Dr Anastassios Pittas, Chief of Endocrinology at Tufts Medical Center in Boston, discusses key data from the American Diabetes Association Scientific Sessions 2022 on the management of common comorbidities in diabetes. 

Dr Pittas looks first at a prespecified analysis of the SURPASS-4 trial, which highlighted the role of tirzepatide on kidney outcomes in patients with type 2 diabetes. 

He then discusses results of the SPLENDID trial in which patients with diabetes who received bariatric surgery for weight loss showed reduced rates of cancer.  

Finally, Dr Pittas reports on a study examining the effect of food insecurity and diet quality on maintaining good cholesterol levels in diabetes.

--

Anastassios G. Pittas, MD, Chief, Division of Endocrinology, Diabetes, and Metabolism; Co-director, Diabetes and Lipid Center; Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts 

Anastassios G. Pittas, MD, has disclosed no relevant financial relationships. 

Dr Anastassios Pittas, Chief of Endocrinology at Tufts Medical Center in Boston, discusses key data from the American Diabetes Association Scientific Sessions 2022 on the management of common comorbidities in diabetes. 

Dr Pittas looks first at a prespecified analysis of the SURPASS-4 trial, which highlighted the role of tirzepatide on kidney outcomes in patients with type 2 diabetes. 

He then discusses results of the SPLENDID trial in which patients with diabetes who received bariatric surgery for weight loss showed reduced rates of cancer.  

Finally, Dr Pittas reports on a study examining the effect of food insecurity and diet quality on maintaining good cholesterol levels in diabetes.

--

Anastassios G. Pittas, MD, Chief, Division of Endocrinology, Diabetes, and Metabolism; Co-director, Diabetes and Lipid Center; Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts 

Anastassios G. Pittas, MD, has disclosed no relevant financial relationships. 

Dr Anastassios Pittas, Chief of Endocrinology at Tufts Medical Center in Boston, discusses key data from the American Diabetes Association Scientific Sessions 2022 on the management of common comorbidities in diabetes. 

Dr Pittas looks first at a prespecified analysis of the SURPASS-4 trial, which highlighted the role of tirzepatide on kidney outcomes in patients with type 2 diabetes. 

He then discusses results of the SPLENDID trial in which patients with diabetes who received bariatric surgery for weight loss showed reduced rates of cancer.  

Finally, Dr Pittas reports on a study examining the effect of food insecurity and diet quality on maintaining good cholesterol levels in diabetes.

--

Anastassios G. Pittas, MD, Chief, Division of Endocrinology, Diabetes, and Metabolism; Co-director, Diabetes and Lipid Center; Professor of Medicine, Tufts University School of Medicine, Boston, Massachusetts 

Anastassios G. Pittas, MD, has disclosed no relevant financial relationships. 

U.S. maternal deaths – those during pregnancy or within 42 days of pregnancy – increased substantially by 33.3% after March 2020 corresponding to the COVID-19 pandemic onset, according to new research published in JAMA Network Open.

Data from the National Center for Health Statistics (NCHS) revealed this rise in maternal deaths was higher than the 22% overall excess death estimate associated with the pandemic in 2020.

Increases were highest for Hispanic and non-Hispanic Black women, exacerbating already high rates of disparity in comparison with White women, wrote Marie E. Thoma, PhD, an associate professor at the University of Maryland, College Park, and Eugene R. Declercq, PhD, a professor at Boston University.

The authors noted that this spike in maternal deaths might be caused either by conditions directly related to COVID-19, such as respiratory or viral infections, or by conditions worsened by pandemic-associated health care disruptions including those for diabetes or cardiovascular disease.

The precise causes, however, could not be discerned from the data, the authors noted.

The NCHS reported an 18.4% increase in U.S. maternal mortality from 2019 to 2020. The relative increase was 44.4% among Hispanic, 25.7% among non-Hispanic Black, and 6.1% among non-Hispanic White women.

“The rise in maternal mortality among Hispanic women was unprecedented,” Dr. Thoma said in an interview. Given a 16.8% increase in overall U.S. mortality in 2020, largely attributed to the COVID-19 pandemic, the authors examined the pandemic’s role in [the higher] maternal death rates for 2020.

“Prior to this report, the NCHS released an e-report that there had been a rise in maternal mortality in 2020, but questions remained about the role of the pandemic in this rise that their report hadn’t addressed,” Dr. Thoma said in an interview “So we decided to look at the data further to assess whether the rise coincided with the pandemic and how this differed by race/ethnicity, whether there were changes in the causes of maternal death, and how often COVID-19 was listed as a contributory factor in those deaths.”

A total of 1,588 maternal deaths (18.8 per 100,000 live births) occurred before the pandemic versus 684 deaths (25.1 per 100,000 live births) during the 2020 phase of the pandemic, for a relative increase of 33.3%.

Direct obstetrical causes of death included diabetes, hypertensive and liver disorders, pregnancy-related infections, and obstetrical hemorrhage and embolism. Indirect causes comprised, among others, nonobstetrical infections and diseases of the circulatory and respiratory systems as well as mental and nervous disorders.

Relative increases in direct causes (27.7%) were mostly associated with diabetes (95.9%), hypertensive disorders (39.0%), and other specified pregnancy-related conditions (48.0%).

COVID-19 was commonly listed as a lethal condition along with other viral diseases (16 of 16 deaths and diseases of the respiratory system (11 of 19 deaths).

Late maternal mortality – defined as more than 42 days but less than 1 year after pregnancy – increased by 41%. “This was surprising as we might anticipate risk being higher during pregnancy given that pregnant women may be more susceptible, but we see that this rise was also found among people in the later postpartum period,” Dr. Thoma said.

Absolute and relative changes were highest for Hispanic women (8.9 per 100,000 live births and 74.2%, respectively) and non-Hispanic Black women (16.8 per 100,000 live births and 40.2%). In contrast, non-Hispanic White women saw increases of just 2.9 per 100,000 live births and 17.2%.

“Overall, we found the rise in maternal mortality in 2020 was concentrated after the start of pandemic, particularly for non-Hispanic Black and Hispanic women, and we saw a dramatic rise in respiratory-related conditions,” Dr. Thoma said.

In a comment, Steven Woolf, MD, MPH, director emeritus of the Center on Society and Health at Virginia Commonwealth University, Richmond, said the findings are very consistent with his and others research showing dramatic increases in overall death rates from many causes during the pandemic, with these ranging from COVID-19 leading conditions such as diabetes, cardiovascular and Alzheimer’s disease to less-studied causes such as drug overdoses and alcoholism caused by the stresses of the pandemic. Again, deaths were likely caused by both COVID-19 infections and disruptions in diagnosis and care.

“So a rise in maternal mortality would unfortunately also be expected, and these researchers have shown that,” he said in an interview. In addition, they have confirmed “the pattern of stark health disparities in the Hispanic and Black populations relative to the White. Our group has shown marked decreases in the life expectancies of the Black and Hispanic populations relative to the White population.”

While he might take issue with the study’s research methodology, Dr. Woolf said, “The work is useful partly because we need to work out the best research methods to do this kind of analysis because we really need to understand the effects on maternal mortality.”

He said sorting out the best way to do this type of research will be important for looking at excess deaths and maternal mortality following other events, for example, in the wake of the Supreme Court’s recent decision to reverse Roe v. Wade.

The authors acknowledged certain study limitations, including the large percentage of COVID-19 cases with a nonspecific underlying cause. According to Dr. Thoma and Dr. Declercq, that reflects a maternal death coding problem that needs to be addressed, as well as a partitioning of data. The latter resulted in small numbers for some categories, with rates suppressed for fewer than 16 deaths because of reduced reliability.

“We found that more specific information is often available on death certificates but is lost in the process of coding,” said Dr. Thoma. “We were able to reclassify many of these causes to a more specific cause that we attributed to be the primary cause of death.”

The authors said future studies of maternal death should examine the contribution of the pandemic to racial and ethnic disparities and should identify specific causes of maternal deaths overall and associated with COVID-19.

In earlier research, the authors previously warned of possible misclassifications of maternal deaths.

They found evidence of both underreporting and overreporting of deaths, with possible overreporting predominant, whereas accurate data are essential for measuring the effectiveness of maternal mortality reduction programs.

Dr. Thoma’s group will continue to monitor mortality trends with the release of 2021 data. “We hope we will see improvements in 2021 given greater access to vaccines, treatments, and fewer health care disruptions,” Dr. Thoma said. “It will be important to continue to stress the importance of COVID-19 vaccines for pregnant and postpartum people.”

This study had no external funding. The authors disclosed no competing interests. Dr. Woolf declared no conflicts of interest.

U.S. maternal deaths – those during pregnancy or within 42 days of pregnancy – increased substantially by 33.3% after March 2020 corresponding to the COVID-19 pandemic onset, according to new research published in JAMA Network Open.

Data from the National Center for Health Statistics (NCHS) revealed this rise in maternal deaths was higher than the 22% overall excess death estimate associated with the pandemic in 2020.

Increases were highest for Hispanic and non-Hispanic Black women, exacerbating already high rates of disparity in comparison with White women, wrote Marie E. Thoma, PhD, an associate professor at the University of Maryland, College Park, and Eugene R. Declercq, PhD, a professor at Boston University.

The authors noted that this spike in maternal deaths might be caused either by conditions directly related to COVID-19, such as respiratory or viral infections, or by conditions worsened by pandemic-associated health care disruptions including those for diabetes or cardiovascular disease.

The precise causes, however, could not be discerned from the data, the authors noted.

The NCHS reported an 18.4% increase in U.S. maternal mortality from 2019 to 2020. The relative increase was 44.4% among Hispanic, 25.7% among non-Hispanic Black, and 6.1% among non-Hispanic White women.

“The rise in maternal mortality among Hispanic women was unprecedented,” Dr. Thoma said in an interview. Given a 16.8% increase in overall U.S. mortality in 2020, largely attributed to the COVID-19 pandemic, the authors examined the pandemic’s role in [the higher] maternal death rates for 2020.

“Prior to this report, the NCHS released an e-report that there had been a rise in maternal mortality in 2020, but questions remained about the role of the pandemic in this rise that their report hadn’t addressed,” Dr. Thoma said in an interview “So we decided to look at the data further to assess whether the rise coincided with the pandemic and how this differed by race/ethnicity, whether there were changes in the causes of maternal death, and how often COVID-19 was listed as a contributory factor in those deaths.”

A total of 1,588 maternal deaths (18.8 per 100,000 live births) occurred before the pandemic versus 684 deaths (25.1 per 100,000 live births) during the 2020 phase of the pandemic, for a relative increase of 33.3%.

Direct obstetrical causes of death included diabetes, hypertensive and liver disorders, pregnancy-related infections, and obstetrical hemorrhage and embolism. Indirect causes comprised, among others, nonobstetrical infections and diseases of the circulatory and respiratory systems as well as mental and nervous disorders.

Relative increases in direct causes (27.7%) were mostly associated with diabetes (95.9%), hypertensive disorders (39.0%), and other specified pregnancy-related conditions (48.0%).

COVID-19 was commonly listed as a lethal condition along with other viral diseases (16 of 16 deaths and diseases of the respiratory system (11 of 19 deaths).

Late maternal mortality – defined as more than 42 days but less than 1 year after pregnancy – increased by 41%. “This was surprising as we might anticipate risk being higher during pregnancy given that pregnant women may be more susceptible, but we see that this rise was also found among people in the later postpartum period,” Dr. Thoma said.

Absolute and relative changes were highest for Hispanic women (8.9 per 100,000 live births and 74.2%, respectively) and non-Hispanic Black women (16.8 per 100,000 live births and 40.2%). In contrast, non-Hispanic White women saw increases of just 2.9 per 100,000 live births and 17.2%.

“Overall, we found the rise in maternal mortality in 2020 was concentrated after the start of pandemic, particularly for non-Hispanic Black and Hispanic women, and we saw a dramatic rise in respiratory-related conditions,” Dr. Thoma said.

In a comment, Steven Woolf, MD, MPH, director emeritus of the Center on Society and Health at Virginia Commonwealth University, Richmond, said the findings are very consistent with his and others research showing dramatic increases in overall death rates from many causes during the pandemic, with these ranging from COVID-19 leading conditions such as diabetes, cardiovascular and Alzheimer’s disease to less-studied causes such as drug overdoses and alcoholism caused by the stresses of the pandemic. Again, deaths were likely caused by both COVID-19 infections and disruptions in diagnosis and care.

“So a rise in maternal mortality would unfortunately also be expected, and these researchers have shown that,” he said in an interview. In addition, they have confirmed “the pattern of stark health disparities in the Hispanic and Black populations relative to the White. Our group has shown marked decreases in the life expectancies of the Black and Hispanic populations relative to the White population.”

While he might take issue with the study’s research methodology, Dr. Woolf said, “The work is useful partly because we need to work out the best research methods to do this kind of analysis because we really need to understand the effects on maternal mortality.”

He said sorting out the best way to do this type of research will be important for looking at excess deaths and maternal mortality following other events, for example, in the wake of the Supreme Court’s recent decision to reverse Roe v. Wade.

The authors acknowledged certain study limitations, including the large percentage of COVID-19 cases with a nonspecific underlying cause. According to Dr. Thoma and Dr. Declercq, that reflects a maternal death coding problem that needs to be addressed, as well as a partitioning of data. The latter resulted in small numbers for some categories, with rates suppressed for fewer than 16 deaths because of reduced reliability.

“We found that more specific information is often available on death certificates but is lost in the process of coding,” said Dr. Thoma. “We were able to reclassify many of these causes to a more specific cause that we attributed to be the primary cause of death.”

The authors said future studies of maternal death should examine the contribution of the pandemic to racial and ethnic disparities and should identify specific causes of maternal deaths overall and associated with COVID-19.

In earlier research, the authors previously warned of possible misclassifications of maternal deaths.

They found evidence of both underreporting and overreporting of deaths, with possible overreporting predominant, whereas accurate data are essential for measuring the effectiveness of maternal mortality reduction programs.

Dr. Thoma’s group will continue to monitor mortality trends with the release of 2021 data. “We hope we will see improvements in 2021 given greater access to vaccines, treatments, and fewer health care disruptions,” Dr. Thoma said. “It will be important to continue to stress the importance of COVID-19 vaccines for pregnant and postpartum people.”

This study had no external funding. The authors disclosed no competing interests. Dr. Woolf declared no conflicts of interest.

U.S. maternal deaths – those during pregnancy or within 42 days of pregnancy – increased substantially by 33.3% after March 2020 corresponding to the COVID-19 pandemic onset, according to new research published in JAMA Network Open.

Data from the National Center for Health Statistics (NCHS) revealed this rise in maternal deaths was higher than the 22% overall excess death estimate associated with the pandemic in 2020.

Increases were highest for Hispanic and non-Hispanic Black women, exacerbating already high rates of disparity in comparison with White women, wrote Marie E. Thoma, PhD, an associate professor at the University of Maryland, College Park, and Eugene R. Declercq, PhD, a professor at Boston University.

The authors noted that this spike in maternal deaths might be caused either by conditions directly related to COVID-19, such as respiratory or viral infections, or by conditions worsened by pandemic-associated health care disruptions including those for diabetes or cardiovascular disease.

The precise causes, however, could not be discerned from the data, the authors noted.

The NCHS reported an 18.4% increase in U.S. maternal mortality from 2019 to 2020. The relative increase was 44.4% among Hispanic, 25.7% among non-Hispanic Black, and 6.1% among non-Hispanic White women.

“The rise in maternal mortality among Hispanic women was unprecedented,” Dr. Thoma said in an interview. Given a 16.8% increase in overall U.S. mortality in 2020, largely attributed to the COVID-19 pandemic, the authors examined the pandemic’s role in [the higher] maternal death rates for 2020.

“Prior to this report, the NCHS released an e-report that there had been a rise in maternal mortality in 2020, but questions remained about the role of the pandemic in this rise that their report hadn’t addressed,” Dr. Thoma said in an interview “So we decided to look at the data further to assess whether the rise coincided with the pandemic and how this differed by race/ethnicity, whether there were changes in the causes of maternal death, and how often COVID-19 was listed as a contributory factor in those deaths.”

A total of 1,588 maternal deaths (18.8 per 100,000 live births) occurred before the pandemic versus 684 deaths (25.1 per 100,000 live births) during the 2020 phase of the pandemic, for a relative increase of 33.3%.

Direct obstetrical causes of death included diabetes, hypertensive and liver disorders, pregnancy-related infections, and obstetrical hemorrhage and embolism. Indirect causes comprised, among others, nonobstetrical infections and diseases of the circulatory and respiratory systems as well as mental and nervous disorders.

Relative increases in direct causes (27.7%) were mostly associated with diabetes (95.9%), hypertensive disorders (39.0%), and other specified pregnancy-related conditions (48.0%).

COVID-19 was commonly listed as a lethal condition along with other viral diseases (16 of 16 deaths and diseases of the respiratory system (11 of 19 deaths).

Late maternal mortality – defined as more than 42 days but less than 1 year after pregnancy – increased by 41%. “This was surprising as we might anticipate risk being higher during pregnancy given that pregnant women may be more susceptible, but we see that this rise was also found among people in the later postpartum period,” Dr. Thoma said.

Absolute and relative changes were highest for Hispanic women (8.9 per 100,000 live births and 74.2%, respectively) and non-Hispanic Black women (16.8 per 100,000 live births and 40.2%). In contrast, non-Hispanic White women saw increases of just 2.9 per 100,000 live births and 17.2%.

“Overall, we found the rise in maternal mortality in 2020 was concentrated after the start of pandemic, particularly for non-Hispanic Black and Hispanic women, and we saw a dramatic rise in respiratory-related conditions,” Dr. Thoma said.

In a comment, Steven Woolf, MD, MPH, director emeritus of the Center on Society and Health at Virginia Commonwealth University, Richmond, said the findings are very consistent with his and others research showing dramatic increases in overall death rates from many causes during the pandemic, with these ranging from COVID-19 leading conditions such as diabetes, cardiovascular and Alzheimer’s disease to less-studied causes such as drug overdoses and alcoholism caused by the stresses of the pandemic. Again, deaths were likely caused by both COVID-19 infections and disruptions in diagnosis and care.

“So a rise in maternal mortality would unfortunately also be expected, and these researchers have shown that,” he said in an interview. In addition, they have confirmed “the pattern of stark health disparities in the Hispanic and Black populations relative to the White. Our group has shown marked decreases in the life expectancies of the Black and Hispanic populations relative to the White population.”

While he might take issue with the study’s research methodology, Dr. Woolf said, “The work is useful partly because we need to work out the best research methods to do this kind of analysis because we really need to understand the effects on maternal mortality.”

He said sorting out the best way to do this type of research will be important for looking at excess deaths and maternal mortality following other events, for example, in the wake of the Supreme Court’s recent decision to reverse Roe v. Wade.

The authors acknowledged certain study limitations, including the large percentage of COVID-19 cases with a nonspecific underlying cause. According to Dr. Thoma and Dr. Declercq, that reflects a maternal death coding problem that needs to be addressed, as well as a partitioning of data. The latter resulted in small numbers for some categories, with rates suppressed for fewer than 16 deaths because of reduced reliability.

“We found that more specific information is often available on death certificates but is lost in the process of coding,” said Dr. Thoma. “We were able to reclassify many of these causes to a more specific cause that we attributed to be the primary cause of death.”

The authors said future studies of maternal death should examine the contribution of the pandemic to racial and ethnic disparities and should identify specific causes of maternal deaths overall and associated with COVID-19.

In earlier research, the authors previously warned of possible misclassifications of maternal deaths.

They found evidence of both underreporting and overreporting of deaths, with possible overreporting predominant, whereas accurate data are essential for measuring the effectiveness of maternal mortality reduction programs.

Dr. Thoma’s group will continue to monitor mortality trends with the release of 2021 data. “We hope we will see improvements in 2021 given greater access to vaccines, treatments, and fewer health care disruptions,” Dr. Thoma said. “It will be important to continue to stress the importance of COVID-19 vaccines for pregnant and postpartum people.”

This study had no external funding. The authors disclosed no competing interests. Dr. Woolf declared no conflicts of interest.

WASHINGTON (Reuters) – A pill used to terminate early pregnancies is unlikely to become available without a prescription for years, if ever, experts told Reuters, as the conservative-leaning U.S. Supreme Court dramatically curbed abortion rights.

The Supreme Court on June 24 overturned the landmark 1973 Roe v. Wade ruling that recognized the constitutional right to an abortion and legalized it nationwide. The new ruling stung abortion rights advocates and was a momentous victory to Republicans and religious conservatives.

Many U.S. states are expected to severely limit or outright ban abortions following the Supreme Court ruling. President Joe Biden’s administration is considering options to increase access to so-called medication abortions, which can be administered at home.

“Today I am directing the Department of Health & Human Services to take steps to ensure these critical medications are available to the fullest extent possible,” Mr. Biden said in remarks from the White House.

The pill, mifepristone, is used in combination with a second drug called misoprostol to induce an abortion up to 10 weeks into a pregnancy and is heavily restricted – only available through a certified doctor’s prescription. Abortion rights activists have stepped up calls to make it available for anyone to buy at pharmacies without a prescription.

“We will double down and use every lever we have to protect access to abortion care,” Secretary of Health and Human Services Xavier Becerra said in a statement, adding the department was committed to ensuring access to “medication abortion that has been approved by the FDA for over 20 years.”

Neither Mr. Biden nor Mr. Becerra addressed making the pills available over-the-counter, a process that could take years according to medical and regulatory experts interviewed by Reuters. They said drugmakers would need to conduct new studies showing directions on the product’s packaging would enable a consumer to safely use it without professional medical guidance.

The two companies that make the pill for the U.S. market have shown no interest in conducting the research. Should they do so, any Food and Drug Administration approval would become a target for lawsuits from abortion opponents that could delay implementation for years, experts said.

“The hard part that I see is getting the evidence or the agreement that no prescriber is needed at all,” said Susan Wood, a former Assistant Commissioner for Women’s Health at the FDA.

“I personally don’t see it happening in the next couple of years,” said Ms. Wood, now director of George Washington University’s Jacobs Institute of Women’s Health.
 

The next battle

Access to abortion pills is expected to become the next big battle, as their use is harder to track. The FDA has already relaxed some restrictions, making it easier for certified doctors to prescribe them.

The agency now allows doctors to prescribe mifepristone after a telehealth visit rather than in-person. Patients can receive it by mail, making it easier for women in U.S. states that already restrict its use.

The White House has already considered making abortion pills available online and from pharmacies abroad, with a prescription. However, the import possibility has been curtailed by Congress in broader legislation about drug regulation.

An over-the-counter designation would make it much easier for pregnant women to access the pills in states that seek to restrict their use. For example, they could more easily be mailed to a patient from a friend or supporter in a state where they are not banned.

An FDA spokesperson declined to comment on whether over-the-counter use of abortion pills has been considered. A spokesperson for Danco Laboratories, a manufacturer of mifepristone, said that it does not plan to seek over-the-counter approval. GenBioPro, the second maker of mifepristone for the U.S. market, did not respond to requests for comment.
 

Are they safe?

Medication abortion involves two drugs, taken over a day or two. The first, mifepristone, blocks the pregnancy-sustaining hormone progesterone. The second, misoprostol, induces uterine contractions.

When taken together, the pills halt the pregnancy and prompt cramping and bleeding to empty the uterus, in a process similar to miscarriage.

Abortion rights activists say the pills have a long track record of being safe and effective, with no risk of overdose or addiction. In several countries, including India and Mexico, women can buy mifepristone and misoprostol without a prescription to induce abortion.

“Medication abortion really does meet all the FDA criteria for an over-the-counter switch,” said Antonia Biggs, associate professor at the University of California, San Francisco’s obstetrics, gynecology and reproductive sciences department.

A recent study by Ms. Biggs and colleagues found that the majority of participants would understand a medication abortion over-the-counter label. Ms. Biggs said she was not in talks with drugmakers over her research.

The Charlotte Lozier Institute and Susan B. Anthony List, which advocate against abortion, have said that the FDA decision to relax restrictions on mifepristone ignored data on complications and put women at risk.

Others point to the decade-long legal fight for over-the-counter Plan B, a form of emergency contraception taken within days of sexual intercourse to prevent a pregnancy. Approval for women 18 and over was granted in 2006 and for use by women of all ages in 2013.

“There was very strong support that you did not need a prescriber,” said Ms. Wood, who resigned from the FDA in 2005 over the delay. “Everybody under the sun agreed except for a small group of people who somehow had an enormous political influence.”

Reuters Health Information © 2022 

WASHINGTON (Reuters) – A pill used to terminate early pregnancies is unlikely to become available without a prescription for years, if ever, experts told Reuters, as the conservative-leaning U.S. Supreme Court dramatically curbed abortion rights.

The Supreme Court on June 24 overturned the landmark 1973 Roe v. Wade ruling that recognized the constitutional right to an abortion and legalized it nationwide. The new ruling stung abortion rights advocates and was a momentous victory to Republicans and religious conservatives.

Many U.S. states are expected to severely limit or outright ban abortions following the Supreme Court ruling. President Joe Biden’s administration is considering options to increase access to so-called medication abortions, which can be administered at home.

“Today I am directing the Department of Health & Human Services to take steps to ensure these critical medications are available to the fullest extent possible,” Mr. Biden said in remarks from the White House.

The pill, mifepristone, is used in combination with a second drug called misoprostol to induce an abortion up to 10 weeks into a pregnancy and is heavily restricted – only available through a certified doctor’s prescription. Abortion rights activists have stepped up calls to make it available for anyone to buy at pharmacies without a prescription.

“We will double down and use every lever we have to protect access to abortion care,” Secretary of Health and Human Services Xavier Becerra said in a statement, adding the department was committed to ensuring access to “medication abortion that has been approved by the FDA for over 20 years.”

Neither Mr. Biden nor Mr. Becerra addressed making the pills available over-the-counter, a process that could take years according to medical and regulatory experts interviewed by Reuters. They said drugmakers would need to conduct new studies showing directions on the product’s packaging would enable a consumer to safely use it without professional medical guidance.

The two companies that make the pill for the U.S. market have shown no interest in conducting the research. Should they do so, any Food and Drug Administration approval would become a target for lawsuits from abortion opponents that could delay implementation for years, experts said.

“The hard part that I see is getting the evidence or the agreement that no prescriber is needed at all,” said Susan Wood, a former Assistant Commissioner for Women’s Health at the FDA.

“I personally don’t see it happening in the next couple of years,” said Ms. Wood, now director of George Washington University’s Jacobs Institute of Women’s Health.
 

The next battle

Access to abortion pills is expected to become the next big battle, as their use is harder to track. The FDA has already relaxed some restrictions, making it easier for certified doctors to prescribe them.

The agency now allows doctors to prescribe mifepristone after a telehealth visit rather than in-person. Patients can receive it by mail, making it easier for women in U.S. states that already restrict its use.

The White House has already considered making abortion pills available online and from pharmacies abroad, with a prescription. However, the import possibility has been curtailed by Congress in broader legislation about drug regulation.

An over-the-counter designation would make it much easier for pregnant women to access the pills in states that seek to restrict their use. For example, they could more easily be mailed to a patient from a friend or supporter in a state where they are not banned.

An FDA spokesperson declined to comment on whether over-the-counter use of abortion pills has been considered. A spokesperson for Danco Laboratories, a manufacturer of mifepristone, said that it does not plan to seek over-the-counter approval. GenBioPro, the second maker of mifepristone for the U.S. market, did not respond to requests for comment.
 

Are they safe?

Medication abortion involves two drugs, taken over a day or two. The first, mifepristone, blocks the pregnancy-sustaining hormone progesterone. The second, misoprostol, induces uterine contractions.

When taken together, the pills halt the pregnancy and prompt cramping and bleeding to empty the uterus, in a process similar to miscarriage.

Abortion rights activists say the pills have a long track record of being safe and effective, with no risk of overdose or addiction. In several countries, including India and Mexico, women can buy mifepristone and misoprostol without a prescription to induce abortion.

“Medication abortion really does meet all the FDA criteria for an over-the-counter switch,” said Antonia Biggs, associate professor at the University of California, San Francisco’s obstetrics, gynecology and reproductive sciences department.

A recent study by Ms. Biggs and colleagues found that the majority of participants would understand a medication abortion over-the-counter label. Ms. Biggs said she was not in talks with drugmakers over her research.

The Charlotte Lozier Institute and Susan B. Anthony List, which advocate against abortion, have said that the FDA decision to relax restrictions on mifepristone ignored data on complications and put women at risk.

Others point to the decade-long legal fight for over-the-counter Plan B, a form of emergency contraception taken within days of sexual intercourse to prevent a pregnancy. Approval for women 18 and over was granted in 2006 and for use by women of all ages in 2013.

“There was very strong support that you did not need a prescriber,” said Ms. Wood, who resigned from the FDA in 2005 over the delay. “Everybody under the sun agreed except for a small group of people who somehow had an enormous political influence.”

Reuters Health Information © 2022 

WASHINGTON (Reuters) – A pill used to terminate early pregnancies is unlikely to become available without a prescription for years, if ever, experts told Reuters, as the conservative-leaning U.S. Supreme Court dramatically curbed abortion rights.

The Supreme Court on June 24 overturned the landmark 1973 Roe v. Wade ruling that recognized the constitutional right to an abortion and legalized it nationwide. The new ruling stung abortion rights advocates and was a momentous victory to Republicans and religious conservatives.

Many U.S. states are expected to severely limit or outright ban abortions following the Supreme Court ruling. President Joe Biden’s administration is considering options to increase access to so-called medication abortions, which can be administered at home.

“Today I am directing the Department of Health & Human Services to take steps to ensure these critical medications are available to the fullest extent possible,” Mr. Biden said in remarks from the White House.

The pill, mifepristone, is used in combination with a second drug called misoprostol to induce an abortion up to 10 weeks into a pregnancy and is heavily restricted – only available through a certified doctor’s prescription. Abortion rights activists have stepped up calls to make it available for anyone to buy at pharmacies without a prescription.

“We will double down and use every lever we have to protect access to abortion care,” Secretary of Health and Human Services Xavier Becerra said in a statement, adding the department was committed to ensuring access to “medication abortion that has been approved by the FDA for over 20 years.”

Neither Mr. Biden nor Mr. Becerra addressed making the pills available over-the-counter, a process that could take years according to medical and regulatory experts interviewed by Reuters. They said drugmakers would need to conduct new studies showing directions on the product’s packaging would enable a consumer to safely use it without professional medical guidance.

The two companies that make the pill for the U.S. market have shown no interest in conducting the research. Should they do so, any Food and Drug Administration approval would become a target for lawsuits from abortion opponents that could delay implementation for years, experts said.

“The hard part that I see is getting the evidence or the agreement that no prescriber is needed at all,” said Susan Wood, a former Assistant Commissioner for Women’s Health at the FDA.

“I personally don’t see it happening in the next couple of years,” said Ms. Wood, now director of George Washington University’s Jacobs Institute of Women’s Health.
 

The next battle

Access to abortion pills is expected to become the next big battle, as their use is harder to track. The FDA has already relaxed some restrictions, making it easier for certified doctors to prescribe them.

The agency now allows doctors to prescribe mifepristone after a telehealth visit rather than in-person. Patients can receive it by mail, making it easier for women in U.S. states that already restrict its use.

The White House has already considered making abortion pills available online and from pharmacies abroad, with a prescription. However, the import possibility has been curtailed by Congress in broader legislation about drug regulation.

An over-the-counter designation would make it much easier for pregnant women to access the pills in states that seek to restrict their use. For example, they could more easily be mailed to a patient from a friend or supporter in a state where they are not banned.

An FDA spokesperson declined to comment on whether over-the-counter use of abortion pills has been considered. A spokesperson for Danco Laboratories, a manufacturer of mifepristone, said that it does not plan to seek over-the-counter approval. GenBioPro, the second maker of mifepristone for the U.S. market, did not respond to requests for comment.
 

Are they safe?

Medication abortion involves two drugs, taken over a day or two. The first, mifepristone, blocks the pregnancy-sustaining hormone progesterone. The second, misoprostol, induces uterine contractions.

When taken together, the pills halt the pregnancy and prompt cramping and bleeding to empty the uterus, in a process similar to miscarriage.

Abortion rights activists say the pills have a long track record of being safe and effective, with no risk of overdose or addiction. In several countries, including India and Mexico, women can buy mifepristone and misoprostol without a prescription to induce abortion.

“Medication abortion really does meet all the FDA criteria for an over-the-counter switch,” said Antonia Biggs, associate professor at the University of California, San Francisco’s obstetrics, gynecology and reproductive sciences department.

A recent study by Ms. Biggs and colleagues found that the majority of participants would understand a medication abortion over-the-counter label. Ms. Biggs said she was not in talks with drugmakers over her research.

The Charlotte Lozier Institute and Susan B. Anthony List, which advocate against abortion, have said that the FDA decision to relax restrictions on mifepristone ignored data on complications and put women at risk.

Others point to the decade-long legal fight for over-the-counter Plan B, a form of emergency contraception taken within days of sexual intercourse to prevent a pregnancy. Approval for women 18 and over was granted in 2006 and for use by women of all ages in 2013.

“There was very strong support that you did not need a prescriber,” said Ms. Wood, who resigned from the FDA in 2005 over the delay. “Everybody under the sun agreed except for a small group of people who somehow had an enormous political influence.”

Reuters Health Information © 2022 

CHICAGO – The American Society of Clinical Oncology recently wrapped its annual meeting in Chicago. Many of us attended virtually, or in person, and were wowed by some of the abstracts and their implications for our patients – some practice changing. Here, I highlight some presentations that stood out to me.

A first-line treatment for metastatic colorectal cancer

The plenary session did not disappoint. In abstract LBA1, investigators presented first-line treatment for patients with metastatic colorectal cancer who were randomized to receive mFOLFOX6 with either bevacizumab or panitumumab in RAS wild-type positive patients. This was the phase 3 PARADIGM trial.

The primary outcome for this study was overall survival. It included 823 patients who were randomized 1:1 with a subset analysis of whether the primary tumor was on the left or right side of the colon. At 61 months follow-up, the median overall survival results for left-sided colon cancer was 38 months versus 34 months. It was statistically significant favoring the panitumumab arm. It improved the curable resection rate for patients with left-sided tumors from 11% in the bevacizumab arm to 18% in the panitumumab arm. Interestingly, patients randomized with right-sided tumors showed no difference in overall survival. The investigator, Takayuki Yoshino, MD, PhD, National Cancer Center Hospital East, Kashiwa, Japan, said the study findings support the use of mFOLFOX6 with panitumumab in left-sided RAS wild type as first-line therapy in metastatic colorectal patients. 
 

A possible new standard of care in breast cancer

Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, received a standing ovation and deserved it. In the phase 3 clinical trial DESTINY-Breast04 (abstract LBA3), she demonstrated that trastuzumab deruxtecan (T-DXd) for patients with metastatic breast cancer who were HER2 low (IHC 1+ or 2+ ISH-), led to a statistically significant and clinically meaningful benefit in both progression free survival and overall survival. In this trial, patients were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of chemotherapy. All patients had at least one to two lines of chemotherapy before entering the trial. Hormone-positive patients were allowed if they had already received and failed, or progressed on hormone therapy. 

Previously, most patients were treated either with eribulin with some receiving capecitabine, gemcitabine or taxane, or hormone therapy if hormone positive.

The progression-free survival was 10.1 versus 5.4 months in hormone-positive patients, and in all patients (hormone receptor positive or negative), there was a likewise improvement of 9.9 versus 5.1 months progression free survival.

Overall survival was equally impressive. In the hormone receptor–positive patients, the hazard ratio was 0.64 with a 23.9 versus 17.5 month survival. If all patients were included, the HR was again 0.64 with 23.4 versus 16.8 month survival. Even the triple-negative breast cancer patients had a HR of 0.48 with 18.2 versus 8.3 months survival. Adverse events were quite tolerable with some nausea, some decreased white count, and only an interstitial lung disease of grade 2 or less in 12%. 

Trastuzumab deruxtecan is a targeted treatment which, in addition to striking its target, also targets other tumor cells that are part of the cancer. The results of this study may lead to a new standard of care of this patient population.

The study by Dr. Modi and colleagues was simultaneously published in the New England Journal of Medicine.
 

Improving outcomes in multiple myeloma

In abstract LBA4, Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, asks if autologous stem cell transplant (ASCT) can improve outcomes after induction with an RVD regimen (lenalidomide, bortezomib, and dexamethasone) and lenalidomide (Revlimid) maintenance for newly diagnosed patients with multiple myeloma in the DETERMINATION study.

The take home here was quite interesting. In fact, there is no difference in overall survival if patients get this standard RVD/lenalidomide maintenance induction with or without ASCT. However, the progression free survival was better with ASCT: 46 versus 67 months (improvement of 21 months). However, there were some caveats. There was toxicity and change in quality of life for a while in those patients receiving ASCT as would be expected. Furthermore, the study only allowed 65 years old or younger and ASCT may not be wise for older patients. The discussant made a strong point that African Americans tend to have higher risk disease with different mutations and might also be better served by have ASCT later.

The conclusion was that, given all the new therapies in myeloma for second line and beyond, ASCT should be a discussion with each new patient and not an automatic decision.

This study was simultaneously published in the New England Journal of Medicine.
 

Adagrasib promising for pretreated patients with NSCLC with KRAS mutation

In patients with advanced or metastatic non–small cell lung cancer (NSCLC), adagrasib was found to be well tolerated and “demonstrates promising efficacy” for patients with the KRAS G12C mutation (KRYSTAL-1, abstract 9002). This was a phase 2 registration trial of 116 patients who were treated with 600 mg of adagrasib twice orally. Patients all had previous chemotherapy or immunotherapy or both. The overall response rate was a surprisingly good 43% (complete response and partial response). Disease control was an incredible 80% if stable disease was included. The duration of response was 8.5 months, progression-free survival was 6.5 months, and overall survival was 12.6 months. Furthermore, 33% of those with brain metastases had a complete response or partial response.

The take-home message is that, since 15% of NSCLC metastatic patients are KRAS mutant G12C, we should be watching for such patients in our biomarker analysis. While we have sotorasib – approved by the Food and Drug Administration for NSCLC – the results of this study suggests we may have another new molecule in the same class.
 

Neoadjuvant chemotherapy with immunotherapy for NSCLC

It may be time to consider neoadjuvant chemotherapy with immunotherapy, such as nivolumab, for patients with NSCLC in order to achieve the best response possible.

In NADIM II, investigators led by Mariano Provencio-Pulla, MD, of the Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, confirmed the superiority of chemotherapy with immunotherapy for patients with resectable stage IIIA NSCLC. NADIM included patients with resectable stage IIIA/B NSCLC who were randomized 2:1 to receive carboplatin taxol neoadjuvant therapy with or without nivolumab before and after surgery. The pathological complete response rates overall were 36% versus 7%, favoring the nivolumab arm, but even higher pCR rates occurred in patients with PD-L1 over 50%.

In closing, always check MMR, KRAS, BRAF, and HER2. For wild-type left-sided mCRC, consider FOLFOX or FOLFIRI with an anti-EGFR. For KRAS mutant or right-sided colon tumor, consider FOLFOX or FOLFIRI with bevacizumab, followed by maintenance 5FU or capecitabine, with or without bevacizumab.

CHICAGO – The American Society of Clinical Oncology recently wrapped its annual meeting in Chicago. Many of us attended virtually, or in person, and were wowed by some of the abstracts and their implications for our patients – some practice changing. Here, I highlight some presentations that stood out to me.

A first-line treatment for metastatic colorectal cancer

The plenary session did not disappoint. In abstract LBA1, investigators presented first-line treatment for patients with metastatic colorectal cancer who were randomized to receive mFOLFOX6 with either bevacizumab or panitumumab in RAS wild-type positive patients. This was the phase 3 PARADIGM trial.

The primary outcome for this study was overall survival. It included 823 patients who were randomized 1:1 with a subset analysis of whether the primary tumor was on the left or right side of the colon. At 61 months follow-up, the median overall survival results for left-sided colon cancer was 38 months versus 34 months. It was statistically significant favoring the panitumumab arm. It improved the curable resection rate for patients with left-sided tumors from 11% in the bevacizumab arm to 18% in the panitumumab arm. Interestingly, patients randomized with right-sided tumors showed no difference in overall survival. The investigator, Takayuki Yoshino, MD, PhD, National Cancer Center Hospital East, Kashiwa, Japan, said the study findings support the use of mFOLFOX6 with panitumumab in left-sided RAS wild type as first-line therapy in metastatic colorectal patients. 
 

A possible new standard of care in breast cancer

Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, received a standing ovation and deserved it. In the phase 3 clinical trial DESTINY-Breast04 (abstract LBA3), she demonstrated that trastuzumab deruxtecan (T-DXd) for patients with metastatic breast cancer who were HER2 low (IHC 1+ or 2+ ISH-), led to a statistically significant and clinically meaningful benefit in both progression free survival and overall survival. In this trial, patients were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of chemotherapy. All patients had at least one to two lines of chemotherapy before entering the trial. Hormone-positive patients were allowed if they had already received and failed, or progressed on hormone therapy. 

Previously, most patients were treated either with eribulin with some receiving capecitabine, gemcitabine or taxane, or hormone therapy if hormone positive.

The progression-free survival was 10.1 versus 5.4 months in hormone-positive patients, and in all patients (hormone receptor positive or negative), there was a likewise improvement of 9.9 versus 5.1 months progression free survival.

Overall survival was equally impressive. In the hormone receptor–positive patients, the hazard ratio was 0.64 with a 23.9 versus 17.5 month survival. If all patients were included, the HR was again 0.64 with 23.4 versus 16.8 month survival. Even the triple-negative breast cancer patients had a HR of 0.48 with 18.2 versus 8.3 months survival. Adverse events were quite tolerable with some nausea, some decreased white count, and only an interstitial lung disease of grade 2 or less in 12%. 

Trastuzumab deruxtecan is a targeted treatment which, in addition to striking its target, also targets other tumor cells that are part of the cancer. The results of this study may lead to a new standard of care of this patient population.

The study by Dr. Modi and colleagues was simultaneously published in the New England Journal of Medicine.
 

Improving outcomes in multiple myeloma

In abstract LBA4, Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, asks if autologous stem cell transplant (ASCT) can improve outcomes after induction with an RVD regimen (lenalidomide, bortezomib, and dexamethasone) and lenalidomide (Revlimid) maintenance for newly diagnosed patients with multiple myeloma in the DETERMINATION study.

The take home here was quite interesting. In fact, there is no difference in overall survival if patients get this standard RVD/lenalidomide maintenance induction with or without ASCT. However, the progression free survival was better with ASCT: 46 versus 67 months (improvement of 21 months). However, there were some caveats. There was toxicity and change in quality of life for a while in those patients receiving ASCT as would be expected. Furthermore, the study only allowed 65 years old or younger and ASCT may not be wise for older patients. The discussant made a strong point that African Americans tend to have higher risk disease with different mutations and might also be better served by have ASCT later.

The conclusion was that, given all the new therapies in myeloma for second line and beyond, ASCT should be a discussion with each new patient and not an automatic decision.

This study was simultaneously published in the New England Journal of Medicine.
 

Adagrasib promising for pretreated patients with NSCLC with KRAS mutation

In patients with advanced or metastatic non–small cell lung cancer (NSCLC), adagrasib was found to be well tolerated and “demonstrates promising efficacy” for patients with the KRAS G12C mutation (KRYSTAL-1, abstract 9002). This was a phase 2 registration trial of 116 patients who were treated with 600 mg of adagrasib twice orally. Patients all had previous chemotherapy or immunotherapy or both. The overall response rate was a surprisingly good 43% (complete response and partial response). Disease control was an incredible 80% if stable disease was included. The duration of response was 8.5 months, progression-free survival was 6.5 months, and overall survival was 12.6 months. Furthermore, 33% of those with brain metastases had a complete response or partial response.

The take-home message is that, since 15% of NSCLC metastatic patients are KRAS mutant G12C, we should be watching for such patients in our biomarker analysis. While we have sotorasib – approved by the Food and Drug Administration for NSCLC – the results of this study suggests we may have another new molecule in the same class.
 

Neoadjuvant chemotherapy with immunotherapy for NSCLC

It may be time to consider neoadjuvant chemotherapy with immunotherapy, such as nivolumab, for patients with NSCLC in order to achieve the best response possible.

In NADIM II, investigators led by Mariano Provencio-Pulla, MD, of the Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, confirmed the superiority of chemotherapy with immunotherapy for patients with resectable stage IIIA NSCLC. NADIM included patients with resectable stage IIIA/B NSCLC who were randomized 2:1 to receive carboplatin taxol neoadjuvant therapy with or without nivolumab before and after surgery. The pathological complete response rates overall were 36% versus 7%, favoring the nivolumab arm, but even higher pCR rates occurred in patients with PD-L1 over 50%.

In closing, always check MMR, KRAS, BRAF, and HER2. For wild-type left-sided mCRC, consider FOLFOX or FOLFIRI with an anti-EGFR. For KRAS mutant or right-sided colon tumor, consider FOLFOX or FOLFIRI with bevacizumab, followed by maintenance 5FU or capecitabine, with or without bevacizumab.

CHICAGO – The American Society of Clinical Oncology recently wrapped its annual meeting in Chicago. Many of us attended virtually, or in person, and were wowed by some of the abstracts and their implications for our patients – some practice changing. Here, I highlight some presentations that stood out to me.

A first-line treatment for metastatic colorectal cancer

The plenary session did not disappoint. In abstract LBA1, investigators presented first-line treatment for patients with metastatic colorectal cancer who were randomized to receive mFOLFOX6 with either bevacizumab or panitumumab in RAS wild-type positive patients. This was the phase 3 PARADIGM trial.

The primary outcome for this study was overall survival. It included 823 patients who were randomized 1:1 with a subset analysis of whether the primary tumor was on the left or right side of the colon. At 61 months follow-up, the median overall survival results for left-sided colon cancer was 38 months versus 34 months. It was statistically significant favoring the panitumumab arm. It improved the curable resection rate for patients with left-sided tumors from 11% in the bevacizumab arm to 18% in the panitumumab arm. Interestingly, patients randomized with right-sided tumors showed no difference in overall survival. The investigator, Takayuki Yoshino, MD, PhD, National Cancer Center Hospital East, Kashiwa, Japan, said the study findings support the use of mFOLFOX6 with panitumumab in left-sided RAS wild type as first-line therapy in metastatic colorectal patients. 
 

A possible new standard of care in breast cancer

Shanu Modi, MD, of Memorial Sloan Kettering Cancer Center, New York, received a standing ovation and deserved it. In the phase 3 clinical trial DESTINY-Breast04 (abstract LBA3), she demonstrated that trastuzumab deruxtecan (T-DXd) for patients with metastatic breast cancer who were HER2 low (IHC 1+ or 2+ ISH-), led to a statistically significant and clinically meaningful benefit in both progression free survival and overall survival. In this trial, patients were randomized 2:1 to receive trastuzumab deruxtecan or physician’s choice of chemotherapy. All patients had at least one to two lines of chemotherapy before entering the trial. Hormone-positive patients were allowed if they had already received and failed, or progressed on hormone therapy. 

Previously, most patients were treated either with eribulin with some receiving capecitabine, gemcitabine or taxane, or hormone therapy if hormone positive.

The progression-free survival was 10.1 versus 5.4 months in hormone-positive patients, and in all patients (hormone receptor positive or negative), there was a likewise improvement of 9.9 versus 5.1 months progression free survival.

Overall survival was equally impressive. In the hormone receptor–positive patients, the hazard ratio was 0.64 with a 23.9 versus 17.5 month survival. If all patients were included, the HR was again 0.64 with 23.4 versus 16.8 month survival. Even the triple-negative breast cancer patients had a HR of 0.48 with 18.2 versus 8.3 months survival. Adverse events were quite tolerable with some nausea, some decreased white count, and only an interstitial lung disease of grade 2 or less in 12%. 

Trastuzumab deruxtecan is a targeted treatment which, in addition to striking its target, also targets other tumor cells that are part of the cancer. The results of this study may lead to a new standard of care of this patient population.

The study by Dr. Modi and colleagues was simultaneously published in the New England Journal of Medicine.
 

Improving outcomes in multiple myeloma

In abstract LBA4, Paul G. Richardson, MD, of the Dana-Farber Cancer Institute, Boston, asks if autologous stem cell transplant (ASCT) can improve outcomes after induction with an RVD regimen (lenalidomide, bortezomib, and dexamethasone) and lenalidomide (Revlimid) maintenance for newly diagnosed patients with multiple myeloma in the DETERMINATION study.

The take home here was quite interesting. In fact, there is no difference in overall survival if patients get this standard RVD/lenalidomide maintenance induction with or without ASCT. However, the progression free survival was better with ASCT: 46 versus 67 months (improvement of 21 months). However, there were some caveats. There was toxicity and change in quality of life for a while in those patients receiving ASCT as would be expected. Furthermore, the study only allowed 65 years old or younger and ASCT may not be wise for older patients. The discussant made a strong point that African Americans tend to have higher risk disease with different mutations and might also be better served by have ASCT later.

The conclusion was that, given all the new therapies in myeloma for second line and beyond, ASCT should be a discussion with each new patient and not an automatic decision.

This study was simultaneously published in the New England Journal of Medicine.
 

Adagrasib promising for pretreated patients with NSCLC with KRAS mutation

In patients with advanced or metastatic non–small cell lung cancer (NSCLC), adagrasib was found to be well tolerated and “demonstrates promising efficacy” for patients with the KRAS G12C mutation (KRYSTAL-1, abstract 9002). This was a phase 2 registration trial of 116 patients who were treated with 600 mg of adagrasib twice orally. Patients all had previous chemotherapy or immunotherapy or both. The overall response rate was a surprisingly good 43% (complete response and partial response). Disease control was an incredible 80% if stable disease was included. The duration of response was 8.5 months, progression-free survival was 6.5 months, and overall survival was 12.6 months. Furthermore, 33% of those with brain metastases had a complete response or partial response.

The take-home message is that, since 15% of NSCLC metastatic patients are KRAS mutant G12C, we should be watching for such patients in our biomarker analysis. While we have sotorasib – approved by the Food and Drug Administration for NSCLC – the results of this study suggests we may have another new molecule in the same class.
 

Neoadjuvant chemotherapy with immunotherapy for NSCLC

It may be time to consider neoadjuvant chemotherapy with immunotherapy, such as nivolumab, for patients with NSCLC in order to achieve the best response possible.

In NADIM II, investigators led by Mariano Provencio-Pulla, MD, of the Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, confirmed the superiority of chemotherapy with immunotherapy for patients with resectable stage IIIA NSCLC. NADIM included patients with resectable stage IIIA/B NSCLC who were randomized 2:1 to receive carboplatin taxol neoadjuvant therapy with or without nivolumab before and after surgery. The pathological complete response rates overall were 36% versus 7%, favoring the nivolumab arm, but even higher pCR rates occurred in patients with PD-L1 over 50%.

In closing, always check MMR, KRAS, BRAF, and HER2. For wild-type left-sided mCRC, consider FOLFOX or FOLFIRI with an anti-EGFR. For KRAS mutant or right-sided colon tumor, consider FOLFOX or FOLFIRI with bevacizumab, followed by maintenance 5FU or capecitabine, with or without bevacizumab.

To the Editor:

Intravascular large cell lymphoma (ILCL) is a rare B-cell lymphoma that is defined by the presence of large neoplastic B cells in the lumen of blood vessels.¹ At least 3 variants of ILCL have been described based on case reports and a small case series: classic, cutaneous, and hemophagocytic. The classic variant presents in elderly patients as nonspecific constitutional symptoms (fever or pain, or less frequently weight loss) or as signs of multiorgan failure (most commonly of the central nervous system). Skin involvement, which is present in nearly half of these patients, can take on multiple morphologies, including retiform purpura, ulcerated nodules, or pseudocellulitis. The cutaneous variant typically presents in middle-aged women with normal hematologic studies. Systemic involvement is less common in this variant of disease than the classic variant, which may partly explain why overall survival is superior in this variant. The hemophagocytic variant manifests as intravascular lymphoma accompanied by hemophagocytic syndrome (fever, hepatosplenomegaly, thrombocytopenia, and bone marrow involvement). Of the 3 variants, the hemophagocytic variant presents with the most rapid, aggressive decline, primarily in patients in Asian countries.¹ We describe a fatal case of classic ILCL, highlighting the importance of maintaining a high index of suspicion with false-negative biopsies.

A 69-year-old man presented to the emergency department for failure to thrive and nonhealing wounds of 1 year’s duration. His medical history was notable for poorly controlled diabetes mellitus, progressive multifocal ischemic and hemorrhagic cerebral infarcts, and bilateral deep venous thromboses. Physical examination revealed large purpuric to brown plaques in a retiform configuration with central necrotic eschars on the thighs and abdomen (Figure 1). There was no palpable lymphadenopathy. Laboratory tests revealed normocytic anemia with a hemoglobin level of 10.5 g/dL (reference range, 12–18 g/dL), elevated lactate dehydrogenase level of 525 U/L (reference range, 118–242 U/L), elevated erythrocyte sedimentation rate of 73 mm/h (reference range, <20 mm/h), antinuclear antibody (ANA) titer of 1:2560 (reference range, <1:80), and polyclonal hypergammaglobulinemia. The patient’s white blood cell and platelet counts, creatinine level, and liver function tests were within reference range. Cryoglobulins, coagulation studies, and cardiolipin antibodies were negative. Chest and abdominal imaging also were negative. An incisional skin biopsy and skin punch biopsy showed thrombotic coagulopathy and dilated vessels. A bone marrow biopsy revealed a hypercellular marrow but no plasma cell neoplasm. A repeat incisional skin biopsy demonstrated large CD20⁺ and CD45⁺ atypical lymphocytes within the small capillaries of the deep dermis and subcutaneous fat (Figure 2), which confirmed ILCL. Too deconditioned to tolerate chemotherapy, the patient opted for palliative care and died 18 months after initial presentation.

The diagnosis of ILCL often is delayed for several reasons.² Patients can present with a variety of signs and symptoms related to small vessel occlusion that can be misattributed to other conditions.^3,4 In our case, the patient’s recurrent infarcts were thought to be due to his poorly controlled diabetes mellitus, which was diagnosed a few weeks prior, and a positive ANA, even though the workup for antiphospholipid syndrome was negative. Interestingly, a positive ANA (without signs or symptoms of lupus or other autoimmune conditions) has been reported in patients with lymphoma.³ A positive antineutrophil cytoplasmic antibody level (without symptoms or other signs of vasculitis) has been reported in patients with ILCL.^4,5 Therefore, distractors are common.

Multiple incisional skin biopsies in the absence of clinical findings (ie, random skin biopsy) are moderately sensitive (77.8%) for the diagnosis of ILCL.² In a study by Matsue et al,² 111 suspected cases of ILCL underwent 3 incisional biopsies of fat-containing areas of the skin, such as the thigh, abdomen, and upper arm. Intravascular large cell lymphoma was confirmed in 26 cases. Seven additional cases were diagnosed as ILCL, 2 by additional skin biopsies (1 by a second round and 1 by a third round) and 5 by internal organ biopsy (4 bone marrow and 1 adrenal gland). The remaining cases ultimately were found to be a diagnostic mimicker of ILCL, including non-ILCL.² Although random skin biopsies are reasonably sensitive for ILCL, multiple biopsies are needed, and in some cases, sampling of an internal organ may be required to establish the diagnosis of ILCL.

The prognosis of ILCL is poor; the 3-year overall survival rate for classic and cutaneous variants is 22% and 56%, respectively.⁶ Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is considered first-line treatment, and the addition of rituximab to the CHOP regimen may improve remission rates and survival.⁷

To the Editor:

Intravascular large cell lymphoma (ILCL) is a rare B-cell lymphoma that is defined by the presence of large neoplastic B cells in the lumen of blood vessels.¹ At least 3 variants of ILCL have been described based on case reports and a small case series: classic, cutaneous, and hemophagocytic. The classic variant presents in elderly patients as nonspecific constitutional symptoms (fever or pain, or less frequently weight loss) or as signs of multiorgan failure (most commonly of the central nervous system). Skin involvement, which is present in nearly half of these patients, can take on multiple morphologies, including retiform purpura, ulcerated nodules, or pseudocellulitis. The cutaneous variant typically presents in middle-aged women with normal hematologic studies. Systemic involvement is less common in this variant of disease than the classic variant, which may partly explain why overall survival is superior in this variant. The hemophagocytic variant manifests as intravascular lymphoma accompanied by hemophagocytic syndrome (fever, hepatosplenomegaly, thrombocytopenia, and bone marrow involvement). Of the 3 variants, the hemophagocytic variant presents with the most rapid, aggressive decline, primarily in patients in Asian countries.¹ We describe a fatal case of classic ILCL, highlighting the importance of maintaining a high index of suspicion with false-negative biopsies.

A 69-year-old man presented to the emergency department for failure to thrive and nonhealing wounds of 1 year’s duration. His medical history was notable for poorly controlled diabetes mellitus, progressive multifocal ischemic and hemorrhagic cerebral infarcts, and bilateral deep venous thromboses. Physical examination revealed large purpuric to brown plaques in a retiform configuration with central necrotic eschars on the thighs and abdomen (Figure 1). There was no palpable lymphadenopathy. Laboratory tests revealed normocytic anemia with a hemoglobin level of 10.5 g/dL (reference range, 12–18 g/dL), elevated lactate dehydrogenase level of 525 U/L (reference range, 118–242 U/L), elevated erythrocyte sedimentation rate of 73 mm/h (reference range, <20 mm/h), antinuclear antibody (ANA) titer of 1:2560 (reference range, <1:80), and polyclonal hypergammaglobulinemia. The patient’s white blood cell and platelet counts, creatinine level, and liver function tests were within reference range. Cryoglobulins, coagulation studies, and cardiolipin antibodies were negative. Chest and abdominal imaging also were negative. An incisional skin biopsy and skin punch biopsy showed thrombotic coagulopathy and dilated vessels. A bone marrow biopsy revealed a hypercellular marrow but no plasma cell neoplasm. A repeat incisional skin biopsy demonstrated large CD20⁺ and CD45⁺ atypical lymphocytes within the small capillaries of the deep dermis and subcutaneous fat (Figure 2), which confirmed ILCL. Too deconditioned to tolerate chemotherapy, the patient opted for palliative care and died 18 months after initial presentation.

The diagnosis of ILCL often is delayed for several reasons.² Patients can present with a variety of signs and symptoms related to small vessel occlusion that can be misattributed to other conditions.^3,4 In our case, the patient’s recurrent infarcts were thought to be due to his poorly controlled diabetes mellitus, which was diagnosed a few weeks prior, and a positive ANA, even though the workup for antiphospholipid syndrome was negative. Interestingly, a positive ANA (without signs or symptoms of lupus or other autoimmune conditions) has been reported in patients with lymphoma.³ A positive antineutrophil cytoplasmic antibody level (without symptoms or other signs of vasculitis) has been reported in patients with ILCL.^4,5 Therefore, distractors are common.

Multiple incisional skin biopsies in the absence of clinical findings (ie, random skin biopsy) are moderately sensitive (77.8%) for the diagnosis of ILCL.² In a study by Matsue et al,² 111 suspected cases of ILCL underwent 3 incisional biopsies of fat-containing areas of the skin, such as the thigh, abdomen, and upper arm. Intravascular large cell lymphoma was confirmed in 26 cases. Seven additional cases were diagnosed as ILCL, 2 by additional skin biopsies (1 by a second round and 1 by a third round) and 5 by internal organ biopsy (4 bone marrow and 1 adrenal gland). The remaining cases ultimately were found to be a diagnostic mimicker of ILCL, including non-ILCL.² Although random skin biopsies are reasonably sensitive for ILCL, multiple biopsies are needed, and in some cases, sampling of an internal organ may be required to establish the diagnosis of ILCL.

The prognosis of ILCL is poor; the 3-year overall survival rate for classic and cutaneous variants is 22% and 56%, respectively.⁶ Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is considered first-line treatment, and the addition of rituximab to the CHOP regimen may improve remission rates and survival.⁷

To the Editor:

Intravascular large cell lymphoma (ILCL) is a rare B-cell lymphoma that is defined by the presence of large neoplastic B cells in the lumen of blood vessels.¹ At least 3 variants of ILCL have been described based on case reports and a small case series: classic, cutaneous, and hemophagocytic. The classic variant presents in elderly patients as nonspecific constitutional symptoms (fever or pain, or less frequently weight loss) or as signs of multiorgan failure (most commonly of the central nervous system). Skin involvement, which is present in nearly half of these patients, can take on multiple morphologies, including retiform purpura, ulcerated nodules, or pseudocellulitis. The cutaneous variant typically presents in middle-aged women with normal hematologic studies. Systemic involvement is less common in this variant of disease than the classic variant, which may partly explain why overall survival is superior in this variant. The hemophagocytic variant manifests as intravascular lymphoma accompanied by hemophagocytic syndrome (fever, hepatosplenomegaly, thrombocytopenia, and bone marrow involvement). Of the 3 variants, the hemophagocytic variant presents with the most rapid, aggressive decline, primarily in patients in Asian countries.¹ We describe a fatal case of classic ILCL, highlighting the importance of maintaining a high index of suspicion with false-negative biopsies.

A 69-year-old man presented to the emergency department for failure to thrive and nonhealing wounds of 1 year’s duration. His medical history was notable for poorly controlled diabetes mellitus, progressive multifocal ischemic and hemorrhagic cerebral infarcts, and bilateral deep venous thromboses. Physical examination revealed large purpuric to brown plaques in a retiform configuration with central necrotic eschars on the thighs and abdomen (Figure 1). There was no palpable lymphadenopathy. Laboratory tests revealed normocytic anemia with a hemoglobin level of 10.5 g/dL (reference range, 12–18 g/dL), elevated lactate dehydrogenase level of 525 U/L (reference range, 118–242 U/L), elevated erythrocyte sedimentation rate of 73 mm/h (reference range, <20 mm/h), antinuclear antibody (ANA) titer of 1:2560 (reference range, <1:80), and polyclonal hypergammaglobulinemia. The patient’s white blood cell and platelet counts, creatinine level, and liver function tests were within reference range. Cryoglobulins, coagulation studies, and cardiolipin antibodies were negative. Chest and abdominal imaging also were negative. An incisional skin biopsy and skin punch biopsy showed thrombotic coagulopathy and dilated vessels. A bone marrow biopsy revealed a hypercellular marrow but no plasma cell neoplasm. A repeat incisional skin biopsy demonstrated large CD20⁺ and CD45⁺ atypical lymphocytes within the small capillaries of the deep dermis and subcutaneous fat (Figure 2), which confirmed ILCL. Too deconditioned to tolerate chemotherapy, the patient opted for palliative care and died 18 months after initial presentation.

The diagnosis of ILCL often is delayed for several reasons.² Patients can present with a variety of signs and symptoms related to small vessel occlusion that can be misattributed to other conditions.^3,4 In our case, the patient’s recurrent infarcts were thought to be due to his poorly controlled diabetes mellitus, which was diagnosed a few weeks prior, and a positive ANA, even though the workup for antiphospholipid syndrome was negative. Interestingly, a positive ANA (without signs or symptoms of lupus or other autoimmune conditions) has been reported in patients with lymphoma.³ A positive antineutrophil cytoplasmic antibody level (without symptoms or other signs of vasculitis) has been reported in patients with ILCL.^4,5 Therefore, distractors are common.

Multiple incisional skin biopsies in the absence of clinical findings (ie, random skin biopsy) are moderately sensitive (77.8%) for the diagnosis of ILCL.² In a study by Matsue et al,² 111 suspected cases of ILCL underwent 3 incisional biopsies of fat-containing areas of the skin, such as the thigh, abdomen, and upper arm. Intravascular large cell lymphoma was confirmed in 26 cases. Seven additional cases were diagnosed as ILCL, 2 by additional skin biopsies (1 by a second round and 1 by a third round) and 5 by internal organ biopsy (4 bone marrow and 1 adrenal gland). The remaining cases ultimately were found to be a diagnostic mimicker of ILCL, including non-ILCL.² Although random skin biopsies are reasonably sensitive for ILCL, multiple biopsies are needed, and in some cases, sampling of an internal organ may be required to establish the diagnosis of ILCL.

The prognosis of ILCL is poor; the 3-year overall survival rate for classic and cutaneous variants is 22% and 56%, respectively.⁶ Anthracycline-based chemotherapy, such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), is considered first-line treatment, and the addition of rituximab to the CHOP regimen may improve remission rates and survival.⁷

To the Editor:

Tumor necrosis factor α (TNF-α) inhibitor–induced lupuslike syndrome (TAILS) is a newly described entity that refers to the onset of subacute cutaneous lupus erythematosus (SCLE) during drug therapy with TNF-α antagonists. The condition is unique because it is thought to occur via a separate pathophysiologic mechanism than all other agents implicated in the development of drug-induced lupus erythematosus (DILE). Infliximab and etanercept are the 2 most common TNF-α antagonists associated with TAILS. Although rare, adalimumab, golimumab, and certolizumab pegol have been reported to induce this state of autoimmunity. We report an uncommon presentation of TAILS in a patient taking certolizumab pegol with a brief discussion of the pathogenesis underlying TAILS.

A 71-year-old woman presented to the dermatology clinic with a rash located on the arms, face, and trunk that she reported as having been present for months. She had a medical history of rheumatoid arthritis and currently was receiving certolizumab pegol injections. Physical examination revealed erythematous patches and plaques with overlying scaling and evidence of atrophic scarring on sun-exposed areas of the body. The lesions predominantly were in a symmetrical distribution across the extensor surfaces of both outer arms as well as the posterior superior thoracic region extending anteriorly along the bilateral supraclavicular area (Figures 1 and 2). A 4-mm punch biopsy was obtained and sent for histologic analysis, along with a sample of the patient’s serum for antinuclear antibody (ANA) testing.

Hematoxylin and eosin–stained tissue sections of the right superior thoracic lesions revealed epidermal atrophy, hyperkeratosis, and vacuolar alteration of the basal layer with apoptosis, consistent with a lichenoid tissue reaction. In addition, both superficial and deep perivascular and periadnexal lymphocytic infiltrates were observed as well as increased dermal mucin. Serologic testing was performed with a comprehensive ANA panel of the patient’s serum (Table). Of note, there was a speckled ANA pattern (1:1280), with elevated anti–double-stranded DNA (anti-dsDNA) and anti–Sjögren syndrome–related antigen A (anti-SSA)(also called anti-Ro antibodies) levels. The patient’s rheumatologist was consulted; certolizumab pegol was removed from the current drug regimen and switched to a daily regimen of hydroxychloroquine and prednisone. Seven weeks after discontinuation of certolizumab pegol, the patient was symptom free and without any cutaneous involvement. Based on the histologic analysis, presence of anti-SSA (Ro) autoantibodies, and the resolution of symptoms following withdrawal of anti–TNF-α therapy, a diagnosis of TAILS was made.

Subacute cutaneous lupus erythematosus, the most common subset of DILE, typically presents with annular polycyclic or papulosquamous skin eruptions on the legs; patients often test positive for anti-SSA/Ro and/or anti–Sjögren syndrome–related antigen B (also called anti-La) antibodies. Pharmaceutical agents linked to the development of SCLE are calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine, the chemotherapeutic agent gemcitabine, and TNF-α antagonists.^1,2 Tumor necrosis factor α antagonists are biologic agents that commonly are used in the management of systemic inflammatory diseases such as ulcerative colitis, Crohn disease, seronegative spondyloarthropathies, and rheumatoid arthritis. Among this family of therapeutics includes adalimumab (humanized monoclonal antibody), infliximab (chimeric monoclonal TNF-α antagonist), etanercept (soluble receptor fusion protein), certolizumab pegol (Fab fraction of a human IgG monoclonal antibody), and golimumab (humanized monoclonal antibody).

Tumor necrosis factor α inhibitor–induced lupuslike syndrome most commonly occurs in women in the fifth decade of life, and it is seen more often in those using infliximab or entanercept.³ Although reports do exist, TAILS rarely complicates treatment with adalimumab, golimumab, or certolizumab.^4,5 Due to the lack of reports, there are no diagnostic criteria nor an acceptable theory regarding the pathogenesis. In one study in France, the estimated incidence was thought to be 0.19% for infliximab and 0.18% for etanercept.⁶ Tumor necrosis factor α inhibitor–induced lupuslike syndrome is unique in that it is thought to occur by a different mechanism than that of other known offending agents in the development of DILE. Molecular mimicry, direct cytotoxicity, altered T-cell gene expression, and disruption of central immune tolerance have all been hypothesized to cause drug-induced systemic lupus erythematosus, SCLE, and chronic cutaneous lupus erythematosus. Tumor necrosis factor α inhibitors, are postulated to cause the induction of SCLE via an independent route separate from not only other drugs that cause SCLE but also all forms of DILE as a whole, making it a distinctive player within the realm of agents known to cause a lupuslike syndrome. The following hypotheses may explain this occurrence:

1. Increased humoral autoimmunity: Under normal circumstances, TNF-α activation leads to upregulation in the production of cytotoxic CD8⁺ T lymphocytes. The upregulation of CD8⁺ T lymphocytes concurrently leads to a simultaneous suppression of B lymphocytes. Inhibiting the effects of TNF-α on the other hand promotes cytotoxic T-lymphocyte suppression, leading to an increased synthesis of B cells and subsequently a state of increased humoral autoimmunity.⁷

2. Infection: The immunosuppressive effects of TNF-α inhibitors are well known, and the propensity to develop microbial infections, such as tuberculosis, is markedly increased on the use of these agents. Infections brought on by TNF-α inhibitor usage are hypothesized to induce a widespread activation of polyclonal B lymphocytes, eventually leading to the formation of antibodies against these polyclonal B lymphocytes and subsequently SCLE.⁸

3. Helper T cell (TH2) response: The inhibition of T_H1 CD4⁺ lymphocytes by TNF-α inversely leads to an increased production of T_H2 CD4⁺ lymphocytes. This increase in the levels of circulating T_H2 CD4⁺ lymphocytes brought on by the action of anti–TNF-α agents is thought to promote the development of SCLE.^9,10

4. Apoptosis theory: Molecules of TNF-α inhibitors are capable of binding to TNF-α receptors on the cell surface. In doing so, cellular apoptosis is triggered, resulting in the release of nucleosomal autoantigens from the apoptotic cells. In susceptible individuals, autoantibodies then begin to form against the nucleosomal autoantigens, leading to an autoimmune reaction that is characterized by SCLE.^11,12

Major histone compatibility (MHC) antigen testing performed by Sontheimer et al¹² established the presence of the HLA class I, HLA-B8, and/or HLA-DR3 haplotypes in patients with SCLE.^13,14 Furthermore, there is a well-known association between the antinuclear profile of known SCLE patients and the presence of anti-SSA (Ro) antibodies.¹³ Therefore, we propose that in susceptible individuals, such as those with the HLA class I, HLA-B8, or HLA-DR3 haplotypes, the initiation of a TNF-α inhibitor causes cellular apoptosis with the subsequent release of nucleosomal and cytoplasmic components (namely that of the Ro autoantigens), inducing a state of autoimmunity. An ensuing immunogenic response is then initiated in predisposed individuals for which anti-SSA (Ro) autoantibodies are produced against these previously mentioned autoantigens.

Drug-induced SCLE is most common in females (71%), with a median age of 58 years. The most common site of cutaneous manifestations is the legs.¹⁵ Although our patient was in the eighth decade of life with predominant cutaneous involvement of the upper extremity, the erythematous plaques with a symmetric, annular, polycyclic appearance in photosensitive regions raised a heightened suspicion for lupus erythematosus. Histology classically involves an interface dermatitis with vacuolar or hydropic change and lymphocytic infiltrates,¹⁶ consistent with the analysis of tissue sections from our patient. Moreover, the speckled ANA profile with positive anti-dsDNA and anti-SSA (Ro) antibodies in the absence of a negative rheumatoid factor and anticyclic citrullinated peptide antibodies strongly favored the diagnosis of SCLE over alternative diagnoses.²

The supraclavicular rash in our patient raises clinical suspicion for the shawl sign of dermatomyositis, which also is associated with musculoskeletal pain and photosensitivity. In addition, skin biopsy revealed vacuolar alteration of the basement membrane zoneand dermal mucin in both lupus erythematosus and dermatomyositis; therefore, skin biopsy is of little use in distinguishing the 2 conditions, and antibody testing must be performed. Although anti-SSA (Ro) antibodies commonly are associated with SCLE, there are reports involving positivity for the extractable nuclear antigen in cases of dermatomyositis.¹⁷ Based on our patient’s current drug regimen, including that of a known offending agent for SCLE, a presumptive diagnosis of TAILS was made. Following withdrawal of certolizumab pegol injections and subsequent resolution of the skin lesions, our patient was given a definitive diagnosis of TAILS based on clinical and pathological assessments.

The clinical diagnosis of TAILS should be made according to the triad of at least 1 serologic and 1 nonserologic American College of Rheumatology criteria, such as anti-SSA (Ro) antibodies and a photosensitive rash, respectively, as well as a relationship between the onset of symptoms and TNF-α inhibitor therapy.¹⁸ Both the definitive diagnosis and the treatment of TAILS can be made via withdrawal of the TNF-α inhibitor, which was true in our case whereby chronologically the onset of use with a TNF-α inhibitor was associated with disease onset. Furthermore, withdrawal led to complete improvement of all signs and symptoms, collectively supporting a diagnosis of TAILS. Notably, switching to a different TNF-α inhibitor has been shown to be safe and effective.¹⁹

To the Editor:

Tumor necrosis factor α (TNF-α) inhibitor–induced lupuslike syndrome (TAILS) is a newly described entity that refers to the onset of subacute cutaneous lupus erythematosus (SCLE) during drug therapy with TNF-α antagonists. The condition is unique because it is thought to occur via a separate pathophysiologic mechanism than all other agents implicated in the development of drug-induced lupus erythematosus (DILE). Infliximab and etanercept are the 2 most common TNF-α antagonists associated with TAILS. Although rare, adalimumab, golimumab, and certolizumab pegol have been reported to induce this state of autoimmunity. We report an uncommon presentation of TAILS in a patient taking certolizumab pegol with a brief discussion of the pathogenesis underlying TAILS.

A 71-year-old woman presented to the dermatology clinic with a rash located on the arms, face, and trunk that she reported as having been present for months. She had a medical history of rheumatoid arthritis and currently was receiving certolizumab pegol injections. Physical examination revealed erythematous patches and plaques with overlying scaling and evidence of atrophic scarring on sun-exposed areas of the body. The lesions predominantly were in a symmetrical distribution across the extensor surfaces of both outer arms as well as the posterior superior thoracic region extending anteriorly along the bilateral supraclavicular area (Figures 1 and 2). A 4-mm punch biopsy was obtained and sent for histologic analysis, along with a sample of the patient’s serum for antinuclear antibody (ANA) testing.

Hematoxylin and eosin–stained tissue sections of the right superior thoracic lesions revealed epidermal atrophy, hyperkeratosis, and vacuolar alteration of the basal layer with apoptosis, consistent with a lichenoid tissue reaction. In addition, both superficial and deep perivascular and periadnexal lymphocytic infiltrates were observed as well as increased dermal mucin. Serologic testing was performed with a comprehensive ANA panel of the patient’s serum (Table). Of note, there was a speckled ANA pattern (1:1280), with elevated anti–double-stranded DNA (anti-dsDNA) and anti–Sjögren syndrome–related antigen A (anti-SSA)(also called anti-Ro antibodies) levels. The patient’s rheumatologist was consulted; certolizumab pegol was removed from the current drug regimen and switched to a daily regimen of hydroxychloroquine and prednisone. Seven weeks after discontinuation of certolizumab pegol, the patient was symptom free and without any cutaneous involvement. Based on the histologic analysis, presence of anti-SSA (Ro) autoantibodies, and the resolution of symptoms following withdrawal of anti–TNF-α therapy, a diagnosis of TAILS was made.

Subacute cutaneous lupus erythematosus, the most common subset of DILE, typically presents with annular polycyclic or papulosquamous skin eruptions on the legs; patients often test positive for anti-SSA/Ro and/or anti–Sjögren syndrome–related antigen B (also called anti-La) antibodies. Pharmaceutical agents linked to the development of SCLE are calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine, the chemotherapeutic agent gemcitabine, and TNF-α antagonists.^1,2 Tumor necrosis factor α antagonists are biologic agents that commonly are used in the management of systemic inflammatory diseases such as ulcerative colitis, Crohn disease, seronegative spondyloarthropathies, and rheumatoid arthritis. Among this family of therapeutics includes adalimumab (humanized monoclonal antibody), infliximab (chimeric monoclonal TNF-α antagonist), etanercept (soluble receptor fusion protein), certolizumab pegol (Fab fraction of a human IgG monoclonal antibody), and golimumab (humanized monoclonal antibody).

Tumor necrosis factor α inhibitor–induced lupuslike syndrome most commonly occurs in women in the fifth decade of life, and it is seen more often in those using infliximab or entanercept.³ Although reports do exist, TAILS rarely complicates treatment with adalimumab, golimumab, or certolizumab.^4,5 Due to the lack of reports, there are no diagnostic criteria nor an acceptable theory regarding the pathogenesis. In one study in France, the estimated incidence was thought to be 0.19% for infliximab and 0.18% for etanercept.⁶ Tumor necrosis factor α inhibitor–induced lupuslike syndrome is unique in that it is thought to occur by a different mechanism than that of other known offending agents in the development of DILE. Molecular mimicry, direct cytotoxicity, altered T-cell gene expression, and disruption of central immune tolerance have all been hypothesized to cause drug-induced systemic lupus erythematosus, SCLE, and chronic cutaneous lupus erythematosus. Tumor necrosis factor α inhibitors, are postulated to cause the induction of SCLE via an independent route separate from not only other drugs that cause SCLE but also all forms of DILE as a whole, making it a distinctive player within the realm of agents known to cause a lupuslike syndrome. The following hypotheses may explain this occurrence:

1. Increased humoral autoimmunity: Under normal circumstances, TNF-α activation leads to upregulation in the production of cytotoxic CD8⁺ T lymphocytes. The upregulation of CD8⁺ T lymphocytes concurrently leads to a simultaneous suppression of B lymphocytes. Inhibiting the effects of TNF-α on the other hand promotes cytotoxic T-lymphocyte suppression, leading to an increased synthesis of B cells and subsequently a state of increased humoral autoimmunity.⁷

2. Infection: The immunosuppressive effects of TNF-α inhibitors are well known, and the propensity to develop microbial infections, such as tuberculosis, is markedly increased on the use of these agents. Infections brought on by TNF-α inhibitor usage are hypothesized to induce a widespread activation of polyclonal B lymphocytes, eventually leading to the formation of antibodies against these polyclonal B lymphocytes and subsequently SCLE.⁸

3. Helper T cell (TH2) response: The inhibition of T_H1 CD4⁺ lymphocytes by TNF-α inversely leads to an increased production of T_H2 CD4⁺ lymphocytes. This increase in the levels of circulating T_H2 CD4⁺ lymphocytes brought on by the action of anti–TNF-α agents is thought to promote the development of SCLE.^9,10

4. Apoptosis theory: Molecules of TNF-α inhibitors are capable of binding to TNF-α receptors on the cell surface. In doing so, cellular apoptosis is triggered, resulting in the release of nucleosomal autoantigens from the apoptotic cells. In susceptible individuals, autoantibodies then begin to form against the nucleosomal autoantigens, leading to an autoimmune reaction that is characterized by SCLE.^11,12

Major histone compatibility (MHC) antigen testing performed by Sontheimer et al¹² established the presence of the HLA class I, HLA-B8, and/or HLA-DR3 haplotypes in patients with SCLE.^13,14 Furthermore, there is a well-known association between the antinuclear profile of known SCLE patients and the presence of anti-SSA (Ro) antibodies.¹³ Therefore, we propose that in susceptible individuals, such as those with the HLA class I, HLA-B8, or HLA-DR3 haplotypes, the initiation of a TNF-α inhibitor causes cellular apoptosis with the subsequent release of nucleosomal and cytoplasmic components (namely that of the Ro autoantigens), inducing a state of autoimmunity. An ensuing immunogenic response is then initiated in predisposed individuals for which anti-SSA (Ro) autoantibodies are produced against these previously mentioned autoantigens.

Drug-induced SCLE is most common in females (71%), with a median age of 58 years. The most common site of cutaneous manifestations is the legs.¹⁵ Although our patient was in the eighth decade of life with predominant cutaneous involvement of the upper extremity, the erythematous plaques with a symmetric, annular, polycyclic appearance in photosensitive regions raised a heightened suspicion for lupus erythematosus. Histology classically involves an interface dermatitis with vacuolar or hydropic change and lymphocytic infiltrates,¹⁶ consistent with the analysis of tissue sections from our patient. Moreover, the speckled ANA profile with positive anti-dsDNA and anti-SSA (Ro) antibodies in the absence of a negative rheumatoid factor and anticyclic citrullinated peptide antibodies strongly favored the diagnosis of SCLE over alternative diagnoses.²

The supraclavicular rash in our patient raises clinical suspicion for the shawl sign of dermatomyositis, which also is associated with musculoskeletal pain and photosensitivity. In addition, skin biopsy revealed vacuolar alteration of the basement membrane zoneand dermal mucin in both lupus erythematosus and dermatomyositis; therefore, skin biopsy is of little use in distinguishing the 2 conditions, and antibody testing must be performed. Although anti-SSA (Ro) antibodies commonly are associated with SCLE, there are reports involving positivity for the extractable nuclear antigen in cases of dermatomyositis.¹⁷ Based on our patient’s current drug regimen, including that of a known offending agent for SCLE, a presumptive diagnosis of TAILS was made. Following withdrawal of certolizumab pegol injections and subsequent resolution of the skin lesions, our patient was given a definitive diagnosis of TAILS based on clinical and pathological assessments.

The clinical diagnosis of TAILS should be made according to the triad of at least 1 serologic and 1 nonserologic American College of Rheumatology criteria, such as anti-SSA (Ro) antibodies and a photosensitive rash, respectively, as well as a relationship between the onset of symptoms and TNF-α inhibitor therapy.¹⁸ Both the definitive diagnosis and the treatment of TAILS can be made via withdrawal of the TNF-α inhibitor, which was true in our case whereby chronologically the onset of use with a TNF-α inhibitor was associated with disease onset. Furthermore, withdrawal led to complete improvement of all signs and symptoms, collectively supporting a diagnosis of TAILS. Notably, switching to a different TNF-α inhibitor has been shown to be safe and effective.¹⁹

To the Editor:

Tumor necrosis factor α (TNF-α) inhibitor–induced lupuslike syndrome (TAILS) is a newly described entity that refers to the onset of subacute cutaneous lupus erythematosus (SCLE) during drug therapy with TNF-α antagonists. The condition is unique because it is thought to occur via a separate pathophysiologic mechanism than all other agents implicated in the development of drug-induced lupus erythematosus (DILE). Infliximab and etanercept are the 2 most common TNF-α antagonists associated with TAILS. Although rare, adalimumab, golimumab, and certolizumab pegol have been reported to induce this state of autoimmunity. We report an uncommon presentation of TAILS in a patient taking certolizumab pegol with a brief discussion of the pathogenesis underlying TAILS.

A 71-year-old woman presented to the dermatology clinic with a rash located on the arms, face, and trunk that she reported as having been present for months. She had a medical history of rheumatoid arthritis and currently was receiving certolizumab pegol injections. Physical examination revealed erythematous patches and plaques with overlying scaling and evidence of atrophic scarring on sun-exposed areas of the body. The lesions predominantly were in a symmetrical distribution across the extensor surfaces of both outer arms as well as the posterior superior thoracic region extending anteriorly along the bilateral supraclavicular area (Figures 1 and 2). A 4-mm punch biopsy was obtained and sent for histologic analysis, along with a sample of the patient’s serum for antinuclear antibody (ANA) testing.

Hematoxylin and eosin–stained tissue sections of the right superior thoracic lesions revealed epidermal atrophy, hyperkeratosis, and vacuolar alteration of the basal layer with apoptosis, consistent with a lichenoid tissue reaction. In addition, both superficial and deep perivascular and periadnexal lymphocytic infiltrates were observed as well as increased dermal mucin. Serologic testing was performed with a comprehensive ANA panel of the patient’s serum (Table). Of note, there was a speckled ANA pattern (1:1280), with elevated anti–double-stranded DNA (anti-dsDNA) and anti–Sjögren syndrome–related antigen A (anti-SSA)(also called anti-Ro antibodies) levels. The patient’s rheumatologist was consulted; certolizumab pegol was removed from the current drug regimen and switched to a daily regimen of hydroxychloroquine and prednisone. Seven weeks after discontinuation of certolizumab pegol, the patient was symptom free and without any cutaneous involvement. Based on the histologic analysis, presence of anti-SSA (Ro) autoantibodies, and the resolution of symptoms following withdrawal of anti–TNF-α therapy, a diagnosis of TAILS was made.

Subacute cutaneous lupus erythematosus, the most common subset of DILE, typically presents with annular polycyclic or papulosquamous skin eruptions on the legs; patients often test positive for anti-SSA/Ro and/or anti–Sjögren syndrome–related antigen B (also called anti-La) antibodies. Pharmaceutical agents linked to the development of SCLE are calcium channel blockers, angiotensin-converting enzyme inhibitors, thiazide diuretics, terbinafine, the chemotherapeutic agent gemcitabine, and TNF-α antagonists.^1,2 Tumor necrosis factor α antagonists are biologic agents that commonly are used in the management of systemic inflammatory diseases such as ulcerative colitis, Crohn disease, seronegative spondyloarthropathies, and rheumatoid arthritis. Among this family of therapeutics includes adalimumab (humanized monoclonal antibody), infliximab (chimeric monoclonal TNF-α antagonist), etanercept (soluble receptor fusion protein), certolizumab pegol (Fab fraction of a human IgG monoclonal antibody), and golimumab (humanized monoclonal antibody).

Tumor necrosis factor α inhibitor–induced lupuslike syndrome most commonly occurs in women in the fifth decade of life, and it is seen more often in those using infliximab or entanercept.³ Although reports do exist, TAILS rarely complicates treatment with adalimumab, golimumab, or certolizumab.^4,5 Due to the lack of reports, there are no diagnostic criteria nor an acceptable theory regarding the pathogenesis. In one study in France, the estimated incidence was thought to be 0.19% for infliximab and 0.18% for etanercept.⁶ Tumor necrosis factor α inhibitor–induced lupuslike syndrome is unique in that it is thought to occur by a different mechanism than that of other known offending agents in the development of DILE. Molecular mimicry, direct cytotoxicity, altered T-cell gene expression, and disruption of central immune tolerance have all been hypothesized to cause drug-induced systemic lupus erythematosus, SCLE, and chronic cutaneous lupus erythematosus. Tumor necrosis factor α inhibitors, are postulated to cause the induction of SCLE via an independent route separate from not only other drugs that cause SCLE but also all forms of DILE as a whole, making it a distinctive player within the realm of agents known to cause a lupuslike syndrome. The following hypotheses may explain this occurrence:

1. Increased humoral autoimmunity: Under normal circumstances, TNF-α activation leads to upregulation in the production of cytotoxic CD8⁺ T lymphocytes. The upregulation of CD8⁺ T lymphocytes concurrently leads to a simultaneous suppression of B lymphocytes. Inhibiting the effects of TNF-α on the other hand promotes cytotoxic T-lymphocyte suppression, leading to an increased synthesis of B cells and subsequently a state of increased humoral autoimmunity.⁷

2. Infection: The immunosuppressive effects of TNF-α inhibitors are well known, and the propensity to develop microbial infections, such as tuberculosis, is markedly increased on the use of these agents. Infections brought on by TNF-α inhibitor usage are hypothesized to induce a widespread activation of polyclonal B lymphocytes, eventually leading to the formation of antibodies against these polyclonal B lymphocytes and subsequently SCLE.⁸

3. Helper T cell (TH2) response: The inhibition of T_H1 CD4⁺ lymphocytes by TNF-α inversely leads to an increased production of T_H2 CD4⁺ lymphocytes. This increase in the levels of circulating T_H2 CD4⁺ lymphocytes brought on by the action of anti–TNF-α agents is thought to promote the development of SCLE.^9,10

4. Apoptosis theory: Molecules of TNF-α inhibitors are capable of binding to TNF-α receptors on the cell surface. In doing so, cellular apoptosis is triggered, resulting in the release of nucleosomal autoantigens from the apoptotic cells. In susceptible individuals, autoantibodies then begin to form against the nucleosomal autoantigens, leading to an autoimmune reaction that is characterized by SCLE.^11,12

Major histone compatibility (MHC) antigen testing performed by Sontheimer et al¹² established the presence of the HLA class I, HLA-B8, and/or HLA-DR3 haplotypes in patients with SCLE.^13,14 Furthermore, there is a well-known association between the antinuclear profile of known SCLE patients and the presence of anti-SSA (Ro) antibodies.¹³ Therefore, we propose that in susceptible individuals, such as those with the HLA class I, HLA-B8, or HLA-DR3 haplotypes, the initiation of a TNF-α inhibitor causes cellular apoptosis with the subsequent release of nucleosomal and cytoplasmic components (namely that of the Ro autoantigens), inducing a state of autoimmunity. An ensuing immunogenic response is then initiated in predisposed individuals for which anti-SSA (Ro) autoantibodies are produced against these previously mentioned autoantigens.

Drug-induced SCLE is most common in females (71%), with a median age of 58 years. The most common site of cutaneous manifestations is the legs.¹⁵ Although our patient was in the eighth decade of life with predominant cutaneous involvement of the upper extremity, the erythematous plaques with a symmetric, annular, polycyclic appearance in photosensitive regions raised a heightened suspicion for lupus erythematosus. Histology classically involves an interface dermatitis with vacuolar or hydropic change and lymphocytic infiltrates,¹⁶ consistent with the analysis of tissue sections from our patient. Moreover, the speckled ANA profile with positive anti-dsDNA and anti-SSA (Ro) antibodies in the absence of a negative rheumatoid factor and anticyclic citrullinated peptide antibodies strongly favored the diagnosis of SCLE over alternative diagnoses.²

The supraclavicular rash in our patient raises clinical suspicion for the shawl sign of dermatomyositis, which also is associated with musculoskeletal pain and photosensitivity. In addition, skin biopsy revealed vacuolar alteration of the basement membrane zoneand dermal mucin in both lupus erythematosus and dermatomyositis; therefore, skin biopsy is of little use in distinguishing the 2 conditions, and antibody testing must be performed. Although anti-SSA (Ro) antibodies commonly are associated with SCLE, there are reports involving positivity for the extractable nuclear antigen in cases of dermatomyositis.¹⁷ Based on our patient’s current drug regimen, including that of a known offending agent for SCLE, a presumptive diagnosis of TAILS was made. Following withdrawal of certolizumab pegol injections and subsequent resolution of the skin lesions, our patient was given a definitive diagnosis of TAILS based on clinical and pathological assessments.

The clinical diagnosis of TAILS should be made according to the triad of at least 1 serologic and 1 nonserologic American College of Rheumatology criteria, such as anti-SSA (Ro) antibodies and a photosensitive rash, respectively, as well as a relationship between the onset of symptoms and TNF-α inhibitor therapy.¹⁸ Both the definitive diagnosis and the treatment of TAILS can be made via withdrawal of the TNF-α inhibitor, which was true in our case whereby chronologically the onset of use with a TNF-α inhibitor was associated with disease onset. Furthermore, withdrawal led to complete improvement of all signs and symptoms, collectively supporting a diagnosis of TAILS. Notably, switching to a different TNF-α inhibitor has been shown to be safe and effective.¹⁹

I’m not hiding anything.

Occasionally I deal with patients and families who seem to think I have some miracle cure for a condition that I’m not telling them about.

I promise, I don’t work that way. Besides the obvious ethical issues, why would I? What could I possibly gain from doing that?

The trouble is that people are blanketed by news headlines, some reputable and some not, about a research study suggesting a new direction in treatment, or that a new drug in development has promise. Often these stories are forwarded to them by well-meaning relatives and friends, or just show up in their social media feed.

While some of these findings may actually lead somewhere, the vast majority don’t. In my career I’ve seen statins touted as potential treatments for MS and Alzheimer’s disease, and vilified as causes of dementia and peripheral neuropathy, all disproved or (to date) still up in the air.

But nonmedical people don’t understand that. It made the news, so it must mean something. I have no problem trying to explain this to them, but it’s never easy.

It’s even harder to explain to the ones who’ve already purchased a costly over-the-counter placebo for such a condition that they wasted their money.

We live in a world of amazing technological achievements, but that doesn’t mean all diseases have been cured and problems fixed. Far from it.

New discoveries are made, but a lot of times it’s a very slow journey to find the solution. One discovery may not lead to THE answer, but hopefully will get you closer to it.

That generally doesn’t happen overnight. The mathematical problem of Goldbach’s Conjecture has been around since 1742 and still hasn’t been definitively answered.

Medicine isn’t math, either. The people and families dealing with these conditions want answers. I don’t blame them. So do I. Believe me, there would be nothing that would bring me more joy as a doctor than to be able to give someone with a serious diagnosis the comfort that comes with saying it’s also curable.

I never have, and never would, withhold such a thing from a patient. Ever. I just wish some of them would believe me when I say that.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’m not hiding anything.

Occasionally I deal with patients and families who seem to think I have some miracle cure for a condition that I’m not telling them about.

I promise, I don’t work that way. Besides the obvious ethical issues, why would I? What could I possibly gain from doing that?

The trouble is that people are blanketed by news headlines, some reputable and some not, about a research study suggesting a new direction in treatment, or that a new drug in development has promise. Often these stories are forwarded to them by well-meaning relatives and friends, or just show up in their social media feed.

While some of these findings may actually lead somewhere, the vast majority don’t. In my career I’ve seen statins touted as potential treatments for MS and Alzheimer’s disease, and vilified as causes of dementia and peripheral neuropathy, all disproved or (to date) still up in the air.

But nonmedical people don’t understand that. It made the news, so it must mean something. I have no problem trying to explain this to them, but it’s never easy.

It’s even harder to explain to the ones who’ve already purchased a costly over-the-counter placebo for such a condition that they wasted their money.

We live in a world of amazing technological achievements, but that doesn’t mean all diseases have been cured and problems fixed. Far from it.

New discoveries are made, but a lot of times it’s a very slow journey to find the solution. One discovery may not lead to THE answer, but hopefully will get you closer to it.

That generally doesn’t happen overnight. The mathematical problem of Goldbach’s Conjecture has been around since 1742 and still hasn’t been definitively answered.

Medicine isn’t math, either. The people and families dealing with these conditions want answers. I don’t blame them. So do I. Believe me, there would be nothing that would bring me more joy as a doctor than to be able to give someone with a serious diagnosis the comfort that comes with saying it’s also curable.

I never have, and never would, withhold such a thing from a patient. Ever. I just wish some of them would believe me when I say that.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

I’m not hiding anything.

Occasionally I deal with patients and families who seem to think I have some miracle cure for a condition that I’m not telling them about.

I promise, I don’t work that way. Besides the obvious ethical issues, why would I? What could I possibly gain from doing that?

The trouble is that people are blanketed by news headlines, some reputable and some not, about a research study suggesting a new direction in treatment, or that a new drug in development has promise. Often these stories are forwarded to them by well-meaning relatives and friends, or just show up in their social media feed.

While some of these findings may actually lead somewhere, the vast majority don’t. In my career I’ve seen statins touted as potential treatments for MS and Alzheimer’s disease, and vilified as causes of dementia and peripheral neuropathy, all disproved or (to date) still up in the air.

But nonmedical people don’t understand that. It made the news, so it must mean something. I have no problem trying to explain this to them, but it’s never easy.

It’s even harder to explain to the ones who’ve already purchased a costly over-the-counter placebo for such a condition that they wasted their money.

We live in a world of amazing technological achievements, but that doesn’t mean all diseases have been cured and problems fixed. Far from it.

New discoveries are made, but a lot of times it’s a very slow journey to find the solution. One discovery may not lead to THE answer, but hopefully will get you closer to it.

That generally doesn’t happen overnight. The mathematical problem of Goldbach’s Conjecture has been around since 1742 and still hasn’t been definitively answered.

Medicine isn’t math, either. The people and families dealing with these conditions want answers. I don’t blame them. So do I. Believe me, there would be nothing that would bring me more joy as a doctor than to be able to give someone with a serious diagnosis the comfort that comes with saying it’s also curable.

I never have, and never would, withhold such a thing from a patient. Ever. I just wish some of them would believe me when I say that.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Poly-L-lactic acid (PLLA) is a synthetic biologic polymer that is suspended in solution and can be injected for soft-tissue augmentation. The stimulatory molecule functions to increase collagen synthesis as a by-product of its degradation.¹ Poly-L-lactic acid measures 40 to 63 μm and is irregularly shaped, which inhibits product mobility and allows for precise tissue augmentation.² Clinical trials of injectable PLLA have proven its safety with no reported cases of infection, allergies, or serious adverse reactions.^3-5 The most common patient concerns generally are transient in nature, such as swelling, tenderness, pain, bruising, and bleeding. Persistent adverse events of PLLA primarily are papule and nodule formation.⁶ Clinical trials showed a variable incidence of papule/nodule formation between 6% and 44%.² Nodule formation remains a major challenge to achieving optimal results from injectable PLLA. We present a case in which a hyperdiluted formulation of PLLA produced a relatively acute (3-week) onset of multiple nodule formations dispersed on the anterior neck. The nodules were resistant to less-invasive treatment modalities and were further requested to be surgically excised.

Case Report

A 38-year-old woman presented for soft-tissue augmentation of the anterior neck using PLLA to achieve correction of skin laxity and static rhytides. She had a history of successful PLLA injections in the temples, knees, chest, and buttocks over a 5-year period. Forty-eight hours prior to injection, 1 PLLA vial was hydrated with 7 cc bacteriostatic water by using a continuous rotation suspension method over the 48 hours. On the day of injection, the PLLA was further hyperdiluted with 2 cc of 2% lidocaine and an additional 7 cc of bacteriostatic water, for a total of 16 cc diluent. The product was injected using a cannula in the anterior and lateral neck. According to the patient, 3 weeks after the procedure she noticed that some nodules began to form at the cannula insertion sites, while others formed distant from those sites; a total of 10 nodules had formed on the anterior neck (Figure 1).

The bacteriostatic water, lidocaine, and PLLA vial were all confirmed not to be expired. The manufacturer was contacted, and no other adverse reactions have been reported with this particular lot number of PLLA. The nodules initially were treated with injections of large boluses of bacteriostatic saline, which was ineffective. Treatment was then attempted using injections of a solution containing 1.0 mL of 5-fluorouracil (5-FU) 50 mg/mL, 0.4 mL of dexamethasone 4 mg/mL, 0.1 mL of triamcinolone 10 mg/mL, and 0.3 mL hyaluronidase. A series of 4 injections was performed in 2- to 4-week intervals. Two of the nodules resolved completely with this treatment. The remaining 8 nodules subjectively improved in size and softened to palpation but did not resolve completely. At 2 of the injection sites, treatment was complicated with steroid atrophy of the overlying skin. At the patient’s request, the remaining nodules were surgically excised (Figure 2). Histopathology revealed exogenous foreign material consistent with dermal filler (Figure 3).

Comment

Causes of Nodule Formation—Two factors that could contribute to nodule formation are inadequate dispersion of molecules and an insufficient volume of dilution. One study demonstrated that hydration for at least 24 hours is required for adequate PLLA dispersion. Furthermore, sonification for 5 minutes after a 2-hour hydration disperses molecules similarly to the 48-hour hydration.⁷ The PLLA in the current case was hydrated for 48 hours using a continuous rotation suspension method. Therefore, this likely did not play a role in our patient’s nodule formation. The volume of dilution has been shown to impact the incidence of nodule formation.⁸ At present, most injectors (60.4%) reconstitute each vial of PLLA with 9 to 10 mL of diluent.⁹ The PLLA in our patient was reconstituted with 16 mL; therefore, we believe that the anatomic location was the main contributor of nodule formation.

Fillers should be injected in the subcutaneous or deep dermal plane of tissue.¹⁰ The platysma is a superficial muscle that is intimately involved with the overlying skin of the anterior neck, and injections in this area could inadvertently be intramuscular. Intramuscular injections have a higher incidence of nodule formation.¹ Our patient had prior PLLA injections without adverse reactions in numerous other sites, supporting the claim that the anterior neck is prone to nodule formation from PLLA injections.

Management of Noninflammatory Nodules—Initial treatment of nodules with injections of saline was ineffective. This treatment can be used in an attempt to disperse the product. Treatment was then attempted with injections of a solution containing 5-FU, dexamethasone, triamcinolone, and hyaluronidase. Combination steroid therapy may be superior to monotherapy.¹¹ Dexamethasone may exhibit a cytoprotective effect on cells such as fibroblasts when used in combination with triamcinolone; monotherapy steroid use with triamcinolone alone induced fibroblast apoptosis at a much higher level.¹² Hyaluronidase works by breaking cross-links in hyaluronic acid, a glycosaminoglycan polysaccharide prevalent in the skin and connective tissue, which increases tissue permeability and aids in delivery of the other injected fluids.¹³ 5-Fluorouracil is an antimetabolite that may aid in treating nodules by discouraging additional fibroblast activity and fibrosis.¹⁴

The combination of 5-FU, dexamethasone, and triamcinolone has been shown to be successful in treating noninflammatory nodules in as few as 1 treatment.¹⁴ In our patient, hyaluronidase also was used in an attempt to aid delivery of the other injected fluids. If nodules do not resolve with 1 injection, it is recommended to wait at least 8 weeks before repeating the injection to prevent steroid atrophy of the overlying skin. In our patient, the intramuscular placement of the filler contributed to the nodules being resistant to this treatment. During excision, the nodules were tightly embedded in the underlying tissue, which may have prevented the solution from being delivered to the nodule (Figure 2).

Conclusion

Injectable PLLA is approved by the US Food and Drug Administration for soft-tissue augmentation of deep nasolabial folds and facial wrinkles. Off-label use of this product may cause higher incidence of nodule formation. Injectors should be cautious of injecting into the anterior neck. If nodules do form, treatment can be attempted with injections of saline. If that treatment fails, another treatment option is injection(s) of a mixture of 5-FU, dexamethasone, triamcinolone, and hyaluronidase separated by 8-week intervals. Finally, surgical excision is a viable treatment option, as presented in our case.

Poly-L-lactic acid (PLLA) is a synthetic biologic polymer that is suspended in solution and can be injected for soft-tissue augmentation. The stimulatory molecule functions to increase collagen synthesis as a by-product of its degradation.¹ Poly-L-lactic acid measures 40 to 63 μm and is irregularly shaped, which inhibits product mobility and allows for precise tissue augmentation.² Clinical trials of injectable PLLA have proven its safety with no reported cases of infection, allergies, or serious adverse reactions.^3-5 The most common patient concerns generally are transient in nature, such as swelling, tenderness, pain, bruising, and bleeding. Persistent adverse events of PLLA primarily are papule and nodule formation.⁶ Clinical trials showed a variable incidence of papule/nodule formation between 6% and 44%.² Nodule formation remains a major challenge to achieving optimal results from injectable PLLA. We present a case in which a hyperdiluted formulation of PLLA produced a relatively acute (3-week) onset of multiple nodule formations dispersed on the anterior neck. The nodules were resistant to less-invasive treatment modalities and were further requested to be surgically excised.

Case Report

A 38-year-old woman presented for soft-tissue augmentation of the anterior neck using PLLA to achieve correction of skin laxity and static rhytides. She had a history of successful PLLA injections in the temples, knees, chest, and buttocks over a 5-year period. Forty-eight hours prior to injection, 1 PLLA vial was hydrated with 7 cc bacteriostatic water by using a continuous rotation suspension method over the 48 hours. On the day of injection, the PLLA was further hyperdiluted with 2 cc of 2% lidocaine and an additional 7 cc of bacteriostatic water, for a total of 16 cc diluent. The product was injected using a cannula in the anterior and lateral neck. According to the patient, 3 weeks after the procedure she noticed that some nodules began to form at the cannula insertion sites, while others formed distant from those sites; a total of 10 nodules had formed on the anterior neck (Figure 1).

The bacteriostatic water, lidocaine, and PLLA vial were all confirmed not to be expired. The manufacturer was contacted, and no other adverse reactions have been reported with this particular lot number of PLLA. The nodules initially were treated with injections of large boluses of bacteriostatic saline, which was ineffective. Treatment was then attempted using injections of a solution containing 1.0 mL of 5-fluorouracil (5-FU) 50 mg/mL, 0.4 mL of dexamethasone 4 mg/mL, 0.1 mL of triamcinolone 10 mg/mL, and 0.3 mL hyaluronidase. A series of 4 injections was performed in 2- to 4-week intervals. Two of the nodules resolved completely with this treatment. The remaining 8 nodules subjectively improved in size and softened to palpation but did not resolve completely. At 2 of the injection sites, treatment was complicated with steroid atrophy of the overlying skin. At the patient’s request, the remaining nodules were surgically excised (Figure 2). Histopathology revealed exogenous foreign material consistent with dermal filler (Figure 3).

Comment

Causes of Nodule Formation—Two factors that could contribute to nodule formation are inadequate dispersion of molecules and an insufficient volume of dilution. One study demonstrated that hydration for at least 24 hours is required for adequate PLLA dispersion. Furthermore, sonification for 5 minutes after a 2-hour hydration disperses molecules similarly to the 48-hour hydration.⁷ The PLLA in the current case was hydrated for 48 hours using a continuous rotation suspension method. Therefore, this likely did not play a role in our patient’s nodule formation. The volume of dilution has been shown to impact the incidence of nodule formation.⁸ At present, most injectors (60.4%) reconstitute each vial of PLLA with 9 to 10 mL of diluent.⁹ The PLLA in our patient was reconstituted with 16 mL; therefore, we believe that the anatomic location was the main contributor of nodule formation.

Fillers should be injected in the subcutaneous or deep dermal plane of tissue.¹⁰ The platysma is a superficial muscle that is intimately involved with the overlying skin of the anterior neck, and injections in this area could inadvertently be intramuscular. Intramuscular injections have a higher incidence of nodule formation.¹ Our patient had prior PLLA injections without adverse reactions in numerous other sites, supporting the claim that the anterior neck is prone to nodule formation from PLLA injections.

Management of Noninflammatory Nodules—Initial treatment of nodules with injections of saline was ineffective. This treatment can be used in an attempt to disperse the product. Treatment was then attempted with injections of a solution containing 5-FU, dexamethasone, triamcinolone, and hyaluronidase. Combination steroid therapy may be superior to monotherapy.¹¹ Dexamethasone may exhibit a cytoprotective effect on cells such as fibroblasts when used in combination with triamcinolone; monotherapy steroid use with triamcinolone alone induced fibroblast apoptosis at a much higher level.¹² Hyaluronidase works by breaking cross-links in hyaluronic acid, a glycosaminoglycan polysaccharide prevalent in the skin and connective tissue, which increases tissue permeability and aids in delivery of the other injected fluids.¹³ 5-Fluorouracil is an antimetabolite that may aid in treating nodules by discouraging additional fibroblast activity and fibrosis.¹⁴

The combination of 5-FU, dexamethasone, and triamcinolone has been shown to be successful in treating noninflammatory nodules in as few as 1 treatment.¹⁴ In our patient, hyaluronidase also was used in an attempt to aid delivery of the other injected fluids. If nodules do not resolve with 1 injection, it is recommended to wait at least 8 weeks before repeating the injection to prevent steroid atrophy of the overlying skin. In our patient, the intramuscular placement of the filler contributed to the nodules being resistant to this treatment. During excision, the nodules were tightly embedded in the underlying tissue, which may have prevented the solution from being delivered to the nodule (Figure 2).

Conclusion

Injectable PLLA is approved by the US Food and Drug Administration for soft-tissue augmentation of deep nasolabial folds and facial wrinkles. Off-label use of this product may cause higher incidence of nodule formation. Injectors should be cautious of injecting into the anterior neck. If nodules do form, treatment can be attempted with injections of saline. If that treatment fails, another treatment option is injection(s) of a mixture of 5-FU, dexamethasone, triamcinolone, and hyaluronidase separated by 8-week intervals. Finally, surgical excision is a viable treatment option, as presented in our case.

Poly-L-lactic acid (PLLA) is a synthetic biologic polymer that is suspended in solution and can be injected for soft-tissue augmentation. The stimulatory molecule functions to increase collagen synthesis as a by-product of its degradation.¹ Poly-L-lactic acid measures 40 to 63 μm and is irregularly shaped, which inhibits product mobility and allows for precise tissue augmentation.² Clinical trials of injectable PLLA have proven its safety with no reported cases of infection, allergies, or serious adverse reactions.^3-5 The most common patient concerns generally are transient in nature, such as swelling, tenderness, pain, bruising, and bleeding. Persistent adverse events of PLLA primarily are papule and nodule formation.⁶ Clinical trials showed a variable incidence of papule/nodule formation between 6% and 44%.² Nodule formation remains a major challenge to achieving optimal results from injectable PLLA. We present a case in which a hyperdiluted formulation of PLLA produced a relatively acute (3-week) onset of multiple nodule formations dispersed on the anterior neck. The nodules were resistant to less-invasive treatment modalities and were further requested to be surgically excised.

Case Report

A 38-year-old woman presented for soft-tissue augmentation of the anterior neck using PLLA to achieve correction of skin laxity and static rhytides. She had a history of successful PLLA injections in the temples, knees, chest, and buttocks over a 5-year period. Forty-eight hours prior to injection, 1 PLLA vial was hydrated with 7 cc bacteriostatic water by using a continuous rotation suspension method over the 48 hours. On the day of injection, the PLLA was further hyperdiluted with 2 cc of 2% lidocaine and an additional 7 cc of bacteriostatic water, for a total of 16 cc diluent. The product was injected using a cannula in the anterior and lateral neck. According to the patient, 3 weeks after the procedure she noticed that some nodules began to form at the cannula insertion sites, while others formed distant from those sites; a total of 10 nodules had formed on the anterior neck (Figure 1).

The bacteriostatic water, lidocaine, and PLLA vial were all confirmed not to be expired. The manufacturer was contacted, and no other adverse reactions have been reported with this particular lot number of PLLA. The nodules initially were treated with injections of large boluses of bacteriostatic saline, which was ineffective. Treatment was then attempted using injections of a solution containing 1.0 mL of 5-fluorouracil (5-FU) 50 mg/mL, 0.4 mL of dexamethasone 4 mg/mL, 0.1 mL of triamcinolone 10 mg/mL, and 0.3 mL hyaluronidase. A series of 4 injections was performed in 2- to 4-week intervals. Two of the nodules resolved completely with this treatment. The remaining 8 nodules subjectively improved in size and softened to palpation but did not resolve completely. At 2 of the injection sites, treatment was complicated with steroid atrophy of the overlying skin. At the patient’s request, the remaining nodules were surgically excised (Figure 2). Histopathology revealed exogenous foreign material consistent with dermal filler (Figure 3).

Comment

Causes of Nodule Formation—Two factors that could contribute to nodule formation are inadequate dispersion of molecules and an insufficient volume of dilution. One study demonstrated that hydration for at least 24 hours is required for adequate PLLA dispersion. Furthermore, sonification for 5 minutes after a 2-hour hydration disperses molecules similarly to the 48-hour hydration.⁷ The PLLA in the current case was hydrated for 48 hours using a continuous rotation suspension method. Therefore, this likely did not play a role in our patient’s nodule formation. The volume of dilution has been shown to impact the incidence of nodule formation.⁸ At present, most injectors (60.4%) reconstitute each vial of PLLA with 9 to 10 mL of diluent.⁹ The PLLA in our patient was reconstituted with 16 mL; therefore, we believe that the anatomic location was the main contributor of nodule formation.

Fillers should be injected in the subcutaneous or deep dermal plane of tissue.¹⁰ The platysma is a superficial muscle that is intimately involved with the overlying skin of the anterior neck, and injections in this area could inadvertently be intramuscular. Intramuscular injections have a higher incidence of nodule formation.¹ Our patient had prior PLLA injections without adverse reactions in numerous other sites, supporting the claim that the anterior neck is prone to nodule formation from PLLA injections.

Management of Noninflammatory Nodules—Initial treatment of nodules with injections of saline was ineffective. This treatment can be used in an attempt to disperse the product. Treatment was then attempted with injections of a solution containing 5-FU, dexamethasone, triamcinolone, and hyaluronidase. Combination steroid therapy may be superior to monotherapy.¹¹ Dexamethasone may exhibit a cytoprotective effect on cells such as fibroblasts when used in combination with triamcinolone; monotherapy steroid use with triamcinolone alone induced fibroblast apoptosis at a much higher level.¹² Hyaluronidase works by breaking cross-links in hyaluronic acid, a glycosaminoglycan polysaccharide prevalent in the skin and connective tissue, which increases tissue permeability and aids in delivery of the other injected fluids.¹³ 5-Fluorouracil is an antimetabolite that may aid in treating nodules by discouraging additional fibroblast activity and fibrosis.¹⁴

The combination of 5-FU, dexamethasone, and triamcinolone has been shown to be successful in treating noninflammatory nodules in as few as 1 treatment.¹⁴ In our patient, hyaluronidase also was used in an attempt to aid delivery of the other injected fluids. If nodules do not resolve with 1 injection, it is recommended to wait at least 8 weeks before repeating the injection to prevent steroid atrophy of the overlying skin. In our patient, the intramuscular placement of the filler contributed to the nodules being resistant to this treatment. During excision, the nodules were tightly embedded in the underlying tissue, which may have prevented the solution from being delivered to the nodule (Figure 2).

Conclusion

Injectable PLLA is approved by the US Food and Drug Administration for soft-tissue augmentation of deep nasolabial folds and facial wrinkles. Off-label use of this product may cause higher incidence of nodule formation. Injectors should be cautious of injecting into the anterior neck. If nodules do form, treatment can be attempted with injections of saline. If that treatment fails, another treatment option is injection(s) of a mixture of 5-FU, dexamethasone, triamcinolone, and hyaluronidase separated by 8-week intervals. Finally, surgical excision is a viable treatment option, as presented in our case.

DENVER – A new study finds that females with male twins are more likely to suffer from migraines without aura than are those with female twins, even though testosterone is thought to be protective. The findings, presented at the annual meeting of the American Headache Society, also hint at a possible role played by the prenatal environment.

The study marks the first time a large-scale twin dataset has been used to assess sex differences in underlying genetic factors of migraine, lead author Morgan Fitzgerald, a senior research associate at the University of California at San Diego, said in a presentation at the conference. The findings were previously published in Frontiers in Pain Research.
 

More than genetics

The researchers analyzed data regarding 51,872 participants in the Swedish Twin Registry. According to Dr. Fitzgerald, the database is ideal because it is large and includes both genders.

Per the database, female twins were more likely to have migraines without aura than were male twins (17.6% vs. 5.5%, respectively), reflecting global numbers that suggest 18% of females and 6% of males have migraines each year.

To better understand heritability, the researchers compared identical twins with fraternal twins, and looked for gender-related correlations, Dr. Fitzgerald said.

One analysis suggests that migraine is equally heritable in men and women with a broad sense heritability of 0.45 (95% confidence interval [CI], 0.40-0.50). However, another analysis model provides evidence “that there are differences in the underlying genetic factors contributing to migraine across males and females,” she said.

Unexpectedly, the researchers also found that females with male twins were more likely to have migraines than were those with female twins (odds ratio, 1.51, 95% CI, 1.26-1.81) even though males are less affected by the headaches.

“These results suggest that the prominent sex difference in migraine prevalence is not entirely accounted for by genetic factors, while demonstrating that masculinization of the prenatal environment may increase migraine risk for females,” the authors wrote in the published study. “This effect points to a potential prenatal neuroendocrine factor in the development of migraine.”
 

Probing the migraine gender gap

Commenting on the research, University of Texas at Dallas neuroscientist and headache researcher Gregory Dussor, PhD, said the new study is “a very unique approach to address the question of nature versus nurture in migraine. It was well designed and used robust statistical modeling.”

As for the findings, “the conclusion that genetics do not explain sex differences in migraine risk by themselves is not surprising given how big of a role hormones in later life are likely to play in the disease and how many factors there are that can influence hormone levels,” he said.

“On the other hand, the surprising part of the findings was that the presence of a male co-twin increases risk of migraine in females. I would have expected to see the opposite, given the lower prevalence of migraine in males and the seemingly protective role that male hormones can play in migraine.”

Overall, the study adds to data implicating environment and hormones in the migraine gender gap, he said. “One thing I wonder from this study is what influence a female co-twin growing up with a male co-twin can have on migraine susceptibility. That female co-twin may end up with a very different set of childhood experiences than if she was with another female co-twin. Twins generally spend an enormous amount of time together and the same sex versus opposite sex experiences are likely to be quite different. This may have an influence on migraine later in life.”

As for the value of the study in terms of diagnosis, treatment, or prevention of migraine, Dr. Dussor said, “it’s possible it could help to identify risk factors for higher migraine susceptibility but it’s far too early to know how this could be used.”

The authors have no disclosures. Dr. Dussor disclosed an NIH-funded grant to study the role of the hormone prolactin in preclinical migraine models.

DENVER – A new study finds that females with male twins are more likely to suffer from migraines without aura than are those with female twins, even though testosterone is thought to be protective. The findings, presented at the annual meeting of the American Headache Society, also hint at a possible role played by the prenatal environment.

The study marks the first time a large-scale twin dataset has been used to assess sex differences in underlying genetic factors of migraine, lead author Morgan Fitzgerald, a senior research associate at the University of California at San Diego, said in a presentation at the conference. The findings were previously published in Frontiers in Pain Research.
 

More than genetics

The researchers analyzed data regarding 51,872 participants in the Swedish Twin Registry. According to Dr. Fitzgerald, the database is ideal because it is large and includes both genders.

Per the database, female twins were more likely to have migraines without aura than were male twins (17.6% vs. 5.5%, respectively), reflecting global numbers that suggest 18% of females and 6% of males have migraines each year.

To better understand heritability, the researchers compared identical twins with fraternal twins, and looked for gender-related correlations, Dr. Fitzgerald said.

One analysis suggests that migraine is equally heritable in men and women with a broad sense heritability of 0.45 (95% confidence interval [CI], 0.40-0.50). However, another analysis model provides evidence “that there are differences in the underlying genetic factors contributing to migraine across males and females,” she said.

Unexpectedly, the researchers also found that females with male twins were more likely to have migraines than were those with female twins (odds ratio, 1.51, 95% CI, 1.26-1.81) even though males are less affected by the headaches.

“These results suggest that the prominent sex difference in migraine prevalence is not entirely accounted for by genetic factors, while demonstrating that masculinization of the prenatal environment may increase migraine risk for females,” the authors wrote in the published study. “This effect points to a potential prenatal neuroendocrine factor in the development of migraine.”
 

Probing the migraine gender gap

Commenting on the research, University of Texas at Dallas neuroscientist and headache researcher Gregory Dussor, PhD, said the new study is “a very unique approach to address the question of nature versus nurture in migraine. It was well designed and used robust statistical modeling.”

As for the findings, “the conclusion that genetics do not explain sex differences in migraine risk by themselves is not surprising given how big of a role hormones in later life are likely to play in the disease and how many factors there are that can influence hormone levels,” he said.

“On the other hand, the surprising part of the findings was that the presence of a male co-twin increases risk of migraine in females. I would have expected to see the opposite, given the lower prevalence of migraine in males and the seemingly protective role that male hormones can play in migraine.”

Overall, the study adds to data implicating environment and hormones in the migraine gender gap, he said. “One thing I wonder from this study is what influence a female co-twin growing up with a male co-twin can have on migraine susceptibility. That female co-twin may end up with a very different set of childhood experiences than if she was with another female co-twin. Twins generally spend an enormous amount of time together and the same sex versus opposite sex experiences are likely to be quite different. This may have an influence on migraine later in life.”

As for the value of the study in terms of diagnosis, treatment, or prevention of migraine, Dr. Dussor said, “it’s possible it could help to identify risk factors for higher migraine susceptibility but it’s far too early to know how this could be used.”

The authors have no disclosures. Dr. Dussor disclosed an NIH-funded grant to study the role of the hormone prolactin in preclinical migraine models.

DENVER – A new study finds that females with male twins are more likely to suffer from migraines without aura than are those with female twins, even though testosterone is thought to be protective. The findings, presented at the annual meeting of the American Headache Society, also hint at a possible role played by the prenatal environment.

The study marks the first time a large-scale twin dataset has been used to assess sex differences in underlying genetic factors of migraine, lead author Morgan Fitzgerald, a senior research associate at the University of California at San Diego, said in a presentation at the conference. The findings were previously published in Frontiers in Pain Research.
 

More than genetics

The researchers analyzed data regarding 51,872 participants in the Swedish Twin Registry. According to Dr. Fitzgerald, the database is ideal because it is large and includes both genders.

Per the database, female twins were more likely to have migraines without aura than were male twins (17.6% vs. 5.5%, respectively), reflecting global numbers that suggest 18% of females and 6% of males have migraines each year.

To better understand heritability, the researchers compared identical twins with fraternal twins, and looked for gender-related correlations, Dr. Fitzgerald said.

One analysis suggests that migraine is equally heritable in men and women with a broad sense heritability of 0.45 (95% confidence interval [CI], 0.40-0.50). However, another analysis model provides evidence “that there are differences in the underlying genetic factors contributing to migraine across males and females,” she said.

Unexpectedly, the researchers also found that females with male twins were more likely to have migraines than were those with female twins (odds ratio, 1.51, 95% CI, 1.26-1.81) even though males are less affected by the headaches.

“These results suggest that the prominent sex difference in migraine prevalence is not entirely accounted for by genetic factors, while demonstrating that masculinization of the prenatal environment may increase migraine risk for females,” the authors wrote in the published study. “This effect points to a potential prenatal neuroendocrine factor in the development of migraine.”
 

Probing the migraine gender gap

Commenting on the research, University of Texas at Dallas neuroscientist and headache researcher Gregory Dussor, PhD, said the new study is “a very unique approach to address the question of nature versus nurture in migraine. It was well designed and used robust statistical modeling.”

As for the findings, “the conclusion that genetics do not explain sex differences in migraine risk by themselves is not surprising given how big of a role hormones in later life are likely to play in the disease and how many factors there are that can influence hormone levels,” he said.

“On the other hand, the surprising part of the findings was that the presence of a male co-twin increases risk of migraine in females. I would have expected to see the opposite, given the lower prevalence of migraine in males and the seemingly protective role that male hormones can play in migraine.”

Overall, the study adds to data implicating environment and hormones in the migraine gender gap, he said. “One thing I wonder from this study is what influence a female co-twin growing up with a male co-twin can have on migraine susceptibility. That female co-twin may end up with a very different set of childhood experiences than if she was with another female co-twin. Twins generally spend an enormous amount of time together and the same sex versus opposite sex experiences are likely to be quite different. This may have an influence on migraine later in life.”

As for the value of the study in terms of diagnosis, treatment, or prevention of migraine, Dr. Dussor said, “it’s possible it could help to identify risk factors for higher migraine susceptibility but it’s far too early to know how this could be used.”

The authors have no disclosures. Dr. Dussor disclosed an NIH-funded grant to study the role of the hormone prolactin in preclinical migraine models.

CHICAGO – Mortality rates from melanoma have fallen in recent years, likely due to the introduction of checkpoint inhibitors, according to a new analysis of the National Cancer Institute SEER database between 1975 and 2019.

“This is very encouraging data and represents the real-world effectiveness of these therapies. The cost of these therapies can be prohibitive for universal treatment access, so the ways to address the accessibility of these treatments and the health care costs need to be supported,” said lead author Navkirat Kaur Kahlon MD, a hematology/oncology fellow at the University of Toledo (Ohio). The study was presented at the annual meeting of the American Society of Clinical Oncology.

According to the American Cancer Society, the 5-year mortality for regional melanoma metastasis is 68%, and 30% for distant metastasis. However, these numbers may underestimate current survival. “People now being diagnosed with melanoma may have a better outlook than these numbers show. Treatments have improved over time, and these numbers are based on people who were diagnosed and treated at least 5 years earlier,” the American Cancer Society wrote.

Other studies have found similar trends. According to Cancer Research UK, 5-year melanoma skin cancer survival approximately doubled, from 46% to 90%, between 1971 and 2010. And, 1-year survival increased from 74% to 96%, but these improvements predated immune checkpoint inhibitors. An analysis of the Canadian Cancer Registry and Canadian Vital Statistics found an increasing incidence of melanoma, but a drop in mortality since 2013. A study of melanoma outcomes in Hungary also found increased incidence, while mortality declined by 16.55% between 2011 and 2019 (P =.013).

“These new drugs, which include immunotherapies and targeted therapies, are effective treatments in the clinical trial data, so the magnitude of drop seen in population mortality was not surprising but very exciting,” Dr. Kahlon said.

The findings are encouraging, but prevention remains the most important strategy. “The utility of sun-protective strategies and policies should be encouraged,” she added.

Cytotoxic chemotherapy has poor efficacy against metastatic melanoma, but novel therapies such as checkpoint inhibitors increased expected survival from months to years. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world population is deriving the same benefit,” Dr. Kahlon said.

The researchers found that the annual percentage change (APC) melanoma mortality rate (MMR) was +1.65% between 1975 and 1988 (P < .01). The APC was 0.01% between 1988 and 2013, which was not statistically significant (P = .85). Between 2013 and 2017, APC was –6.24% (P < .01), and it was –1.56% between 2017 and 2019 (P = .53).

The increase in melanoma mortality between 1975 and 1988 may be due to changes in the way that SEER data was collected. “It is possible that this increase was at least in part due to better capturing of the data. There may also be a contribution of increased mortality due to increased incidence of diagnoses related to increased UV exposure. From the 1920s, increased sun exposure and bronzed skin became fashionable. In the 1940s-1960s, tanning oils and lotions became more popular, and there may have been an increase in UV exposure during that time, which later led to an increase in diagnosis and, without effective therapies, mortality. Further, the use of indoor tanning beds from the 1970s onward may have contributed to increased UV exposure, incidence, and mortality,” she said.

On the other hand, the researchers noted a slowing of mortality reduction between 2017 and 2019. This was not a surprise, Dr. Kahlon said, since by that time most novel therapies were being introduced in the adjuvant setting. “The mortality benefit, if any, from adjuvant treatments is seen over a longer period and may not yet be captured in SEER data. Even the clinical trial data for most of these treatments have not shown an overall survival advantage and require more time for the data to mature. It will be interesting to see how these trends change in the near future,” Dr. Kahlon said.

The study was limited by its retrospective nature. Dr. Kahlon has no relevant financial disclosures.

CHICAGO – Mortality rates from melanoma have fallen in recent years, likely due to the introduction of checkpoint inhibitors, according to a new analysis of the National Cancer Institute SEER database between 1975 and 2019.

“This is very encouraging data and represents the real-world effectiveness of these therapies. The cost of these therapies can be prohibitive for universal treatment access, so the ways to address the accessibility of these treatments and the health care costs need to be supported,” said lead author Navkirat Kaur Kahlon MD, a hematology/oncology fellow at the University of Toledo (Ohio). The study was presented at the annual meeting of the American Society of Clinical Oncology.

According to the American Cancer Society, the 5-year mortality for regional melanoma metastasis is 68%, and 30% for distant metastasis. However, these numbers may underestimate current survival. “People now being diagnosed with melanoma may have a better outlook than these numbers show. Treatments have improved over time, and these numbers are based on people who were diagnosed and treated at least 5 years earlier,” the American Cancer Society wrote.

Other studies have found similar trends. According to Cancer Research UK, 5-year melanoma skin cancer survival approximately doubled, from 46% to 90%, between 1971 and 2010. And, 1-year survival increased from 74% to 96%, but these improvements predated immune checkpoint inhibitors. An analysis of the Canadian Cancer Registry and Canadian Vital Statistics found an increasing incidence of melanoma, but a drop in mortality since 2013. A study of melanoma outcomes in Hungary also found increased incidence, while mortality declined by 16.55% between 2011 and 2019 (P =.013).

“These new drugs, which include immunotherapies and targeted therapies, are effective treatments in the clinical trial data, so the magnitude of drop seen in population mortality was not surprising but very exciting,” Dr. Kahlon said.

The findings are encouraging, but prevention remains the most important strategy. “The utility of sun-protective strategies and policies should be encouraged,” she added.

Cytotoxic chemotherapy has poor efficacy against metastatic melanoma, but novel therapies such as checkpoint inhibitors increased expected survival from months to years. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world population is deriving the same benefit,” Dr. Kahlon said.

The researchers found that the annual percentage change (APC) melanoma mortality rate (MMR) was +1.65% between 1975 and 1988 (P < .01). The APC was 0.01% between 1988 and 2013, which was not statistically significant (P = .85). Between 2013 and 2017, APC was –6.24% (P < .01), and it was –1.56% between 2017 and 2019 (P = .53).

The increase in melanoma mortality between 1975 and 1988 may be due to changes in the way that SEER data was collected. “It is possible that this increase was at least in part due to better capturing of the data. There may also be a contribution of increased mortality due to increased incidence of diagnoses related to increased UV exposure. From the 1920s, increased sun exposure and bronzed skin became fashionable. In the 1940s-1960s, tanning oils and lotions became more popular, and there may have been an increase in UV exposure during that time, which later led to an increase in diagnosis and, without effective therapies, mortality. Further, the use of indoor tanning beds from the 1970s onward may have contributed to increased UV exposure, incidence, and mortality,” she said.

On the other hand, the researchers noted a slowing of mortality reduction between 2017 and 2019. This was not a surprise, Dr. Kahlon said, since by that time most novel therapies were being introduced in the adjuvant setting. “The mortality benefit, if any, from adjuvant treatments is seen over a longer period and may not yet be captured in SEER data. Even the clinical trial data for most of these treatments have not shown an overall survival advantage and require more time for the data to mature. It will be interesting to see how these trends change in the near future,” Dr. Kahlon said.

The study was limited by its retrospective nature. Dr. Kahlon has no relevant financial disclosures.

CHICAGO – Mortality rates from melanoma have fallen in recent years, likely due to the introduction of checkpoint inhibitors, according to a new analysis of the National Cancer Institute SEER database between 1975 and 2019.

“This is very encouraging data and represents the real-world effectiveness of these therapies. The cost of these therapies can be prohibitive for universal treatment access, so the ways to address the accessibility of these treatments and the health care costs need to be supported,” said lead author Navkirat Kaur Kahlon MD, a hematology/oncology fellow at the University of Toledo (Ohio). The study was presented at the annual meeting of the American Society of Clinical Oncology.

According to the American Cancer Society, the 5-year mortality for regional melanoma metastasis is 68%, and 30% for distant metastasis. However, these numbers may underestimate current survival. “People now being diagnosed with melanoma may have a better outlook than these numbers show. Treatments have improved over time, and these numbers are based on people who were diagnosed and treated at least 5 years earlier,” the American Cancer Society wrote.

Other studies have found similar trends. According to Cancer Research UK, 5-year melanoma skin cancer survival approximately doubled, from 46% to 90%, between 1971 and 2010. And, 1-year survival increased from 74% to 96%, but these improvements predated immune checkpoint inhibitors. An analysis of the Canadian Cancer Registry and Canadian Vital Statistics found an increasing incidence of melanoma, but a drop in mortality since 2013. A study of melanoma outcomes in Hungary also found increased incidence, while mortality declined by 16.55% between 2011 and 2019 (P =.013).

“These new drugs, which include immunotherapies and targeted therapies, are effective treatments in the clinical trial data, so the magnitude of drop seen in population mortality was not surprising but very exciting,” Dr. Kahlon said.

The findings are encouraging, but prevention remains the most important strategy. “The utility of sun-protective strategies and policies should be encouraged,” she added.

Cytotoxic chemotherapy has poor efficacy against metastatic melanoma, but novel therapies such as checkpoint inhibitors increased expected survival from months to years. “Given the magnitude of benefit compared to traditional chemotherapy in clinical trials, we decided to see if the real-world population is deriving the same benefit,” Dr. Kahlon said.

The researchers found that the annual percentage change (APC) melanoma mortality rate (MMR) was +1.65% between 1975 and 1988 (P < .01). The APC was 0.01% between 1988 and 2013, which was not statistically significant (P = .85). Between 2013 and 2017, APC was –6.24% (P < .01), and it was –1.56% between 2017 and 2019 (P = .53).

The increase in melanoma mortality between 1975 and 1988 may be due to changes in the way that SEER data was collected. “It is possible that this increase was at least in part due to better capturing of the data. There may also be a contribution of increased mortality due to increased incidence of diagnoses related to increased UV exposure. From the 1920s, increased sun exposure and bronzed skin became fashionable. In the 1940s-1960s, tanning oils and lotions became more popular, and there may have been an increase in UV exposure during that time, which later led to an increase in diagnosis and, without effective therapies, mortality. Further, the use of indoor tanning beds from the 1970s onward may have contributed to increased UV exposure, incidence, and mortality,” she said.

On the other hand, the researchers noted a slowing of mortality reduction between 2017 and 2019. This was not a surprise, Dr. Kahlon said, since by that time most novel therapies were being introduced in the adjuvant setting. “The mortality benefit, if any, from adjuvant treatments is seen over a longer period and may not yet be captured in SEER data. Even the clinical trial data for most of these treatments have not shown an overall survival advantage and require more time for the data to mature. It will be interesting to see how these trends change in the near future,” Dr. Kahlon said.

The study was limited by its retrospective nature. Dr. Kahlon has no relevant financial disclosures.