Clinical Topics & News

The “twincretin” era for treating patients with type 2 diabetes has begun, with the Food and Drug Administration’s approval of tirzepatide for this indication on May 13, making it the first approved agent that works as a dual agonist for the two principal human incretins.

Tirzepatide represents “an important advance in the treatment of type 2 diabetes,” the FDA’s Patrick Archdeacon, MD, associate director of the division of diabetes, lipid disorders, and obesity, said in a statement released by the agency.

That advance is based on tirzepatide’s engineering, which gives it agonist properties for both the glucagonlike peptide–1 (GLP-1) receptor, as well as the glucose-dependent insulinotropic polypeptide (GIP). Several agents are already approved for U.S. use from the class with single-agonist activity on the GLP-1 receptor, including semaglutide (Ozempic for treating patients with type 2 diabetes; Wegovy for weight loss).

The FDA’s approved label includes all three dosages of tirzepatide that underwent testing in the pivotal trials: 5 mg, 10 mg, and 15 mg, each delivered by subcutaneous injection once a week. Also approved was the 2.5-mg/week dose used when starting a patient on the agent. Gradual up-titration appears to minimize possible gastrointestinal adverse effects during initial tirzepatide use.

Tirzepatide, which will be marketed by Lilly as Mounjaro, will hit the U.S. market with much anticipation, based on results from five pivotal trials, all reported during the past year or so, that established the drug’s unprecedented efficacy for reducing hemoglobin A1c levels as well as triggering significant weight loss in most patients with a generally benign safety profile.
 

‘Impressive’ effects

The effects from tirzepatide on A1c and weight seen in these studies was “impressive, and will likely drive use of this agent,” commented Carol H. Wysham, MD, an endocrinologist at the MultiCare Rockwood Clinic in Spokane, Wash.

Tirzepatide received good notices in several editorials that accompanied the published reports of the pivotal trials. The first of these, a commentary from two U.K.-based endocrinologists, said that “tirzepatide appears to represent an advancement over current GLP-1 analogues, providing enhanced glycemic and weight benefits without an added penalty in terms of gastrointestinal adverse effects.”

The pivotal trials included head-to-head comparisons between tirzepatide and a 1.0-mg/week dose of semaglutide, as well as comparisons with each of two long-acting insulin analogs, insulin glargine (Lantus) and insulin degludec (Tresiba).

“These are the most important comparators,” Dr. Wysham said.

“Tirzepatide was appropriately compared with the best-in-class and most effective glucose-lowering agents currently available,” said Ildiko Lingvay, MD, an endocrinologist and professor at the University of Texas Southwestern Medical Center in Dallas.

“Given its outstanding efficacy at both lowering glucose and weight, I expect tirzepatide to have quick uptake among patients with diabetes,” Dr. Lingvay said. “The only limiting factor will be cost,” she added in an interview, highlighting the major stumbling block that could limit tirzepatide’s uptake.

“As with any new medication, access will be the biggest barrier to uptake,” agreed Alice Y.Y. Cheng, MD, an endocrinologist at the University of Toronto.
 

Lingering uncertainties

The timing of the comparison with semaglutide leaves some unanswered questions. The SURPASS-2 trial compared the three primary tirzepatide regimens (5 mg, 10 mg, and 15 mg/week) with a 1.0-mg/week dose of semaglutide, which was at the time the only approved dosage of semaglutide for patients with type 2 diabetes. Since then, a 2.0-mg/week dosage of semaglutide (Ozempic) received U.S. approval for treating patients with type 2 diabetes, and a 2.4-mg/week dosage (Wegovy) received an FDA nod for treating people with obesity.

The lack of head-to-head data for tirzepatide against the 2.0-mg/week dose of semaglutide “leaves a clinical gap,” said Dr. Cheng. Tirzepatide “represents an advance over semaglutide at the 1-mg/week dose, but we do not know for sure compared to the higher dose.”

Another important limitation for tirzepatide right now is that the agent’s obligatory cardiovascular outcome trial, SURPASS CVOT, with about 12,500 enrolled patients, will not have findings out until about 2025, leaving uncertainty until then about tirzepatide’s cardiovascular effects.

“We are missing the cardiovascular outcome data – very important data will come” from that trial, noted Dr. Wysham. “There will be some reluctance to use the agent in high-risk patients until we see the results.”

Given tirzepatide’s proven efficacy so far, the missing cardiovascular results “are not a limitation for most patients, but for patients with preexisting cardiovascular disease I will continue to use agents with proven benefits until the SURPASS CVOT results come out,” Dr. Lingvay said.

And then there is the cost issue, something that Lilly had not yet publicly addressed at the time that the FDA announced its decision.

An analysis of cost effectiveness published by the U.S. Institute for Clinical and Economic Review in February 2022 concluded that tirzepatide had a better impact on patient quality of life, compared with 1.0 mg/week semaglutide for treating patients with type 2 diabetes, which gave it a modest pricing cushion, compared with semaglutide of about $5,500 per quality-adjusted life-year gained. But the researchers who prepared the report admitted that tirzepatide’s cost-effectiveness was hard to estimate without knowing the drug’s actual price.  

Dr. Wysham has financial ties to AstraZeneca, Abbott, Boehringer Ingelheim, Intercept, Janssen, Mylan, Novo Nordisk, and Sanofi. Dr. Lingvay has dies to Lilly, Novo Nordisk, Sanofi, Boehringer Ingelheim, Merck, Pfizer, and Mylan, Intarcia, MannKind, Valeritas, and several other drug and device makers.

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

The “twincretin” era for treating patients with type 2 diabetes has begun, with the Food and Drug Administration’s approval of tirzepatide for this indication on May 13, making it the first approved agent that works as a dual agonist for the two principal human incretins.

Tirzepatide represents “an important advance in the treatment of type 2 diabetes,” the FDA’s Patrick Archdeacon, MD, associate director of the division of diabetes, lipid disorders, and obesity, said in a statement released by the agency.

That advance is based on tirzepatide’s engineering, which gives it agonist properties for both the glucagonlike peptide–1 (GLP-1) receptor, as well as the glucose-dependent insulinotropic polypeptide (GIP). Several agents are already approved for U.S. use from the class with single-agonist activity on the GLP-1 receptor, including semaglutide (Ozempic for treating patients with type 2 diabetes; Wegovy for weight loss).

The FDA’s approved label includes all three dosages of tirzepatide that underwent testing in the pivotal trials: 5 mg, 10 mg, and 15 mg, each delivered by subcutaneous injection once a week. Also approved was the 2.5-mg/week dose used when starting a patient on the agent. Gradual up-titration appears to minimize possible gastrointestinal adverse effects during initial tirzepatide use.

Tirzepatide, which will be marketed by Lilly as Mounjaro, will hit the U.S. market with much anticipation, based on results from five pivotal trials, all reported during the past year or so, that established the drug’s unprecedented efficacy for reducing hemoglobin A1c levels as well as triggering significant weight loss in most patients with a generally benign safety profile.
 

‘Impressive’ effects

The effects from tirzepatide on A1c and weight seen in these studies was “impressive, and will likely drive use of this agent,” commented Carol H. Wysham, MD, an endocrinologist at the MultiCare Rockwood Clinic in Spokane, Wash.

Tirzepatide received good notices in several editorials that accompanied the published reports of the pivotal trials. The first of these, a commentary from two U.K.-based endocrinologists, said that “tirzepatide appears to represent an advancement over current GLP-1 analogues, providing enhanced glycemic and weight benefits without an added penalty in terms of gastrointestinal adverse effects.”

The pivotal trials included head-to-head comparisons between tirzepatide and a 1.0-mg/week dose of semaglutide, as well as comparisons with each of two long-acting insulin analogs, insulin glargine (Lantus) and insulin degludec (Tresiba).

“These are the most important comparators,” Dr. Wysham said.

“Tirzepatide was appropriately compared with the best-in-class and most effective glucose-lowering agents currently available,” said Ildiko Lingvay, MD, an endocrinologist and professor at the University of Texas Southwestern Medical Center in Dallas.

“Given its outstanding efficacy at both lowering glucose and weight, I expect tirzepatide to have quick uptake among patients with diabetes,” Dr. Lingvay said. “The only limiting factor will be cost,” she added in an interview, highlighting the major stumbling block that could limit tirzepatide’s uptake.

“As with any new medication, access will be the biggest barrier to uptake,” agreed Alice Y.Y. Cheng, MD, an endocrinologist at the University of Toronto.
 

Lingering uncertainties

The timing of the comparison with semaglutide leaves some unanswered questions. The SURPASS-2 trial compared the three primary tirzepatide regimens (5 mg, 10 mg, and 15 mg/week) with a 1.0-mg/week dose of semaglutide, which was at the time the only approved dosage of semaglutide for patients with type 2 diabetes. Since then, a 2.0-mg/week dosage of semaglutide (Ozempic) received U.S. approval for treating patients with type 2 diabetes, and a 2.4-mg/week dosage (Wegovy) received an FDA nod for treating people with obesity.

The lack of head-to-head data for tirzepatide against the 2.0-mg/week dose of semaglutide “leaves a clinical gap,” said Dr. Cheng. Tirzepatide “represents an advance over semaglutide at the 1-mg/week dose, but we do not know for sure compared to the higher dose.”

Another important limitation for tirzepatide right now is that the agent’s obligatory cardiovascular outcome trial, SURPASS CVOT, with about 12,500 enrolled patients, will not have findings out until about 2025, leaving uncertainty until then about tirzepatide’s cardiovascular effects.

“We are missing the cardiovascular outcome data – very important data will come” from that trial, noted Dr. Wysham. “There will be some reluctance to use the agent in high-risk patients until we see the results.”

Given tirzepatide’s proven efficacy so far, the missing cardiovascular results “are not a limitation for most patients, but for patients with preexisting cardiovascular disease I will continue to use agents with proven benefits until the SURPASS CVOT results come out,” Dr. Lingvay said.

And then there is the cost issue, something that Lilly had not yet publicly addressed at the time that the FDA announced its decision.

An analysis of cost effectiveness published by the U.S. Institute for Clinical and Economic Review in February 2022 concluded that tirzepatide had a better impact on patient quality of life, compared with 1.0 mg/week semaglutide for treating patients with type 2 diabetes, which gave it a modest pricing cushion, compared with semaglutide of about $5,500 per quality-adjusted life-year gained. But the researchers who prepared the report admitted that tirzepatide’s cost-effectiveness was hard to estimate without knowing the drug’s actual price.  

Dr. Wysham has financial ties to AstraZeneca, Abbott, Boehringer Ingelheim, Intercept, Janssen, Mylan, Novo Nordisk, and Sanofi. Dr. Lingvay has dies to Lilly, Novo Nordisk, Sanofi, Boehringer Ingelheim, Merck, Pfizer, and Mylan, Intarcia, MannKind, Valeritas, and several other drug and device makers.

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

The “twincretin” era for treating patients with type 2 diabetes has begun, with the Food and Drug Administration’s approval of tirzepatide for this indication on May 13, making it the first approved agent that works as a dual agonist for the two principal human incretins.

Tirzepatide represents “an important advance in the treatment of type 2 diabetes,” the FDA’s Patrick Archdeacon, MD, associate director of the division of diabetes, lipid disorders, and obesity, said in a statement released by the agency.

That advance is based on tirzepatide’s engineering, which gives it agonist properties for both the glucagonlike peptide–1 (GLP-1) receptor, as well as the glucose-dependent insulinotropic polypeptide (GIP). Several agents are already approved for U.S. use from the class with single-agonist activity on the GLP-1 receptor, including semaglutide (Ozempic for treating patients with type 2 diabetes; Wegovy for weight loss).

The FDA’s approved label includes all three dosages of tirzepatide that underwent testing in the pivotal trials: 5 mg, 10 mg, and 15 mg, each delivered by subcutaneous injection once a week. Also approved was the 2.5-mg/week dose used when starting a patient on the agent. Gradual up-titration appears to minimize possible gastrointestinal adverse effects during initial tirzepatide use.

Tirzepatide, which will be marketed by Lilly as Mounjaro, will hit the U.S. market with much anticipation, based on results from five pivotal trials, all reported during the past year or so, that established the drug’s unprecedented efficacy for reducing hemoglobin A1c levels as well as triggering significant weight loss in most patients with a generally benign safety profile.
 

‘Impressive’ effects

The effects from tirzepatide on A1c and weight seen in these studies was “impressive, and will likely drive use of this agent,” commented Carol H. Wysham, MD, an endocrinologist at the MultiCare Rockwood Clinic in Spokane, Wash.

Tirzepatide received good notices in several editorials that accompanied the published reports of the pivotal trials. The first of these, a commentary from two U.K.-based endocrinologists, said that “tirzepatide appears to represent an advancement over current GLP-1 analogues, providing enhanced glycemic and weight benefits without an added penalty in terms of gastrointestinal adverse effects.”

The pivotal trials included head-to-head comparisons between tirzepatide and a 1.0-mg/week dose of semaglutide, as well as comparisons with each of two long-acting insulin analogs, insulin glargine (Lantus) and insulin degludec (Tresiba).

“These are the most important comparators,” Dr. Wysham said.

“Tirzepatide was appropriately compared with the best-in-class and most effective glucose-lowering agents currently available,” said Ildiko Lingvay, MD, an endocrinologist and professor at the University of Texas Southwestern Medical Center in Dallas.

“Given its outstanding efficacy at both lowering glucose and weight, I expect tirzepatide to have quick uptake among patients with diabetes,” Dr. Lingvay said. “The only limiting factor will be cost,” she added in an interview, highlighting the major stumbling block that could limit tirzepatide’s uptake.

“As with any new medication, access will be the biggest barrier to uptake,” agreed Alice Y.Y. Cheng, MD, an endocrinologist at the University of Toronto.
 

Lingering uncertainties

The timing of the comparison with semaglutide leaves some unanswered questions. The SURPASS-2 trial compared the three primary tirzepatide regimens (5 mg, 10 mg, and 15 mg/week) with a 1.0-mg/week dose of semaglutide, which was at the time the only approved dosage of semaglutide for patients with type 2 diabetes. Since then, a 2.0-mg/week dosage of semaglutide (Ozempic) received U.S. approval for treating patients with type 2 diabetes, and a 2.4-mg/week dosage (Wegovy) received an FDA nod for treating people with obesity.

The lack of head-to-head data for tirzepatide against the 2.0-mg/week dose of semaglutide “leaves a clinical gap,” said Dr. Cheng. Tirzepatide “represents an advance over semaglutide at the 1-mg/week dose, but we do not know for sure compared to the higher dose.”

Another important limitation for tirzepatide right now is that the agent’s obligatory cardiovascular outcome trial, SURPASS CVOT, with about 12,500 enrolled patients, will not have findings out until about 2025, leaving uncertainty until then about tirzepatide’s cardiovascular effects.

“We are missing the cardiovascular outcome data – very important data will come” from that trial, noted Dr. Wysham. “There will be some reluctance to use the agent in high-risk patients until we see the results.”

Given tirzepatide’s proven efficacy so far, the missing cardiovascular results “are not a limitation for most patients, but for patients with preexisting cardiovascular disease I will continue to use agents with proven benefits until the SURPASS CVOT results come out,” Dr. Lingvay said.

And then there is the cost issue, something that Lilly had not yet publicly addressed at the time that the FDA announced its decision.

An analysis of cost effectiveness published by the U.S. Institute for Clinical and Economic Review in February 2022 concluded that tirzepatide had a better impact on patient quality of life, compared with 1.0 mg/week semaglutide for treating patients with type 2 diabetes, which gave it a modest pricing cushion, compared with semaglutide of about $5,500 per quality-adjusted life-year gained. But the researchers who prepared the report admitted that tirzepatide’s cost-effectiveness was hard to estimate without knowing the drug’s actual price.  

Dr. Wysham has financial ties to AstraZeneca, Abbott, Boehringer Ingelheim, Intercept, Janssen, Mylan, Novo Nordisk, and Sanofi. Dr. Lingvay has dies to Lilly, Novo Nordisk, Sanofi, Boehringer Ingelheim, Merck, Pfizer, and Mylan, Intarcia, MannKind, Valeritas, and several other drug and device makers.

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

A relationship between consumption of dairy products and risk of various cancers has been intensively investigated in the past but yielded inconclusive or conflicting results. Now a large new study comparing Chinese dairy consumption with that in the United Kingdom, shows that increased dairy consumption was linked to higher risks of liver cancer and female breast cancer.

The study, by researchers from Oxford University’s department of population health, and Peking University and the Chinese Academy of Medical Sciences in Beijing, used data from the China Kadoorie Biobank Study, a long-term prospective study involving more than over 510,000 participants recruited from 10 geographically diverse areas across China, including both rural and urban regions. They compared this to data from the UK biobank.

Subjects were 59% female, 41% male, aged 30-79 years, and had no history of cancer at recruitment between 2004 and 2008. Food questionnaires were completed at the outset and participants followed for an average of 11 years, using national cancer and death registries and health insurance records to identify new cancer diagnoses, including both fatal and nonfatal events.

Participants were categorized into three groups according to how often they consumed dairy products (primarily milk):

• Regular consumers (at least once a week): 20.4% of the cohort.
• Monthly consumers: 11.1%.
• Nonconsumers who never or rarely consumed dairy products: 68.5%.

Average dairy consumption was 37.9 g/day overall and 80.8 g/day among regular consumers. This compares with an average consumption of around 300 g/day in participants in the UK Biobank cohort.

Over the course of the study, 29,277 new cancer cases were recorded, including 6,282 lung, 2,582 female breast, 3,577 stomach, 3,350 colorectal, and 3,191 liver cancer cases.

Analyses correlating cases with consumption took into account a range of other factors potentially affecting cancer risk, including age, sex, region, family history of cancer, socioeconomic status (education and income), lifestyle factors (alcohol intake, smoking, physical activity, soy consumption, and fresh fruit intake), body mass index, chronic hepatitis B virus infection, and female reproductive factors.

Higher dairy intakes linked with risk of liver and breast cancers

Results revealed that higher regular dairy intake was associated with significantly higher risks of liver cancer and female breast cancer, both common types of cancer in China. Analyses indicated that for each 50-g/day intake, the risks increased by 12% and 17%, respectively.

There was also an increase in total cancer diagnoses, and an increased risk of lymphoma, though this was not statistically significant after correction for confounders. No association was found between dairy products and colorectal cancer, prostate cancer, or any other site-specific cancer.

The research, published in BMC Medicine, is the first major study to investigate dairy consumption and cancer risk in Chinese adults. The results conflict with previous studies on Western populations, which have suggested that dairy products may be associated with a lower risk of colorectal cancer and a higher risk of prostate cancer but have found no clear link for breast or other types of cancer.

Lead researchers Maria Kakkoura, PhD, MSc, and associate professor Huaidong Du, MD, PhD, told this news organization that, although they don’t know the reason for the difference, “there is clear evidence that colorectal cancer has a different incidence pattern in China, compared with Western countries. Other risk factors, like adiposity, may have a stronger effect on the risk of colorectal cancer in Western countries than in China.” Notably, the mean body mass index in the study population was around 23 kg/m², they said – by contrast in the United Kingdom it is 27.6 kg/m2.

Effects not necessarily causal

Ian Givens, PhD, professor of food chain nutrition at the University of Reading (England), said the study was “potentially very important for Chinese people, if it can be confirmed that dairy products affect the risk of breast and/or liver cancer differently in Chinese subjects to those in Western Societies, especially as dairy consumption in China is much lower than in most Western diets.”

He added: “As always it needs to be kept in mind that this type of study can only establish associations with disease risk, not cause.”

Dr. Kakkoura, nutritional epidemiologist at Oxford (England) University’s department of population health, said: “This was the first major study to investigate the link between dairy products and cancer risk in a Chinese population. Further studies are needed to validate these current findings, establish if these associations are causal, and investigate the potential underlying mechanisms involved.”

The researchers said that, while the results do not prove causation, “there are several plausible biological mechanisms that may explain these associations.” They pointed to higher dairy consumption potentially increasing levels of insulinlike growth factor-I, known to promote cell proliferation and associated with higher risks of several types of cancer.

In addition, estrogen and progesterone present in cows’ milk may play a role in increasing breast cancer risk, whilst saturated and trans-fatty acids from dairy products may increase the risk of liver cancer. As many Chinese people are lactase deficient, dairy products may also be broken down into products that affect cancer risk.

No justification for dietary change

Confounding factors may also have influenced the results, commented Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow at Aston University, Birmingham, England. “Those in the study who consumed dairy were more likely to live in cities and have other health conditions, including cardiovascular disease and diabetes – although some of these factors were considered in the analysis, not all of these covariates were, which could influence the findings.

“In my view this study alone does not provide strong evidence that reducing dairy intake would reduce cancer risk.”

He added: “Although the paper suggests a 12% increased relative risk for female breast cancer, this does not equate to 12 more cases per 100 individuals – in absolute terms this would be more like 1 or 2 cases per 1,000 people.”

Similarly, Kevin McConway, PhD, emeritus professor of applied statistics at the Open University, Milton Keynes, England, said: “An issue is that there were many differences between the people that consumed different amounts of dairy products, apart from their difference in dairy consumption. For instance, of those who never or rarely consumed dairy products, fewer than a third lived in urban areas, but of regular dairy consumers (at least once a week), 83% lived in urban areas. Regular consumers were considerably more likely to be well educated than those who never or rarely consumed dairy products, and there were other differences too. 

“So if, as the researchers found, a greater proportion of the regular consumers than of the never or rare consumers had a cancer diagnosis, that could have been because of their different dairy consumption, or it could have been (in part or entirely) because of the different places they lived, or their different education levels, or any of the other factors on which the groups differed.

“One can never be sure that all the relevant factors have been adjusted for. That’s why the researchers rightly say that these results can’t establish whether the associations between dairy consumption and the risks of some cancers, that they found, are there because the dairy consumption differences change the cancer risks in a cause-and-effect way. They might, or they might not.”

He cautioned: “I don’t think anyone should decide to change their individual diet solely because of the results of this new study.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, London, told this news organization: “This early-stage study found an association between dairy consumption and the risks of certain cancers, but that doesn’t mean that they’re causing them or that people need to avoid dairy. Dairy products can be part of a healthy balanced diet and, in the U.K., the Food Standards Agency regulates them to make sure they’re safe. There’s good evidence that dairy reduces the risk of bowel cancer, but no clear evidence for other cancer types, and this is no different for people who are lactose intolerant.”

A version of this article first appeared on Medscape UK.

A relationship between consumption of dairy products and risk of various cancers has been intensively investigated in the past but yielded inconclusive or conflicting results. Now a large new study comparing Chinese dairy consumption with that in the United Kingdom, shows that increased dairy consumption was linked to higher risks of liver cancer and female breast cancer.

The study, by researchers from Oxford University’s department of population health, and Peking University and the Chinese Academy of Medical Sciences in Beijing, used data from the China Kadoorie Biobank Study, a long-term prospective study involving more than over 510,000 participants recruited from 10 geographically diverse areas across China, including both rural and urban regions. They compared this to data from the UK biobank.

Subjects were 59% female, 41% male, aged 30-79 years, and had no history of cancer at recruitment between 2004 and 2008. Food questionnaires were completed at the outset and participants followed for an average of 11 years, using national cancer and death registries and health insurance records to identify new cancer diagnoses, including both fatal and nonfatal events.

Participants were categorized into three groups according to how often they consumed dairy products (primarily milk):

• Regular consumers (at least once a week): 20.4% of the cohort.
• Monthly consumers: 11.1%.
• Nonconsumers who never or rarely consumed dairy products: 68.5%.

Average dairy consumption was 37.9 g/day overall and 80.8 g/day among regular consumers. This compares with an average consumption of around 300 g/day in participants in the UK Biobank cohort.

Over the course of the study, 29,277 new cancer cases were recorded, including 6,282 lung, 2,582 female breast, 3,577 stomach, 3,350 colorectal, and 3,191 liver cancer cases.

Analyses correlating cases with consumption took into account a range of other factors potentially affecting cancer risk, including age, sex, region, family history of cancer, socioeconomic status (education and income), lifestyle factors (alcohol intake, smoking, physical activity, soy consumption, and fresh fruit intake), body mass index, chronic hepatitis B virus infection, and female reproductive factors.

Higher dairy intakes linked with risk of liver and breast cancers

Results revealed that higher regular dairy intake was associated with significantly higher risks of liver cancer and female breast cancer, both common types of cancer in China. Analyses indicated that for each 50-g/day intake, the risks increased by 12% and 17%, respectively.

There was also an increase in total cancer diagnoses, and an increased risk of lymphoma, though this was not statistically significant after correction for confounders. No association was found between dairy products and colorectal cancer, prostate cancer, or any other site-specific cancer.

The research, published in BMC Medicine, is the first major study to investigate dairy consumption and cancer risk in Chinese adults. The results conflict with previous studies on Western populations, which have suggested that dairy products may be associated with a lower risk of colorectal cancer and a higher risk of prostate cancer but have found no clear link for breast or other types of cancer.

Lead researchers Maria Kakkoura, PhD, MSc, and associate professor Huaidong Du, MD, PhD, told this news organization that, although they don’t know the reason for the difference, “there is clear evidence that colorectal cancer has a different incidence pattern in China, compared with Western countries. Other risk factors, like adiposity, may have a stronger effect on the risk of colorectal cancer in Western countries than in China.” Notably, the mean body mass index in the study population was around 23 kg/m², they said – by contrast in the United Kingdom it is 27.6 kg/m2.

Effects not necessarily causal

Ian Givens, PhD, professor of food chain nutrition at the University of Reading (England), said the study was “potentially very important for Chinese people, if it can be confirmed that dairy products affect the risk of breast and/or liver cancer differently in Chinese subjects to those in Western Societies, especially as dairy consumption in China is much lower than in most Western diets.”

He added: “As always it needs to be kept in mind that this type of study can only establish associations with disease risk, not cause.”

Dr. Kakkoura, nutritional epidemiologist at Oxford (England) University’s department of population health, said: “This was the first major study to investigate the link between dairy products and cancer risk in a Chinese population. Further studies are needed to validate these current findings, establish if these associations are causal, and investigate the potential underlying mechanisms involved.”

The researchers said that, while the results do not prove causation, “there are several plausible biological mechanisms that may explain these associations.” They pointed to higher dairy consumption potentially increasing levels of insulinlike growth factor-I, known to promote cell proliferation and associated with higher risks of several types of cancer.

In addition, estrogen and progesterone present in cows’ milk may play a role in increasing breast cancer risk, whilst saturated and trans-fatty acids from dairy products may increase the risk of liver cancer. As many Chinese people are lactase deficient, dairy products may also be broken down into products that affect cancer risk.

No justification for dietary change

Confounding factors may also have influenced the results, commented Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow at Aston University, Birmingham, England. “Those in the study who consumed dairy were more likely to live in cities and have other health conditions, including cardiovascular disease and diabetes – although some of these factors were considered in the analysis, not all of these covariates were, which could influence the findings.

“In my view this study alone does not provide strong evidence that reducing dairy intake would reduce cancer risk.”

He added: “Although the paper suggests a 12% increased relative risk for female breast cancer, this does not equate to 12 more cases per 100 individuals – in absolute terms this would be more like 1 or 2 cases per 1,000 people.”

Similarly, Kevin McConway, PhD, emeritus professor of applied statistics at the Open University, Milton Keynes, England, said: “An issue is that there were many differences between the people that consumed different amounts of dairy products, apart from their difference in dairy consumption. For instance, of those who never or rarely consumed dairy products, fewer than a third lived in urban areas, but of regular dairy consumers (at least once a week), 83% lived in urban areas. Regular consumers were considerably more likely to be well educated than those who never or rarely consumed dairy products, and there were other differences too. 

“So if, as the researchers found, a greater proportion of the regular consumers than of the never or rare consumers had a cancer diagnosis, that could have been because of their different dairy consumption, or it could have been (in part or entirely) because of the different places they lived, or their different education levels, or any of the other factors on which the groups differed.

“One can never be sure that all the relevant factors have been adjusted for. That’s why the researchers rightly say that these results can’t establish whether the associations between dairy consumption and the risks of some cancers, that they found, are there because the dairy consumption differences change the cancer risks in a cause-and-effect way. They might, or they might not.”

He cautioned: “I don’t think anyone should decide to change their individual diet solely because of the results of this new study.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, London, told this news organization: “This early-stage study found an association between dairy consumption and the risks of certain cancers, but that doesn’t mean that they’re causing them or that people need to avoid dairy. Dairy products can be part of a healthy balanced diet and, in the U.K., the Food Standards Agency regulates them to make sure they’re safe. There’s good evidence that dairy reduces the risk of bowel cancer, but no clear evidence for other cancer types, and this is no different for people who are lactose intolerant.”

A version of this article first appeared on Medscape UK.

A relationship between consumption of dairy products and risk of various cancers has been intensively investigated in the past but yielded inconclusive or conflicting results. Now a large new study comparing Chinese dairy consumption with that in the United Kingdom, shows that increased dairy consumption was linked to higher risks of liver cancer and female breast cancer.

The study, by researchers from Oxford University’s department of population health, and Peking University and the Chinese Academy of Medical Sciences in Beijing, used data from the China Kadoorie Biobank Study, a long-term prospective study involving more than over 510,000 participants recruited from 10 geographically diverse areas across China, including both rural and urban regions. They compared this to data from the UK biobank.

Subjects were 59% female, 41% male, aged 30-79 years, and had no history of cancer at recruitment between 2004 and 2008. Food questionnaires were completed at the outset and participants followed for an average of 11 years, using national cancer and death registries and health insurance records to identify new cancer diagnoses, including both fatal and nonfatal events.

Participants were categorized into three groups according to how often they consumed dairy products (primarily milk):

• Regular consumers (at least once a week): 20.4% of the cohort.
• Monthly consumers: 11.1%.
• Nonconsumers who never or rarely consumed dairy products: 68.5%.

Average dairy consumption was 37.9 g/day overall and 80.8 g/day among regular consumers. This compares with an average consumption of around 300 g/day in participants in the UK Biobank cohort.

Over the course of the study, 29,277 new cancer cases were recorded, including 6,282 lung, 2,582 female breast, 3,577 stomach, 3,350 colorectal, and 3,191 liver cancer cases.

Analyses correlating cases with consumption took into account a range of other factors potentially affecting cancer risk, including age, sex, region, family history of cancer, socioeconomic status (education and income), lifestyle factors (alcohol intake, smoking, physical activity, soy consumption, and fresh fruit intake), body mass index, chronic hepatitis B virus infection, and female reproductive factors.

Higher dairy intakes linked with risk of liver and breast cancers

Results revealed that higher regular dairy intake was associated with significantly higher risks of liver cancer and female breast cancer, both common types of cancer in China. Analyses indicated that for each 50-g/day intake, the risks increased by 12% and 17%, respectively.

There was also an increase in total cancer diagnoses, and an increased risk of lymphoma, though this was not statistically significant after correction for confounders. No association was found between dairy products and colorectal cancer, prostate cancer, or any other site-specific cancer.

The research, published in BMC Medicine, is the first major study to investigate dairy consumption and cancer risk in Chinese adults. The results conflict with previous studies on Western populations, which have suggested that dairy products may be associated with a lower risk of colorectal cancer and a higher risk of prostate cancer but have found no clear link for breast or other types of cancer.

Lead researchers Maria Kakkoura, PhD, MSc, and associate professor Huaidong Du, MD, PhD, told this news organization that, although they don’t know the reason for the difference, “there is clear evidence that colorectal cancer has a different incidence pattern in China, compared with Western countries. Other risk factors, like adiposity, may have a stronger effect on the risk of colorectal cancer in Western countries than in China.” Notably, the mean body mass index in the study population was around 23 kg/m², they said – by contrast in the United Kingdom it is 27.6 kg/m2.

Effects not necessarily causal

Ian Givens, PhD, professor of food chain nutrition at the University of Reading (England), said the study was “potentially very important for Chinese people, if it can be confirmed that dairy products affect the risk of breast and/or liver cancer differently in Chinese subjects to those in Western Societies, especially as dairy consumption in China is much lower than in most Western diets.”

He added: “As always it needs to be kept in mind that this type of study can only establish associations with disease risk, not cause.”

Dr. Kakkoura, nutritional epidemiologist at Oxford (England) University’s department of population health, said: “This was the first major study to investigate the link between dairy products and cancer risk in a Chinese population. Further studies are needed to validate these current findings, establish if these associations are causal, and investigate the potential underlying mechanisms involved.”

The researchers said that, while the results do not prove causation, “there are several plausible biological mechanisms that may explain these associations.” They pointed to higher dairy consumption potentially increasing levels of insulinlike growth factor-I, known to promote cell proliferation and associated with higher risks of several types of cancer.

In addition, estrogen and progesterone present in cows’ milk may play a role in increasing breast cancer risk, whilst saturated and trans-fatty acids from dairy products may increase the risk of liver cancer. As many Chinese people are lactase deficient, dairy products may also be broken down into products that affect cancer risk.

No justification for dietary change

Confounding factors may also have influenced the results, commented Duane Mellor, PhD, RD, RNutr, registered dietitian and senior teaching fellow at Aston University, Birmingham, England. “Those in the study who consumed dairy were more likely to live in cities and have other health conditions, including cardiovascular disease and diabetes – although some of these factors were considered in the analysis, not all of these covariates were, which could influence the findings.

“In my view this study alone does not provide strong evidence that reducing dairy intake would reduce cancer risk.”

He added: “Although the paper suggests a 12% increased relative risk for female breast cancer, this does not equate to 12 more cases per 100 individuals – in absolute terms this would be more like 1 or 2 cases per 1,000 people.”

Similarly, Kevin McConway, PhD, emeritus professor of applied statistics at the Open University, Milton Keynes, England, said: “An issue is that there were many differences between the people that consumed different amounts of dairy products, apart from their difference in dairy consumption. For instance, of those who never or rarely consumed dairy products, fewer than a third lived in urban areas, but of regular dairy consumers (at least once a week), 83% lived in urban areas. Regular consumers were considerably more likely to be well educated than those who never or rarely consumed dairy products, and there were other differences too. 

“So if, as the researchers found, a greater proportion of the regular consumers than of the never or rare consumers had a cancer diagnosis, that could have been because of their different dairy consumption, or it could have been (in part or entirely) because of the different places they lived, or their different education levels, or any of the other factors on which the groups differed.

“One can never be sure that all the relevant factors have been adjusted for. That’s why the researchers rightly say that these results can’t establish whether the associations between dairy consumption and the risks of some cancers, that they found, are there because the dairy consumption differences change the cancer risks in a cause-and-effect way. They might, or they might not.”

He cautioned: “I don’t think anyone should decide to change their individual diet solely because of the results of this new study.”

Commenting on the study, Fiona Osgun, senior health information manager at Cancer Research UK, London, told this news organization: “This early-stage study found an association between dairy consumption and the risks of certain cancers, but that doesn’t mean that they’re causing them or that people need to avoid dairy. Dairy products can be part of a healthy balanced diet and, in the U.K., the Food Standards Agency regulates them to make sure they’re safe. There’s good evidence that dairy reduces the risk of bowel cancer, but no clear evidence for other cancer types, and this is no different for people who are lactose intolerant.”

A version of this article first appeared on Medscape UK.

Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.

The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.

“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.

The findings were presented at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
 

A better fix than insulin?

Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.

Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.

“We’ve been looking for different ways of treating hyperglycemia for quite some time, and one of the obvious ways is to use insulin therapy,” Dr. Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”

Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.

An advantage to a GLP-1 agonist-like exenatide, Dr. Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.

A case for more study

To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.

The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.

On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.

The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care versus 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).

However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).

There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.

“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Dr. Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
 

Value to clinicians

Commenting on the findings, Yvonne Chun, PhD, honorary senior clinical lecturer at University of Edinburgh, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.

“The results are of value to clinicians, as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Dr. Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”

However, Dr. Chun noted that more study is needed before exenatide can replace standard care. Dr. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Dr. Chun and others.

“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale – a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Dr. Chun said. “The primary outcome used in the presented trial – an 8-point improvement on NIHSS – seemed too ambitious and does not inform disability of the patient post stroke.”

Dr. Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.

“I can see the day patients will come in with acute stroke, and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use, and it doesn’t cause hypoglycemia,” Dr. Bladin said. “And from the moment that patient arrives the glucose control is underway.”

Dr. Bladin and Dr. Chun reported no relevant financial relationships. Study funding was not disclosed.

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

Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.

The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.

“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.

The findings were presented at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
 

A better fix than insulin?

Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.

Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.

“We’ve been looking for different ways of treating hyperglycemia for quite some time, and one of the obvious ways is to use insulin therapy,” Dr. Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”

Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.

An advantage to a GLP-1 agonist-like exenatide, Dr. Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.

A case for more study

To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.

The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.

On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.

The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care versus 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).

However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).

There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.

“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Dr. Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
 

Value to clinicians

Commenting on the findings, Yvonne Chun, PhD, honorary senior clinical lecturer at University of Edinburgh, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.

“The results are of value to clinicians, as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Dr. Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”

However, Dr. Chun noted that more study is needed before exenatide can replace standard care. Dr. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Dr. Chun and others.

“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale – a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Dr. Chun said. “The primary outcome used in the presented trial – an 8-point improvement on NIHSS – seemed too ambitious and does not inform disability of the patient post stroke.”

Dr. Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.

“I can see the day patients will come in with acute stroke, and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use, and it doesn’t cause hypoglycemia,” Dr. Bladin said. “And from the moment that patient arrives the glucose control is underway.”

Dr. Bladin and Dr. Chun reported no relevant financial relationships. Study funding was not disclosed.

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

Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.

The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.

“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.

The findings were presented at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
 

A better fix than insulin?

Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.

Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.

“We’ve been looking for different ways of treating hyperglycemia for quite some time, and one of the obvious ways is to use insulin therapy,” Dr. Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”

Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.

An advantage to a GLP-1 agonist-like exenatide, Dr. Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.

A case for more study

To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.

The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.

On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.

The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care versus 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).

However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).

There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.

“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Dr. Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
 

Value to clinicians

Commenting on the findings, Yvonne Chun, PhD, honorary senior clinical lecturer at University of Edinburgh, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.

“The results are of value to clinicians, as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Dr. Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”

However, Dr. Chun noted that more study is needed before exenatide can replace standard care. Dr. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Dr. Chun and others.

“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale – a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Dr. Chun said. “The primary outcome used in the presented trial – an 8-point improvement on NIHSS – seemed too ambitious and does not inform disability of the patient post stroke.”

Dr. Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.

“I can see the day patients will come in with acute stroke, and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use, and it doesn’t cause hypoglycemia,” Dr. Bladin said. “And from the moment that patient arrives the glucose control is underway.”

Dr. Bladin and Dr. Chun reported no relevant financial relationships. Study funding was not disclosed.

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

Type 2 diabetes was associated with a 20% increased risk of tooth loss after adjusting for multiple other risk factors in a meta-analysis of 22 recent observational studies from around the world.

The risk of tooth loss with type 2 diabetes (versus no diabetes) ranged from 15% higher in cross-sectional studies to 29% higher in cohort studies to five times higher in case-control studies.

“For diabetes, there are various known complications that are considered in [patient] treatment and management, including neuropathy, nephropathy, cardiovascular [disease] and hypertension, and kidney disease,” senior author Abdolhalim Rajabi, PhD, told this news organization in an email.

“However, a chronic complication of this disease, which may be less noticeable and less tangible, is missing teeth, which can also exacerbate other complications in patients with diabetes,” Dr. Rajabi, a biostatistician at Golestan University of Medical Sciences, Gorgan, Iran, continued.

The meta-analysis showed that “physicians should pay attention to [dental health] in the management and control of diabetic patients,” he summarized.

The analysis by Amir Reza Ahmadian, DDS, dean of the Faculty of Dentistry, Golestan University of Medical Sciences, and colleagues was recently published in BMC Endocrine Disorders.

“Our study is the first comprehensive meta-analysis about the association between [type 2 diabetes] and tooth loss,” Dr. Ahmadian and colleagues write. It summarizes articles in dentistry and medicine about “an important question:” the relationship between type 2 diabetes and tooth loss.  

Nevertheless, “large-scale prospective studies are needed to validate the current results in the future,” they conclude.
 

Oral complications of diabetes

Diabetes increases the risk of oral disease directly by a gingival inflammatory response and indirectly by decreased saliva production due to antidiabetic medications.

Oral complications arising from this include dry mouth, tooth decay, and periodontal disease (gum disease). The latter ranges from gingivitis (gum inflammation) to severe periodontal disease (periodontitis) that can lead to tooth loss, the authors explain.

About a third of people with diabetes have severe periodontal disease, and the American Diabetes Association estimates that one in five cases of tooth loss in adults is related to diabetes.

Tooth loss has decreased over the past decades but is still a major health problem and is associated with poorer quality of life as well as risk of cardiovascular disease, hypertension, stroke, and cancer.

Previous studies and meta-analyses of the relationship between type 2 diabetes and tooth loss have reported inconsistent findings, and they did not include several more recent studies.

Therefore, Dr. Ahmadian and colleagues performed a meta-analysis of 13 cross-sectional, six cohort, and three case-control studies that investigated the link between type 2 diabetes and tooth loss published from 2007 to 2021.

Eleven studies were from North and South America: Brazil (2), Columbia (1), Mexico (2), and the United States (6). Seven studies were from Europe: Belgium (1), Finland (2), France (1), Germany (2), and Portugal (1). Four studies were from the Middle East and Asia: Saudi Arabia (1), South Korea (1), Thailand (1), and Yemen (1).

Diabetes was diagnosed based on glucose or A1c levels in half the studies and based on self-report in the other studies. Most studies investigated any tooth loss (16 studies) and the rest only considered loss of five or more teeth.

The meta-analysis included 677,532 patients, ranging from 60 to 379,021 patients per study. Most studies (77%) were judged to be of moderate or high quality.

The studies adjusted for confounders, including age, sex, place of residence, education, lifestyle factors (smoking, alcohol consumption, physical activity), use of medications and vitamin supplements, and health insurance.

Overall, after adjusting for confounders, participants with type 2 diabetes had a significantly (20%) greater risk of tooth loss than participants without diabetes (adjusted odds ratio, 1.20; P < 0.001).

The association persisted in the different study types. The risk of tooth loss was highest in the case-control studies (OR, 5.10), but was also significantly higher in the cohort (OR, 1.29) and cross-sectional studies (OR, 1.15).

The association “was also present in other subgroups, including ... method of diagnosing type 2 diabetes, continent, study quality, and number of tooth loss,” the researchers write.

“This event seems to be in line with what has been reported in other epidemiologic studies, as several cases have supported the link between diabetes, periodontal disease, and tooth decay,” which “are two common reasons for the endpoint of the tooth loss parameter,” they note.

The researchers did not find any publication bias. However, most of the studies were cross-sectional, so they cannot determine a causal relationship between diabetes and tooth loss.

The authors have reported no relevant financial disclosures.

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

Type 2 diabetes was associated with a 20% increased risk of tooth loss after adjusting for multiple other risk factors in a meta-analysis of 22 recent observational studies from around the world.

The risk of tooth loss with type 2 diabetes (versus no diabetes) ranged from 15% higher in cross-sectional studies to 29% higher in cohort studies to five times higher in case-control studies.

“For diabetes, there are various known complications that are considered in [patient] treatment and management, including neuropathy, nephropathy, cardiovascular [disease] and hypertension, and kidney disease,” senior author Abdolhalim Rajabi, PhD, told this news organization in an email.

“However, a chronic complication of this disease, which may be less noticeable and less tangible, is missing teeth, which can also exacerbate other complications in patients with diabetes,” Dr. Rajabi, a biostatistician at Golestan University of Medical Sciences, Gorgan, Iran, continued.

The meta-analysis showed that “physicians should pay attention to [dental health] in the management and control of diabetic patients,” he summarized.

The analysis by Amir Reza Ahmadian, DDS, dean of the Faculty of Dentistry, Golestan University of Medical Sciences, and colleagues was recently published in BMC Endocrine Disorders.

“Our study is the first comprehensive meta-analysis about the association between [type 2 diabetes] and tooth loss,” Dr. Ahmadian and colleagues write. It summarizes articles in dentistry and medicine about “an important question:” the relationship between type 2 diabetes and tooth loss.  

Nevertheless, “large-scale prospective studies are needed to validate the current results in the future,” they conclude.
 

Oral complications of diabetes

Diabetes increases the risk of oral disease directly by a gingival inflammatory response and indirectly by decreased saliva production due to antidiabetic medications.

Oral complications arising from this include dry mouth, tooth decay, and periodontal disease (gum disease). The latter ranges from gingivitis (gum inflammation) to severe periodontal disease (periodontitis) that can lead to tooth loss, the authors explain.

About a third of people with diabetes have severe periodontal disease, and the American Diabetes Association estimates that one in five cases of tooth loss in adults is related to diabetes.

Tooth loss has decreased over the past decades but is still a major health problem and is associated with poorer quality of life as well as risk of cardiovascular disease, hypertension, stroke, and cancer.

Previous studies and meta-analyses of the relationship between type 2 diabetes and tooth loss have reported inconsistent findings, and they did not include several more recent studies.

Therefore, Dr. Ahmadian and colleagues performed a meta-analysis of 13 cross-sectional, six cohort, and three case-control studies that investigated the link between type 2 diabetes and tooth loss published from 2007 to 2021.

Eleven studies were from North and South America: Brazil (2), Columbia (1), Mexico (2), and the United States (6). Seven studies were from Europe: Belgium (1), Finland (2), France (1), Germany (2), and Portugal (1). Four studies were from the Middle East and Asia: Saudi Arabia (1), South Korea (1), Thailand (1), and Yemen (1).

Diabetes was diagnosed based on glucose or A1c levels in half the studies and based on self-report in the other studies. Most studies investigated any tooth loss (16 studies) and the rest only considered loss of five or more teeth.

The meta-analysis included 677,532 patients, ranging from 60 to 379,021 patients per study. Most studies (77%) were judged to be of moderate or high quality.

The studies adjusted for confounders, including age, sex, place of residence, education, lifestyle factors (smoking, alcohol consumption, physical activity), use of medications and vitamin supplements, and health insurance.

Overall, after adjusting for confounders, participants with type 2 diabetes had a significantly (20%) greater risk of tooth loss than participants without diabetes (adjusted odds ratio, 1.20; P < 0.001).

The association persisted in the different study types. The risk of tooth loss was highest in the case-control studies (OR, 5.10), but was also significantly higher in the cohort (OR, 1.29) and cross-sectional studies (OR, 1.15).

The association “was also present in other subgroups, including ... method of diagnosing type 2 diabetes, continent, study quality, and number of tooth loss,” the researchers write.

“This event seems to be in line with what has been reported in other epidemiologic studies, as several cases have supported the link between diabetes, periodontal disease, and tooth decay,” which “are two common reasons for the endpoint of the tooth loss parameter,” they note.

The researchers did not find any publication bias. However, most of the studies were cross-sectional, so they cannot determine a causal relationship between diabetes and tooth loss.

The authors have reported no relevant financial disclosures.

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

Type 2 diabetes was associated with a 20% increased risk of tooth loss after adjusting for multiple other risk factors in a meta-analysis of 22 recent observational studies from around the world.

The risk of tooth loss with type 2 diabetes (versus no diabetes) ranged from 15% higher in cross-sectional studies to 29% higher in cohort studies to five times higher in case-control studies.

“For diabetes, there are various known complications that are considered in [patient] treatment and management, including neuropathy, nephropathy, cardiovascular [disease] and hypertension, and kidney disease,” senior author Abdolhalim Rajabi, PhD, told this news organization in an email.

“However, a chronic complication of this disease, which may be less noticeable and less tangible, is missing teeth, which can also exacerbate other complications in patients with diabetes,” Dr. Rajabi, a biostatistician at Golestan University of Medical Sciences, Gorgan, Iran, continued.

The meta-analysis showed that “physicians should pay attention to [dental health] in the management and control of diabetic patients,” he summarized.

The analysis by Amir Reza Ahmadian, DDS, dean of the Faculty of Dentistry, Golestan University of Medical Sciences, and colleagues was recently published in BMC Endocrine Disorders.

“Our study is the first comprehensive meta-analysis about the association between [type 2 diabetes] and tooth loss,” Dr. Ahmadian and colleagues write. It summarizes articles in dentistry and medicine about “an important question:” the relationship between type 2 diabetes and tooth loss.  

Nevertheless, “large-scale prospective studies are needed to validate the current results in the future,” they conclude.
 

Oral complications of diabetes

Diabetes increases the risk of oral disease directly by a gingival inflammatory response and indirectly by decreased saliva production due to antidiabetic medications.

Oral complications arising from this include dry mouth, tooth decay, and periodontal disease (gum disease). The latter ranges from gingivitis (gum inflammation) to severe periodontal disease (periodontitis) that can lead to tooth loss, the authors explain.

About a third of people with diabetes have severe periodontal disease, and the American Diabetes Association estimates that one in five cases of tooth loss in adults is related to diabetes.

Tooth loss has decreased over the past decades but is still a major health problem and is associated with poorer quality of life as well as risk of cardiovascular disease, hypertension, stroke, and cancer.

Previous studies and meta-analyses of the relationship between type 2 diabetes and tooth loss have reported inconsistent findings, and they did not include several more recent studies.

Therefore, Dr. Ahmadian and colleagues performed a meta-analysis of 13 cross-sectional, six cohort, and three case-control studies that investigated the link between type 2 diabetes and tooth loss published from 2007 to 2021.

Eleven studies were from North and South America: Brazil (2), Columbia (1), Mexico (2), and the United States (6). Seven studies were from Europe: Belgium (1), Finland (2), France (1), Germany (2), and Portugal (1). Four studies were from the Middle East and Asia: Saudi Arabia (1), South Korea (1), Thailand (1), and Yemen (1).

Diabetes was diagnosed based on glucose or A1c levels in half the studies and based on self-report in the other studies. Most studies investigated any tooth loss (16 studies) and the rest only considered loss of five or more teeth.

The meta-analysis included 677,532 patients, ranging from 60 to 379,021 patients per study. Most studies (77%) were judged to be of moderate or high quality.

The studies adjusted for confounders, including age, sex, place of residence, education, lifestyle factors (smoking, alcohol consumption, physical activity), use of medications and vitamin supplements, and health insurance.

Overall, after adjusting for confounders, participants with type 2 diabetes had a significantly (20%) greater risk of tooth loss than participants without diabetes (adjusted odds ratio, 1.20; P < 0.001).

The association persisted in the different study types. The risk of tooth loss was highest in the case-control studies (OR, 5.10), but was also significantly higher in the cohort (OR, 1.29) and cross-sectional studies (OR, 1.15).

The association “was also present in other subgroups, including ... method of diagnosing type 2 diabetes, continent, study quality, and number of tooth loss,” the researchers write.

“This event seems to be in line with what has been reported in other epidemiologic studies, as several cases have supported the link between diabetes, periodontal disease, and tooth decay,” which “are two common reasons for the endpoint of the tooth loss parameter,” they note.

The researchers did not find any publication bias. However, most of the studies were cross-sectional, so they cannot determine a causal relationship between diabetes and tooth loss.

The authors have reported no relevant financial disclosures.

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

Nasopharyngeal carcinoma (NPC) differs from other head and neck (H&N) cancers in its epidemiology and treatment. Unlike other H&N cancers, NPC has a distinct geographical distribution with a much higher incidence in endemic areas, such as southern China, than in areas where it is relatively uncommon, such as the United States.¹ The etiology of NPC varies based on the geographical distribution, with Epstein-Barr virus (EBV) thought to be the primary etiologic agent in endemic areas. On the other hand, in North America 2 additional subsets of NPC have been identified: human papillomavirus (HPV)–positive/EBV-negative and HPV-negative/EBV-negative.^2,3 NPC arises from the epithelial lining of the nasopharynx, often in the fossa of Rosenmuller, and is the most seen tumor in the nasopharynx.⁴ NPC is less surgically accessible than other H&N cancers, and surgery to the nasopharynx poses more risks given the proximity of critical surrounding structures. NPC is radiosensitive, and therefore radiotherapy (RT), in combination with chemotherapy for locally advanced tumors, has become the mainstay of treatment for nonmetastatic NPC.⁴

NPC often presents with an asymptomatic neck mass or with symptoms of epistaxis, nasal obstruction, and otitis media.⁵ Advanced cases of NPC can present with direct extension into the skull base, paranasal sinuses, and orbit, as well as involvement of cranial nerves. Radiation planning for tumors of the nasopharynx is complicated by the need to deliver an adequate dose to the tumor while limiting dose and toxicity to nearby critical structures such as the brainstem, optic chiasm, eyes, spinal cord (SC), temporal lobes, and cochleae. Achieving an adequate dose to nasopharyngeal primary tumors is especially complicated for T4 tumors invading the skull base with intracranial extension, in direct contact with these critical structures (Table 1).

Case Presentation

A 34-year-old male patient with no previous medical history presented to the emergency department with worsening diplopia, nasal obstruction, facial pain, and neck stiffness. The patient reported a 3 pack-year smoking history with recent smoking cessation. His physical examination was notable for a right abducens nerve palsy and an ulcerated nasopharyngeal mass on endoscopy.

Computed tomography (CT) scan revealed a 7-cm mass in the nasopharynx, eroding through the skull base with destruction and replacement of the clivus by tumor. Also noted was erosion of the petrous apices, carotid canals, sella turcica, dens, and the bilateral occipital condyles. There was intracranial extension with replacement of portions of the cavernous sinuses as well as mass effect on the prepontine cistern. Additional brain imaging studies, including magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, were obtained for completion of the staging workup. The MRI correlated with the findings noted on CT and demonstrated involvement of Meckel cave, foramen ovale, foramen rotundum, Dorello canal, and the hypoglossal canals. No cervical lymphadenopathy or distant metastases were noted on imaging. Pathology from biopsy revealed poorly differentiated squamous cell carcinoma, EBV-negative, strongly p16-positive, HPV-16 positive, and P53-negative.

RT planning was complicated by the tumor’s contact with the brainstem and upper cervical SC, as well as proximity of the tumor to the optic apparatus. The patient underwent 2 replanning CT scans at 26 Gy and 44 Gy to evaluate for tumor shrinkage. These CT scans demonstrated shrinkage of the tumor away from critical neural structures, allowing the treatment volume to be reduced away from these structures in order to achieve required dose tolerances (brainstem < 54 Gy, optic nerves and chiasm < 50 Gy, SC < 45 Gy for this case). The replanning CT scan at 44 Gy, 5 weeks after treatment initiation, demonstrated that dramatic tumor shrinkage had occurred early in treatment, with separation of the remaining tumor from the area of the SC and brainstem with which it was initially in contact (Figure 1). This improvement allowed for shrinkage of the high-dose radiation field away from these critical neural structures.

Discussion

RT for NPC is complicated by the proximity of these tumors to critical surrounding neural structures. It is challenging to achieve the required dose constraints to surrounding neural tissues while delivering the usual 70-Gy dose to the gross tumor, especially when the tumor comes into direct contact with these structures.

This case provides an example of response-adapted RT using imaging during treatment to shrink the high-dose target as the tumor shrinks away from critical surrounding structures.⁷ This strategy permits delivery of the maximum dose to the tumor while minimizing radiation dose, and therefore risk of toxicity, to normal surrounding structures. While it is typical to deliver 70 Gy to the full extent of tumor involvement for H&N tumors, this was not possible in this case as the tumor was in contact with the brainstem and upper cervical SC. Delivering the full 70 Gy to these areas of tumor would have placed this patient at substantial risk of brainstem and/or SC toxicity. This report demonstrates that response-adapted RT with shrinking fields can allow for tumor control while avoiding toxicity to critical neural structures for cases of locally advanced NPC in which tumor is abutting these structures.

Bony regeneration of the skull base following RT has been reported in the literature, but in limited reviews. Early reports used plain radiography to follow changes. Unger and colleagues demonstrated the regeneration of bone using skull radiographs 4 to 6 months after completion of RT for NPC.⁸ More recent literature details the ability of bone to regenerate after RT based on CT findings. Fang and colleagues reported on 90 cases of NPC with skull base destruction, with 63% having bony regeneration on posttreatment CT.⁹ Most of the patients in Fang’s report had bony regeneration within 1 year of treatment, and in general, bony regeneration became more evident on imaging with longer follow-up. Of note, local control was significantly greater in patients with regeneration vs persistent destruction (77% vs 21%, P < .001). On multivariate analysis, complete tumor response was significantly associated with bony regeneration; other factors such as age, sex, radiation dose, and chemotherapy were not significantly associated with the likelihood of bony regeneration.

Our report details a nasopharyngeal tumor that destroyed the skull base with no intact bony barrier. In such cases, concern arises regarding craniospinal instability with tumor regression if there is not simultaneous bone regeneration. Tumor invasion of the skull base and C1-2 vertebral bodies and complications from treatment of such tumor extent can lead to symptoms of craniospinal instability, including pain, difficulty with neck range of motion, and loss of strength and sensation in the upper and lower extremities.¹⁰ A case report of a woman treated with chemoradiation for a plasmacytoma of the skull base detailed her posttreatment presentation with quadriparesis resulting from craniospinal instability after tumor regression.¹¹ Such instability is generally treated surgically, and during this woman’s surgery, there was an injury to the right vertebral artery, although this did not cause any additional neurologic deficits.

Conclusions

There is a paucity of literature on bony regeneration in patients with skull base destruction from advanced NPC, and in particular, the ability of skull base regeneration to occur during treatment simultaneous with tumor regression. Our patient had HPV-positive/EBV-negative NPC, but it is unclear how this subtype affected his prognosis. Factors such as tumor histology, radiosensitivity with rapid tumor regression, and young age may have all contributed to the rapidity of bone regeneration in our patient. This case report demonstrates that an impressive tumor response to chemoradiation with simultaneous bony regeneration is possible among patients presenting with tumor destruction of the skull base, precluding the need for neurosurgical intervention.

Nasopharyngeal carcinoma (NPC) differs from other head and neck (H&N) cancers in its epidemiology and treatment. Unlike other H&N cancers, NPC has a distinct geographical distribution with a much higher incidence in endemic areas, such as southern China, than in areas where it is relatively uncommon, such as the United States.¹ The etiology of NPC varies based on the geographical distribution, with Epstein-Barr virus (EBV) thought to be the primary etiologic agent in endemic areas. On the other hand, in North America 2 additional subsets of NPC have been identified: human papillomavirus (HPV)–positive/EBV-negative and HPV-negative/EBV-negative.^2,3 NPC arises from the epithelial lining of the nasopharynx, often in the fossa of Rosenmuller, and is the most seen tumor in the nasopharynx.⁴ NPC is less surgically accessible than other H&N cancers, and surgery to the nasopharynx poses more risks given the proximity of critical surrounding structures. NPC is radiosensitive, and therefore radiotherapy (RT), in combination with chemotherapy for locally advanced tumors, has become the mainstay of treatment for nonmetastatic NPC.⁴

NPC often presents with an asymptomatic neck mass or with symptoms of epistaxis, nasal obstruction, and otitis media.⁵ Advanced cases of NPC can present with direct extension into the skull base, paranasal sinuses, and orbit, as well as involvement of cranial nerves. Radiation planning for tumors of the nasopharynx is complicated by the need to deliver an adequate dose to the tumor while limiting dose and toxicity to nearby critical structures such as the brainstem, optic chiasm, eyes, spinal cord (SC), temporal lobes, and cochleae. Achieving an adequate dose to nasopharyngeal primary tumors is especially complicated for T4 tumors invading the skull base with intracranial extension, in direct contact with these critical structures (Table 1).

Case Presentation

A 34-year-old male patient with no previous medical history presented to the emergency department with worsening diplopia, nasal obstruction, facial pain, and neck stiffness. The patient reported a 3 pack-year smoking history with recent smoking cessation. His physical examination was notable for a right abducens nerve palsy and an ulcerated nasopharyngeal mass on endoscopy.

Computed tomography (CT) scan revealed a 7-cm mass in the nasopharynx, eroding through the skull base with destruction and replacement of the clivus by tumor. Also noted was erosion of the petrous apices, carotid canals, sella turcica, dens, and the bilateral occipital condyles. There was intracranial extension with replacement of portions of the cavernous sinuses as well as mass effect on the prepontine cistern. Additional brain imaging studies, including magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, were obtained for completion of the staging workup. The MRI correlated with the findings noted on CT and demonstrated involvement of Meckel cave, foramen ovale, foramen rotundum, Dorello canal, and the hypoglossal canals. No cervical lymphadenopathy or distant metastases were noted on imaging. Pathology from biopsy revealed poorly differentiated squamous cell carcinoma, EBV-negative, strongly p16-positive, HPV-16 positive, and P53-negative.

RT planning was complicated by the tumor’s contact with the brainstem and upper cervical SC, as well as proximity of the tumor to the optic apparatus. The patient underwent 2 replanning CT scans at 26 Gy and 44 Gy to evaluate for tumor shrinkage. These CT scans demonstrated shrinkage of the tumor away from critical neural structures, allowing the treatment volume to be reduced away from these structures in order to achieve required dose tolerances (brainstem < 54 Gy, optic nerves and chiasm < 50 Gy, SC < 45 Gy for this case). The replanning CT scan at 44 Gy, 5 weeks after treatment initiation, demonstrated that dramatic tumor shrinkage had occurred early in treatment, with separation of the remaining tumor from the area of the SC and brainstem with which it was initially in contact (Figure 1). This improvement allowed for shrinkage of the high-dose radiation field away from these critical neural structures.

Discussion

RT for NPC is complicated by the proximity of these tumors to critical surrounding neural structures. It is challenging to achieve the required dose constraints to surrounding neural tissues while delivering the usual 70-Gy dose to the gross tumor, especially when the tumor comes into direct contact with these structures.

This case provides an example of response-adapted RT using imaging during treatment to shrink the high-dose target as the tumor shrinks away from critical surrounding structures.⁷ This strategy permits delivery of the maximum dose to the tumor while minimizing radiation dose, and therefore risk of toxicity, to normal surrounding structures. While it is typical to deliver 70 Gy to the full extent of tumor involvement for H&N tumors, this was not possible in this case as the tumor was in contact with the brainstem and upper cervical SC. Delivering the full 70 Gy to these areas of tumor would have placed this patient at substantial risk of brainstem and/or SC toxicity. This report demonstrates that response-adapted RT with shrinking fields can allow for tumor control while avoiding toxicity to critical neural structures for cases of locally advanced NPC in which tumor is abutting these structures.

Bony regeneration of the skull base following RT has been reported in the literature, but in limited reviews. Early reports used plain radiography to follow changes. Unger and colleagues demonstrated the regeneration of bone using skull radiographs 4 to 6 months after completion of RT for NPC.⁸ More recent literature details the ability of bone to regenerate after RT based on CT findings. Fang and colleagues reported on 90 cases of NPC with skull base destruction, with 63% having bony regeneration on posttreatment CT.⁹ Most of the patients in Fang’s report had bony regeneration within 1 year of treatment, and in general, bony regeneration became more evident on imaging with longer follow-up. Of note, local control was significantly greater in patients with regeneration vs persistent destruction (77% vs 21%, P < .001). On multivariate analysis, complete tumor response was significantly associated with bony regeneration; other factors such as age, sex, radiation dose, and chemotherapy were not significantly associated with the likelihood of bony regeneration.

Our report details a nasopharyngeal tumor that destroyed the skull base with no intact bony barrier. In such cases, concern arises regarding craniospinal instability with tumor regression if there is not simultaneous bone regeneration. Tumor invasion of the skull base and C1-2 vertebral bodies and complications from treatment of such tumor extent can lead to symptoms of craniospinal instability, including pain, difficulty with neck range of motion, and loss of strength and sensation in the upper and lower extremities.¹⁰ A case report of a woman treated with chemoradiation for a plasmacytoma of the skull base detailed her posttreatment presentation with quadriparesis resulting from craniospinal instability after tumor regression.¹¹ Such instability is generally treated surgically, and during this woman’s surgery, there was an injury to the right vertebral artery, although this did not cause any additional neurologic deficits.

Conclusions

There is a paucity of literature on bony regeneration in patients with skull base destruction from advanced NPC, and in particular, the ability of skull base regeneration to occur during treatment simultaneous with tumor regression. Our patient had HPV-positive/EBV-negative NPC, but it is unclear how this subtype affected his prognosis. Factors such as tumor histology, radiosensitivity with rapid tumor regression, and young age may have all contributed to the rapidity of bone regeneration in our patient. This case report demonstrates that an impressive tumor response to chemoradiation with simultaneous bony regeneration is possible among patients presenting with tumor destruction of the skull base, precluding the need for neurosurgical intervention.

Nasopharyngeal carcinoma (NPC) differs from other head and neck (H&N) cancers in its epidemiology and treatment. Unlike other H&N cancers, NPC has a distinct geographical distribution with a much higher incidence in endemic areas, such as southern China, than in areas where it is relatively uncommon, such as the United States.¹ The etiology of NPC varies based on the geographical distribution, with Epstein-Barr virus (EBV) thought to be the primary etiologic agent in endemic areas. On the other hand, in North America 2 additional subsets of NPC have been identified: human papillomavirus (HPV)–positive/EBV-negative and HPV-negative/EBV-negative.^2,3 NPC arises from the epithelial lining of the nasopharynx, often in the fossa of Rosenmuller, and is the most seen tumor in the nasopharynx.⁴ NPC is less surgically accessible than other H&N cancers, and surgery to the nasopharynx poses more risks given the proximity of critical surrounding structures. NPC is radiosensitive, and therefore radiotherapy (RT), in combination with chemotherapy for locally advanced tumors, has become the mainstay of treatment for nonmetastatic NPC.⁴

NPC often presents with an asymptomatic neck mass or with symptoms of epistaxis, nasal obstruction, and otitis media.⁵ Advanced cases of NPC can present with direct extension into the skull base, paranasal sinuses, and orbit, as well as involvement of cranial nerves. Radiation planning for tumors of the nasopharynx is complicated by the need to deliver an adequate dose to the tumor while limiting dose and toxicity to nearby critical structures such as the brainstem, optic chiasm, eyes, spinal cord (SC), temporal lobes, and cochleae. Achieving an adequate dose to nasopharyngeal primary tumors is especially complicated for T4 tumors invading the skull base with intracranial extension, in direct contact with these critical structures (Table 1).

Case Presentation

A 34-year-old male patient with no previous medical history presented to the emergency department with worsening diplopia, nasal obstruction, facial pain, and neck stiffness. The patient reported a 3 pack-year smoking history with recent smoking cessation. His physical examination was notable for a right abducens nerve palsy and an ulcerated nasopharyngeal mass on endoscopy.

Computed tomography (CT) scan revealed a 7-cm mass in the nasopharynx, eroding through the skull base with destruction and replacement of the clivus by tumor. Also noted was erosion of the petrous apices, carotid canals, sella turcica, dens, and the bilateral occipital condyles. There was intracranial extension with replacement of portions of the cavernous sinuses as well as mass effect on the prepontine cistern. Additional brain imaging studies, including magnetic resonance imaging (MRI) and positron emission tomography (PET) scans, were obtained for completion of the staging workup. The MRI correlated with the findings noted on CT and demonstrated involvement of Meckel cave, foramen ovale, foramen rotundum, Dorello canal, and the hypoglossal canals. No cervical lymphadenopathy or distant metastases were noted on imaging. Pathology from biopsy revealed poorly differentiated squamous cell carcinoma, EBV-negative, strongly p16-positive, HPV-16 positive, and P53-negative.

RT planning was complicated by the tumor’s contact with the brainstem and upper cervical SC, as well as proximity of the tumor to the optic apparatus. The patient underwent 2 replanning CT scans at 26 Gy and 44 Gy to evaluate for tumor shrinkage. These CT scans demonstrated shrinkage of the tumor away from critical neural structures, allowing the treatment volume to be reduced away from these structures in order to achieve required dose tolerances (brainstem < 54 Gy, optic nerves and chiasm < 50 Gy, SC < 45 Gy for this case). The replanning CT scan at 44 Gy, 5 weeks after treatment initiation, demonstrated that dramatic tumor shrinkage had occurred early in treatment, with separation of the remaining tumor from the area of the SC and brainstem with which it was initially in contact (Figure 1). This improvement allowed for shrinkage of the high-dose radiation field away from these critical neural structures.

Discussion

RT for NPC is complicated by the proximity of these tumors to critical surrounding neural structures. It is challenging to achieve the required dose constraints to surrounding neural tissues while delivering the usual 70-Gy dose to the gross tumor, especially when the tumor comes into direct contact with these structures.

This case provides an example of response-adapted RT using imaging during treatment to shrink the high-dose target as the tumor shrinks away from critical surrounding structures.⁷ This strategy permits delivery of the maximum dose to the tumor while minimizing radiation dose, and therefore risk of toxicity, to normal surrounding structures. While it is typical to deliver 70 Gy to the full extent of tumor involvement for H&N tumors, this was not possible in this case as the tumor was in contact with the brainstem and upper cervical SC. Delivering the full 70 Gy to these areas of tumor would have placed this patient at substantial risk of brainstem and/or SC toxicity. This report demonstrates that response-adapted RT with shrinking fields can allow for tumor control while avoiding toxicity to critical neural structures for cases of locally advanced NPC in which tumor is abutting these structures.

Bony regeneration of the skull base following RT has been reported in the literature, but in limited reviews. Early reports used plain radiography to follow changes. Unger and colleagues demonstrated the regeneration of bone using skull radiographs 4 to 6 months after completion of RT for NPC.⁸ More recent literature details the ability of bone to regenerate after RT based on CT findings. Fang and colleagues reported on 90 cases of NPC with skull base destruction, with 63% having bony regeneration on posttreatment CT.⁹ Most of the patients in Fang’s report had bony regeneration within 1 year of treatment, and in general, bony regeneration became more evident on imaging with longer follow-up. Of note, local control was significantly greater in patients with regeneration vs persistent destruction (77% vs 21%, P < .001). On multivariate analysis, complete tumor response was significantly associated with bony regeneration; other factors such as age, sex, radiation dose, and chemotherapy were not significantly associated with the likelihood of bony regeneration.

Our report details a nasopharyngeal tumor that destroyed the skull base with no intact bony barrier. In such cases, concern arises regarding craniospinal instability with tumor regression if there is not simultaneous bone regeneration. Tumor invasion of the skull base and C1-2 vertebral bodies and complications from treatment of such tumor extent can lead to symptoms of craniospinal instability, including pain, difficulty with neck range of motion, and loss of strength and sensation in the upper and lower extremities.¹⁰ A case report of a woman treated with chemoradiation for a plasmacytoma of the skull base detailed her posttreatment presentation with quadriparesis resulting from craniospinal instability after tumor regression.¹¹ Such instability is generally treated surgically, and during this woman’s surgery, there was an injury to the right vertebral artery, although this did not cause any additional neurologic deficits.

Conclusions

There is a paucity of literature on bony regeneration in patients with skull base destruction from advanced NPC, and in particular, the ability of skull base regeneration to occur during treatment simultaneous with tumor regression. Our patient had HPV-positive/EBV-negative NPC, but it is unclear how this subtype affected his prognosis. Factors such as tumor histology, radiosensitivity with rapid tumor regression, and young age may have all contributed to the rapidity of bone regeneration in our patient. This case report demonstrates that an impressive tumor response to chemoradiation with simultaneous bony regeneration is possible among patients presenting with tumor destruction of the skull base, precluding the need for neurosurgical intervention.

Use of race-based diabetes screening thresholds could reduce the disparity that arises from current screening guidelines in the United States, new research suggests.

In August 2021, the U.S. Preventive Services Task Force (USPSTF) lowered the recommended age for type 2 diabetes screening from 40 to 35 years among people with a body mass index of 25 kg/m² or greater.

However, the diabetes rate among ethnic minorities aged 35-70 years in the United States is not just higher overall but, in certain populations, also occurs more frequently at a younger age and at lower BMIs, the new study indicates.

Among people with a BMI below 25 kg/m², the diabetes prevalence is two to four times higher among Asian, Black, and Hispanic Americans than among the U.S. White population.

And the authors of the new study, led by Rahul Aggarwal, MD, predict that if screening begins at age 35 years, the BMI cut-off equivalent to 25 kg/m² for White Americans would be 18.5 kg/m2 for Hispanic and Black Americans and 20 kg/m² for Asian Americans.

“While diabetes has often been thought of as a disease that primarily affects adults with overweight or [obesity], our findings suggest that normal-weight adults in minority groups have surprisingly high rates of diabetes,” Dr. Aggarwal, senior resident physician in internal medicine at Harvard Medical School, Boston, told this news organization.

“Assessing diabetes risks in certain racial/ethnic groups will be necessary, even if these adults do not have overweight or [obesity],” he added.

Not screening in this way “is a missed opportunity for early intervention,” he noted.  

And both the authors and an editorialist stress that the issue isn’t just theoretical.

“USPSTF recommendations influence what payers choose to cover, which in turn determines access to preventative services ... Addressing the staggering inequities in diabetes outcomes will require substantial investments in diabetes prevention and treatment, but making screening more equitable is a good place to start,” said senior author Dhruv S. Kazi, MD, of the Smith Center for Outcomes Research in Cardiology and director of the Cardiac Critical Care Unit at Beth Israel, Boston.
 

Screen minorities at a younger age if current BMI threshold kept

In their study, based on data from the National Health and Nutrition Examination Survey (NHANES) for 2011-2018, Dr. Aggarwal and colleagues also calculated that, if the BMI threshold is kept at 25 kg/m², then the equivalent age cut-offs for Asian, Black, and Hispanic Americans would be 23, 21, and 25 years, respectively, compared with 35 years for White Americans.

The findings were published online  in the Annals of Internal Medicine.

The prevalence of diabetes in those aged 35-70 years in the NHANES population was 17.3% for Asian Americans and 12.5% for those who were White (odds ratio, 1.51 vs. Whites). Among Black Americans and Mexican Americans, the prevalence was 20.7% and 20.6%, respectively, almost twice the prevalence in Whites (OR, 1.85 and 1.80). For other Hispanic Americans, the prevalence was 16.4% (OR, 1.37 vs. Whites). All of those differences were significant, compared with White Americans.

Undiagnosed diabetes was also significantly more common among minority populations, at 27.6%, 22.8%, 21.2%, and 23.5% for Asian, Black, Mexican, and other Hispanic Americans, respectively, versus 12.5% for White Americans.
 

‘The time has come for USPSTF to offer more concrete guidance’

“While there is more work to be done on carefully examining the long-term risk–benefit trade-off of various diabetes screening, I believe the time has come for USPSTF to offer more concrete guidance on the use of lower thresholds for screening higher-risk individuals,” Dr. Kazi told this news organization.

The author of an accompanying editorial agrees, noting that in a recent commentary the USPSTF, itself, “acknowledged the persistent inequalities across the screening-to-treatment continuum that result in racial/ethnic health disparities in the United States.”

And the USPSTF “emphasized the need to improve systems of care to ensure equitable and consistent delivery of high-quality preventive and treatment services, with special attention to racial/ethnic groups who may experience worse health outcomes,” continues Quyen Ngo-Metzger, MD, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California.

For other conditions, including cancer, cardiovascular disease, and infectious disease, the USPSTF already recommends risk-based preventive services.

“To address the current inequity in diabetes screening, the USPSTF should apply the same consideration to its diabetes screening recommendation,” she notes.
 

‘Implementation will require an eye for pragmatism’

Asked about how this recommendation might be carried out in the real world, Dr. Aggarwal said in an interview that, because all three minority groups with normal weight had similar diabetes risk profiles to White adults with overweight, “one way for clinicians to easily implement these findings is by screening all Asian, Black, and Hispanic adults ages 35-70 years with normal weight for diabetes, similarly to how all White adults ages 35-70 years with overweight are currently recommended for screening.”

Dr. Kazi said: “I believe that implementation will require an eye for pragmatism,” noting that another option would be to have screening algorithms embedded in the electronic health record to flag individuals who qualify.

In any case, “the simplicity of the current one-size-fits-all approach is alluring, but it is profoundly inequitable. The more I look at the empiric evidence on diabetes burden in our communities, the more the status quo becomes untenable.”

However, Dr. Kazi also noted, “the benefit of any screening program relates to what we do with the information. The key is to ensure that folks identified as having diabetes – or better still prediabetes – receive timely lifestyle and pharmacological interventions to avert its long-term complications.”

This study was supported by institutional funds from the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology. Dr. Aggarwal, Dr. Kazi, and Dr. Ngo-Metzger have reported no relevant relationships.

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

Use of race-based diabetes screening thresholds could reduce the disparity that arises from current screening guidelines in the United States, new research suggests.

In August 2021, the U.S. Preventive Services Task Force (USPSTF) lowered the recommended age for type 2 diabetes screening from 40 to 35 years among people with a body mass index of 25 kg/m² or greater.

However, the diabetes rate among ethnic minorities aged 35-70 years in the United States is not just higher overall but, in certain populations, also occurs more frequently at a younger age and at lower BMIs, the new study indicates.

Among people with a BMI below 25 kg/m², the diabetes prevalence is two to four times higher among Asian, Black, and Hispanic Americans than among the U.S. White population.

And the authors of the new study, led by Rahul Aggarwal, MD, predict that if screening begins at age 35 years, the BMI cut-off equivalent to 25 kg/m² for White Americans would be 18.5 kg/m2 for Hispanic and Black Americans and 20 kg/m² for Asian Americans.

“While diabetes has often been thought of as a disease that primarily affects adults with overweight or [obesity], our findings suggest that normal-weight adults in minority groups have surprisingly high rates of diabetes,” Dr. Aggarwal, senior resident physician in internal medicine at Harvard Medical School, Boston, told this news organization.

“Assessing diabetes risks in certain racial/ethnic groups will be necessary, even if these adults do not have overweight or [obesity],” he added.

Not screening in this way “is a missed opportunity for early intervention,” he noted.  

And both the authors and an editorialist stress that the issue isn’t just theoretical.

“USPSTF recommendations influence what payers choose to cover, which in turn determines access to preventative services ... Addressing the staggering inequities in diabetes outcomes will require substantial investments in diabetes prevention and treatment, but making screening more equitable is a good place to start,” said senior author Dhruv S. Kazi, MD, of the Smith Center for Outcomes Research in Cardiology and director of the Cardiac Critical Care Unit at Beth Israel, Boston.
 

Screen minorities at a younger age if current BMI threshold kept

In their study, based on data from the National Health and Nutrition Examination Survey (NHANES) for 2011-2018, Dr. Aggarwal and colleagues also calculated that, if the BMI threshold is kept at 25 kg/m², then the equivalent age cut-offs for Asian, Black, and Hispanic Americans would be 23, 21, and 25 years, respectively, compared with 35 years for White Americans.

The findings were published online  in the Annals of Internal Medicine.

The prevalence of diabetes in those aged 35-70 years in the NHANES population was 17.3% for Asian Americans and 12.5% for those who were White (odds ratio, 1.51 vs. Whites). Among Black Americans and Mexican Americans, the prevalence was 20.7% and 20.6%, respectively, almost twice the prevalence in Whites (OR, 1.85 and 1.80). For other Hispanic Americans, the prevalence was 16.4% (OR, 1.37 vs. Whites). All of those differences were significant, compared with White Americans.

Undiagnosed diabetes was also significantly more common among minority populations, at 27.6%, 22.8%, 21.2%, and 23.5% for Asian, Black, Mexican, and other Hispanic Americans, respectively, versus 12.5% for White Americans.
 

‘The time has come for USPSTF to offer more concrete guidance’

“While there is more work to be done on carefully examining the long-term risk–benefit trade-off of various diabetes screening, I believe the time has come for USPSTF to offer more concrete guidance on the use of lower thresholds for screening higher-risk individuals,” Dr. Kazi told this news organization.

The author of an accompanying editorial agrees, noting that in a recent commentary the USPSTF, itself, “acknowledged the persistent inequalities across the screening-to-treatment continuum that result in racial/ethnic health disparities in the United States.”

And the USPSTF “emphasized the need to improve systems of care to ensure equitable and consistent delivery of high-quality preventive and treatment services, with special attention to racial/ethnic groups who may experience worse health outcomes,” continues Quyen Ngo-Metzger, MD, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California.

For other conditions, including cancer, cardiovascular disease, and infectious disease, the USPSTF already recommends risk-based preventive services.

“To address the current inequity in diabetes screening, the USPSTF should apply the same consideration to its diabetes screening recommendation,” she notes.
 

‘Implementation will require an eye for pragmatism’

Asked about how this recommendation might be carried out in the real world, Dr. Aggarwal said in an interview that, because all three minority groups with normal weight had similar diabetes risk profiles to White adults with overweight, “one way for clinicians to easily implement these findings is by screening all Asian, Black, and Hispanic adults ages 35-70 years with normal weight for diabetes, similarly to how all White adults ages 35-70 years with overweight are currently recommended for screening.”

Dr. Kazi said: “I believe that implementation will require an eye for pragmatism,” noting that another option would be to have screening algorithms embedded in the electronic health record to flag individuals who qualify.

In any case, “the simplicity of the current one-size-fits-all approach is alluring, but it is profoundly inequitable. The more I look at the empiric evidence on diabetes burden in our communities, the more the status quo becomes untenable.”

However, Dr. Kazi also noted, “the benefit of any screening program relates to what we do with the information. The key is to ensure that folks identified as having diabetes – or better still prediabetes – receive timely lifestyle and pharmacological interventions to avert its long-term complications.”

This study was supported by institutional funds from the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology. Dr. Aggarwal, Dr. Kazi, and Dr. Ngo-Metzger have reported no relevant relationships.

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

Use of race-based diabetes screening thresholds could reduce the disparity that arises from current screening guidelines in the United States, new research suggests.

In August 2021, the U.S. Preventive Services Task Force (USPSTF) lowered the recommended age for type 2 diabetes screening from 40 to 35 years among people with a body mass index of 25 kg/m² or greater.

However, the diabetes rate among ethnic minorities aged 35-70 years in the United States is not just higher overall but, in certain populations, also occurs more frequently at a younger age and at lower BMIs, the new study indicates.

Among people with a BMI below 25 kg/m², the diabetes prevalence is two to four times higher among Asian, Black, and Hispanic Americans than among the U.S. White population.

And the authors of the new study, led by Rahul Aggarwal, MD, predict that if screening begins at age 35 years, the BMI cut-off equivalent to 25 kg/m² for White Americans would be 18.5 kg/m2 for Hispanic and Black Americans and 20 kg/m² for Asian Americans.

“While diabetes has often been thought of as a disease that primarily affects adults with overweight or [obesity], our findings suggest that normal-weight adults in minority groups have surprisingly high rates of diabetes,” Dr. Aggarwal, senior resident physician in internal medicine at Harvard Medical School, Boston, told this news organization.

“Assessing diabetes risks in certain racial/ethnic groups will be necessary, even if these adults do not have overweight or [obesity],” he added.

Not screening in this way “is a missed opportunity for early intervention,” he noted.  

And both the authors and an editorialist stress that the issue isn’t just theoretical.

“USPSTF recommendations influence what payers choose to cover, which in turn determines access to preventative services ... Addressing the staggering inequities in diabetes outcomes will require substantial investments in diabetes prevention and treatment, but making screening more equitable is a good place to start,” said senior author Dhruv S. Kazi, MD, of the Smith Center for Outcomes Research in Cardiology and director of the Cardiac Critical Care Unit at Beth Israel, Boston.
 

Screen minorities at a younger age if current BMI threshold kept

In their study, based on data from the National Health and Nutrition Examination Survey (NHANES) for 2011-2018, Dr. Aggarwal and colleagues also calculated that, if the BMI threshold is kept at 25 kg/m², then the equivalent age cut-offs for Asian, Black, and Hispanic Americans would be 23, 21, and 25 years, respectively, compared with 35 years for White Americans.

The findings were published online  in the Annals of Internal Medicine.

The prevalence of diabetes in those aged 35-70 years in the NHANES population was 17.3% for Asian Americans and 12.5% for those who were White (odds ratio, 1.51 vs. Whites). Among Black Americans and Mexican Americans, the prevalence was 20.7% and 20.6%, respectively, almost twice the prevalence in Whites (OR, 1.85 and 1.80). For other Hispanic Americans, the prevalence was 16.4% (OR, 1.37 vs. Whites). All of those differences were significant, compared with White Americans.

Undiagnosed diabetes was also significantly more common among minority populations, at 27.6%, 22.8%, 21.2%, and 23.5% for Asian, Black, Mexican, and other Hispanic Americans, respectively, versus 12.5% for White Americans.
 

‘The time has come for USPSTF to offer more concrete guidance’

“While there is more work to be done on carefully examining the long-term risk–benefit trade-off of various diabetes screening, I believe the time has come for USPSTF to offer more concrete guidance on the use of lower thresholds for screening higher-risk individuals,” Dr. Kazi told this news organization.

The author of an accompanying editorial agrees, noting that in a recent commentary the USPSTF, itself, “acknowledged the persistent inequalities across the screening-to-treatment continuum that result in racial/ethnic health disparities in the United States.”

And the USPSTF “emphasized the need to improve systems of care to ensure equitable and consistent delivery of high-quality preventive and treatment services, with special attention to racial/ethnic groups who may experience worse health outcomes,” continues Quyen Ngo-Metzger, MD, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California.

For other conditions, including cancer, cardiovascular disease, and infectious disease, the USPSTF already recommends risk-based preventive services.

“To address the current inequity in diabetes screening, the USPSTF should apply the same consideration to its diabetes screening recommendation,” she notes.
 

‘Implementation will require an eye for pragmatism’

Asked about how this recommendation might be carried out in the real world, Dr. Aggarwal said in an interview that, because all three minority groups with normal weight had similar diabetes risk profiles to White adults with overweight, “one way for clinicians to easily implement these findings is by screening all Asian, Black, and Hispanic adults ages 35-70 years with normal weight for diabetes, similarly to how all White adults ages 35-70 years with overweight are currently recommended for screening.”

Dr. Kazi said: “I believe that implementation will require an eye for pragmatism,” noting that another option would be to have screening algorithms embedded in the electronic health record to flag individuals who qualify.

In any case, “the simplicity of the current one-size-fits-all approach is alluring, but it is profoundly inequitable. The more I look at the empiric evidence on diabetes burden in our communities, the more the status quo becomes untenable.”

However, Dr. Kazi also noted, “the benefit of any screening program relates to what we do with the information. The key is to ensure that folks identified as having diabetes – or better still prediabetes – receive timely lifestyle and pharmacological interventions to avert its long-term complications.”

This study was supported by institutional funds from the Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology. Dr. Aggarwal, Dr. Kazi, and Dr. Ngo-Metzger have reported no relevant relationships.

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

Long-term use of a proton-pump inhibitor (PPI) was associated with an increased risk of being diagnosed with type 2 diabetes in a large, population-based case-control study in Italy.

The risk of diabetes increased from 19% to 56% as treatment duration increased from 8 weeks to more than 2 years, and prolonged treatment was associated with an even higher risk of diabetes in the youngest patients (age 40-65) and those with the most comorbidities.

The results suggest that “physicians should therefore avoid unnecessary prescription of this class of drugs, particularly for long-term use,” say Stefano Ciardullo, MD, University of Milano-Bicocca, Italy, and colleagues, in their article recently published online in the Journal of Clinical Endocrinology & Metabolism.

“Nonetheless, epidemiologic evidence on the topic remains conflicting,” they acknowledge, adding that “future studies are still needed to validate our findings.”

If the results are confirmed, these “may have important implications for both public health and clinical practice, given the high number of patients being treated with PPIs and the influence of diabetes on morbidity and mortality related to its possible micro- and macrovascular complications,” Dr. Ciardullo and colleagues conclude.
 

Not enough data to support a change in practice

The current findings align with a recent analysis of three prospective cohort studies of U.S. health care workers that showed a progressively increased risk of diabetes with longer treatment with PPIs, David A. Leiman, MD, MSHP, who was not involved with the current study, told this news organization in an email. “But the effect size remains relatively small and may be explained by residual or unmeasured confounding,” he cautioned.

“Ultimately, there do not seem to be enough data to support a change in clinical practice from this study alone, and, as a result, clinicians should continue to inform patients of the best available evidence regarding the benefits and risks of PPIs,” said Dr. Leiman, assistant professor of medicine, Division of Gastroenterology, Duke University Medical Center, Durham, N.C.

“Recent best practice advice from the American Gastroenterological Association does not recommend screening for insulin resistance among PPI users [and recommends that the decision to discontinue PPIs] should be based solely on the lack of an indication for PPI use, and not because of concern for PPI-associated adverse events,” he noted.

“Clinicians should be prepared to discuss the described risks associated with PPIs,” said Dr. Leiman, but they should “also feel comfortable affirming their safety profile and substantial efficacy in managing symptoms and preventing complications when prescribed for the appropriate indication.”

First-choice therapy for acid-related disorders

PPIs have become first-choice therapy for patients with acid-related disorders such as gastroesophageal reflux disease, Barrett esophagus, and peptic ulcer, and to prevent gastrointestinal bleeding while on nonsteroidal anti-inflammatory drugs (NSAIDs), Dr. Ciardullo and colleagues explain.

However, several studies have identified potential fractures, hypomagnesemia, gastric carcinoids, chronic kidney disease, dementia, and Clostridium difficile diarrhea with prolonged use of PPIs, and these agents can cause changes in the gut microbiome that may play a role in diabetes and other metabolic diseases.

To investigate a potential association between PPIs and type 2 diabetes, the researchers analyzed data from 777,420 patients age 40 and older who were newly treated with PPIs between 2010 and 2015 in Lombardy, Italy.

Of these, 50,540 patients were diagnosed with type 2 diabetes during follow-up until 2020 (a mean follow-up of 6.2 years and a diabetes incidence of 10.6 cases per 1,000 person-years).

The researchers matched 50,535 patients diagnosed with diabetes during follow-up with 50,535 control patients who had the same age, sex, and clinical status.

Patients were a mean age of 66 years and half were men. The most prescribed PPIs were pantoprazole and omeprazole, and the patients diagnosed with diabetes were more likely to use antihypertensives and lipid-lowering drugs.

Compared with patients who received PPIs for less than 8 weeks, those who received PPIs for 8 weeks to 6 months had a 19% increased risk of being diagnosed with diabetes during follow-up (odds ratio, 1.19; 95% confidence interval, 1.15-1.24), after adjusting for age, clinical profile, comorbidities, medical therapy, and PPI type.

Patients who received PPIs for 6 months to 2 years had a 43% increased risk of the outcome (OR, 1.43; 95% CI, 1.38-1.49), and those who received PPIs for more than 2 years had a 56% increased risk of the outcome (OR, 1.56; 95% CI, 1.49-1.64).

The researchers acknowledge limitations including that the study was not a randomized controlled trial, and it lacked information about over-the-counter medications and unmeasured confounders such as body mass index or family history of diabetes that may have affected the outcomes.

Dr. Leiman added that patients may have had prediabetes or undiagnosed diabetes and symptoms such as heartburn or dyspepsia arising from complications of insulin resistance, for which PPIs might have been prescribed.

The study was funded by a grant from the Italian Ministry of Education, University and Research. Dr. Ciardullo and Dr. Leiman have reported no relevant financial relationships.

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

Long-term use of a proton-pump inhibitor (PPI) was associated with an increased risk of being diagnosed with type 2 diabetes in a large, population-based case-control study in Italy.

The risk of diabetes increased from 19% to 56% as treatment duration increased from 8 weeks to more than 2 years, and prolonged treatment was associated with an even higher risk of diabetes in the youngest patients (age 40-65) and those with the most comorbidities.

The results suggest that “physicians should therefore avoid unnecessary prescription of this class of drugs, particularly for long-term use,” say Stefano Ciardullo, MD, University of Milano-Bicocca, Italy, and colleagues, in their article recently published online in the Journal of Clinical Endocrinology & Metabolism.

“Nonetheless, epidemiologic evidence on the topic remains conflicting,” they acknowledge, adding that “future studies are still needed to validate our findings.”

If the results are confirmed, these “may have important implications for both public health and clinical practice, given the high number of patients being treated with PPIs and the influence of diabetes on morbidity and mortality related to its possible micro- and macrovascular complications,” Dr. Ciardullo and colleagues conclude.
 

Not enough data to support a change in practice

The current findings align with a recent analysis of three prospective cohort studies of U.S. health care workers that showed a progressively increased risk of diabetes with longer treatment with PPIs, David A. Leiman, MD, MSHP, who was not involved with the current study, told this news organization in an email. “But the effect size remains relatively small and may be explained by residual or unmeasured confounding,” he cautioned.

“Ultimately, there do not seem to be enough data to support a change in clinical practice from this study alone, and, as a result, clinicians should continue to inform patients of the best available evidence regarding the benefits and risks of PPIs,” said Dr. Leiman, assistant professor of medicine, Division of Gastroenterology, Duke University Medical Center, Durham, N.C.

“Recent best practice advice from the American Gastroenterological Association does not recommend screening for insulin resistance among PPI users [and recommends that the decision to discontinue PPIs] should be based solely on the lack of an indication for PPI use, and not because of concern for PPI-associated adverse events,” he noted.

“Clinicians should be prepared to discuss the described risks associated with PPIs,” said Dr. Leiman, but they should “also feel comfortable affirming their safety profile and substantial efficacy in managing symptoms and preventing complications when prescribed for the appropriate indication.”

First-choice therapy for acid-related disorders

PPIs have become first-choice therapy for patients with acid-related disorders such as gastroesophageal reflux disease, Barrett esophagus, and peptic ulcer, and to prevent gastrointestinal bleeding while on nonsteroidal anti-inflammatory drugs (NSAIDs), Dr. Ciardullo and colleagues explain.

However, several studies have identified potential fractures, hypomagnesemia, gastric carcinoids, chronic kidney disease, dementia, and Clostridium difficile diarrhea with prolonged use of PPIs, and these agents can cause changes in the gut microbiome that may play a role in diabetes and other metabolic diseases.

To investigate a potential association between PPIs and type 2 diabetes, the researchers analyzed data from 777,420 patients age 40 and older who were newly treated with PPIs between 2010 and 2015 in Lombardy, Italy.

Of these, 50,540 patients were diagnosed with type 2 diabetes during follow-up until 2020 (a mean follow-up of 6.2 years and a diabetes incidence of 10.6 cases per 1,000 person-years).

The researchers matched 50,535 patients diagnosed with diabetes during follow-up with 50,535 control patients who had the same age, sex, and clinical status.

Patients were a mean age of 66 years and half were men. The most prescribed PPIs were pantoprazole and omeprazole, and the patients diagnosed with diabetes were more likely to use antihypertensives and lipid-lowering drugs.

Compared with patients who received PPIs for less than 8 weeks, those who received PPIs for 8 weeks to 6 months had a 19% increased risk of being diagnosed with diabetes during follow-up (odds ratio, 1.19; 95% confidence interval, 1.15-1.24), after adjusting for age, clinical profile, comorbidities, medical therapy, and PPI type.

Patients who received PPIs for 6 months to 2 years had a 43% increased risk of the outcome (OR, 1.43; 95% CI, 1.38-1.49), and those who received PPIs for more than 2 years had a 56% increased risk of the outcome (OR, 1.56; 95% CI, 1.49-1.64).

The researchers acknowledge limitations including that the study was not a randomized controlled trial, and it lacked information about over-the-counter medications and unmeasured confounders such as body mass index or family history of diabetes that may have affected the outcomes.

Dr. Leiman added that patients may have had prediabetes or undiagnosed diabetes and symptoms such as heartburn or dyspepsia arising from complications of insulin resistance, for which PPIs might have been prescribed.

The study was funded by a grant from the Italian Ministry of Education, University and Research. Dr. Ciardullo and Dr. Leiman have reported no relevant financial relationships.

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

Long-term use of a proton-pump inhibitor (PPI) was associated with an increased risk of being diagnosed with type 2 diabetes in a large, population-based case-control study in Italy.

The risk of diabetes increased from 19% to 56% as treatment duration increased from 8 weeks to more than 2 years, and prolonged treatment was associated with an even higher risk of diabetes in the youngest patients (age 40-65) and those with the most comorbidities.

The results suggest that “physicians should therefore avoid unnecessary prescription of this class of drugs, particularly for long-term use,” say Stefano Ciardullo, MD, University of Milano-Bicocca, Italy, and colleagues, in their article recently published online in the Journal of Clinical Endocrinology & Metabolism.

“Nonetheless, epidemiologic evidence on the topic remains conflicting,” they acknowledge, adding that “future studies are still needed to validate our findings.”

If the results are confirmed, these “may have important implications for both public health and clinical practice, given the high number of patients being treated with PPIs and the influence of diabetes on morbidity and mortality related to its possible micro- and macrovascular complications,” Dr. Ciardullo and colleagues conclude.
 

Not enough data to support a change in practice

The current findings align with a recent analysis of three prospective cohort studies of U.S. health care workers that showed a progressively increased risk of diabetes with longer treatment with PPIs, David A. Leiman, MD, MSHP, who was not involved with the current study, told this news organization in an email. “But the effect size remains relatively small and may be explained by residual or unmeasured confounding,” he cautioned.

“Ultimately, there do not seem to be enough data to support a change in clinical practice from this study alone, and, as a result, clinicians should continue to inform patients of the best available evidence regarding the benefits and risks of PPIs,” said Dr. Leiman, assistant professor of medicine, Division of Gastroenterology, Duke University Medical Center, Durham, N.C.

“Recent best practice advice from the American Gastroenterological Association does not recommend screening for insulin resistance among PPI users [and recommends that the decision to discontinue PPIs] should be based solely on the lack of an indication for PPI use, and not because of concern for PPI-associated adverse events,” he noted.

“Clinicians should be prepared to discuss the described risks associated with PPIs,” said Dr. Leiman, but they should “also feel comfortable affirming their safety profile and substantial efficacy in managing symptoms and preventing complications when prescribed for the appropriate indication.”

First-choice therapy for acid-related disorders

PPIs have become first-choice therapy for patients with acid-related disorders such as gastroesophageal reflux disease, Barrett esophagus, and peptic ulcer, and to prevent gastrointestinal bleeding while on nonsteroidal anti-inflammatory drugs (NSAIDs), Dr. Ciardullo and colleagues explain.

However, several studies have identified potential fractures, hypomagnesemia, gastric carcinoids, chronic kidney disease, dementia, and Clostridium difficile diarrhea with prolonged use of PPIs, and these agents can cause changes in the gut microbiome that may play a role in diabetes and other metabolic diseases.

To investigate a potential association between PPIs and type 2 diabetes, the researchers analyzed data from 777,420 patients age 40 and older who were newly treated with PPIs between 2010 and 2015 in Lombardy, Italy.

Of these, 50,540 patients were diagnosed with type 2 diabetes during follow-up until 2020 (a mean follow-up of 6.2 years and a diabetes incidence of 10.6 cases per 1,000 person-years).

The researchers matched 50,535 patients diagnosed with diabetes during follow-up with 50,535 control patients who had the same age, sex, and clinical status.

Patients were a mean age of 66 years and half were men. The most prescribed PPIs were pantoprazole and omeprazole, and the patients diagnosed with diabetes were more likely to use antihypertensives and lipid-lowering drugs.

Compared with patients who received PPIs for less than 8 weeks, those who received PPIs for 8 weeks to 6 months had a 19% increased risk of being diagnosed with diabetes during follow-up (odds ratio, 1.19; 95% confidence interval, 1.15-1.24), after adjusting for age, clinical profile, comorbidities, medical therapy, and PPI type.

Patients who received PPIs for 6 months to 2 years had a 43% increased risk of the outcome (OR, 1.43; 95% CI, 1.38-1.49), and those who received PPIs for more than 2 years had a 56% increased risk of the outcome (OR, 1.56; 95% CI, 1.49-1.64).

The researchers acknowledge limitations including that the study was not a randomized controlled trial, and it lacked information about over-the-counter medications and unmeasured confounders such as body mass index or family history of diabetes that may have affected the outcomes.

Dr. Leiman added that patients may have had prediabetes or undiagnosed diabetes and symptoms such as heartburn or dyspepsia arising from complications of insulin resistance, for which PPIs might have been prescribed.

The study was funded by a grant from the Italian Ministry of Education, University and Research. Dr. Ciardullo and Dr. Leiman have reported no relevant financial relationships.

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

Following a vegan diet for at least 3 months helped people with overweight or type 2 diabetes shed the pounds, but had only a marginal effect on hemoglobin A1c levels, on average, new research indicates.

No effect was seen on blood pressure, triglycerides, or high-density lipoprotein cholesterol. HbA1c was reduced by a mean of –0.18 percentage points (P = .002), and there was a small reduction in total cholesterol and low-density lipoprotein cholesterol, on average, across all the studies examined in this meta-analysis.

The work, which compared a number of trials looking at vegan diets versus “normal” eating or other kinds of weight loss diets, “indicates with reasonable certainty that adhering to a vegan diet for at least 12 weeks may result in clinically meaningful weight loss [and] can be used in the management of overweight and type 2 diabetes,” said Anne-Ditte Termannsen, PhD, who reported the findings during a press conference at the European Congress on Obesity 2022, where the work was also presented as a poster.

A vegan diet most likely led to weight loss because it is “associated with a reduced calorie intake due to a lower content of fat and higher content of dietary fiber,” added Dr. Termannsen of the Steno Diabetes Center Copenhagen.

Asked to comment, Janet Cade, PhD, who leads the Nutritional Epidemiology Group at the University of Leeds (England) said the results are likely attributable to fewer calories in the vegan diet, compared with the “control” diets. “Of course, a vegan diet can be healthier in a range of ways, such as higher fruit and vegetables, more fiber and antioxidants; however, the same would be true of a vegetarian diet,” she noted.

And she warned that longer-term data are needed on health outcomes associated with vegan diets, noting, “there have been links to poorer bone health and osteoporosis in people consuming a vegan diet.”

Gunter Kuhnle, PhD, professor of nutrition and food science, University of Reading (England) told the UK Science Media Centre: “The authors conducted a systematic review of intervention studies and found that, compared with no dietary interventions, vegan diets showed the strongest association with body-weight reduction.”

However, “When comparing vegan diets with other dietary interventions – such as the Mediterranean diet – the association was much weaker,” he noted.
 

Vegan, habitual, or a range of weight-loss diets

Dr. Termannsen and colleagues set out to look at the effect of a plant-based diet on cardiometabolic risk factors in people with overweight or type 2 diabetes. They searched the literature for randomized controlled trials with adult participants with overweight (body mass index ≥ 25 kg/m²), prediabetes, or type 2 diabetes.

Participants followed a vegan diet that lasted at least 12 weeks; habitual diets without any changes or energy restriction; a Mediterranean diet; a host of different “diabetes” diets; a low-fat diet; or portion-controlled diets.

“The vegan diets were nearly all low-fat vegan diets but vary substantially regarding the protein, fat, carbohydrate content. All but one study was ad libitum fat, and there were no energy restrictions,” Dr. Termannsen said.

Control diets were more varied. “Some continued their habitual diet, and about half were energy restricted and the others were not,” she acknowledged.

Outcomes comprised body weight, BMI, HbA1c, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, which were assessed across studies.

A total of 11 trials were included in the meta-analysis, and studies were a mean duration of 19 weeks. A total of 796 participants were included.

Compared with control diets, those on vegan diets lost on average –4.1 kg (–9 lb) (P < .001), with a range of –5.9 kg to –2.4 kg.

BMI dropped by –1.38 kg/m² (P < .001). Total cholesterol dropped by –0.30 mmol/L (–11.6 mg/dL; P = .007) and LDL cholesterol by –0.24 mmol/L (–9.28 mg/dL; P = .005).

Further analyses found even greater reductions in body weight and BMI when vegan diets were compared with continuing a normal diet without dietary changes, on average, at –7.4 kg (–16.3 lb) (P < .001) and –2.78 kg/m² (P < .001) respectively.

When compared with other intervention diets, however, body weight dropped by –2.7 kg (–6 lb; P < .001) and BMI by –0.87 kg/m² (P < .001).

Commenting on limitations of studies compared to the real world, Dr. Termannsen said: “Some studies reported high adherence to their diet, usually due to a high level of support, suggesting that providing continued face-to-face contact with participants may partly explain the adherence differences.”

“This also questions the long-term feasibility of the diet and the applicability of this as long-term care,” she added.

Following a vegan diet requires good planning to ensure adequate nutrition and avoid any deficiencies, she urged. “We need to remember that the menu plans in the studies were created by dietitians.”

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

Following a vegan diet for at least 3 months helped people with overweight or type 2 diabetes shed the pounds, but had only a marginal effect on hemoglobin A1c levels, on average, new research indicates.

No effect was seen on blood pressure, triglycerides, or high-density lipoprotein cholesterol. HbA1c was reduced by a mean of –0.18 percentage points (P = .002), and there was a small reduction in total cholesterol and low-density lipoprotein cholesterol, on average, across all the studies examined in this meta-analysis.

The work, which compared a number of trials looking at vegan diets versus “normal” eating or other kinds of weight loss diets, “indicates with reasonable certainty that adhering to a vegan diet for at least 12 weeks may result in clinically meaningful weight loss [and] can be used in the management of overweight and type 2 diabetes,” said Anne-Ditte Termannsen, PhD, who reported the findings during a press conference at the European Congress on Obesity 2022, where the work was also presented as a poster.

A vegan diet most likely led to weight loss because it is “associated with a reduced calorie intake due to a lower content of fat and higher content of dietary fiber,” added Dr. Termannsen of the Steno Diabetes Center Copenhagen.

Asked to comment, Janet Cade, PhD, who leads the Nutritional Epidemiology Group at the University of Leeds (England) said the results are likely attributable to fewer calories in the vegan diet, compared with the “control” diets. “Of course, a vegan diet can be healthier in a range of ways, such as higher fruit and vegetables, more fiber and antioxidants; however, the same would be true of a vegetarian diet,” she noted.

And she warned that longer-term data are needed on health outcomes associated with vegan diets, noting, “there have been links to poorer bone health and osteoporosis in people consuming a vegan diet.”

Gunter Kuhnle, PhD, professor of nutrition and food science, University of Reading (England) told the UK Science Media Centre: “The authors conducted a systematic review of intervention studies and found that, compared with no dietary interventions, vegan diets showed the strongest association with body-weight reduction.”

However, “When comparing vegan diets with other dietary interventions – such as the Mediterranean diet – the association was much weaker,” he noted.
 

Vegan, habitual, or a range of weight-loss diets

Dr. Termannsen and colleagues set out to look at the effect of a plant-based diet on cardiometabolic risk factors in people with overweight or type 2 diabetes. They searched the literature for randomized controlled trials with adult participants with overweight (body mass index ≥ 25 kg/m²), prediabetes, or type 2 diabetes.

Participants followed a vegan diet that lasted at least 12 weeks; habitual diets without any changes or energy restriction; a Mediterranean diet; a host of different “diabetes” diets; a low-fat diet; or portion-controlled diets.

“The vegan diets were nearly all low-fat vegan diets but vary substantially regarding the protein, fat, carbohydrate content. All but one study was ad libitum fat, and there were no energy restrictions,” Dr. Termannsen said.

Control diets were more varied. “Some continued their habitual diet, and about half were energy restricted and the others were not,” she acknowledged.

Outcomes comprised body weight, BMI, HbA1c, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, which were assessed across studies.

A total of 11 trials were included in the meta-analysis, and studies were a mean duration of 19 weeks. A total of 796 participants were included.

Compared with control diets, those on vegan diets lost on average –4.1 kg (–9 lb) (P < .001), with a range of –5.9 kg to –2.4 kg.

BMI dropped by –1.38 kg/m² (P < .001). Total cholesterol dropped by –0.30 mmol/L (–11.6 mg/dL; P = .007) and LDL cholesterol by –0.24 mmol/L (–9.28 mg/dL; P = .005).

Further analyses found even greater reductions in body weight and BMI when vegan diets were compared with continuing a normal diet without dietary changes, on average, at –7.4 kg (–16.3 lb) (P < .001) and –2.78 kg/m² (P < .001) respectively.

When compared with other intervention diets, however, body weight dropped by –2.7 kg (–6 lb; P < .001) and BMI by –0.87 kg/m² (P < .001).

Commenting on limitations of studies compared to the real world, Dr. Termannsen said: “Some studies reported high adherence to their diet, usually due to a high level of support, suggesting that providing continued face-to-face contact with participants may partly explain the adherence differences.”

“This also questions the long-term feasibility of the diet and the applicability of this as long-term care,” she added.

Following a vegan diet requires good planning to ensure adequate nutrition and avoid any deficiencies, she urged. “We need to remember that the menu plans in the studies were created by dietitians.”

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

Following a vegan diet for at least 3 months helped people with overweight or type 2 diabetes shed the pounds, but had only a marginal effect on hemoglobin A1c levels, on average, new research indicates.

No effect was seen on blood pressure, triglycerides, or high-density lipoprotein cholesterol. HbA1c was reduced by a mean of –0.18 percentage points (P = .002), and there was a small reduction in total cholesterol and low-density lipoprotein cholesterol, on average, across all the studies examined in this meta-analysis.

The work, which compared a number of trials looking at vegan diets versus “normal” eating or other kinds of weight loss diets, “indicates with reasonable certainty that adhering to a vegan diet for at least 12 weeks may result in clinically meaningful weight loss [and] can be used in the management of overweight and type 2 diabetes,” said Anne-Ditte Termannsen, PhD, who reported the findings during a press conference at the European Congress on Obesity 2022, where the work was also presented as a poster.

A vegan diet most likely led to weight loss because it is “associated with a reduced calorie intake due to a lower content of fat and higher content of dietary fiber,” added Dr. Termannsen of the Steno Diabetes Center Copenhagen.

Asked to comment, Janet Cade, PhD, who leads the Nutritional Epidemiology Group at the University of Leeds (England) said the results are likely attributable to fewer calories in the vegan diet, compared with the “control” diets. “Of course, a vegan diet can be healthier in a range of ways, such as higher fruit and vegetables, more fiber and antioxidants; however, the same would be true of a vegetarian diet,” she noted.

And she warned that longer-term data are needed on health outcomes associated with vegan diets, noting, “there have been links to poorer bone health and osteoporosis in people consuming a vegan diet.”

Gunter Kuhnle, PhD, professor of nutrition and food science, University of Reading (England) told the UK Science Media Centre: “The authors conducted a systematic review of intervention studies and found that, compared with no dietary interventions, vegan diets showed the strongest association with body-weight reduction.”

However, “When comparing vegan diets with other dietary interventions – such as the Mediterranean diet – the association was much weaker,” he noted.
 

Vegan, habitual, or a range of weight-loss diets

Dr. Termannsen and colleagues set out to look at the effect of a plant-based diet on cardiometabolic risk factors in people with overweight or type 2 diabetes. They searched the literature for randomized controlled trials with adult participants with overweight (body mass index ≥ 25 kg/m²), prediabetes, or type 2 diabetes.

Participants followed a vegan diet that lasted at least 12 weeks; habitual diets without any changes or energy restriction; a Mediterranean diet; a host of different “diabetes” diets; a low-fat diet; or portion-controlled diets.

“The vegan diets were nearly all low-fat vegan diets but vary substantially regarding the protein, fat, carbohydrate content. All but one study was ad libitum fat, and there were no energy restrictions,” Dr. Termannsen said.

Control diets were more varied. “Some continued their habitual diet, and about half were energy restricted and the others were not,” she acknowledged.

Outcomes comprised body weight, BMI, HbA1c, systolic and diastolic blood pressure, total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides, which were assessed across studies.

A total of 11 trials were included in the meta-analysis, and studies were a mean duration of 19 weeks. A total of 796 participants were included.

Compared with control diets, those on vegan diets lost on average –4.1 kg (–9 lb) (P < .001), with a range of –5.9 kg to –2.4 kg.

BMI dropped by –1.38 kg/m² (P < .001). Total cholesterol dropped by –0.30 mmol/L (–11.6 mg/dL; P = .007) and LDL cholesterol by –0.24 mmol/L (–9.28 mg/dL; P = .005).

Further analyses found even greater reductions in body weight and BMI when vegan diets were compared with continuing a normal diet without dietary changes, on average, at –7.4 kg (–16.3 lb) (P < .001) and –2.78 kg/m² (P < .001) respectively.

When compared with other intervention diets, however, body weight dropped by –2.7 kg (–6 lb; P < .001) and BMI by –0.87 kg/m² (P < .001).

Commenting on limitations of studies compared to the real world, Dr. Termannsen said: “Some studies reported high adherence to their diet, usually due to a high level of support, suggesting that providing continued face-to-face contact with participants may partly explain the adherence differences.”

“This also questions the long-term feasibility of the diet and the applicability of this as long-term care,” she added.

Following a vegan diet requires good planning to ensure adequate nutrition and avoid any deficiencies, she urged. “We need to remember that the menu plans in the studies were created by dietitians.”

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

The COVID-19 pandemic has brought about unprecedented changes and challenges to medical practice, including new public health measure legislation, local and national medical authority recommendations, nursing home and other ancillary health center protocols, and novel clinical decision-making considerations.^1-3 In July 2020, the American Academy of Dermatology (AAD) addressed the changing landscape in dermatologic surgery, in part, by publishing recommendations on practice protocols during the COVID-19 pandemic.⁴ The guidelines recommended deferred treatment of superficial basal cell carcinomas (BCCs) for 6 months and all other BCC subtypes for 3 to 6 months. Furthermore, the guidelines recommended deferring treatment of all actinic keratoses and squamous cell carcinomas (SCCs) in situ “for now.” Squamous cell carcinoma treatment was to be guided by prognostic variables, such as location, size, depth, differentiation, perineural or lymphovascular invasion, recurrence, and immunosuppression. The guidelines recommended melanoma in situ (MIS) treatment be deferred for 3 months and invasive melanoma with histologic clearance obtained on excisional biopsy for 3 months. Other general recommendations included triaging clinics, rebooking according to clinical priority, using telehealth where possible, screening patients for COVID-19 signs and symptoms, staggering appointment times, spacing patient chairs, limiting support persons to 1, removing possible sources of infection in the waiting room, ensuring all patients sanitized their hands on arrival, rationing personal protective equipment, considering N95 masks for periorificial surgery, and using dissolving sutures to minimize multiple presentations.⁴

The American College of Mohs Surgery (ACMS), with guidance from its sister societies and the National Comprehensive Cancer Network, also communicated COVID-19–related recommendations to its members via intermittent newsletters during the initial peak of the pandemic in March and June 2020.⁵ General social distancing and office recommendations were similar to those released by the AAD. Recommendations for skin cancer treatment included deferring all BCCs for up to 3 months, with exceptions for highly symptomatic cancers and those with potential for substantial rapid growth. Squamous cell carcinoma in situ and small, well-differentiated SCCs were deferred, with priority placed on SCCs that were rapidly enlarging, poorly differentiated, demonstrated perineural invasion, were ulcerated, or were symptomatic. Patients with major risk factors were prioritized for treatment. Melanoma in situ was deferred for 2 to 3 months.⁵

State-level guidance from the Texas Dermatological Society (TDS) communicated in April 2020 stated that skin cancers with a potential for rapid progression and metastasis, such as melanoma and SCC, may require treatment as determined by the physician.⁶ The potential risk of serious adverse medical outcomes from not treating these cancers should be carefully documented. General practice measures for preventing the spread of COVID-19 were also recommended.⁶

In the setting of emerging novel recommendations, the practice of Mohs micrographic surgery (MMS) was notably impacted by the COVID-19 pandemic. According to one survey study from the United Kingdom conducted in April and May 2020, 49% of MMS services ceased and 36% were reduced during the infancy of the COVID-19 pandemic.⁷ Mohs micrographic surgery was largely suspended because of a lack of personal protective equipment and safety concerns, according to respondents. Additionally, respondents reported 77% of departments experienced redeployment of physicians and nurses to intensive care and medical wards. Thirty-five percent reported a reduction in the proportion of flaps/grafts to primary closures performed, 74% reported a decrease in outside referrals for repair by other specialties, 81% reported increased usage of dissolvable sutures, and 29% reported an increase in prophylactic antibiotic prescriptions.⁷ Another study from Italy reported a 46.5% reduction in dermatologic surgeries performed during the initial lockdown of the COVID-19 pandemic. Patients canceled 52.9% of procedures, and 12.5% were cancelled because of confirmed or suspected COVID-19 infection.⁸ Patient perceptions of MMS have also been impacted by the COVID-19 pandemic. According to a survey study of patients in the United Kingdom undergoing MMS during the pandemic, 47% were worried the hospital would cancel their surgery, 54% were anxious about using public transportation to attend their appointment, 30% were concerned about transmitting COVID-19 to household or family members, and 19% were worried about their ability to socially distance in the hospital.⁹

Evidence is also emerging that suggests the potential negative impact of the COVID-19 pandemic on morbidity and mortality outcomes in patients with skin cancer. One European study found an increase in Breslow thickness in primary melanomas diagnosed following the initial COVID-19 lockdown (0.88-mm average thickness prelockdown vs 1.96-mm average thickness postlockdown).¹⁰ An Italian study observed similar results—an increase in median Breslow thickness during the initial COVID-19 lockdown period of 0.5 mm from 0.4 mm during the prelockdown time period.¹¹ Also providing evidence for potentially poor patient outcomes, one study modeled the impact of backlog in cutaneous melanoma referrals in the United Kingdom on patient survival and predicted 138 attributable lives lost for a 1-month delay and 1171 lives lost for a 6-month delay. The model further predicted a 3.1% to 12.5% reduction in 10-year net survival incurred from a 3-month delay in melanoma treatment, with the largest reduction seen in the patient population older than 80 years.¹²

Although the COVID-19 pandemic has been observed to impact MMS practice, patient perceptions, and clinical outcomes, it is unknown how the COVID-19 pandemic and corresponding rapidly evolving recommendations in dermatologic surgery have impacted the characteristics of cutaneous tumors treated by MMS.

Our study sought to determine the characteristics of skin cancers treated by MMS during the peak of government-mandated medical practice restrictions and business shutdowns in response to the COVID-19 pandemic and to compare them with characteristics of skin cancers treated during a prepandemic control period.

Methods

A retrospective chart review was conducted with approval from our institutional review board at the University of Texas Medical Branch (Galveston, Texas). Included in the chart review were all cutaneous malignancies treated by MMS at our outpatient, office-based surgical center from March 15, 2020, to April 30, 2020; this period corresponded to the peak of the COVID-19–related government-mandated medical and business shutdowns in our geographic region (southeast Texas). All cases performed were in compliance with national- and state-level guidance. Data were also collected for all cutaneous malignancies treated by MMS at our office from March 15, 2019, to April 30, 2019, as well as March 15, 2018, to April 30, 2018; these periods represented prepandemic control periods.

Data were collected for 516 surgeries performed on 458 patients and included patient age, preoperative clinical size, postoperative defect size, number of Mohs stages to achieve clearance, MMS appropriate use criteria (AUC) location (categorized as high-, medium-, or low-risk tumor location),¹³ and tumor type (categorized as BCC, SCC, or MIS). All variables were examined for unusual or missing values. Five patients with rare tumor types were observed and removed from the data set.

Statistical Analysis—An a priori power analysis for a power set at 0.85 determined sample sizes of 105 per group. Bivariate analyses were performed to compare variables for patients undergoing MMS during the pandemic vs prepandemic periods. Continuous outcome variables—Mohs stages, preoperative size, postoperative size, and patient age—were categorized for the analysis. Preoperative tumor size was dichotomized, with less than 2 cm² as the referent category vs 2 cm² or greater, and postoperative defect size was dichotomized with less than 3.6 cm² as the referent category vs 3.6 cm² or greater. Mohs stage was dichotomized as 1 stage (referent) vs more than 1 stage, and patient age was dichotomized as younger than 65 years (referent) vs 65 years or older.

Multivariate analyses were also performed to compare preoperative and postoperative sizes for patients undergoing MMS during the pandemic vs prepandemic periods, controlling for Mohs AUC location. Bivariate unadjusted and multivariate analyses were performed using a GENMOD logistic regression procedure in SAS (SAS Institute) to account for correlation in clustered data because a patient could be included for more than 1 surgery in the data set. Data were analyzed using SAS 9.4 for Windows. Because outcome variables tended to be skewed and not distributed normally, outcome variables were recorded as medians with interquartile ranges where possible to give a more accurate representation of the data than could be demonstrated with means with standard deviations.

Results

One hundred thirty-eight skin cancers were treated during the COVID-19 pandemic from March 15, 2020, to April 30, 2020, and 378 skin cancers were treated during the prepandemic control periods of March 15, 2019, to April 30, 2019, and March 15, 2018, to April 30, 2018. Tumor type treated during the pandemic period was more likely to be SCC or MIS (representing generally more severe tumor types) vs BCC when compared with the prepandemic periods, with an odds ratio (OR) of 1.763 (95% CI, 1.17-2.66). This outcome was statistically significant (P=.01).

Tumors treated during the pandemic period were more likely to have necessitated more than one Mohs stage for clearance compared to the prepandemic periods, though this difference was not statistically significant (OR, 1.461; 95% CI, 0.97-2.19; P=.056). Neither AUC location of treated tumors nor age were significantly different between prepandemic and pandemic periods (P=.58 and P=.84, respectively). Table 1 includes all bivariate analysis results.

Additionally, although mean preoperative and postoperative sizes were larger for each AUC location during the pandemic vs prepandemic periods, these differences did not reach statistical significance on multivariate analysis (P=.71 and P=.50, respectively)(Table 2).

Our practice has followed best practice guidelines dictated by our governing professional societies during the COVID-19 pandemic in the treatment of skin cancers by MMS, specifically highly symptomatic BCCs (in accordance with ACMS guidance), SCCs with high-risk features (in accordance with AAD, ACMS, and TDS guidance), and tumors with high risk for progression and metastasis such as melanomas (in accordance with TDS guidance). Melanoma in situ was also treated during the COVID-19 pandemic in accordance with the latter TDS guidance, particularly in light of the potential for upstaging to melanoma following resection (a phenomenon demonstrated to occur in 5%–29% of biopsied MIS lesions).¹⁴

In following best practice guidelines, our results suggested tumors treated by MMS were more severe, as evidenced by a statistically significant higher proportion of SCC and MIS tumors (representing more severe tumor types) vs BCC when compared to the prepandemic period. Supporting this conclusion, we observed larger pretreatment and posttreatment tumor sizes for all AUC locations and more tumors necessitating 2 or more stages for clearance during the pandemic vs prepandemic periods, though these differences did not reach statistical significance. We postulate these findings may be attributed to allocation of finite medical resources to the treatment of larger and more aggressive skin cancers. Additionally, these findings may be explained, in part, by limitations on patient case load imposed by social distancing measures and governing body regulations in effect during the study period, including those put forth by the AAD, ACMS, and TDS. Of note, our practice observed no hospitalizations or 911 calls during the studied period. This suggests no allocation of precious hospital resources away from patients with COVID-19 in our treatment of high-risk skin cancers.

The changing characteristics of cutaneous tumors treated by MMS during the pandemic are of clinical relevance. Larger postoperative wound sizes as observed during the pandemic, albeit not statistically significant, presumably affect reconstructive decisions. With larger wounds tending to necessitate repair by techniques higher on the reconstructive ladder, greater patient morbidity and cost are expected.¹⁵ As the cost-effectiveness of dermatology services remains a critical issue, this is an area ripe for future follow-up research. Furthermore, our observation that tumors tended to necessitate 2 or more stages for clearance during the pandemic more often than prepandemic periods, though not statistically significant, presumably affected operating times. Longer operating times during the pandemic may be of importance when making clinical decisions for patients for whom limiting health care exposure may be of particular concern. With more SCC and MIS tumors being treated relative to BCCs during the pandemic, one might expect greater size and severity of the BCCs we observe in the proceeding months to years.

As the ongoing COVID-19 pandemic continues to impact the landscape of cutaneous oncology, the need for adaptability is imperative. With 3- and 6-month skin cancer treatment deferrals lapsed, uncertainty surrounds ideal management of existing and new skin cancers arising during the pandemic. This study adds to a growing body of literature elucidating the impact of the COVID-19 pandemic on MMS practice; however, further studies and a tincture of time are needed to guide future best practice standards.

Acknowledgment—The authors acknowledge Gwen Baillargeon, MS (Galveston, Texas), who was the statistician for this article.

The COVID-19 pandemic has brought about unprecedented changes and challenges to medical practice, including new public health measure legislation, local and national medical authority recommendations, nursing home and other ancillary health center protocols, and novel clinical decision-making considerations.^1-3 In July 2020, the American Academy of Dermatology (AAD) addressed the changing landscape in dermatologic surgery, in part, by publishing recommendations on practice protocols during the COVID-19 pandemic.⁴ The guidelines recommended deferred treatment of superficial basal cell carcinomas (BCCs) for 6 months and all other BCC subtypes for 3 to 6 months. Furthermore, the guidelines recommended deferring treatment of all actinic keratoses and squamous cell carcinomas (SCCs) in situ “for now.” Squamous cell carcinoma treatment was to be guided by prognostic variables, such as location, size, depth, differentiation, perineural or lymphovascular invasion, recurrence, and immunosuppression. The guidelines recommended melanoma in situ (MIS) treatment be deferred for 3 months and invasive melanoma with histologic clearance obtained on excisional biopsy for 3 months. Other general recommendations included triaging clinics, rebooking according to clinical priority, using telehealth where possible, screening patients for COVID-19 signs and symptoms, staggering appointment times, spacing patient chairs, limiting support persons to 1, removing possible sources of infection in the waiting room, ensuring all patients sanitized their hands on arrival, rationing personal protective equipment, considering N95 masks for periorificial surgery, and using dissolving sutures to minimize multiple presentations.⁴

The American College of Mohs Surgery (ACMS), with guidance from its sister societies and the National Comprehensive Cancer Network, also communicated COVID-19–related recommendations to its members via intermittent newsletters during the initial peak of the pandemic in March and June 2020.⁵ General social distancing and office recommendations were similar to those released by the AAD. Recommendations for skin cancer treatment included deferring all BCCs for up to 3 months, with exceptions for highly symptomatic cancers and those with potential for substantial rapid growth. Squamous cell carcinoma in situ and small, well-differentiated SCCs were deferred, with priority placed on SCCs that were rapidly enlarging, poorly differentiated, demonstrated perineural invasion, were ulcerated, or were symptomatic. Patients with major risk factors were prioritized for treatment. Melanoma in situ was deferred for 2 to 3 months.⁵

State-level guidance from the Texas Dermatological Society (TDS) communicated in April 2020 stated that skin cancers with a potential for rapid progression and metastasis, such as melanoma and SCC, may require treatment as determined by the physician.⁶ The potential risk of serious adverse medical outcomes from not treating these cancers should be carefully documented. General practice measures for preventing the spread of COVID-19 were also recommended.⁶

In the setting of emerging novel recommendations, the practice of Mohs micrographic surgery (MMS) was notably impacted by the COVID-19 pandemic. According to one survey study from the United Kingdom conducted in April and May 2020, 49% of MMS services ceased and 36% were reduced during the infancy of the COVID-19 pandemic.⁷ Mohs micrographic surgery was largely suspended because of a lack of personal protective equipment and safety concerns, according to respondents. Additionally, respondents reported 77% of departments experienced redeployment of physicians and nurses to intensive care and medical wards. Thirty-five percent reported a reduction in the proportion of flaps/grafts to primary closures performed, 74% reported a decrease in outside referrals for repair by other specialties, 81% reported increased usage of dissolvable sutures, and 29% reported an increase in prophylactic antibiotic prescriptions.⁷ Another study from Italy reported a 46.5% reduction in dermatologic surgeries performed during the initial lockdown of the COVID-19 pandemic. Patients canceled 52.9% of procedures, and 12.5% were cancelled because of confirmed or suspected COVID-19 infection.⁸ Patient perceptions of MMS have also been impacted by the COVID-19 pandemic. According to a survey study of patients in the United Kingdom undergoing MMS during the pandemic, 47% were worried the hospital would cancel their surgery, 54% were anxious about using public transportation to attend their appointment, 30% were concerned about transmitting COVID-19 to household or family members, and 19% were worried about their ability to socially distance in the hospital.⁹

Evidence is also emerging that suggests the potential negative impact of the COVID-19 pandemic on morbidity and mortality outcomes in patients with skin cancer. One European study found an increase in Breslow thickness in primary melanomas diagnosed following the initial COVID-19 lockdown (0.88-mm average thickness prelockdown vs 1.96-mm average thickness postlockdown).¹⁰ An Italian study observed similar results—an increase in median Breslow thickness during the initial COVID-19 lockdown period of 0.5 mm from 0.4 mm during the prelockdown time period.¹¹ Also providing evidence for potentially poor patient outcomes, one study modeled the impact of backlog in cutaneous melanoma referrals in the United Kingdom on patient survival and predicted 138 attributable lives lost for a 1-month delay and 1171 lives lost for a 6-month delay. The model further predicted a 3.1% to 12.5% reduction in 10-year net survival incurred from a 3-month delay in melanoma treatment, with the largest reduction seen in the patient population older than 80 years.¹²

Although the COVID-19 pandemic has been observed to impact MMS practice, patient perceptions, and clinical outcomes, it is unknown how the COVID-19 pandemic and corresponding rapidly evolving recommendations in dermatologic surgery have impacted the characteristics of cutaneous tumors treated by MMS.

Our study sought to determine the characteristics of skin cancers treated by MMS during the peak of government-mandated medical practice restrictions and business shutdowns in response to the COVID-19 pandemic and to compare them with characteristics of skin cancers treated during a prepandemic control period.

Methods

A retrospective chart review was conducted with approval from our institutional review board at the University of Texas Medical Branch (Galveston, Texas). Included in the chart review were all cutaneous malignancies treated by MMS at our outpatient, office-based surgical center from March 15, 2020, to April 30, 2020; this period corresponded to the peak of the COVID-19–related government-mandated medical and business shutdowns in our geographic region (southeast Texas). All cases performed were in compliance with national- and state-level guidance. Data were also collected for all cutaneous malignancies treated by MMS at our office from March 15, 2019, to April 30, 2019, as well as March 15, 2018, to April 30, 2018; these periods represented prepandemic control periods.

Data were collected for 516 surgeries performed on 458 patients and included patient age, preoperative clinical size, postoperative defect size, number of Mohs stages to achieve clearance, MMS appropriate use criteria (AUC) location (categorized as high-, medium-, or low-risk tumor location),¹³ and tumor type (categorized as BCC, SCC, or MIS). All variables were examined for unusual or missing values. Five patients with rare tumor types were observed and removed from the data set.

Statistical Analysis—An a priori power analysis for a power set at 0.85 determined sample sizes of 105 per group. Bivariate analyses were performed to compare variables for patients undergoing MMS during the pandemic vs prepandemic periods. Continuous outcome variables—Mohs stages, preoperative size, postoperative size, and patient age—were categorized for the analysis. Preoperative tumor size was dichotomized, with less than 2 cm² as the referent category vs 2 cm² or greater, and postoperative defect size was dichotomized with less than 3.6 cm² as the referent category vs 3.6 cm² or greater. Mohs stage was dichotomized as 1 stage (referent) vs more than 1 stage, and patient age was dichotomized as younger than 65 years (referent) vs 65 years or older.

Multivariate analyses were also performed to compare preoperative and postoperative sizes for patients undergoing MMS during the pandemic vs prepandemic periods, controlling for Mohs AUC location. Bivariate unadjusted and multivariate analyses were performed using a GENMOD logistic regression procedure in SAS (SAS Institute) to account for correlation in clustered data because a patient could be included for more than 1 surgery in the data set. Data were analyzed using SAS 9.4 for Windows. Because outcome variables tended to be skewed and not distributed normally, outcome variables were recorded as medians with interquartile ranges where possible to give a more accurate representation of the data than could be demonstrated with means with standard deviations.

Results

One hundred thirty-eight skin cancers were treated during the COVID-19 pandemic from March 15, 2020, to April 30, 2020, and 378 skin cancers were treated during the prepandemic control periods of March 15, 2019, to April 30, 2019, and March 15, 2018, to April 30, 2018. Tumor type treated during the pandemic period was more likely to be SCC or MIS (representing generally more severe tumor types) vs BCC when compared with the prepandemic periods, with an odds ratio (OR) of 1.763 (95% CI, 1.17-2.66). This outcome was statistically significant (P=.01).

Tumors treated during the pandemic period were more likely to have necessitated more than one Mohs stage for clearance compared to the prepandemic periods, though this difference was not statistically significant (OR, 1.461; 95% CI, 0.97-2.19; P=.056). Neither AUC location of treated tumors nor age were significantly different between prepandemic and pandemic periods (P=.58 and P=.84, respectively). Table 1 includes all bivariate analysis results.

Additionally, although mean preoperative and postoperative sizes were larger for each AUC location during the pandemic vs prepandemic periods, these differences did not reach statistical significance on multivariate analysis (P=.71 and P=.50, respectively)(Table 2).

Our practice has followed best practice guidelines dictated by our governing professional societies during the COVID-19 pandemic in the treatment of skin cancers by MMS, specifically highly symptomatic BCCs (in accordance with ACMS guidance), SCCs with high-risk features (in accordance with AAD, ACMS, and TDS guidance), and tumors with high risk for progression and metastasis such as melanomas (in accordance with TDS guidance). Melanoma in situ was also treated during the COVID-19 pandemic in accordance with the latter TDS guidance, particularly in light of the potential for upstaging to melanoma following resection (a phenomenon demonstrated to occur in 5%–29% of biopsied MIS lesions).¹⁴

In following best practice guidelines, our results suggested tumors treated by MMS were more severe, as evidenced by a statistically significant higher proportion of SCC and MIS tumors (representing more severe tumor types) vs BCC when compared to the prepandemic period. Supporting this conclusion, we observed larger pretreatment and posttreatment tumor sizes for all AUC locations and more tumors necessitating 2 or more stages for clearance during the pandemic vs prepandemic periods, though these differences did not reach statistical significance. We postulate these findings may be attributed to allocation of finite medical resources to the treatment of larger and more aggressive skin cancers. Additionally, these findings may be explained, in part, by limitations on patient case load imposed by social distancing measures and governing body regulations in effect during the study period, including those put forth by the AAD, ACMS, and TDS. Of note, our practice observed no hospitalizations or 911 calls during the studied period. This suggests no allocation of precious hospital resources away from patients with COVID-19 in our treatment of high-risk skin cancers.

The changing characteristics of cutaneous tumors treated by MMS during the pandemic are of clinical relevance. Larger postoperative wound sizes as observed during the pandemic, albeit not statistically significant, presumably affect reconstructive decisions. With larger wounds tending to necessitate repair by techniques higher on the reconstructive ladder, greater patient morbidity and cost are expected.¹⁵ As the cost-effectiveness of dermatology services remains a critical issue, this is an area ripe for future follow-up research. Furthermore, our observation that tumors tended to necessitate 2 or more stages for clearance during the pandemic more often than prepandemic periods, though not statistically significant, presumably affected operating times. Longer operating times during the pandemic may be of importance when making clinical decisions for patients for whom limiting health care exposure may be of particular concern. With more SCC and MIS tumors being treated relative to BCCs during the pandemic, one might expect greater size and severity of the BCCs we observe in the proceeding months to years.

As the ongoing COVID-19 pandemic continues to impact the landscape of cutaneous oncology, the need for adaptability is imperative. With 3- and 6-month skin cancer treatment deferrals lapsed, uncertainty surrounds ideal management of existing and new skin cancers arising during the pandemic. This study adds to a growing body of literature elucidating the impact of the COVID-19 pandemic on MMS practice; however, further studies and a tincture of time are needed to guide future best practice standards.

Acknowledgment—The authors acknowledge Gwen Baillargeon, MS (Galveston, Texas), who was the statistician for this article.

The COVID-19 pandemic has brought about unprecedented changes and challenges to medical practice, including new public health measure legislation, local and national medical authority recommendations, nursing home and other ancillary health center protocols, and novel clinical decision-making considerations.^1-3 In July 2020, the American Academy of Dermatology (AAD) addressed the changing landscape in dermatologic surgery, in part, by publishing recommendations on practice protocols during the COVID-19 pandemic.⁴ The guidelines recommended deferred treatment of superficial basal cell carcinomas (BCCs) for 6 months and all other BCC subtypes for 3 to 6 months. Furthermore, the guidelines recommended deferring treatment of all actinic keratoses and squamous cell carcinomas (SCCs) in situ “for now.” Squamous cell carcinoma treatment was to be guided by prognostic variables, such as location, size, depth, differentiation, perineural or lymphovascular invasion, recurrence, and immunosuppression. The guidelines recommended melanoma in situ (MIS) treatment be deferred for 3 months and invasive melanoma with histologic clearance obtained on excisional biopsy for 3 months. Other general recommendations included triaging clinics, rebooking according to clinical priority, using telehealth where possible, screening patients for COVID-19 signs and symptoms, staggering appointment times, spacing patient chairs, limiting support persons to 1, removing possible sources of infection in the waiting room, ensuring all patients sanitized their hands on arrival, rationing personal protective equipment, considering N95 masks for periorificial surgery, and using dissolving sutures to minimize multiple presentations.⁴

The American College of Mohs Surgery (ACMS), with guidance from its sister societies and the National Comprehensive Cancer Network, also communicated COVID-19–related recommendations to its members via intermittent newsletters during the initial peak of the pandemic in March and June 2020.⁵ General social distancing and office recommendations were similar to those released by the AAD. Recommendations for skin cancer treatment included deferring all BCCs for up to 3 months, with exceptions for highly symptomatic cancers and those with potential for substantial rapid growth. Squamous cell carcinoma in situ and small, well-differentiated SCCs were deferred, with priority placed on SCCs that were rapidly enlarging, poorly differentiated, demonstrated perineural invasion, were ulcerated, or were symptomatic. Patients with major risk factors were prioritized for treatment. Melanoma in situ was deferred for 2 to 3 months.⁵

State-level guidance from the Texas Dermatological Society (TDS) communicated in April 2020 stated that skin cancers with a potential for rapid progression and metastasis, such as melanoma and SCC, may require treatment as determined by the physician.⁶ The potential risk of serious adverse medical outcomes from not treating these cancers should be carefully documented. General practice measures for preventing the spread of COVID-19 were also recommended.⁶

In the setting of emerging novel recommendations, the practice of Mohs micrographic surgery (MMS) was notably impacted by the COVID-19 pandemic. According to one survey study from the United Kingdom conducted in April and May 2020, 49% of MMS services ceased and 36% were reduced during the infancy of the COVID-19 pandemic.⁷ Mohs micrographic surgery was largely suspended because of a lack of personal protective equipment and safety concerns, according to respondents. Additionally, respondents reported 77% of departments experienced redeployment of physicians and nurses to intensive care and medical wards. Thirty-five percent reported a reduction in the proportion of flaps/grafts to primary closures performed, 74% reported a decrease in outside referrals for repair by other specialties, 81% reported increased usage of dissolvable sutures, and 29% reported an increase in prophylactic antibiotic prescriptions.⁷ Another study from Italy reported a 46.5% reduction in dermatologic surgeries performed during the initial lockdown of the COVID-19 pandemic. Patients canceled 52.9% of procedures, and 12.5% were cancelled because of confirmed or suspected COVID-19 infection.⁸ Patient perceptions of MMS have also been impacted by the COVID-19 pandemic. According to a survey study of patients in the United Kingdom undergoing MMS during the pandemic, 47% were worried the hospital would cancel their surgery, 54% were anxious about using public transportation to attend their appointment, 30% were concerned about transmitting COVID-19 to household or family members, and 19% were worried about their ability to socially distance in the hospital.⁹

Evidence is also emerging that suggests the potential negative impact of the COVID-19 pandemic on morbidity and mortality outcomes in patients with skin cancer. One European study found an increase in Breslow thickness in primary melanomas diagnosed following the initial COVID-19 lockdown (0.88-mm average thickness prelockdown vs 1.96-mm average thickness postlockdown).¹⁰ An Italian study observed similar results—an increase in median Breslow thickness during the initial COVID-19 lockdown period of 0.5 mm from 0.4 mm during the prelockdown time period.¹¹ Also providing evidence for potentially poor patient outcomes, one study modeled the impact of backlog in cutaneous melanoma referrals in the United Kingdom on patient survival and predicted 138 attributable lives lost for a 1-month delay and 1171 lives lost for a 6-month delay. The model further predicted a 3.1% to 12.5% reduction in 10-year net survival incurred from a 3-month delay in melanoma treatment, with the largest reduction seen in the patient population older than 80 years.¹²

Although the COVID-19 pandemic has been observed to impact MMS practice, patient perceptions, and clinical outcomes, it is unknown how the COVID-19 pandemic and corresponding rapidly evolving recommendations in dermatologic surgery have impacted the characteristics of cutaneous tumors treated by MMS.

Our study sought to determine the characteristics of skin cancers treated by MMS during the peak of government-mandated medical practice restrictions and business shutdowns in response to the COVID-19 pandemic and to compare them with characteristics of skin cancers treated during a prepandemic control period.

Methods

A retrospective chart review was conducted with approval from our institutional review board at the University of Texas Medical Branch (Galveston, Texas). Included in the chart review were all cutaneous malignancies treated by MMS at our outpatient, office-based surgical center from March 15, 2020, to April 30, 2020; this period corresponded to the peak of the COVID-19–related government-mandated medical and business shutdowns in our geographic region (southeast Texas). All cases performed were in compliance with national- and state-level guidance. Data were also collected for all cutaneous malignancies treated by MMS at our office from March 15, 2019, to April 30, 2019, as well as March 15, 2018, to April 30, 2018; these periods represented prepandemic control periods.

Data were collected for 516 surgeries performed on 458 patients and included patient age, preoperative clinical size, postoperative defect size, number of Mohs stages to achieve clearance, MMS appropriate use criteria (AUC) location (categorized as high-, medium-, or low-risk tumor location),¹³ and tumor type (categorized as BCC, SCC, or MIS). All variables were examined for unusual or missing values. Five patients with rare tumor types were observed and removed from the data set.

Statistical Analysis—An a priori power analysis for a power set at 0.85 determined sample sizes of 105 per group. Bivariate analyses were performed to compare variables for patients undergoing MMS during the pandemic vs prepandemic periods. Continuous outcome variables—Mohs stages, preoperative size, postoperative size, and patient age—were categorized for the analysis. Preoperative tumor size was dichotomized, with less than 2 cm² as the referent category vs 2 cm² or greater, and postoperative defect size was dichotomized with less than 3.6 cm² as the referent category vs 3.6 cm² or greater. Mohs stage was dichotomized as 1 stage (referent) vs more than 1 stage, and patient age was dichotomized as younger than 65 years (referent) vs 65 years or older.

Multivariate analyses were also performed to compare preoperative and postoperative sizes for patients undergoing MMS during the pandemic vs prepandemic periods, controlling for Mohs AUC location. Bivariate unadjusted and multivariate analyses were performed using a GENMOD logistic regression procedure in SAS (SAS Institute) to account for correlation in clustered data because a patient could be included for more than 1 surgery in the data set. Data were analyzed using SAS 9.4 for Windows. Because outcome variables tended to be skewed and not distributed normally, outcome variables were recorded as medians with interquartile ranges where possible to give a more accurate representation of the data than could be demonstrated with means with standard deviations.

Results

One hundred thirty-eight skin cancers were treated during the COVID-19 pandemic from March 15, 2020, to April 30, 2020, and 378 skin cancers were treated during the prepandemic control periods of March 15, 2019, to April 30, 2019, and March 15, 2018, to April 30, 2018. Tumor type treated during the pandemic period was more likely to be SCC or MIS (representing generally more severe tumor types) vs BCC when compared with the prepandemic periods, with an odds ratio (OR) of 1.763 (95% CI, 1.17-2.66). This outcome was statistically significant (P=.01).

Tumors treated during the pandemic period were more likely to have necessitated more than one Mohs stage for clearance compared to the prepandemic periods, though this difference was not statistically significant (OR, 1.461; 95% CI, 0.97-2.19; P=.056). Neither AUC location of treated tumors nor age were significantly different between prepandemic and pandemic periods (P=.58 and P=.84, respectively). Table 1 includes all bivariate analysis results.

Additionally, although mean preoperative and postoperative sizes were larger for each AUC location during the pandemic vs prepandemic periods, these differences did not reach statistical significance on multivariate analysis (P=.71 and P=.50, respectively)(Table 2).

Our practice has followed best practice guidelines dictated by our governing professional societies during the COVID-19 pandemic in the treatment of skin cancers by MMS, specifically highly symptomatic BCCs (in accordance with ACMS guidance), SCCs with high-risk features (in accordance with AAD, ACMS, and TDS guidance), and tumors with high risk for progression and metastasis such as melanomas (in accordance with TDS guidance). Melanoma in situ was also treated during the COVID-19 pandemic in accordance with the latter TDS guidance, particularly in light of the potential for upstaging to melanoma following resection (a phenomenon demonstrated to occur in 5%–29% of biopsied MIS lesions).¹⁴

In following best practice guidelines, our results suggested tumors treated by MMS were more severe, as evidenced by a statistically significant higher proportion of SCC and MIS tumors (representing more severe tumor types) vs BCC when compared to the prepandemic period. Supporting this conclusion, we observed larger pretreatment and posttreatment tumor sizes for all AUC locations and more tumors necessitating 2 or more stages for clearance during the pandemic vs prepandemic periods, though these differences did not reach statistical significance. We postulate these findings may be attributed to allocation of finite medical resources to the treatment of larger and more aggressive skin cancers. Additionally, these findings may be explained, in part, by limitations on patient case load imposed by social distancing measures and governing body regulations in effect during the study period, including those put forth by the AAD, ACMS, and TDS. Of note, our practice observed no hospitalizations or 911 calls during the studied period. This suggests no allocation of precious hospital resources away from patients with COVID-19 in our treatment of high-risk skin cancers.

The changing characteristics of cutaneous tumors treated by MMS during the pandemic are of clinical relevance. Larger postoperative wound sizes as observed during the pandemic, albeit not statistically significant, presumably affect reconstructive decisions. With larger wounds tending to necessitate repair by techniques higher on the reconstructive ladder, greater patient morbidity and cost are expected.¹⁵ As the cost-effectiveness of dermatology services remains a critical issue, this is an area ripe for future follow-up research. Furthermore, our observation that tumors tended to necessitate 2 or more stages for clearance during the pandemic more often than prepandemic periods, though not statistically significant, presumably affected operating times. Longer operating times during the pandemic may be of importance when making clinical decisions for patients for whom limiting health care exposure may be of particular concern. With more SCC and MIS tumors being treated relative to BCCs during the pandemic, one might expect greater size and severity of the BCCs we observe in the proceeding months to years.

As the ongoing COVID-19 pandemic continues to impact the landscape of cutaneous oncology, the need for adaptability is imperative. With 3- and 6-month skin cancer treatment deferrals lapsed, uncertainty surrounds ideal management of existing and new skin cancers arising during the pandemic. This study adds to a growing body of literature elucidating the impact of the COVID-19 pandemic on MMS practice; however, further studies and a tincture of time are needed to guide future best practice standards.

Acknowledgment—The authors acknowledge Gwen Baillargeon, MS (Galveston, Texas), who was the statistician for this article.

Moderate to severe anxiety, depression, and shortness of breath indicate increased risk for nonfatal self-injury (NFSI) among patients newly diagnosed with cancer, according to a Canadian study.

In a population-based, case-control study, each of these symptoms was associated with an increase of at least 60% in the risk for NFSI in the following 180 days, the investigators report.

“Clinicians should know that self-injury is a real problem after a cancer diagnosis,” lead investigator Julie Hallet, MD, an associate scientist at Sunnybrook Health Sciences Centre in Toronto, told this news organization.

Self-injury “does not necessarily represent an attempted suicide,” she added. “While our data do not allow us to know what the intent was, we know from other work that the repercussions of distress in patients with cancer are much broader than suicide. Self-injury can be a means to cope with psychological difficulties for some patients, without intent for suicide.”

The study was published online in JAMA Oncology.
 

Nine common symptoms

The study included adults who were diagnosed with cancer between Jan. 1, 2007, and March 31, 2019, and had completed the Edmonton Symptom Assessment System (ESAS) evaluation within 36 months of their index cancer diagnosis. ESAS evaluates nine common cancer-associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, on a patient-reported scale of 0 (absence of symptom) to 10 (worst possible symptom).

The analysis included 406 patients who had visited an emergency department for an NFSI within 180 days of their ESAS evaluation, as well as 1,624 matched control patients with cancer who did not have an NFSI. Case patients and control patients were matched according to age at cancer diagnosis, sex, prior self-injury within 5 years of being diagnosed with cancer, and cancer type. Nonmatched covariates included psychiatric illness and therapy received before NFSI, comorbidity burden, material deprivation, and cancer stage.
 

Toward tailored intervention

A higher proportion of case patients than control patients reported moderate to severe scores for all nine ESAS symptoms. In an adjusted analysis, moderate to severe anxiety (odds ratio, 1.61), depression (OR, 1.66), and shortness of breath (OR, 1.65) were independently associated with higher odds of subsequent NFSI. Each 10-point increase in total ESAS score also was associated with increased risk (OR, 1.51).

“These findings are important to enhance the use of screening ESAS scores to better support patients,” say the authors. “Scores from ESAS assessments can be used to identify patients at higher risk of NFSI, indicating higher level of distress, and help direct tailored assessment and intervention.”

In prior work, Dr. Hallet’s group showed that NFSI occurs in 3 of every 1,000 patients with cancer. NFSI is more frequent among younger patients and those with a history of prior mental illness. “Identifying patients at risk in clinical practice requires you to inquire about a patient’s prior history, identify high symptom scores and ask about them, and trigger intervention pathways when risk is identified,” said Dr. Hallet.

“For example, a young patient with head and neck cancer and a prior history of mental illness who reports high scores for anxiety and drowsiness would be at high risk of self-injury,” she added. Such a patient should be referred to psycho-oncology, psychiatry, or social work. “To facilitate this, we are working on prognostic scores that can be integrated in clinical practice, such as an electronic medical record, to flag patients at risk,” said Dr. Hallet. “Future work will also need to identify the optimal care pathways for at-risk patients.”
 

Self-injury vs. suicidality

Commenting on the study for this news organization, Madeline Li, MD, PhD, a psychiatrist and clinician-scientist at Toronto’s Princess Margaret Cancer Centre, said that the findings are “underwhelming” because they tell us what is already known – that “NFSI is associated with distress, and cancer is a stressor.” It would have been more interesting to ask how to distinguish patients at risk for suicide from those at risk for self-harm without suicide, she added.

“The way these authors formulated NFSI included both self-harm intent and suicidal intent,” she explained. The researchers compared patients who were at risk for these two types of events with patients without NFSI. “When we see self-harm without suicidal intent in the emergency room, it’s mostly people making cries for help,” said Dr. Li. “These are people who cut their wrists or take small overdoses on purpose without the intent to die. It would have been more interesting to see if there are different risk factors for people who are just going to self-harm vs. those who are actually going to attempt suicide.”

The study’s identification of risk factors for NSFI is important because “it does tell us that when there’s anxiety, depression, and shortness of breath, we should pay attention to these patients and do something about it,” said Dr. Li. Still, research in cancer psychiatry needs to shift its focus from identifying and addressing existing risk factors to preventing them from developing, she added.

“We need to move earlier and provide emotional and mental health support to cancer patients to prevent them from becoming suicidal, rather than intervening when somebody already is,” Dr. Li concluded.

The study was funded by the Hanna Research Award from the division of surgical oncology at the Odette Cancer Centre–Sunnybrook Health Sciences Centre and by a Sunnybrook Health Sciences Centre Alternate Funding Plan Innovation grant. It was also supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Hallet has received personal fees from Ipsen Biopharmaceuticals Canada and AAA outside the submitted work. Dr. Li reported no relevant financial relationships.

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

Moderate to severe anxiety, depression, and shortness of breath indicate increased risk for nonfatal self-injury (NFSI) among patients newly diagnosed with cancer, according to a Canadian study.

In a population-based, case-control study, each of these symptoms was associated with an increase of at least 60% in the risk for NFSI in the following 180 days, the investigators report.

“Clinicians should know that self-injury is a real problem after a cancer diagnosis,” lead investigator Julie Hallet, MD, an associate scientist at Sunnybrook Health Sciences Centre in Toronto, told this news organization.

Self-injury “does not necessarily represent an attempted suicide,” she added. “While our data do not allow us to know what the intent was, we know from other work that the repercussions of distress in patients with cancer are much broader than suicide. Self-injury can be a means to cope with psychological difficulties for some patients, without intent for suicide.”

The study was published online in JAMA Oncology.
 

Nine common symptoms

The study included adults who were diagnosed with cancer between Jan. 1, 2007, and March 31, 2019, and had completed the Edmonton Symptom Assessment System (ESAS) evaluation within 36 months of their index cancer diagnosis. ESAS evaluates nine common cancer-associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, on a patient-reported scale of 0 (absence of symptom) to 10 (worst possible symptom).

The analysis included 406 patients who had visited an emergency department for an NFSI within 180 days of their ESAS evaluation, as well as 1,624 matched control patients with cancer who did not have an NFSI. Case patients and control patients were matched according to age at cancer diagnosis, sex, prior self-injury within 5 years of being diagnosed with cancer, and cancer type. Nonmatched covariates included psychiatric illness and therapy received before NFSI, comorbidity burden, material deprivation, and cancer stage.
 

Toward tailored intervention

A higher proportion of case patients than control patients reported moderate to severe scores for all nine ESAS symptoms. In an adjusted analysis, moderate to severe anxiety (odds ratio, 1.61), depression (OR, 1.66), and shortness of breath (OR, 1.65) were independently associated with higher odds of subsequent NFSI. Each 10-point increase in total ESAS score also was associated with increased risk (OR, 1.51).

“These findings are important to enhance the use of screening ESAS scores to better support patients,” say the authors. “Scores from ESAS assessments can be used to identify patients at higher risk of NFSI, indicating higher level of distress, and help direct tailored assessment and intervention.”

In prior work, Dr. Hallet’s group showed that NFSI occurs in 3 of every 1,000 patients with cancer. NFSI is more frequent among younger patients and those with a history of prior mental illness. “Identifying patients at risk in clinical practice requires you to inquire about a patient’s prior history, identify high symptom scores and ask about them, and trigger intervention pathways when risk is identified,” said Dr. Hallet.

“For example, a young patient with head and neck cancer and a prior history of mental illness who reports high scores for anxiety and drowsiness would be at high risk of self-injury,” she added. Such a patient should be referred to psycho-oncology, psychiatry, or social work. “To facilitate this, we are working on prognostic scores that can be integrated in clinical practice, such as an electronic medical record, to flag patients at risk,” said Dr. Hallet. “Future work will also need to identify the optimal care pathways for at-risk patients.”
 

Self-injury vs. suicidality

Commenting on the study for this news organization, Madeline Li, MD, PhD, a psychiatrist and clinician-scientist at Toronto’s Princess Margaret Cancer Centre, said that the findings are “underwhelming” because they tell us what is already known – that “NFSI is associated with distress, and cancer is a stressor.” It would have been more interesting to ask how to distinguish patients at risk for suicide from those at risk for self-harm without suicide, she added.

“The way these authors formulated NFSI included both self-harm intent and suicidal intent,” she explained. The researchers compared patients who were at risk for these two types of events with patients without NFSI. “When we see self-harm without suicidal intent in the emergency room, it’s mostly people making cries for help,” said Dr. Li. “These are people who cut their wrists or take small overdoses on purpose without the intent to die. It would have been more interesting to see if there are different risk factors for people who are just going to self-harm vs. those who are actually going to attempt suicide.”

The study’s identification of risk factors for NSFI is important because “it does tell us that when there’s anxiety, depression, and shortness of breath, we should pay attention to these patients and do something about it,” said Dr. Li. Still, research in cancer psychiatry needs to shift its focus from identifying and addressing existing risk factors to preventing them from developing, she added.

“We need to move earlier and provide emotional and mental health support to cancer patients to prevent them from becoming suicidal, rather than intervening when somebody already is,” Dr. Li concluded.

The study was funded by the Hanna Research Award from the division of surgical oncology at the Odette Cancer Centre–Sunnybrook Health Sciences Centre and by a Sunnybrook Health Sciences Centre Alternate Funding Plan Innovation grant. It was also supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Hallet has received personal fees from Ipsen Biopharmaceuticals Canada and AAA outside the submitted work. Dr. Li reported no relevant financial relationships.

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

Moderate to severe anxiety, depression, and shortness of breath indicate increased risk for nonfatal self-injury (NFSI) among patients newly diagnosed with cancer, according to a Canadian study.

In a population-based, case-control study, each of these symptoms was associated with an increase of at least 60% in the risk for NFSI in the following 180 days, the investigators report.

“Clinicians should know that self-injury is a real problem after a cancer diagnosis,” lead investigator Julie Hallet, MD, an associate scientist at Sunnybrook Health Sciences Centre in Toronto, told this news organization.

Self-injury “does not necessarily represent an attempted suicide,” she added. “While our data do not allow us to know what the intent was, we know from other work that the repercussions of distress in patients with cancer are much broader than suicide. Self-injury can be a means to cope with psychological difficulties for some patients, without intent for suicide.”

The study was published online in JAMA Oncology.
 

Nine common symptoms

The study included adults who were diagnosed with cancer between Jan. 1, 2007, and March 31, 2019, and had completed the Edmonton Symptom Assessment System (ESAS) evaluation within 36 months of their index cancer diagnosis. ESAS evaluates nine common cancer-associated symptoms, including pain, tiredness, nausea, depression, anxiety, drowsiness, appetite, well-being, and shortness of breath, on a patient-reported scale of 0 (absence of symptom) to 10 (worst possible symptom).

The analysis included 406 patients who had visited an emergency department for an NFSI within 180 days of their ESAS evaluation, as well as 1,624 matched control patients with cancer who did not have an NFSI. Case patients and control patients were matched according to age at cancer diagnosis, sex, prior self-injury within 5 years of being diagnosed with cancer, and cancer type. Nonmatched covariates included psychiatric illness and therapy received before NFSI, comorbidity burden, material deprivation, and cancer stage.
 

Toward tailored intervention

A higher proportion of case patients than control patients reported moderate to severe scores for all nine ESAS symptoms. In an adjusted analysis, moderate to severe anxiety (odds ratio, 1.61), depression (OR, 1.66), and shortness of breath (OR, 1.65) were independently associated with higher odds of subsequent NFSI. Each 10-point increase in total ESAS score also was associated with increased risk (OR, 1.51).

“These findings are important to enhance the use of screening ESAS scores to better support patients,” say the authors. “Scores from ESAS assessments can be used to identify patients at higher risk of NFSI, indicating higher level of distress, and help direct tailored assessment and intervention.”

In prior work, Dr. Hallet’s group showed that NFSI occurs in 3 of every 1,000 patients with cancer. NFSI is more frequent among younger patients and those with a history of prior mental illness. “Identifying patients at risk in clinical practice requires you to inquire about a patient’s prior history, identify high symptom scores and ask about them, and trigger intervention pathways when risk is identified,” said Dr. Hallet.

“For example, a young patient with head and neck cancer and a prior history of mental illness who reports high scores for anxiety and drowsiness would be at high risk of self-injury,” she added. Such a patient should be referred to psycho-oncology, psychiatry, or social work. “To facilitate this, we are working on prognostic scores that can be integrated in clinical practice, such as an electronic medical record, to flag patients at risk,” said Dr. Hallet. “Future work will also need to identify the optimal care pathways for at-risk patients.”
 

Self-injury vs. suicidality

Commenting on the study for this news organization, Madeline Li, MD, PhD, a psychiatrist and clinician-scientist at Toronto’s Princess Margaret Cancer Centre, said that the findings are “underwhelming” because they tell us what is already known – that “NFSI is associated with distress, and cancer is a stressor.” It would have been more interesting to ask how to distinguish patients at risk for suicide from those at risk for self-harm without suicide, she added.

“The way these authors formulated NFSI included both self-harm intent and suicidal intent,” she explained. The researchers compared patients who were at risk for these two types of events with patients without NFSI. “When we see self-harm without suicidal intent in the emergency room, it’s mostly people making cries for help,” said Dr. Li. “These are people who cut their wrists or take small overdoses on purpose without the intent to die. It would have been more interesting to see if there are different risk factors for people who are just going to self-harm vs. those who are actually going to attempt suicide.”

The study’s identification of risk factors for NSFI is important because “it does tell us that when there’s anxiety, depression, and shortness of breath, we should pay attention to these patients and do something about it,” said Dr. Li. Still, research in cancer psychiatry needs to shift its focus from identifying and addressing existing risk factors to preventing them from developing, she added.

“We need to move earlier and provide emotional and mental health support to cancer patients to prevent them from becoming suicidal, rather than intervening when somebody already is,” Dr. Li concluded.

The study was funded by the Hanna Research Award from the division of surgical oncology at the Odette Cancer Centre–Sunnybrook Health Sciences Centre and by a Sunnybrook Health Sciences Centre Alternate Funding Plan Innovation grant. It was also supported by ICES, which is funded by an annual grant from the Ontario Ministry of Health and Long-Term Care. Dr. Hallet has received personal fees from Ipsen Biopharmaceuticals Canada and AAA outside the submitted work. Dr. Li reported no relevant financial relationships.

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