/dL/min versus –3.6 mg/dL/min (P = .03).

“To our knowledge, no [prior] studies have been powered for postprandial assessments of glycemia, which are better indicators of diabetes risk than fasting assessment,” the authors underlined.

IF plus early time-restricted eating was also associated with greater reductions in postprandial insulin AUC versus calorie restriction at 6 months (P = .04). However, the differences between the IF plus early time-restricted eating and calorie restriction groups for postmeal insulin did not remain significant at 18 months of follow-up.

Both IF plus early time-restricted eating and calorie restriction were associated with greater reductions in A1c levels at 6 months versus standard care, but there was no significant difference between the two active interventions (P = .46).

Both interventions were also associated with improvements in markers of cardiovascular risk versus standard care, such as systolic blood pressure at 2 months, diastolic blood pressure at 6 months, and fasting triglycerides at both time points, with no significant differences between the two intervention groups.

IF plus early time-restricted eating and calorie restriction were also both associated with greater reductions in BMI and fat mass in the first 6 months, as well as in waist circumference.
 

Calorie restriction easier to stick to, less likely to cause fatigue

When offered the chance to modify their diet plan at 6 months, 46% of participants in the IF plus early time-restricted eating group said they would maintain 3 days of restrictions per week, while 51% chose to reduce the restrictions to 2 days per week.

In contrast, 97% of those who completed the calorie-restriction plan indicated they would continue with their current diet plan.

At 18 months, 42% of participants in the IF plus early time-restricted eating group said they still undertook 2-3 days of restrictions per week, while 78% of those assigned to calorie restriction reported that they followed a calorie-restricted diet.

Fatigue was more common with IF plus early time-restricted eating, reported by 56% of participants versus 37% of those following calorie restriction, and 35% of those in the standard care group at 6 months. Headaches and constipation were more common in the intervention groups than with standard care.

The study was supported by a National Health and Medical Research Council Project Grant, an Australian Government Research Training Program Scholarship from the University of Adelaide, and a Diabetes Australia Research Program Grant.

No relevant financial relationships were declared.
 

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