BOSTON – Requests for a medical waiver to avoid a second COVID-19 vaccine dose or a booster after cutaneous reactions to the first dose are not justified on the basis of risk, according to an analysis of several large sets of data presented at the annual meeting of the American Academy of Dermatology.

According to the data, “there are no serious adverse consequences from these cutaneous reactions,” said Esther Freeman, MD, PhD, director of Global Health Dermatology, Massachusetts General Hospital, Boston.

This is important because the risk of vaccine hesitancy goes up dramatically in patients who experience reactions to the first vaccine dose, according to follow-up of more than 50,000 employees vaccinated in the Mass General Brigham Healthcare System (MGBHS). According to Dr. Freeman, there was almost a fourfold increase in the rate of second-dose refusals for those with cutaneous reactions and a more than fourfold increase in those who developed angioedema.

Before the data were available, skin reactions were a source of concern among dermatologists and others involved in monitoring vaccine-related adverse events. Injection site reactions (ISRs) are associated with essentially every injectable vaccine, so these were expected, but a small proportion of patients developed large red plaques in the injection arm 7-8 days after the inoculation.

“These delayed reactions caused a lot of initial panic,” said Dr. Freeman, who counted herself among those alarmed about what the reactions might signify. “Was this cellulitis? Would the next dose cause anaphylaxis? We were concerned.”

This concern dissipated with the availability of more data. In a global registry that has so far captured more than 1,000 cutaneous reactions from 52 participating countries, it appears that about 2% of patients have a cutaneous reaction other than an ISR after the first dose. All resolve with minimal skin care or no treatment.

After the second dose, the proportion is lower. If there is a reaction, it typically occurs earlier and resolves more quickly.

“What we have learned is that fewer than half of patients who had a reaction to the first dose have a reaction to the second, and those who did have a reaction had a milder course,” said Dr. Freeman.

These data are “incredibly reassuring” on many levels, she explained. In addition, it allows clinicians to confidently explain to patients that there are no serious sequelae from the rashes, whether immediate or delayed, from the available COVID-19 vaccines.

“Every skin reaction I have seen is something we can treat through,” she added, noting that most reactions resolve with little or no supportive care. Following skin reactions, particularly the delayed lesions, it is not uncommon for patients to refuse a second shot. Some request a medical waiver to avoid further vaccine exposure. According to Dr. Freeman, this is unwarranted.

“I have granted exactly zero waivers,” she said. She explains to patients that these reactions have not been predictive of serious events, such as anaphylaxis. Although the trigger of the hypersensitivity reaction remains unknown, there is no evidence of serious consequences.

Delayed skin reactions are more commonly associated with the Moderna than the Pfizer vaccine. One notable difference between these vaccines is the greater content of mRNA in the Moderna formulation, but Freeman said that this is only one potential hypothesis for higher frequency of reactions to this version of the vaccine.

Patients with a history of allergic disease are more likely to develop a reaction but not significantly more likely to have a reaction that is more difficult to manage, according to Kimberly G. Blumenthal, MD, quality and safety officer for allergy, and codirector of the clinical epidemiology program in the division of rheumatology, allergy, and immunology at Mass General.

Massachusetts General Hospital

Anaphylaxis has been associated with COVD-19 vaccines just as it has with essentially every injectable vaccine, Dr. Blumenthal said during the same session. But the risk is very low, and it stays low even among those with a history of severe hypersensitivity reactions in the past.

Among the data collected from more than 52,000 vaccinated MGBHS employees, 0.9% had a history of severe allergic reaction to a prior vaccine. Of these, 11.6% had an allergic reaction to the COVID-19 vaccine. This was more than twice the 4.6% rate of allergic reactions among employees without a history of allergic reactions, but serious consequences were rare in both groups.

Of those with a reaction to the first dose, all but 2.4% took a subsequent dose. Again, serious reactions were exceedingly rare. These serious reactions did include anaphylaxis and hospitalization in 3% of patients, but there were no fatalities and all resolved.

The absence of serious sequelae from a reaction to a COVID-19 vaccine must be considered within the context of the benefit, which includes protection from death and hospitalization from the virus, according to Dr. Blumenthal. Citing the evidence that first-shot reactions are a source of vaccine hesitancy, she agreed that it is important to educate patients about relative risks.

“Even in our own cohort of MGBHS employees, we have people, including those who had been provaccine in the past, become hesitant,” commented Dr. Blumenthal, who said there are data from the Kaiser Permanente System showing similar vaccine reluctance following a first-shot reaction.

After more than 500 million doses of the Moderna and Pfizer vaccines had been administered worldwide, there was not a single reported death from anaphylaxis. Although Dr. Blumenthal said that an unconfirmed death of this type had been recently reported, she emphasized that this single death, if valid, is dwarfed by the lives saved with vaccination.

Asked about her strategy for counseling patients with vaccine hesitancy, Dr. Freeman said the body of safety data is large and compelling. There is overwhelming evidence of a favorable benefit-to-risk ratio overall and among those with a first-shot reaction.

“I can reassure them on the basis of the data,” Dr. Freeman said in an interview. “Less than half will have a reaction to the second shot and even if they do have a reaction, it is likely to be less severe.”

Although the main message is that vaccination is potentially lifesaving and far outweighs any risks, Freeman specifically gives this message to those hesitant to take a second shot after a first-shot reaction: “I can get you through it.”

Dr. Freeman encouraged health care professionals to report cases of COVID-19 vaccine–related dermatologic side effects to the American Academy of Dermatology / International League of Dermatologic Societies COVID-19 dermatology registry. Dermatologic manifestations of COVID-19 can also be reported to the registry.

Dr. Freeman disclosed receiving grants/research funding from the International League of Dermatologic Societies and from the National Institutes of Health. Dr. Blumenthal disclosed no relevant financial relationships.

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

BOSTON – Requests for a medical waiver to avoid a second COVID-19 vaccine dose or a booster after cutaneous reactions to the first dose are not justified on the basis of risk, according to an analysis of several large sets of data presented at the annual meeting of the American Academy of Dermatology.

According to the data, “there are no serious adverse consequences from these cutaneous reactions,” said Esther Freeman, MD, PhD, director of Global Health Dermatology, Massachusetts General Hospital, Boston.

This is important because the risk of vaccine hesitancy goes up dramatically in patients who experience reactions to the first vaccine dose, according to follow-up of more than 50,000 employees vaccinated in the Mass General Brigham Healthcare System (MGBHS). According to Dr. Freeman, there was almost a fourfold increase in the rate of second-dose refusals for those with cutaneous reactions and a more than fourfold increase in those who developed angioedema.

Before the data were available, skin reactions were a source of concern among dermatologists and others involved in monitoring vaccine-related adverse events. Injection site reactions (ISRs) are associated with essentially every injectable vaccine, so these were expected, but a small proportion of patients developed large red plaques in the injection arm 7-8 days after the inoculation.

“These delayed reactions caused a lot of initial panic,” said Dr. Freeman, who counted herself among those alarmed about what the reactions might signify. “Was this cellulitis? Would the next dose cause anaphylaxis? We were concerned.”

This concern dissipated with the availability of more data. In a global registry that has so far captured more than 1,000 cutaneous reactions from 52 participating countries, it appears that about 2% of patients have a cutaneous reaction other than an ISR after the first dose. All resolve with minimal skin care or no treatment.

After the second dose, the proportion is lower. If there is a reaction, it typically occurs earlier and resolves more quickly.

“What we have learned is that fewer than half of patients who had a reaction to the first dose have a reaction to the second, and those who did have a reaction had a milder course,” said Dr. Freeman.

These data are “incredibly reassuring” on many levels, she explained. In addition, it allows clinicians to confidently explain to patients that there are no serious sequelae from the rashes, whether immediate or delayed, from the available COVID-19 vaccines.

“Every skin reaction I have seen is something we can treat through,” she added, noting that most reactions resolve with little or no supportive care. Following skin reactions, particularly the delayed lesions, it is not uncommon for patients to refuse a second shot. Some request a medical waiver to avoid further vaccine exposure. According to Dr. Freeman, this is unwarranted.

“I have granted exactly zero waivers,” she said. She explains to patients that these reactions have not been predictive of serious events, such as anaphylaxis. Although the trigger of the hypersensitivity reaction remains unknown, there is no evidence of serious consequences.

Delayed skin reactions are more commonly associated with the Moderna than the Pfizer vaccine. One notable difference between these vaccines is the greater content of mRNA in the Moderna formulation, but Freeman said that this is only one potential hypothesis for higher frequency of reactions to this version of the vaccine.

Patients with a history of allergic disease are more likely to develop a reaction but not significantly more likely to have a reaction that is more difficult to manage, according to Kimberly G. Blumenthal, MD, quality and safety officer for allergy, and codirector of the clinical epidemiology program in the division of rheumatology, allergy, and immunology at Mass General.

Massachusetts General Hospital

Anaphylaxis has been associated with COVD-19 vaccines just as it has with essentially every injectable vaccine, Dr. Blumenthal said during the same session. But the risk is very low, and it stays low even among those with a history of severe hypersensitivity reactions in the past.

Among the data collected from more than 52,000 vaccinated MGBHS employees, 0.9% had a history of severe allergic reaction to a prior vaccine. Of these, 11.6% had an allergic reaction to the COVID-19 vaccine. This was more than twice the 4.6% rate of allergic reactions among employees without a history of allergic reactions, but serious consequences were rare in both groups.

Of those with a reaction to the first dose, all but 2.4% took a subsequent dose. Again, serious reactions were exceedingly rare. These serious reactions did include anaphylaxis and hospitalization in 3% of patients, but there were no fatalities and all resolved.

The absence of serious sequelae from a reaction to a COVID-19 vaccine must be considered within the context of the benefit, which includes protection from death and hospitalization from the virus, according to Dr. Blumenthal. Citing the evidence that first-shot reactions are a source of vaccine hesitancy, she agreed that it is important to educate patients about relative risks.

“Even in our own cohort of MGBHS employees, we have people, including those who had been provaccine in the past, become hesitant,” commented Dr. Blumenthal, who said there are data from the Kaiser Permanente System showing similar vaccine reluctance following a first-shot reaction.

After more than 500 million doses of the Moderna and Pfizer vaccines had been administered worldwide, there was not a single reported death from anaphylaxis. Although Dr. Blumenthal said that an unconfirmed death of this type had been recently reported, she emphasized that this single death, if valid, is dwarfed by the lives saved with vaccination.

Asked about her strategy for counseling patients with vaccine hesitancy, Dr. Freeman said the body of safety data is large and compelling. There is overwhelming evidence of a favorable benefit-to-risk ratio overall and among those with a first-shot reaction.

“I can reassure them on the basis of the data,” Dr. Freeman said in an interview. “Less than half will have a reaction to the second shot and even if they do have a reaction, it is likely to be less severe.”

Although the main message is that vaccination is potentially lifesaving and far outweighs any risks, Freeman specifically gives this message to those hesitant to take a second shot after a first-shot reaction: “I can get you through it.”

Dr. Freeman encouraged health care professionals to report cases of COVID-19 vaccine–related dermatologic side effects to the American Academy of Dermatology / International League of Dermatologic Societies COVID-19 dermatology registry. Dermatologic manifestations of COVID-19 can also be reported to the registry.

Dr. Freeman disclosed receiving grants/research funding from the International League of Dermatologic Societies and from the National Institutes of Health. Dr. Blumenthal disclosed no relevant financial relationships.

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

BOSTON – Requests for a medical waiver to avoid a second COVID-19 vaccine dose or a booster after cutaneous reactions to the first dose are not justified on the basis of risk, according to an analysis of several large sets of data presented at the annual meeting of the American Academy of Dermatology.

According to the data, “there are no serious adverse consequences from these cutaneous reactions,” said Esther Freeman, MD, PhD, director of Global Health Dermatology, Massachusetts General Hospital, Boston.

This is important because the risk of vaccine hesitancy goes up dramatically in patients who experience reactions to the first vaccine dose, according to follow-up of more than 50,000 employees vaccinated in the Mass General Brigham Healthcare System (MGBHS). According to Dr. Freeman, there was almost a fourfold increase in the rate of second-dose refusals for those with cutaneous reactions and a more than fourfold increase in those who developed angioedema.

Before the data were available, skin reactions were a source of concern among dermatologists and others involved in monitoring vaccine-related adverse events. Injection site reactions (ISRs) are associated with essentially every injectable vaccine, so these were expected, but a small proportion of patients developed large red plaques in the injection arm 7-8 days after the inoculation.

“These delayed reactions caused a lot of initial panic,” said Dr. Freeman, who counted herself among those alarmed about what the reactions might signify. “Was this cellulitis? Would the next dose cause anaphylaxis? We were concerned.”

This concern dissipated with the availability of more data. In a global registry that has so far captured more than 1,000 cutaneous reactions from 52 participating countries, it appears that about 2% of patients have a cutaneous reaction other than an ISR after the first dose. All resolve with minimal skin care or no treatment.

After the second dose, the proportion is lower. If there is a reaction, it typically occurs earlier and resolves more quickly.

“What we have learned is that fewer than half of patients who had a reaction to the first dose have a reaction to the second, and those who did have a reaction had a milder course,” said Dr. Freeman.

These data are “incredibly reassuring” on many levels, she explained. In addition, it allows clinicians to confidently explain to patients that there are no serious sequelae from the rashes, whether immediate or delayed, from the available COVID-19 vaccines.

“Every skin reaction I have seen is something we can treat through,” she added, noting that most reactions resolve with little or no supportive care. Following skin reactions, particularly the delayed lesions, it is not uncommon for patients to refuse a second shot. Some request a medical waiver to avoid further vaccine exposure. According to Dr. Freeman, this is unwarranted.

“I have granted exactly zero waivers,” she said. She explains to patients that these reactions have not been predictive of serious events, such as anaphylaxis. Although the trigger of the hypersensitivity reaction remains unknown, there is no evidence of serious consequences.

Delayed skin reactions are more commonly associated with the Moderna than the Pfizer vaccine. One notable difference between these vaccines is the greater content of mRNA in the Moderna formulation, but Freeman said that this is only one potential hypothesis for higher frequency of reactions to this version of the vaccine.

Patients with a history of allergic disease are more likely to develop a reaction but not significantly more likely to have a reaction that is more difficult to manage, according to Kimberly G. Blumenthal, MD, quality and safety officer for allergy, and codirector of the clinical epidemiology program in the division of rheumatology, allergy, and immunology at Mass General.

Massachusetts General Hospital

Anaphylaxis has been associated with COVD-19 vaccines just as it has with essentially every injectable vaccine, Dr. Blumenthal said during the same session. But the risk is very low, and it stays low even among those with a history of severe hypersensitivity reactions in the past.

Among the data collected from more than 52,000 vaccinated MGBHS employees, 0.9% had a history of severe allergic reaction to a prior vaccine. Of these, 11.6% had an allergic reaction to the COVID-19 vaccine. This was more than twice the 4.6% rate of allergic reactions among employees without a history of allergic reactions, but serious consequences were rare in both groups.

Of those with a reaction to the first dose, all but 2.4% took a subsequent dose. Again, serious reactions were exceedingly rare. These serious reactions did include anaphylaxis and hospitalization in 3% of patients, but there were no fatalities and all resolved.

The absence of serious sequelae from a reaction to a COVID-19 vaccine must be considered within the context of the benefit, which includes protection from death and hospitalization from the virus, according to Dr. Blumenthal. Citing the evidence that first-shot reactions are a source of vaccine hesitancy, she agreed that it is important to educate patients about relative risks.

“Even in our own cohort of MGBHS employees, we have people, including those who had been provaccine in the past, become hesitant,” commented Dr. Blumenthal, who said there are data from the Kaiser Permanente System showing similar vaccine reluctance following a first-shot reaction.

After more than 500 million doses of the Moderna and Pfizer vaccines had been administered worldwide, there was not a single reported death from anaphylaxis. Although Dr. Blumenthal said that an unconfirmed death of this type had been recently reported, she emphasized that this single death, if valid, is dwarfed by the lives saved with vaccination.

Asked about her strategy for counseling patients with vaccine hesitancy, Dr. Freeman said the body of safety data is large and compelling. There is overwhelming evidence of a favorable benefit-to-risk ratio overall and among those with a first-shot reaction.

“I can reassure them on the basis of the data,” Dr. Freeman said in an interview. “Less than half will have a reaction to the second shot and even if they do have a reaction, it is likely to be less severe.”

Although the main message is that vaccination is potentially lifesaving and far outweighs any risks, Freeman specifically gives this message to those hesitant to take a second shot after a first-shot reaction: “I can get you through it.”

Dr. Freeman encouraged health care professionals to report cases of COVID-19 vaccine–related dermatologic side effects to the American Academy of Dermatology / International League of Dermatologic Societies COVID-19 dermatology registry. Dermatologic manifestations of COVID-19 can also be reported to the registry.

Dr. Freeman disclosed receiving grants/research funding from the International League of Dermatologic Societies and from the National Institutes of Health. Dr. Blumenthal disclosed no relevant financial relationships.

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

When an individual develops a terminal illness, those closest to them often start to grieve long before the person dies. Although a common syndrome, it often goes unrecognized and unaddressed.

A new review proposes a way of defining this specific type of grief in the hope that better, more precise descriptive categories will inform therapeutic interventions to help those facing a life-changing loss.

It is “vital” to reduce pre-death grief, inasmuch as numerous studies show that it can result in higher rates of prolonged grief disorder, lead author Jonathan Singer, PhD, visiting assistant professor of clinical psychology, Texas Tech University, Lubbock, told this news organization.

Texas Tech University

‘Typical’ versus ‘impairing’ grief

“Most deaths worldwide are attributed to a chronic or life-limiting Illness,” the authors write. The experience of grief before the loss of a family member “has been studied frequently, but there have been conceptualization issues, which is problematic, as it hinders the potential advancement of the field in differentiating typical grief from more impairing grief before the death,” Dr. Singer said. “Further complicating the picture is the sheer number of terms used to describe grief before death.”

Dr. Singer said that when he started conducting research in this field, he “realized someone had to combine the articles that have been published in order to create definitions that will advance the field, so risk and protective factors could be identified and interventions could be tested.”

For the current study, the investigators searched six databases to find research that “evaluated family members’ or friends’ grief related to an individual currently living with a life-limiting illness.” They excluded studies that evaluated grief after death.

Of 9,568 records reviewed, the researchers selected 134 full-text articles that met inclusion criteria. Most studies (57.46%) were quantitative; 23.88% were qualitative, and 17.91% used mixed methods. Most studies were retrospective, although 14.93% were prospective, and 3% included both prospective and retrospective analyses.

Most participants reported that the family member/friend was diagnosed either with “late-stage dementia” or “advanced cancer.” The majority (58%) were adult children of the individual with the illness, followed by spouses/partners (28.1%) and other relatives/friends (13.9%) in studies that reported the relationship to the participant and the person with the illness.

Various scales were used in the studies to measure grief, particularly the Marwit-Meuser-Caregiver Grief Inventory (n = 28), the Anticipatory Grief Scale (n = 18), and the Prolonged Grief–12 (n = 13).
 

A new name

Owing to the large number of articles included in the review, the researchers limited the analysis to those in which a given term was used in ≥ 1 articles.

The researchers found 18 different terms used by family members/friends of individuals with life-limiting illness to describe grief, including AG (used in the most studies, n = 54); pre-death grief (n = 18), grief (n = 12), pre-loss grief (n = 6), caregiver grief (n = 5), and anticipatory mourning (n = 4). These 18 terms were associated with greater than or equal to 30 different definitions across all of the various studies.

“Definitions of these terms differed drastically,” and many studies used the term AG without defining it.

Nineteen studies used multiple terms within a single article, and the terms were “used interchangeably, with the same definition applied,” the researchers report.

For example, one study defined AG as “the process associated with grieving the eventual loss of a family member in advance of their inevitable death,” while another defined AG as “a series of losses based on a loved one’s progression of cognitive and physical decline.”

On the basis of this analysis, the researchers chose the term “pre-death grief,” which encompasses IRG and AG.

Dr. Singer explained that IRG is “present-oriented” and involves the “longing and yearning for the family member to be as they were before the illness.” AG is “future oriented” and is defined as “family members’ grief experience while the person with the life-limiting illness is alive but that is focused on feared or anticipated losses that will occur after the person’s death.”

The study was intended “to advance the field and provide the knowledge and definitions in order to create and test an evidence-based intervention,” Dr. Singer said.

He pointed to interventions (for example: behavioral activation, meaning-centered grief therapy) that could be tested to reduce pre-death grief or specific interventions that focus on addressing IRG or AG. “For example, cognitive behavior therapy might be used to challenge worry about life without the person, which would be classified as AG.”

Dr. Singer feels it is “vital” to reduce pre-death grief, insofar as numerous studies have shown that high rates of pre-death grief “result in higher rates of prolonged grief disorder.”
 

‘Paradoxical reality’

Francesca Falzarano, PhD, a postdoctoral associate in medicine, Weill Cornell Medicine, New York, called the article a “timely piece drawing much-needed attention to an all-too-often overlooked experience lived by those affected by terminal illnesses.”

Dr. Falzarano, who was not involved in the review, said that “from her own experience” as both a caregiver and behavioral scientist conducting research in this area, the concept of pre-death grief is a paradoxical reality – “how do we grieve someone we haven’t lost yet?”

The experience of pre-death grief is “quite distinct from grief after bereavement” because there is no end date. Rather, the person “cycles back and forth between preparing themselves for an impending death while also attending to whatever is happening in the current moment.” It’s also “unique in that both patients and caregivers individually and collectively grieve losses over the course of the illness,” she noted.

“We as researchers absolutely need to focus our attention on achieving consensus on an appropriate definition for pre-death grief that adequately encompasses its complexity and multidimensionality,” she said.

The authors and Dr. Falzarano report no relevant financial relationships.

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

When an individual develops a terminal illness, those closest to them often start to grieve long before the person dies. Although a common syndrome, it often goes unrecognized and unaddressed.

A new review proposes a way of defining this specific type of grief in the hope that better, more precise descriptive categories will inform therapeutic interventions to help those facing a life-changing loss.

It is “vital” to reduce pre-death grief, inasmuch as numerous studies show that it can result in higher rates of prolonged grief disorder, lead author Jonathan Singer, PhD, visiting assistant professor of clinical psychology, Texas Tech University, Lubbock, told this news organization.

Texas Tech University

‘Typical’ versus ‘impairing’ grief

“Most deaths worldwide are attributed to a chronic or life-limiting Illness,” the authors write. The experience of grief before the loss of a family member “has been studied frequently, but there have been conceptualization issues, which is problematic, as it hinders the potential advancement of the field in differentiating typical grief from more impairing grief before the death,” Dr. Singer said. “Further complicating the picture is the sheer number of terms used to describe grief before death.”

Dr. Singer said that when he started conducting research in this field, he “realized someone had to combine the articles that have been published in order to create definitions that will advance the field, so risk and protective factors could be identified and interventions could be tested.”

For the current study, the investigators searched six databases to find research that “evaluated family members’ or friends’ grief related to an individual currently living with a life-limiting illness.” They excluded studies that evaluated grief after death.

Of 9,568 records reviewed, the researchers selected 134 full-text articles that met inclusion criteria. Most studies (57.46%) were quantitative; 23.88% were qualitative, and 17.91% used mixed methods. Most studies were retrospective, although 14.93% were prospective, and 3% included both prospective and retrospective analyses.

Most participants reported that the family member/friend was diagnosed either with “late-stage dementia” or “advanced cancer.” The majority (58%) were adult children of the individual with the illness, followed by spouses/partners (28.1%) and other relatives/friends (13.9%) in studies that reported the relationship to the participant and the person with the illness.

Various scales were used in the studies to measure grief, particularly the Marwit-Meuser-Caregiver Grief Inventory (n = 28), the Anticipatory Grief Scale (n = 18), and the Prolonged Grief–12 (n = 13).
 

A new name

Owing to the large number of articles included in the review, the researchers limited the analysis to those in which a given term was used in ≥ 1 articles.

The researchers found 18 different terms used by family members/friends of individuals with life-limiting illness to describe grief, including AG (used in the most studies, n = 54); pre-death grief (n = 18), grief (n = 12), pre-loss grief (n = 6), caregiver grief (n = 5), and anticipatory mourning (n = 4). These 18 terms were associated with greater than or equal to 30 different definitions across all of the various studies.

“Definitions of these terms differed drastically,” and many studies used the term AG without defining it.

Nineteen studies used multiple terms within a single article, and the terms were “used interchangeably, with the same definition applied,” the researchers report.

For example, one study defined AG as “the process associated with grieving the eventual loss of a family member in advance of their inevitable death,” while another defined AG as “a series of losses based on a loved one’s progression of cognitive and physical decline.”

On the basis of this analysis, the researchers chose the term “pre-death grief,” which encompasses IRG and AG.

Dr. Singer explained that IRG is “present-oriented” and involves the “longing and yearning for the family member to be as they were before the illness.” AG is “future oriented” and is defined as “family members’ grief experience while the person with the life-limiting illness is alive but that is focused on feared or anticipated losses that will occur after the person’s death.”

The study was intended “to advance the field and provide the knowledge and definitions in order to create and test an evidence-based intervention,” Dr. Singer said.

He pointed to interventions (for example: behavioral activation, meaning-centered grief therapy) that could be tested to reduce pre-death grief or specific interventions that focus on addressing IRG or AG. “For example, cognitive behavior therapy might be used to challenge worry about life without the person, which would be classified as AG.”

Dr. Singer feels it is “vital” to reduce pre-death grief, insofar as numerous studies have shown that high rates of pre-death grief “result in higher rates of prolonged grief disorder.”
 

‘Paradoxical reality’

Francesca Falzarano, PhD, a postdoctoral associate in medicine, Weill Cornell Medicine, New York, called the article a “timely piece drawing much-needed attention to an all-too-often overlooked experience lived by those affected by terminal illnesses.”

Dr. Falzarano, who was not involved in the review, said that “from her own experience” as both a caregiver and behavioral scientist conducting research in this area, the concept of pre-death grief is a paradoxical reality – “how do we grieve someone we haven’t lost yet?”

The experience of pre-death grief is “quite distinct from grief after bereavement” because there is no end date. Rather, the person “cycles back and forth between preparing themselves for an impending death while also attending to whatever is happening in the current moment.” It’s also “unique in that both patients and caregivers individually and collectively grieve losses over the course of the illness,” she noted.

“We as researchers absolutely need to focus our attention on achieving consensus on an appropriate definition for pre-death grief that adequately encompasses its complexity and multidimensionality,” she said.

The authors and Dr. Falzarano report no relevant financial relationships.

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

When an individual develops a terminal illness, those closest to them often start to grieve long before the person dies. Although a common syndrome, it often goes unrecognized and unaddressed.

A new review proposes a way of defining this specific type of grief in the hope that better, more precise descriptive categories will inform therapeutic interventions to help those facing a life-changing loss.

It is “vital” to reduce pre-death grief, inasmuch as numerous studies show that it can result in higher rates of prolonged grief disorder, lead author Jonathan Singer, PhD, visiting assistant professor of clinical psychology, Texas Tech University, Lubbock, told this news organization.

Texas Tech University

‘Typical’ versus ‘impairing’ grief

“Most deaths worldwide are attributed to a chronic or life-limiting Illness,” the authors write. The experience of grief before the loss of a family member “has been studied frequently, but there have been conceptualization issues, which is problematic, as it hinders the potential advancement of the field in differentiating typical grief from more impairing grief before the death,” Dr. Singer said. “Further complicating the picture is the sheer number of terms used to describe grief before death.”

Dr. Singer said that when he started conducting research in this field, he “realized someone had to combine the articles that have been published in order to create definitions that will advance the field, so risk and protective factors could be identified and interventions could be tested.”

For the current study, the investigators searched six databases to find research that “evaluated family members’ or friends’ grief related to an individual currently living with a life-limiting illness.” They excluded studies that evaluated grief after death.

Of 9,568 records reviewed, the researchers selected 134 full-text articles that met inclusion criteria. Most studies (57.46%) were quantitative; 23.88% were qualitative, and 17.91% used mixed methods. Most studies were retrospective, although 14.93% were prospective, and 3% included both prospective and retrospective analyses.

Most participants reported that the family member/friend was diagnosed either with “late-stage dementia” or “advanced cancer.” The majority (58%) were adult children of the individual with the illness, followed by spouses/partners (28.1%) and other relatives/friends (13.9%) in studies that reported the relationship to the participant and the person with the illness.

Various scales were used in the studies to measure grief, particularly the Marwit-Meuser-Caregiver Grief Inventory (n = 28), the Anticipatory Grief Scale (n = 18), and the Prolonged Grief–12 (n = 13).
 

A new name

Owing to the large number of articles included in the review, the researchers limited the analysis to those in which a given term was used in ≥ 1 articles.

The researchers found 18 different terms used by family members/friends of individuals with life-limiting illness to describe grief, including AG (used in the most studies, n = 54); pre-death grief (n = 18), grief (n = 12), pre-loss grief (n = 6), caregiver grief (n = 5), and anticipatory mourning (n = 4). These 18 terms were associated with greater than or equal to 30 different definitions across all of the various studies.

“Definitions of these terms differed drastically,” and many studies used the term AG without defining it.

Nineteen studies used multiple terms within a single article, and the terms were “used interchangeably, with the same definition applied,” the researchers report.

For example, one study defined AG as “the process associated with grieving the eventual loss of a family member in advance of their inevitable death,” while another defined AG as “a series of losses based on a loved one’s progression of cognitive and physical decline.”

On the basis of this analysis, the researchers chose the term “pre-death grief,” which encompasses IRG and AG.

Dr. Singer explained that IRG is “present-oriented” and involves the “longing and yearning for the family member to be as they were before the illness.” AG is “future oriented” and is defined as “family members’ grief experience while the person with the life-limiting illness is alive but that is focused on feared or anticipated losses that will occur after the person’s death.”

The study was intended “to advance the field and provide the knowledge and definitions in order to create and test an evidence-based intervention,” Dr. Singer said.

He pointed to interventions (for example: behavioral activation, meaning-centered grief therapy) that could be tested to reduce pre-death grief or specific interventions that focus on addressing IRG or AG. “For example, cognitive behavior therapy might be used to challenge worry about life without the person, which would be classified as AG.”

Dr. Singer feels it is “vital” to reduce pre-death grief, insofar as numerous studies have shown that high rates of pre-death grief “result in higher rates of prolonged grief disorder.”
 

‘Paradoxical reality’

Francesca Falzarano, PhD, a postdoctoral associate in medicine, Weill Cornell Medicine, New York, called the article a “timely piece drawing much-needed attention to an all-too-often overlooked experience lived by those affected by terminal illnesses.”

Dr. Falzarano, who was not involved in the review, said that “from her own experience” as both a caregiver and behavioral scientist conducting research in this area, the concept of pre-death grief is a paradoxical reality – “how do we grieve someone we haven’t lost yet?”

The experience of pre-death grief is “quite distinct from grief after bereavement” because there is no end date. Rather, the person “cycles back and forth between preparing themselves for an impending death while also attending to whatever is happening in the current moment.” It’s also “unique in that both patients and caregivers individually and collectively grieve losses over the course of the illness,” she noted.

“We as researchers absolutely need to focus our attention on achieving consensus on an appropriate definition for pre-death grief that adequately encompasses its complexity and multidimensionality,” she said.

The authors and Dr. Falzarano report no relevant financial relationships.

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

There is a link between cannabis exposure during pregnancy and higher fasting glucose levels and adiposity in the offspring in early childhood, a new study suggests.

Research looking at the effect of prenatal exposure to cannabis on offspring is growing. It is known to affect childhood cognition and behavior; however, there is little work to date on how it affects metabolic outcomes, said lead author Brianna F. Moore, PhD.

“Officially, the American Academy of Obstetricians and Gynecologists recommends that women do not use cannabis during pregnancy or while breastfeeding to limit the effects on offspring. There’s really a lot we don’t know, but researchers across the country are starting to look into this more, and there are signs that it isn’t great for the offspring,” Dr. Moore, assistant professor at the Colorado School of Public Health in Aurora, said in an interview.

And she noted that while some women turn to cannabis to manage the challenging symptoms of pregnancy, “Clinicians should encourage pregnant women to refrain from using cannabis; it is best for these pregnant women to talk to their physicians about alternative ways of managing these symptoms.”

The findings were published online March 31 in the Journal of Clinical Endocrinology & Metabolism.
 

Study of mother and 5-year-old child pairs

The researchers assessed 103 sets of mothers and children from the Healthy Start study. At 27 weeks of gestation, the investigators assessed 12 metabolites of cannabis/cannabinoids in urine samples. Results from these samples were used to categorize fetal exposure to cannabis as either not exposed or exposed. They found that about 15% of the mothers had traceable amounts of cannabinoids, suggesting fetal cannabis exposure.

At follow-up, the study team assessed fat-free mass and fat mass using air displacement plethysmography among the offspring around age 5. They used generalized linear models to approximate the relationship between fetal exposure to cannabis with metabolic measures such as insulin, glucose, and homeostatic model assessment of insulin resistance (HOMA-IR), and adiposity measures such as body mass index, fat-free mass, fat mass, adiposity, and BMI z-scores.

The findings showed that, compared with nonexposed offspring, exposed offspring had greater:

• Fasting glucose (5.6 mg/dL; 95% confidence interval [CI], 0.8-10.3).
• Fat-free mass (1.2 kg; 95% CI, 0.4-2.0).
• Fat mass (1.0 kg; 95% CI, 0.3-1.7).
• Adiposity (2.6%; 95% CI, 0.1-5.2).

“This finding may suggest that fetal exposure to cannabis contributes to higher fasting glucose levels via a direct effect on the pancreatic β-cells. However, we cannot draw conclusions about β-cell response to glucose because we did not perform oral glucose tolerance tests,” the study authors wrote.

Notably, however, there was no relationship between BMI z-scores, BMI, or HOMA-IR and fasting insulin, the study team found.

Study limitations include the small sample size and lack of self-report data on cannabis use to differentiate between direct use and exposure to cannabis, Dr. Moore acknowledged.

Given the small sample size, the researchers were unable to look at dose-response, which future studies will focus on, Dr. Moore noted. Future efforts will also focus on comparing the effects of tetrahydrocannabinol (THC) and cannabidiol (CBD), Dr. Moore added.

“This is a relatively new field, so there’s still work to be done. This is just one study, and we need to study this more in other cohorts to confirm our findings,” she concluded.

Dr. Moore has reported no relevant financial relationships.

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

There is a link between cannabis exposure during pregnancy and higher fasting glucose levels and adiposity in the offspring in early childhood, a new study suggests.

Research looking at the effect of prenatal exposure to cannabis on offspring is growing. It is known to affect childhood cognition and behavior; however, there is little work to date on how it affects metabolic outcomes, said lead author Brianna F. Moore, PhD.

“Officially, the American Academy of Obstetricians and Gynecologists recommends that women do not use cannabis during pregnancy or while breastfeeding to limit the effects on offspring. There’s really a lot we don’t know, but researchers across the country are starting to look into this more, and there are signs that it isn’t great for the offspring,” Dr. Moore, assistant professor at the Colorado School of Public Health in Aurora, said in an interview.

And she noted that while some women turn to cannabis to manage the challenging symptoms of pregnancy, “Clinicians should encourage pregnant women to refrain from using cannabis; it is best for these pregnant women to talk to their physicians about alternative ways of managing these symptoms.”

The findings were published online March 31 in the Journal of Clinical Endocrinology & Metabolism.
 

Study of mother and 5-year-old child pairs

The researchers assessed 103 sets of mothers and children from the Healthy Start study. At 27 weeks of gestation, the investigators assessed 12 metabolites of cannabis/cannabinoids in urine samples. Results from these samples were used to categorize fetal exposure to cannabis as either not exposed or exposed. They found that about 15% of the mothers had traceable amounts of cannabinoids, suggesting fetal cannabis exposure.

At follow-up, the study team assessed fat-free mass and fat mass using air displacement plethysmography among the offspring around age 5. They used generalized linear models to approximate the relationship between fetal exposure to cannabis with metabolic measures such as insulin, glucose, and homeostatic model assessment of insulin resistance (HOMA-IR), and adiposity measures such as body mass index, fat-free mass, fat mass, adiposity, and BMI z-scores.

The findings showed that, compared with nonexposed offspring, exposed offspring had greater:

• Fasting glucose (5.6 mg/dL; 95% confidence interval [CI], 0.8-10.3).
• Fat-free mass (1.2 kg; 95% CI, 0.4-2.0).
• Fat mass (1.0 kg; 95% CI, 0.3-1.7).
• Adiposity (2.6%; 95% CI, 0.1-5.2).

“This finding may suggest that fetal exposure to cannabis contributes to higher fasting glucose levels via a direct effect on the pancreatic β-cells. However, we cannot draw conclusions about β-cell response to glucose because we did not perform oral glucose tolerance tests,” the study authors wrote.

Notably, however, there was no relationship between BMI z-scores, BMI, or HOMA-IR and fasting insulin, the study team found.

Study limitations include the small sample size and lack of self-report data on cannabis use to differentiate between direct use and exposure to cannabis, Dr. Moore acknowledged.

Given the small sample size, the researchers were unable to look at dose-response, which future studies will focus on, Dr. Moore noted. Future efforts will also focus on comparing the effects of tetrahydrocannabinol (THC) and cannabidiol (CBD), Dr. Moore added.

“This is a relatively new field, so there’s still work to be done. This is just one study, and we need to study this more in other cohorts to confirm our findings,” she concluded.

Dr. Moore has reported no relevant financial relationships.

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

There is a link between cannabis exposure during pregnancy and higher fasting glucose levels and adiposity in the offspring in early childhood, a new study suggests.

Research looking at the effect of prenatal exposure to cannabis on offspring is growing. It is known to affect childhood cognition and behavior; however, there is little work to date on how it affects metabolic outcomes, said lead author Brianna F. Moore, PhD.

“Officially, the American Academy of Obstetricians and Gynecologists recommends that women do not use cannabis during pregnancy or while breastfeeding to limit the effects on offspring. There’s really a lot we don’t know, but researchers across the country are starting to look into this more, and there are signs that it isn’t great for the offspring,” Dr. Moore, assistant professor at the Colorado School of Public Health in Aurora, said in an interview.

And she noted that while some women turn to cannabis to manage the challenging symptoms of pregnancy, “Clinicians should encourage pregnant women to refrain from using cannabis; it is best for these pregnant women to talk to their physicians about alternative ways of managing these symptoms.”

The findings were published online March 31 in the Journal of Clinical Endocrinology & Metabolism.
 

Study of mother and 5-year-old child pairs

The researchers assessed 103 sets of mothers and children from the Healthy Start study. At 27 weeks of gestation, the investigators assessed 12 metabolites of cannabis/cannabinoids in urine samples. Results from these samples were used to categorize fetal exposure to cannabis as either not exposed or exposed. They found that about 15% of the mothers had traceable amounts of cannabinoids, suggesting fetal cannabis exposure.

At follow-up, the study team assessed fat-free mass and fat mass using air displacement plethysmography among the offspring around age 5. They used generalized linear models to approximate the relationship between fetal exposure to cannabis with metabolic measures such as insulin, glucose, and homeostatic model assessment of insulin resistance (HOMA-IR), and adiposity measures such as body mass index, fat-free mass, fat mass, adiposity, and BMI z-scores.

The findings showed that, compared with nonexposed offspring, exposed offspring had greater:

• Fasting glucose (5.6 mg/dL; 95% confidence interval [CI], 0.8-10.3).
• Fat-free mass (1.2 kg; 95% CI, 0.4-2.0).
• Fat mass (1.0 kg; 95% CI, 0.3-1.7).
• Adiposity (2.6%; 95% CI, 0.1-5.2).

“This finding may suggest that fetal exposure to cannabis contributes to higher fasting glucose levels via a direct effect on the pancreatic β-cells. However, we cannot draw conclusions about β-cell response to glucose because we did not perform oral glucose tolerance tests,” the study authors wrote.

Notably, however, there was no relationship between BMI z-scores, BMI, or HOMA-IR and fasting insulin, the study team found.

Study limitations include the small sample size and lack of self-report data on cannabis use to differentiate between direct use and exposure to cannabis, Dr. Moore acknowledged.

Given the small sample size, the researchers were unable to look at dose-response, which future studies will focus on, Dr. Moore noted. Future efforts will also focus on comparing the effects of tetrahydrocannabinol (THC) and cannabidiol (CBD), Dr. Moore added.

“This is a relatively new field, so there’s still work to be done. This is just one study, and we need to study this more in other cohorts to confirm our findings,” she concluded.

Dr. Moore has reported no relevant financial relationships.

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

A new score to gauge histologic remission in ulcerative colitis (UC), based simply on the presence or absence of neutrophils, is effective and easier to use than other indices, according to authors of a study published online in Gut.
 

Researchers, led by Xianyong Gui, MD, a surgical pathologist at the University of Washington, Seattle, developed the index, called the Paddington International Virtual Chromoendoscopy Score (PICaSSO) Histologic Remission Index (PHRI). They wrote that, when the index was plugged into an artificial intelligence (AI) model, the algorithm accurately determined histologic remission.

“Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity, and 86% accuracy,” the authors noted.

Histologic remission has been previously proposed as a treatment target for UC and many indices have been developed to score disease activity, but they haven’t been widely used because of their complexity, the authors wrote. They believe this index can be applied easily and efficiently in clinical practice. “Since a pathologist needs only to identify neutrophils, which is a part of routine in reading biopsy slides as clinical histopathological evaluation, one can have the PHRI score immediately without making additional effort and spending extra time. Thus, the PHRI score can also be easily included into the pathology reports.”

The researchers found that the index correlates strongly with endoscopic activity and predicts UC clinical outcomes, including hospitalization, colectomy, and initiation or changes in treatment caused by UC flare-up.

Dr. Gui’s team developed the index using 614 biopsies from 307 patients with UC from 11 centers in Europe and North America who were prospectively enrolled in the PICaSSO study.

The index was a collaboration between pathologists and endoscopists who wanted a histologic score that would align with the endoscopic score and go beyond endoscopic evaluation. It eliminates consideration of ulceration/erosion, often a factor in other indices because variability can be high without contributing much to accuracy.
 

Keen interest in histologic remission

David T. Rubin, MD, chief of gastroenterology, hepatology and nutrition and the codirector of the Digestive Diseases Center at the University of Chicago, noted continued interest in whether histologic findings (biopsies) of the mucosa are a clinically important and reachable treatment goal with UC.

“It’s important to acknowledge that it is not yet a target of treatment, in part because of a variety of challenges and unknowns related to it,” he said.

The current study addresses a major barrier to incorporation of histology in the clinical management of patients with UC: individual interpretation. “Development of this simplified novel scoring approach with artificial intelligence could be a major step forward. We are hopeful that this type of AI approach will eliminate some of the barriers to use of histology as a marker of treatment control. It is of interest to note that this novel score correlated to the endoscopic appearance, but didn’t necessarily demonstrate superiority to it. This is important, since we have hypothesized that histology may provide more information about outcomes than endoscopy alone,” Dr. Rubin said.

He added that PHRI will need broader validation and incorporation into meaningful interventions before it can be incorporated into clinical practice, but that “this type of technological innovation is what the field needs in order to move forward.”

The authors and Dr. Rubin declared no relevant financial conflicts. Two coauthors are funded by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham in the United Kingdom.

A new score to gauge histologic remission in ulcerative colitis (UC), based simply on the presence or absence of neutrophils, is effective and easier to use than other indices, according to authors of a study published online in Gut.
 

Researchers, led by Xianyong Gui, MD, a surgical pathologist at the University of Washington, Seattle, developed the index, called the Paddington International Virtual Chromoendoscopy Score (PICaSSO) Histologic Remission Index (PHRI). They wrote that, when the index was plugged into an artificial intelligence (AI) model, the algorithm accurately determined histologic remission.

“Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity, and 86% accuracy,” the authors noted.

Histologic remission has been previously proposed as a treatment target for UC and many indices have been developed to score disease activity, but they haven’t been widely used because of their complexity, the authors wrote. They believe this index can be applied easily and efficiently in clinical practice. “Since a pathologist needs only to identify neutrophils, which is a part of routine in reading biopsy slides as clinical histopathological evaluation, one can have the PHRI score immediately without making additional effort and spending extra time. Thus, the PHRI score can also be easily included into the pathology reports.”

The researchers found that the index correlates strongly with endoscopic activity and predicts UC clinical outcomes, including hospitalization, colectomy, and initiation or changes in treatment caused by UC flare-up.

Dr. Gui’s team developed the index using 614 biopsies from 307 patients with UC from 11 centers in Europe and North America who were prospectively enrolled in the PICaSSO study.

The index was a collaboration between pathologists and endoscopists who wanted a histologic score that would align with the endoscopic score and go beyond endoscopic evaluation. It eliminates consideration of ulceration/erosion, often a factor in other indices because variability can be high without contributing much to accuracy.
 

Keen interest in histologic remission

David T. Rubin, MD, chief of gastroenterology, hepatology and nutrition and the codirector of the Digestive Diseases Center at the University of Chicago, noted continued interest in whether histologic findings (biopsies) of the mucosa are a clinically important and reachable treatment goal with UC.

“It’s important to acknowledge that it is not yet a target of treatment, in part because of a variety of challenges and unknowns related to it,” he said.

The current study addresses a major barrier to incorporation of histology in the clinical management of patients with UC: individual interpretation. “Development of this simplified novel scoring approach with artificial intelligence could be a major step forward. We are hopeful that this type of AI approach will eliminate some of the barriers to use of histology as a marker of treatment control. It is of interest to note that this novel score correlated to the endoscopic appearance, but didn’t necessarily demonstrate superiority to it. This is important, since we have hypothesized that histology may provide more information about outcomes than endoscopy alone,” Dr. Rubin said.

He added that PHRI will need broader validation and incorporation into meaningful interventions before it can be incorporated into clinical practice, but that “this type of technological innovation is what the field needs in order to move forward.”

The authors and Dr. Rubin declared no relevant financial conflicts. Two coauthors are funded by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham in the United Kingdom.

A new score to gauge histologic remission in ulcerative colitis (UC), based simply on the presence or absence of neutrophils, is effective and easier to use than other indices, according to authors of a study published online in Gut.
 

Researchers, led by Xianyong Gui, MD, a surgical pathologist at the University of Washington, Seattle, developed the index, called the Paddington International Virtual Chromoendoscopy Score (PICaSSO) Histologic Remission Index (PHRI). They wrote that, when the index was plugged into an artificial intelligence (AI) model, the algorithm accurately determined histologic remission.

“Our preliminary AI algorithm differentiated active from quiescent UC with 78% sensitivity, 91.7% specificity, and 86% accuracy,” the authors noted.

Histologic remission has been previously proposed as a treatment target for UC and many indices have been developed to score disease activity, but they haven’t been widely used because of their complexity, the authors wrote. They believe this index can be applied easily and efficiently in clinical practice. “Since a pathologist needs only to identify neutrophils, which is a part of routine in reading biopsy slides as clinical histopathological evaluation, one can have the PHRI score immediately without making additional effort and spending extra time. Thus, the PHRI score can also be easily included into the pathology reports.”

The researchers found that the index correlates strongly with endoscopic activity and predicts UC clinical outcomes, including hospitalization, colectomy, and initiation or changes in treatment caused by UC flare-up.

Dr. Gui’s team developed the index using 614 biopsies from 307 patients with UC from 11 centers in Europe and North America who were prospectively enrolled in the PICaSSO study.

The index was a collaboration between pathologists and endoscopists who wanted a histologic score that would align with the endoscopic score and go beyond endoscopic evaluation. It eliminates consideration of ulceration/erosion, often a factor in other indices because variability can be high without contributing much to accuracy.
 

Keen interest in histologic remission

David T. Rubin, MD, chief of gastroenterology, hepatology and nutrition and the codirector of the Digestive Diseases Center at the University of Chicago, noted continued interest in whether histologic findings (biopsies) of the mucosa are a clinically important and reachable treatment goal with UC.

“It’s important to acknowledge that it is not yet a target of treatment, in part because of a variety of challenges and unknowns related to it,” he said.

The current study addresses a major barrier to incorporation of histology in the clinical management of patients with UC: individual interpretation. “Development of this simplified novel scoring approach with artificial intelligence could be a major step forward. We are hopeful that this type of AI approach will eliminate some of the barriers to use of histology as a marker of treatment control. It is of interest to note that this novel score correlated to the endoscopic appearance, but didn’t necessarily demonstrate superiority to it. This is important, since we have hypothesized that histology may provide more information about outcomes than endoscopy alone,” Dr. Rubin said.

He added that PHRI will need broader validation and incorporation into meaningful interventions before it can be incorporated into clinical practice, but that “this type of technological innovation is what the field needs in order to move forward.”

The authors and Dr. Rubin declared no relevant financial conflicts. Two coauthors are funded by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham in the United Kingdom.

The Osteopathic Medical Board of California has revoked a psychiatrist’s license because it found that he sexually assaulted two patients after giving them ketamine and that he had an affair with the sister of another patient.

In its decision, the board stated that the psychiatrist, Cuyler Burns Goodwin, DO, committed gross negligence, violated ethical standards, departed from the standard of care, and was guilty of sexual misconduct.

“Even if one were to believe respondent’s denial of sexual assaults on Patient B and Patient C, his overall course of conduct in committing multiple other ethical violations and violations of the Medical Practice Act in connection with Patient A’s Sister, Patient B, and Patient C; his attitude toward and lack of insight into his offenses; and his lack of candor at hearing demonstrate that revocation of respondent’s license is required for protection of the public,” the board wrote in its March 8 order.

The board seeks to recover almost $65,000 in costs for the investigation, including for legal fees and expert testimony. The psychiatrist is not currently facing any criminal charges.
 

Family-run business

Dr. Goodwin received his medical license in 2013 and opened Sequoia Mind Health, a practice in Santa Rosa, Calif., soon after completing his residency at the University of California San Francisco, according to the board.

The allegations leading to the revocation of his license occurred at the Sequoia Mind Health practice, a family-run business that employed Dr. Goodwin’s mother as the office manager, his wife as the sole registered nurse, and his sister who worked reception for a time. Dr. Goodwin closed the practice in October 2019.

Until 2020, he worked as an emergency services psychiatrist for Sonoma County Behavioral Health. Other positions included stints at John George Psychiatric Pavilion in San Leandro, at Mendocino County Jail from 2018 to 2021, and at Lake County Jail from 2020 to 2021.

Since closing his practice, he also worked as a psychiatrist for Redwood Quality Management Company in Ukiah, Calif.

The board notified Dr. Goodwin in November 2020 that it was opening an investigation into his conduct.
 

Affair with patient’s sister

Patient A came to Dr. Goodwin in 2017 as an uninsured, homebound, 24-year-old with schizophrenia. He had not received previous mental health treatment and was entirely dependent on his family because of the severity of his symptoms.

Dr. Goodwin agreed to make home visits to provide medication management and psychotherapy and was paid in cash by the patient’s sister, who was a point of contact for the family.

The sister and Dr. Goodwin developed a friendship and, after commiserating about their troubled marriages, began a sexual relationship in 2018 and decided they would divorce their spouses and marry each other.

However, in November 2018, the sister became pregnant and, at her request, Dr. Goodwin prescribed misoprostol to induce an abortion. The affair and the abortion were later discovered by the sister’s family, who agreed to not file a complaint with the medical board in exchange for Dr. Goodwin’s agreeing to cease communications with the sister.

Nevertheless, the two continued the affair and in February 2019 the patient’s father and mother each separately complained to the medical board. The sister also sent a letter to the board urging against disciplinary action – but later acknowledged that the letter was prepared by Dr. Goodwin.

The family removed Patient A from Dr. Goodwin’s care in 2019. The sister’s relationship with Patient A and her family was damaged; she subsequently divorced her husband and moved out of state. She later told the board she regretted the relationship and knew it was wrong.

When Dr. Goodwin was initially interviewed in 2019 by the medical board, he refused to discuss the relationship or the misoprostol prescription. Then, at a later hearing, he said he did not see anything wrong with the relationship and did not believe it affected the care of Patient A.

The medical board’s expert witness said Dr. Goodwin’s behavior “showed he either had no knowledge of ethical boundaries or chose to ignore them, showing poor judgment and ‘cluelessness’ about the potential adverse effects of having a sexual relationship with Sister, which had the significant potential to compromise Patient A’s treatment.”
 

Sexual assault

Patient B came to Dr. Goodwin in 2017 to help taper her anxiety and depression medications. She informed him she had experienced multiple sexual assaults. He helped her taper off the drugs within a month and then hired her to work part-time at the practice’s reception desk.

After her symptoms worsened again after a traumatic event, Dr. Goodwin recommended the use of ketamine. Patient B received five ketamine treatments in a month with only Dr. Goodwin present in the room.

During one of those treatments he asked her questions about her sex life.  Another night in the office he asked her to have a glass of wine with him and then allegedly sexually assaulted her.

Patient B soon quit the job via text, telling him his behavior was inappropriate. She told Dr. Goodwin she would not say anything about the assault but asked for a letter of recommendation for another job. Dr. Goodwin texted back that she was “100% right,” and he would give her a great recommendation, which he later did.

A year later, in 2019, Pamela Albro, PhD, a psychologist who provided therapy at Sequoia Mind Health, contacted Patient B to ask why she quit.

When Patient B told her about the assault, the therapist asked to share her name with Patient C, who had a similar experience. Patient B agreed and then submitted a police report and a complaint to the medical board in March 2019.

Dr. Goodwin denied Patient B’s allegations and “offered evasive and non-credible testimony” about Patient B’s text messages, the board said.
 

Another patient-employee

Patient C attended Dr. Goodwin’s clinic in May 2017 after a suicide attempt that required hospitalization. She told Dr. Goodwin she had experienced sexual trauma and assault in the past. Dr. Goodwin referred Patient C to Dr. Albro for therapy, managed her medications himself, and hired her to work at the clinic’s reception desk, even though she was still a patient.

Patient C worked 32 hours a week and took on other duties that included assisting in the administration of transcranial magnetic stimulation to clinic patients.

In late 2017, Dr. Goodwin recommended ketamine for Patient C and she received seven treatments from December 2017 through April 2019. There were no records of vital signs monitoring during the treatments, and Dr. Goodwin’s wife was present for only two sessions.

During the first treatment, where Patient C said she was feeling “out of it,” Dr. Goodwin allegedly sexually assaulted her.

Because of the ketamine, she told the medical board she was unable to speak or yell but said, “I screamed in my head.” After Dr. Goodwin left the room, she said she felt afraid, ashamed, and wanted to go home. Dr. Goodwin walked her to the lobby where her husband was waiting.

The patient did not tell her husband about the assault because she said she felt ashamed, and said she did not report Dr. Goodwin because it was not safe.
 

Disciplinary hearing

Patient C continued to work for Dr. Goodwin, calling it a confusing time in her life. She later learned about the affair with Patient A’s sister and about Patient B’s experience and resigned from the clinic in July 2019.

She still did not discuss the assault until early 2021 when the board contacted her again. She confided to her primary care physician, who noted that her PTSD symptoms had worsened.

Dr. Goodwin said in the disciplinary hearing that hiring Patient B and Patient C was “boundary crossing,” but he denied allegations of asking inappropriate questions or of sexual assault. The board, however, characterized the testimony of Patient B and Patient C as credible.

All of Dr. Goodwin’s other employers said at his disciplinary hearing that they believed he was a good psychiatrist and that they had never seen any unprofessional behavior.

The revocation of Dr. Goodwin’s license will be effective as of April 7. Dr. Goodwin’s attorney, Marvin H. Firestone, MD, JD, told this news organization he had “no comment” on the medical board’s decision or about his client.

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

The Osteopathic Medical Board of California has revoked a psychiatrist’s license because it found that he sexually assaulted two patients after giving them ketamine and that he had an affair with the sister of another patient.

In its decision, the board stated that the psychiatrist, Cuyler Burns Goodwin, DO, committed gross negligence, violated ethical standards, departed from the standard of care, and was guilty of sexual misconduct.

“Even if one were to believe respondent’s denial of sexual assaults on Patient B and Patient C, his overall course of conduct in committing multiple other ethical violations and violations of the Medical Practice Act in connection with Patient A’s Sister, Patient B, and Patient C; his attitude toward and lack of insight into his offenses; and his lack of candor at hearing demonstrate that revocation of respondent’s license is required for protection of the public,” the board wrote in its March 8 order.

The board seeks to recover almost $65,000 in costs for the investigation, including for legal fees and expert testimony. The psychiatrist is not currently facing any criminal charges.
 

Family-run business

Dr. Goodwin received his medical license in 2013 and opened Sequoia Mind Health, a practice in Santa Rosa, Calif., soon after completing his residency at the University of California San Francisco, according to the board.

The allegations leading to the revocation of his license occurred at the Sequoia Mind Health practice, a family-run business that employed Dr. Goodwin’s mother as the office manager, his wife as the sole registered nurse, and his sister who worked reception for a time. Dr. Goodwin closed the practice in October 2019.

Until 2020, he worked as an emergency services psychiatrist for Sonoma County Behavioral Health. Other positions included stints at John George Psychiatric Pavilion in San Leandro, at Mendocino County Jail from 2018 to 2021, and at Lake County Jail from 2020 to 2021.

Since closing his practice, he also worked as a psychiatrist for Redwood Quality Management Company in Ukiah, Calif.

The board notified Dr. Goodwin in November 2020 that it was opening an investigation into his conduct.
 

Affair with patient’s sister

Patient A came to Dr. Goodwin in 2017 as an uninsured, homebound, 24-year-old with schizophrenia. He had not received previous mental health treatment and was entirely dependent on his family because of the severity of his symptoms.

Dr. Goodwin agreed to make home visits to provide medication management and psychotherapy and was paid in cash by the patient’s sister, who was a point of contact for the family.

The sister and Dr. Goodwin developed a friendship and, after commiserating about their troubled marriages, began a sexual relationship in 2018 and decided they would divorce their spouses and marry each other.

However, in November 2018, the sister became pregnant and, at her request, Dr. Goodwin prescribed misoprostol to induce an abortion. The affair and the abortion were later discovered by the sister’s family, who agreed to not file a complaint with the medical board in exchange for Dr. Goodwin’s agreeing to cease communications with the sister.

Nevertheless, the two continued the affair and in February 2019 the patient’s father and mother each separately complained to the medical board. The sister also sent a letter to the board urging against disciplinary action – but later acknowledged that the letter was prepared by Dr. Goodwin.

The family removed Patient A from Dr. Goodwin’s care in 2019. The sister’s relationship with Patient A and her family was damaged; she subsequently divorced her husband and moved out of state. She later told the board she regretted the relationship and knew it was wrong.

When Dr. Goodwin was initially interviewed in 2019 by the medical board, he refused to discuss the relationship or the misoprostol prescription. Then, at a later hearing, he said he did not see anything wrong with the relationship and did not believe it affected the care of Patient A.

The medical board’s expert witness said Dr. Goodwin’s behavior “showed he either had no knowledge of ethical boundaries or chose to ignore them, showing poor judgment and ‘cluelessness’ about the potential adverse effects of having a sexual relationship with Sister, which had the significant potential to compromise Patient A’s treatment.”
 

Sexual assault

Patient B came to Dr. Goodwin in 2017 to help taper her anxiety and depression medications. She informed him she had experienced multiple sexual assaults. He helped her taper off the drugs within a month and then hired her to work part-time at the practice’s reception desk.

After her symptoms worsened again after a traumatic event, Dr. Goodwin recommended the use of ketamine. Patient B received five ketamine treatments in a month with only Dr. Goodwin present in the room.

During one of those treatments he asked her questions about her sex life.  Another night in the office he asked her to have a glass of wine with him and then allegedly sexually assaulted her.

Patient B soon quit the job via text, telling him his behavior was inappropriate. She told Dr. Goodwin she would not say anything about the assault but asked for a letter of recommendation for another job. Dr. Goodwin texted back that she was “100% right,” and he would give her a great recommendation, which he later did.

A year later, in 2019, Pamela Albro, PhD, a psychologist who provided therapy at Sequoia Mind Health, contacted Patient B to ask why she quit.

When Patient B told her about the assault, the therapist asked to share her name with Patient C, who had a similar experience. Patient B agreed and then submitted a police report and a complaint to the medical board in March 2019.

Dr. Goodwin denied Patient B’s allegations and “offered evasive and non-credible testimony” about Patient B’s text messages, the board said.
 

Another patient-employee

Patient C attended Dr. Goodwin’s clinic in May 2017 after a suicide attempt that required hospitalization. She told Dr. Goodwin she had experienced sexual trauma and assault in the past. Dr. Goodwin referred Patient C to Dr. Albro for therapy, managed her medications himself, and hired her to work at the clinic’s reception desk, even though she was still a patient.

Patient C worked 32 hours a week and took on other duties that included assisting in the administration of transcranial magnetic stimulation to clinic patients.

In late 2017, Dr. Goodwin recommended ketamine for Patient C and she received seven treatments from December 2017 through April 2019. There were no records of vital signs monitoring during the treatments, and Dr. Goodwin’s wife was present for only two sessions.

During the first treatment, where Patient C said she was feeling “out of it,” Dr. Goodwin allegedly sexually assaulted her.

Because of the ketamine, she told the medical board she was unable to speak or yell but said, “I screamed in my head.” After Dr. Goodwin left the room, she said she felt afraid, ashamed, and wanted to go home. Dr. Goodwin walked her to the lobby where her husband was waiting.

The patient did not tell her husband about the assault because she said she felt ashamed, and said she did not report Dr. Goodwin because it was not safe.
 

Disciplinary hearing

Patient C continued to work for Dr. Goodwin, calling it a confusing time in her life. She later learned about the affair with Patient A’s sister and about Patient B’s experience and resigned from the clinic in July 2019.

She still did not discuss the assault until early 2021 when the board contacted her again. She confided to her primary care physician, who noted that her PTSD symptoms had worsened.

Dr. Goodwin said in the disciplinary hearing that hiring Patient B and Patient C was “boundary crossing,” but he denied allegations of asking inappropriate questions or of sexual assault. The board, however, characterized the testimony of Patient B and Patient C as credible.

All of Dr. Goodwin’s other employers said at his disciplinary hearing that they believed he was a good psychiatrist and that they had never seen any unprofessional behavior.

The revocation of Dr. Goodwin’s license will be effective as of April 7. Dr. Goodwin’s attorney, Marvin H. Firestone, MD, JD, told this news organization he had “no comment” on the medical board’s decision or about his client.

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

The Osteopathic Medical Board of California has revoked a psychiatrist’s license because it found that he sexually assaulted two patients after giving them ketamine and that he had an affair with the sister of another patient.

In its decision, the board stated that the psychiatrist, Cuyler Burns Goodwin, DO, committed gross negligence, violated ethical standards, departed from the standard of care, and was guilty of sexual misconduct.

“Even if one were to believe respondent’s denial of sexual assaults on Patient B and Patient C, his overall course of conduct in committing multiple other ethical violations and violations of the Medical Practice Act in connection with Patient A’s Sister, Patient B, and Patient C; his attitude toward and lack of insight into his offenses; and his lack of candor at hearing demonstrate that revocation of respondent’s license is required for protection of the public,” the board wrote in its March 8 order.

The board seeks to recover almost $65,000 in costs for the investigation, including for legal fees and expert testimony. The psychiatrist is not currently facing any criminal charges.
 

Family-run business

Dr. Goodwin received his medical license in 2013 and opened Sequoia Mind Health, a practice in Santa Rosa, Calif., soon after completing his residency at the University of California San Francisco, according to the board.

The allegations leading to the revocation of his license occurred at the Sequoia Mind Health practice, a family-run business that employed Dr. Goodwin’s mother as the office manager, his wife as the sole registered nurse, and his sister who worked reception for a time. Dr. Goodwin closed the practice in October 2019.

Until 2020, he worked as an emergency services psychiatrist for Sonoma County Behavioral Health. Other positions included stints at John George Psychiatric Pavilion in San Leandro, at Mendocino County Jail from 2018 to 2021, and at Lake County Jail from 2020 to 2021.

Since closing his practice, he also worked as a psychiatrist for Redwood Quality Management Company in Ukiah, Calif.

The board notified Dr. Goodwin in November 2020 that it was opening an investigation into his conduct.
 

Affair with patient’s sister

Patient A came to Dr. Goodwin in 2017 as an uninsured, homebound, 24-year-old with schizophrenia. He had not received previous mental health treatment and was entirely dependent on his family because of the severity of his symptoms.

Dr. Goodwin agreed to make home visits to provide medication management and psychotherapy and was paid in cash by the patient’s sister, who was a point of contact for the family.

The sister and Dr. Goodwin developed a friendship and, after commiserating about their troubled marriages, began a sexual relationship in 2018 and decided they would divorce their spouses and marry each other.

However, in November 2018, the sister became pregnant and, at her request, Dr. Goodwin prescribed misoprostol to induce an abortion. The affair and the abortion were later discovered by the sister’s family, who agreed to not file a complaint with the medical board in exchange for Dr. Goodwin’s agreeing to cease communications with the sister.

Nevertheless, the two continued the affair and in February 2019 the patient’s father and mother each separately complained to the medical board. The sister also sent a letter to the board urging against disciplinary action – but later acknowledged that the letter was prepared by Dr. Goodwin.

The family removed Patient A from Dr. Goodwin’s care in 2019. The sister’s relationship with Patient A and her family was damaged; she subsequently divorced her husband and moved out of state. She later told the board she regretted the relationship and knew it was wrong.

When Dr. Goodwin was initially interviewed in 2019 by the medical board, he refused to discuss the relationship or the misoprostol prescription. Then, at a later hearing, he said he did not see anything wrong with the relationship and did not believe it affected the care of Patient A.

The medical board’s expert witness said Dr. Goodwin’s behavior “showed he either had no knowledge of ethical boundaries or chose to ignore them, showing poor judgment and ‘cluelessness’ about the potential adverse effects of having a sexual relationship with Sister, which had the significant potential to compromise Patient A’s treatment.”
 

Sexual assault

Patient B came to Dr. Goodwin in 2017 to help taper her anxiety and depression medications. She informed him she had experienced multiple sexual assaults. He helped her taper off the drugs within a month and then hired her to work part-time at the practice’s reception desk.

After her symptoms worsened again after a traumatic event, Dr. Goodwin recommended the use of ketamine. Patient B received five ketamine treatments in a month with only Dr. Goodwin present in the room.

During one of those treatments he asked her questions about her sex life.  Another night in the office he asked her to have a glass of wine with him and then allegedly sexually assaulted her.

Patient B soon quit the job via text, telling him his behavior was inappropriate. She told Dr. Goodwin she would not say anything about the assault but asked for a letter of recommendation for another job. Dr. Goodwin texted back that she was “100% right,” and he would give her a great recommendation, which he later did.

A year later, in 2019, Pamela Albro, PhD, a psychologist who provided therapy at Sequoia Mind Health, contacted Patient B to ask why she quit.

When Patient B told her about the assault, the therapist asked to share her name with Patient C, who had a similar experience. Patient B agreed and then submitted a police report and a complaint to the medical board in March 2019.

Dr. Goodwin denied Patient B’s allegations and “offered evasive and non-credible testimony” about Patient B’s text messages, the board said.
 

Another patient-employee

Patient C attended Dr. Goodwin’s clinic in May 2017 after a suicide attempt that required hospitalization. She told Dr. Goodwin she had experienced sexual trauma and assault in the past. Dr. Goodwin referred Patient C to Dr. Albro for therapy, managed her medications himself, and hired her to work at the clinic’s reception desk, even though she was still a patient.

Patient C worked 32 hours a week and took on other duties that included assisting in the administration of transcranial magnetic stimulation to clinic patients.

In late 2017, Dr. Goodwin recommended ketamine for Patient C and she received seven treatments from December 2017 through April 2019. There were no records of vital signs monitoring during the treatments, and Dr. Goodwin’s wife was present for only two sessions.

During the first treatment, where Patient C said she was feeling “out of it,” Dr. Goodwin allegedly sexually assaulted her.

Because of the ketamine, she told the medical board she was unable to speak or yell but said, “I screamed in my head.” After Dr. Goodwin left the room, she said she felt afraid, ashamed, and wanted to go home. Dr. Goodwin walked her to the lobby where her husband was waiting.

The patient did not tell her husband about the assault because she said she felt ashamed, and said she did not report Dr. Goodwin because it was not safe.
 

Disciplinary hearing

Patient C continued to work for Dr. Goodwin, calling it a confusing time in her life. She later learned about the affair with Patient A’s sister and about Patient B’s experience and resigned from the clinic in July 2019.

She still did not discuss the assault until early 2021 when the board contacted her again. She confided to her primary care physician, who noted that her PTSD symptoms had worsened.

Dr. Goodwin said in the disciplinary hearing that hiring Patient B and Patient C was “boundary crossing,” but he denied allegations of asking inappropriate questions or of sexual assault. The board, however, characterized the testimony of Patient B and Patient C as credible.

All of Dr. Goodwin’s other employers said at his disciplinary hearing that they believed he was a good psychiatrist and that they had never seen any unprofessional behavior.

The revocation of Dr. Goodwin’s license will be effective as of April 7. Dr. Goodwin’s attorney, Marvin H. Firestone, MD, JD, told this news organization he had “no comment” on the medical board’s decision or about his client.

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

A new U.K. study shows no link between brain tumors and cell phone use, even among individuals who used their phones every day and/or had used them for over 10 years.

“These results support the accumulating evidence that mobile phone use under usual conditions does not increase brain tumor risk,” study author Kirstin Pirie, MSc, from the cancer epidemiology unit at Oxford (England) Population Health, said in a statement.

However, an important limitation of the study is that it involved only women who were middle-aged and older; these people generally use cell phones less than younger women or men, the authors noted. In this study’s cohort, mobile phone use was low, with only 18% of users talking on the phone for 30 minutes or more each week.

The results were published in the Journal of the National Cancer Institute.

This study is a “welcome addition to the body of knowledge looking at the risk from mobile phones, and specifically in relation to certain types of tumor genesis. It is a well-designed, prospective study that identifies no causal link,” commented Malcolm Sperrin from Oxford University Hospitals, who was not involved in the research.

“There is always a need for further research work, especially as phones, wireless, etc., become ubiquitous, but this study should allay many existing concerns,” he commented on the UK Science Media Centre.

Concerns about a cancer risk, particularly brain tumors, have been circulating for decades, and to date, there have been some 30 epidemiologic studies on this issue.

In 2011, the International Agency for Research on Cancer announced that cell phones are “possibly carcinogenic.” That conclusion was based largely on the results of the large INTERPHONE international case-control study and a series of Swedish studies led by Hardell Lennart, MD.

In the latest article, the U.K. researchers suggest that a “likely explanation for the previous positive results is that for a very slow growing tumor, there may be detection bias if cellular telephone users seek medical advice because of awareness of typical symptoms of acoustic neuroma, such as unilateral hearing problems, earlier than nonusers.

“The totality of human evidence, from observational studies, time trends, and bioassays, suggests little or no increase in the risk of cellular telephone users developing a brain tumor,” the U.K. researchers concluded.

Commenting on the U.K. study, Joachim Schüz, PhD, branch head of the section of environment and radiation at the IARC, noted that “mobile technologies are improving all the time, so that the more recent generations emit substantially lower output power.

“Nevertheless, given the lack of evidence for heavy users, advising mobile phone users to reduce unnecessary exposures remains a good precautionary approach,” Dr. Schuz said in a statement.
 

Details of U.K. study

The U.K. study was conducted by researchers from Oxford Population Health and IARC, who used data from the ongoing UK Million Women Study. This study began in 1996 and has recruited 1.3 million women born from 1935 to 1950 (which amounts to 1 in every 4 women) through the U.K. National Health Service Breast Screening Programme. These women complete regular postal questionnaires about sociodemographic, medical, and lifestyle factors.

Questions about cell phone use were completed by about 776,000 women in 2001 (when they were 50-65 years old). About half of these women also answered these questions about mobile phone use 10 years later, in 2011 (when they were aged 60-75).

The answers indicated that by 2011, the majority of women (75%) aged between 60 and 64 years used a mobile phone, while just under half of those aged between 75 and 79 years used one.

These women were then followed for an average of 14 years through linkage to their NHS records.

The researchers looked for any mention of brain tumors, including glioma, acoustic neuroma, meningioma, and pituitary gland tumors, as well as eye tumors.

During the 14 year follow-up period, 3,268 (0.42%) of the participants developed a brain tumor, but there was no significant difference in that risk between individuals who had never used a mobile phone and those who were mobile phone users. These included tumors in the temporal and parietal lobes, which are the most exposed areas of the brain.

There was also no difference in the risk of developing tumors between women who reported using a mobile phone daily, those who used them for at least 20 minutes a week, and those who had used a mobile phone for over 10 years.

In addition, among the individuals who did develop a tumor, the incidence of right- and left-sided tumors was similar among mobile phone users, even though mobile phone use tends to involve the right side considerably more than the left side, the researchers noted.

The study was funded by the UK Medical Research Council and Cancer Research UK.

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

A new U.K. study shows no link between brain tumors and cell phone use, even among individuals who used their phones every day and/or had used them for over 10 years.

“These results support the accumulating evidence that mobile phone use under usual conditions does not increase brain tumor risk,” study author Kirstin Pirie, MSc, from the cancer epidemiology unit at Oxford (England) Population Health, said in a statement.

However, an important limitation of the study is that it involved only women who were middle-aged and older; these people generally use cell phones less than younger women or men, the authors noted. In this study’s cohort, mobile phone use was low, with only 18% of users talking on the phone for 30 minutes or more each week.

The results were published in the Journal of the National Cancer Institute.

This study is a “welcome addition to the body of knowledge looking at the risk from mobile phones, and specifically in relation to certain types of tumor genesis. It is a well-designed, prospective study that identifies no causal link,” commented Malcolm Sperrin from Oxford University Hospitals, who was not involved in the research.

“There is always a need for further research work, especially as phones, wireless, etc., become ubiquitous, but this study should allay many existing concerns,” he commented on the UK Science Media Centre.

Concerns about a cancer risk, particularly brain tumors, have been circulating for decades, and to date, there have been some 30 epidemiologic studies on this issue.

In 2011, the International Agency for Research on Cancer announced that cell phones are “possibly carcinogenic.” That conclusion was based largely on the results of the large INTERPHONE international case-control study and a series of Swedish studies led by Hardell Lennart, MD.

In the latest article, the U.K. researchers suggest that a “likely explanation for the previous positive results is that for a very slow growing tumor, there may be detection bias if cellular telephone users seek medical advice because of awareness of typical symptoms of acoustic neuroma, such as unilateral hearing problems, earlier than nonusers.

“The totality of human evidence, from observational studies, time trends, and bioassays, suggests little or no increase in the risk of cellular telephone users developing a brain tumor,” the U.K. researchers concluded.

Commenting on the U.K. study, Joachim Schüz, PhD, branch head of the section of environment and radiation at the IARC, noted that “mobile technologies are improving all the time, so that the more recent generations emit substantially lower output power.

“Nevertheless, given the lack of evidence for heavy users, advising mobile phone users to reduce unnecessary exposures remains a good precautionary approach,” Dr. Schuz said in a statement.
 

Details of U.K. study

The U.K. study was conducted by researchers from Oxford Population Health and IARC, who used data from the ongoing UK Million Women Study. This study began in 1996 and has recruited 1.3 million women born from 1935 to 1950 (which amounts to 1 in every 4 women) through the U.K. National Health Service Breast Screening Programme. These women complete regular postal questionnaires about sociodemographic, medical, and lifestyle factors.

Questions about cell phone use were completed by about 776,000 women in 2001 (when they were 50-65 years old). About half of these women also answered these questions about mobile phone use 10 years later, in 2011 (when they were aged 60-75).

The answers indicated that by 2011, the majority of women (75%) aged between 60 and 64 years used a mobile phone, while just under half of those aged between 75 and 79 years used one.

These women were then followed for an average of 14 years through linkage to their NHS records.

The researchers looked for any mention of brain tumors, including glioma, acoustic neuroma, meningioma, and pituitary gland tumors, as well as eye tumors.

During the 14 year follow-up period, 3,268 (0.42%) of the participants developed a brain tumor, but there was no significant difference in that risk between individuals who had never used a mobile phone and those who were mobile phone users. These included tumors in the temporal and parietal lobes, which are the most exposed areas of the brain.

There was also no difference in the risk of developing tumors between women who reported using a mobile phone daily, those who used them for at least 20 minutes a week, and those who had used a mobile phone for over 10 years.

In addition, among the individuals who did develop a tumor, the incidence of right- and left-sided tumors was similar among mobile phone users, even though mobile phone use tends to involve the right side considerably more than the left side, the researchers noted.

The study was funded by the UK Medical Research Council and Cancer Research UK.

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

A new U.K. study shows no link between brain tumors and cell phone use, even among individuals who used their phones every day and/or had used them for over 10 years.

“These results support the accumulating evidence that mobile phone use under usual conditions does not increase brain tumor risk,” study author Kirstin Pirie, MSc, from the cancer epidemiology unit at Oxford (England) Population Health, said in a statement.

However, an important limitation of the study is that it involved only women who were middle-aged and older; these people generally use cell phones less than younger women or men, the authors noted. In this study’s cohort, mobile phone use was low, with only 18% of users talking on the phone for 30 minutes or more each week.

The results were published in the Journal of the National Cancer Institute.

This study is a “welcome addition to the body of knowledge looking at the risk from mobile phones, and specifically in relation to certain types of tumor genesis. It is a well-designed, prospective study that identifies no causal link,” commented Malcolm Sperrin from Oxford University Hospitals, who was not involved in the research.

“There is always a need for further research work, especially as phones, wireless, etc., become ubiquitous, but this study should allay many existing concerns,” he commented on the UK Science Media Centre.

Concerns about a cancer risk, particularly brain tumors, have been circulating for decades, and to date, there have been some 30 epidemiologic studies on this issue.

In 2011, the International Agency for Research on Cancer announced that cell phones are “possibly carcinogenic.” That conclusion was based largely on the results of the large INTERPHONE international case-control study and a series of Swedish studies led by Hardell Lennart, MD.

In the latest article, the U.K. researchers suggest that a “likely explanation for the previous positive results is that for a very slow growing tumor, there may be detection bias if cellular telephone users seek medical advice because of awareness of typical symptoms of acoustic neuroma, such as unilateral hearing problems, earlier than nonusers.

“The totality of human evidence, from observational studies, time trends, and bioassays, suggests little or no increase in the risk of cellular telephone users developing a brain tumor,” the U.K. researchers concluded.

Commenting on the U.K. study, Joachim Schüz, PhD, branch head of the section of environment and radiation at the IARC, noted that “mobile technologies are improving all the time, so that the more recent generations emit substantially lower output power.

“Nevertheless, given the lack of evidence for heavy users, advising mobile phone users to reduce unnecessary exposures remains a good precautionary approach,” Dr. Schuz said in a statement.
 

Details of U.K. study

The U.K. study was conducted by researchers from Oxford Population Health and IARC, who used data from the ongoing UK Million Women Study. This study began in 1996 and has recruited 1.3 million women born from 1935 to 1950 (which amounts to 1 in every 4 women) through the U.K. National Health Service Breast Screening Programme. These women complete regular postal questionnaires about sociodemographic, medical, and lifestyle factors.

Questions about cell phone use were completed by about 776,000 women in 2001 (when they were 50-65 years old). About half of these women also answered these questions about mobile phone use 10 years later, in 2011 (when they were aged 60-75).

The answers indicated that by 2011, the majority of women (75%) aged between 60 and 64 years used a mobile phone, while just under half of those aged between 75 and 79 years used one.

These women were then followed for an average of 14 years through linkage to their NHS records.

The researchers looked for any mention of brain tumors, including glioma, acoustic neuroma, meningioma, and pituitary gland tumors, as well as eye tumors.

During the 14 year follow-up period, 3,268 (0.42%) of the participants developed a brain tumor, but there was no significant difference in that risk between individuals who had never used a mobile phone and those who were mobile phone users. These included tumors in the temporal and parietal lobes, which are the most exposed areas of the brain.

There was also no difference in the risk of developing tumors between women who reported using a mobile phone daily, those who used them for at least 20 minutes a week, and those who had used a mobile phone for over 10 years.

In addition, among the individuals who did develop a tumor, the incidence of right- and left-sided tumors was similar among mobile phone users, even though mobile phone use tends to involve the right side considerably more than the left side, the researchers noted.

The study was funded by the UK Medical Research Council and Cancer Research UK.

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

Pointing a finger at COVID-19

The battle against COVID-19 is seemingly never ending. It’s been 2 years and still we struggle against the virus. But now, a new hero rises against the eternal menace, a powerful weapon against this scourge of humanity. And that weapon? Finger length.

Before you break out the sad trombone, hear us out. One of the big questions around COVID-19 is the role testosterone plays in its severity: Does low testosterone increase or decrease the odds of contracting severe COVID-19? To help answer that question, English researchers have published a study analyzing finger length ratios in both COVID-19 patients and a healthy control group. That seems random, but high testosterone in the womb leads to longer ring fingers in adulthood, while high estrogen leads to longer index fingers.

PxHere

According to the researchers, those who had significant left hand–right hand differences in the ratio between the second and fourth digits, as well as the third and fifth digits, were significantly more likely to have severe COVID-19 compared with those with more even ratios. Those with “feminized” short little fingers were also at risk. Those large ratio differences indicate low testosterone and high estrogen, which may explain why elderly men are at such high risk for severe COVID-19. Testosterone naturally falls off as men get older.

The results add credence to clinical trials looking to use testosterone-boosting drugs against COVID-19, the researchers said. It also gives credence to LOTME’s brand-new 12-step finger strength fitness routine and our branded finger weights. Now just $19.95! It’s the bargain of the century! Boost your testosterone naturally and protect yourself from COVID-19! We promise it’s not a scam.
 

Some emergencies need a superhero

Last week, we learned about the most boring person in the world. This week just happens to be opposite week, so we’re looking at a candidate for the most interesting person. Someone who can swoop down from the sky to save the injured and helpless. Someone who can go where helicopters fear to tread. Someone with jet engines for arms. Superhero-type stuff.

Richard Browning/Gravity Industries

The Great North Air Ambulance Service (GNAAS), a charitable organization located in the United Kingdom, recently announced that one of its members has completed training on the Gravity Industries Jet Suit. The suit “has two engines on each arm and a larger engine on the back [that] provide up to 317 pounds of thrust,” Interesting Engineering explained.

GNAAS is putting the suit into operation in England’s Lake District National Park, which includes mountainous terrain that is not very hospitable to helicopter landings. A paramedic using the suit can reach hikers stranded on mountainsides much faster than rescuers who have to run or hike from the nearest helicopter landing site.

“Everyone looks at the wow factor and the fact we are the world’s first jet suit paramedics, but for us, it’s about delivering patient care,” GNAAS’ Andy Mawson told Interesting Engineering. Sounds like superhero-speak to us.

So if you’re in the Lake District and have taken a bit of a tumble, you can call a superhero on your cell phone or you can use this to summon one.
 

Why we’re rejecting food as medicine

Humans have been using food to treat ailments much longer than we’ve had the advances of modern medicine. So why have we rejected its worth in our treatment processes? And what can be done to change that? The Center for Food as Medicine and the Hunter College NYC Food Policy Center just released a 335-page report that answers those questions.

phototake/ThinkStock

First, the why: Meals in health care settings are not medically designed to help with the specific needs of the patient. Produce-prescription and nutrition-incentive programs don’t have the government funds to fully support them. And a lot of medical schools don’t even require students to take a basic nutrition course. So there’s a lack of knowledge and a disconnect between health care providers and food as a resource.

Then there’s a lack of trust in the food industry and their validity. Social media uses food as a means of promoting “pseudoscientific alternative medicine” or spreading false info, pushing away legitimate providers. The food industry has had its fingers in food science studies and an almost mafia-esque chokehold on American dietary guidelines. No wonder food for medicine is getting the boot!

To change the situation, the report offers 10 key recommendations on how to advance the idea of incorporating food into medicine for treatment and prevention. They include boosting the funding for research, making hospitals more food-as-medicine focused, expanding federal programs, and improving public awareness on the role nutrition can play in medical treatment or prevention.

So maybe instead of rejecting food outright, we should be looking a little deeper at how we can use it to our advantage. Just a thought: Ice cream as an antidepressant.
 

Being rude is a good thing, apparently

If you’ve ever been called argumentative, stubborn, or unpleasant, then this LOTME is for you. Researchers at the University of Geneva have found that people who are more stubborn and hate to conform have brains that are more protected against Alzheimer’s disease. That type of personality seems to preserve the part of the brain that usually deteriorates as we grow older.

Piqsels

The original hypothesis that personality may have a protective effect against brain degeneration led the investigators to conduct cognitive and personality assessments of 65 elderly participants over a 5-year period. Researchers have been attempting to create vaccines to protect against Alzheimer’s disease, but these new findings offer a nonbiological way to help.

“For a long time, the brain is able to compensate by activating alternative networks; when the first clinical signs appear, however, it is unfortunately often too late. The identification of early biomarkers is therefore essential for … effective disease management,” lead author Panteleimon Giannakopoulos, MD, said in a Study Finds report.

You may be wondering how people with more agreeable and less confrontational personalities can seek help. Well, researchers are working on that, too. It’s a complex situation, but as always, we’re rooting for you, science!

At least now you can take solace in the fact that your elderly next-door neighbor who yells at you for stepping on his lawn is probably more protected against Alzheimer’s disease.

Pointing a finger at COVID-19

The battle against COVID-19 is seemingly never ending. It’s been 2 years and still we struggle against the virus. But now, a new hero rises against the eternal menace, a powerful weapon against this scourge of humanity. And that weapon? Finger length.

Before you break out the sad trombone, hear us out. One of the big questions around COVID-19 is the role testosterone plays in its severity: Does low testosterone increase or decrease the odds of contracting severe COVID-19? To help answer that question, English researchers have published a study analyzing finger length ratios in both COVID-19 patients and a healthy control group. That seems random, but high testosterone in the womb leads to longer ring fingers in adulthood, while high estrogen leads to longer index fingers.

PxHere

According to the researchers, those who had significant left hand–right hand differences in the ratio between the second and fourth digits, as well as the third and fifth digits, were significantly more likely to have severe COVID-19 compared with those with more even ratios. Those with “feminized” short little fingers were also at risk. Those large ratio differences indicate low testosterone and high estrogen, which may explain why elderly men are at such high risk for severe COVID-19. Testosterone naturally falls off as men get older.

The results add credence to clinical trials looking to use testosterone-boosting drugs against COVID-19, the researchers said. It also gives credence to LOTME’s brand-new 12-step finger strength fitness routine and our branded finger weights. Now just $19.95! It’s the bargain of the century! Boost your testosterone naturally and protect yourself from COVID-19! We promise it’s not a scam.
 

Some emergencies need a superhero

Last week, we learned about the most boring person in the world. This week just happens to be opposite week, so we’re looking at a candidate for the most interesting person. Someone who can swoop down from the sky to save the injured and helpless. Someone who can go where helicopters fear to tread. Someone with jet engines for arms. Superhero-type stuff.

Richard Browning/Gravity Industries

The Great North Air Ambulance Service (GNAAS), a charitable organization located in the United Kingdom, recently announced that one of its members has completed training on the Gravity Industries Jet Suit. The suit “has two engines on each arm and a larger engine on the back [that] provide up to 317 pounds of thrust,” Interesting Engineering explained.

GNAAS is putting the suit into operation in England’s Lake District National Park, which includes mountainous terrain that is not very hospitable to helicopter landings. A paramedic using the suit can reach hikers stranded on mountainsides much faster than rescuers who have to run or hike from the nearest helicopter landing site.

“Everyone looks at the wow factor and the fact we are the world’s first jet suit paramedics, but for us, it’s about delivering patient care,” GNAAS’ Andy Mawson told Interesting Engineering. Sounds like superhero-speak to us.

So if you’re in the Lake District and have taken a bit of a tumble, you can call a superhero on your cell phone or you can use this to summon one.
 

Why we’re rejecting food as medicine

Humans have been using food to treat ailments much longer than we’ve had the advances of modern medicine. So why have we rejected its worth in our treatment processes? And what can be done to change that? The Center for Food as Medicine and the Hunter College NYC Food Policy Center just released a 335-page report that answers those questions.

phototake/ThinkStock

First, the why: Meals in health care settings are not medically designed to help with the specific needs of the patient. Produce-prescription and nutrition-incentive programs don’t have the government funds to fully support them. And a lot of medical schools don’t even require students to take a basic nutrition course. So there’s a lack of knowledge and a disconnect between health care providers and food as a resource.

Then there’s a lack of trust in the food industry and their validity. Social media uses food as a means of promoting “pseudoscientific alternative medicine” or spreading false info, pushing away legitimate providers. The food industry has had its fingers in food science studies and an almost mafia-esque chokehold on American dietary guidelines. No wonder food for medicine is getting the boot!

To change the situation, the report offers 10 key recommendations on how to advance the idea of incorporating food into medicine for treatment and prevention. They include boosting the funding for research, making hospitals more food-as-medicine focused, expanding federal programs, and improving public awareness on the role nutrition can play in medical treatment or prevention.

So maybe instead of rejecting food outright, we should be looking a little deeper at how we can use it to our advantage. Just a thought: Ice cream as an antidepressant.
 

Being rude is a good thing, apparently

If you’ve ever been called argumentative, stubborn, or unpleasant, then this LOTME is for you. Researchers at the University of Geneva have found that people who are more stubborn and hate to conform have brains that are more protected against Alzheimer’s disease. That type of personality seems to preserve the part of the brain that usually deteriorates as we grow older.

Piqsels

The original hypothesis that personality may have a protective effect against brain degeneration led the investigators to conduct cognitive and personality assessments of 65 elderly participants over a 5-year period. Researchers have been attempting to create vaccines to protect against Alzheimer’s disease, but these new findings offer a nonbiological way to help.

“For a long time, the brain is able to compensate by activating alternative networks; when the first clinical signs appear, however, it is unfortunately often too late. The identification of early biomarkers is therefore essential for … effective disease management,” lead author Panteleimon Giannakopoulos, MD, said in a Study Finds report.

You may be wondering how people with more agreeable and less confrontational personalities can seek help. Well, researchers are working on that, too. It’s a complex situation, but as always, we’re rooting for you, science!

At least now you can take solace in the fact that your elderly next-door neighbor who yells at you for stepping on his lawn is probably more protected against Alzheimer’s disease.

Pointing a finger at COVID-19

The battle against COVID-19 is seemingly never ending. It’s been 2 years and still we struggle against the virus. But now, a new hero rises against the eternal menace, a powerful weapon against this scourge of humanity. And that weapon? Finger length.

Before you break out the sad trombone, hear us out. One of the big questions around COVID-19 is the role testosterone plays in its severity: Does low testosterone increase or decrease the odds of contracting severe COVID-19? To help answer that question, English researchers have published a study analyzing finger length ratios in both COVID-19 patients and a healthy control group. That seems random, but high testosterone in the womb leads to longer ring fingers in adulthood, while high estrogen leads to longer index fingers.

PxHere

According to the researchers, those who had significant left hand–right hand differences in the ratio between the second and fourth digits, as well as the third and fifth digits, were significantly more likely to have severe COVID-19 compared with those with more even ratios. Those with “feminized” short little fingers were also at risk. Those large ratio differences indicate low testosterone and high estrogen, which may explain why elderly men are at such high risk for severe COVID-19. Testosterone naturally falls off as men get older.

The results add credence to clinical trials looking to use testosterone-boosting drugs against COVID-19, the researchers said. It also gives credence to LOTME’s brand-new 12-step finger strength fitness routine and our branded finger weights. Now just $19.95! It’s the bargain of the century! Boost your testosterone naturally and protect yourself from COVID-19! We promise it’s not a scam.
 

Some emergencies need a superhero

Last week, we learned about the most boring person in the world. This week just happens to be opposite week, so we’re looking at a candidate for the most interesting person. Someone who can swoop down from the sky to save the injured and helpless. Someone who can go where helicopters fear to tread. Someone with jet engines for arms. Superhero-type stuff.

Richard Browning/Gravity Industries

The Great North Air Ambulance Service (GNAAS), a charitable organization located in the United Kingdom, recently announced that one of its members has completed training on the Gravity Industries Jet Suit. The suit “has two engines on each arm and a larger engine on the back [that] provide up to 317 pounds of thrust,” Interesting Engineering explained.

GNAAS is putting the suit into operation in England’s Lake District National Park, which includes mountainous terrain that is not very hospitable to helicopter landings. A paramedic using the suit can reach hikers stranded on mountainsides much faster than rescuers who have to run or hike from the nearest helicopter landing site.

“Everyone looks at the wow factor and the fact we are the world’s first jet suit paramedics, but for us, it’s about delivering patient care,” GNAAS’ Andy Mawson told Interesting Engineering. Sounds like superhero-speak to us.

So if you’re in the Lake District and have taken a bit of a tumble, you can call a superhero on your cell phone or you can use this to summon one.
 

Why we’re rejecting food as medicine

Humans have been using food to treat ailments much longer than we’ve had the advances of modern medicine. So why have we rejected its worth in our treatment processes? And what can be done to change that? The Center for Food as Medicine and the Hunter College NYC Food Policy Center just released a 335-page report that answers those questions.

phototake/ThinkStock

First, the why: Meals in health care settings are not medically designed to help with the specific needs of the patient. Produce-prescription and nutrition-incentive programs don’t have the government funds to fully support them. And a lot of medical schools don’t even require students to take a basic nutrition course. So there’s a lack of knowledge and a disconnect between health care providers and food as a resource.

Then there’s a lack of trust in the food industry and their validity. Social media uses food as a means of promoting “pseudoscientific alternative medicine” or spreading false info, pushing away legitimate providers. The food industry has had its fingers in food science studies and an almost mafia-esque chokehold on American dietary guidelines. No wonder food for medicine is getting the boot!

To change the situation, the report offers 10 key recommendations on how to advance the idea of incorporating food into medicine for treatment and prevention. They include boosting the funding for research, making hospitals more food-as-medicine focused, expanding federal programs, and improving public awareness on the role nutrition can play in medical treatment or prevention.

So maybe instead of rejecting food outright, we should be looking a little deeper at how we can use it to our advantage. Just a thought: Ice cream as an antidepressant.
 

Being rude is a good thing, apparently

If you’ve ever been called argumentative, stubborn, or unpleasant, then this LOTME is for you. Researchers at the University of Geneva have found that people who are more stubborn and hate to conform have brains that are more protected against Alzheimer’s disease. That type of personality seems to preserve the part of the brain that usually deteriorates as we grow older.

Piqsels

The original hypothesis that personality may have a protective effect against brain degeneration led the investigators to conduct cognitive and personality assessments of 65 elderly participants over a 5-year period. Researchers have been attempting to create vaccines to protect against Alzheimer’s disease, but these new findings offer a nonbiological way to help.

“For a long time, the brain is able to compensate by activating alternative networks; when the first clinical signs appear, however, it is unfortunately often too late. The identification of early biomarkers is therefore essential for … effective disease management,” lead author Panteleimon Giannakopoulos, MD, said in a Study Finds report.

You may be wondering how people with more agreeable and less confrontational personalities can seek help. Well, researchers are working on that, too. It’s a complex situation, but as always, we’re rooting for you, science!

At least now you can take solace in the fact that your elderly next-door neighbor who yells at you for stepping on his lawn is probably more protected against Alzheimer’s disease.

Verrucous carcinoma is a rare cancer with the greatest predilection for the foot. Multiple case reports with only a few large case series have been published. ^1-3 Plantar verrucous carcinoma is characterized as a slowly but relentlessly enlarging warty tumor with low metastatic potential and high risk for local invasion. The tumor occurs most frequently in patients aged 60 to 70 years, predominantly in White males. ¹ It often is misdiagnosed for years as an ulcer or wart that is highly resistant to therapy. Size typically ranges from 1 to 12 cm in greatest dimension. ¹

The pathogenesis of plantar verrucous carcinoma remains unclear, but some contributing factors have been proposed, including trauma, chronic irritation, infection, and poor local hygiene.² This tumor has been reported to occur in chronic foot ulcerations, particularly in the diabetic population.⁴ It has been proposed that abnormal expression of the p53 tumor suppressor protein and several types of human papillomavirus (HPV) may have a role in the pathogenesis of verrucous carcinoma.⁵

The pathologic hallmarks of this tumor include a verrucous/hyperkeratotic surface with a deeply endophytic, broad, pushing base. Tumor cells are well differentiated, and atypia is either absent or confined to 1 or 2 layers at the base of the tumor. Overt invasion at the base is lacking, except in cases with a component of conventional invasive squamous cell carcinoma. Human papillomavirus viropathic changes are classically absent.^1,3 Studies of the histopathology of verrucous carcinoma have been complicated by similar entities, nomenclatural uncertainty, and variable diagnostic criteria. For example, epithelioma cuniculatum variously has been defined as being synonymous with verrucous carcinoma, a distinct clinical verrucous carcinoma subtype occurring on the soles, a histologic subtype (characterized by prominent burrowing sinuses), or a separate entity entirely.^1,2,6,7 Furthermore, in the genital area, several different types of carcinomas have verruciform features but display distinct microscopic findings and outcomes from verrucous carcinoma.⁸

Verrucous carcinoma represents an unusual variant of squamous cell carcinoma and is treated as such. Treatments have included laser surgery; immunotherapy; retinoid therapy; and chemotherapy by oral, intralesional, or iontophoretic routes in select patients.⁹ Radiotherapy presents another option, though reports have described progression to aggressive squamous cell carcinoma in some cases.⁹ Surgery is the best course of treatment, and as more case reports have been published, a transition from radical resection to wide excision with tumor-free margins is the treatment of choice.^2,3,10,11 To minimize soft-tissue deficits, Mohs micrographic surgery has been discussed as a treatment option for verrucous carcinoma.^11-13

Few studies have described verrucous carcinoma recurrence, and none have systematically examined recurrence rate, risk factors, or prognosis.^3,9,14 In our retrospective review of 19 new cases of verrucous carcinoma of the foot, we examined 5 recurrent tumors despite negative margin surgical resection and report risk factors and surgical management of these lesions.

Methods

Patient cases were identified through the University of Michigan (Ann Arbor, Michigan) pathology database from 1995 to 2019 based on the primary diagnosis of verrucous carcinoma located on the foot. Nineteen cases were identified and were included in demographic and clinical presentation analyses. Medical records were reviewed to abstract selected clinical data and outcomes of analysis.

Of the 19 cases, 16 were treated at the University of Michigan and are included in the treatment analyses. Specific attention was then paid to the cases with a clinical recurrence despite negative surgical margins. We compared the clinical and surgical differences between recurrent cases and nonrecurrent cases.

Pathology was rereviewed for selected cases, including 2 cases with recurrence and matched primary, 2 cases with recurrence (for which the matched primary was unavailable for review), and 5 representative primary cases that were not complicated by recurrence. Pathology review was conducted in a blinded manner by one of the authors (P.W.H) who is a board-certified dermatopathologist for approximate depth of invasion from the granular layer, perineural invasion, bone invasion, infiltrative growth, presence of conventional squamous cell carcinoma, and margin status.

Statistical analysis was performed when appropriate using an N1 χ² test or Student t test.

Results

Demographics and Comorbidities—The median age of the patients at the time of diagnosis was 55 years (range, 34–77 years). There were 12 males and 7 females (Table 1). Two patients were Black and 17 were White. Almost all patients had additional comorbidities including tobacco use (68%), alcohol use (47%), and diabetes (47%). Only 1 patient had an autoimmune disease and was on chronic steroids. No significant difference was found between the demographics of patients with recurrent lesions and those without recurrence.

Tumor Location and Clinical Presentation—The most common clinical presentation included a nonhealing ulceration with warty edges, pain, bleeding, and lowered mobility. In most cases, there was history of prior treatment over a duration ranging from 1 to 8 years, with a median of 5 years prior to biopsy-based diagnosis (Table 1). Six patients had a history of osteomyelitis, diagnosed by imaging or biopsy, within a year before tumor diagnosis. The size of the primary tumor ranged from 2.4 to 6 cm, with a mean of 4 cm (P=.20). The clinical presentation, time before diagnosis, and size of the tumors did not differ significantly between recurrent and nonrecurrent cases.

The tumor location for the recurrent cases differed significantly compared to nonrecurrent cases. All 5 of the patients with a recurrence presented with a tumor on the nonglabrous part of the foot. Four patients (80%) had lesions on the dorsal or lateral aspect of the great toe (P=.002), and 1 patient (20%) had a lesion on the low ankle (P=.09)(Table 1). Of the nonrecurrent cases, 1 patient (7%) presented with a tumor on the plantar surface of the great toe (P=.002), 13 patients (93%) presented with tumors on the distal plantar surface of the foot (P=.0002), and 1 patient with a plantar foot tumor (Figure 1) also had verrucous carcinoma on the thumb (Table 1 and Figure 2).

Histopathology—Available pathology slides for recurrent cases of verrucous carcinoma were reviewed alongside representative cases of verrucous carcinomas that did not progress to recurrence. The diagnosis of verrucous carcinoma was confirmed in all cases, with no evidence of conventional squamous cell carcinoma, perineural invasion, extension beyond the dermis, or bone invasion in any case. The median size of the tumors was 4.2 cm and 4 cm for nonrecurrent and recurrent specimens, respectively. Recurrences displayed a trend toward increased depth compared to primary tumors without recurrence (average depth, 5.5 mm vs 3.7 mm); however, this did not reach statistical significance (P=.24). Primary tumors that progressed to recurrence (n=2) displayed similar findings to the other cases, with invasive depths of 3.5 and 5.5 mm, and there was no evidence of conventional squamous cell carcinoma, perineural invasion, or extension beyond the dermis.

Treatment of Nonrecurrent Cases—Of the 16 total cases treated at the University of Michigan, surgery was the primary mode of therapy in every case (Tables 2 and 3). Of the 11 nonrecurrent cases, 7 patients had wide local excision with a dermal regeneration template, and delayed split-thickness graft reconstruction. Three cases had wide local excision with metatarsal resection, dermal regeneration template, and delayed skin grafting. One case had a great toe amputation. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (8/11 [73%] reported). Three cases had positive margins at the time of primary resection; 2 were treated with further resection, and 1 had a below the knee amputation (BKA). Follow-up on average was 12 months, with a range of 3 to 36 months.

Treatment of Recurrent Cases—For the 5 patients with recurrence, surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (4/5 [80%] reported). On average, follow-up for this group of patients was 29 months, with a range of 12 to 60 months (Table 3).

Another patient with recurrence (patient 13) presented with a chronic great toe ulcer of 5 years’ duration that formed on the dorsal aspect of the great toe after a previously excised wart (Figure 4A). This patient underwent mid-proximal metatarsal amputation with 2-cm margins and subsequent skin graft. Pathologic margins were negative. Within 6 months, there was hyperkeratosis and a draining wound (Figure 4B). Biopsy results confirmed recurrent disease that was treated with re-resection, including complete metatarsal amputation with negative margins and skin graft placement. Verrucous carcinoma recurred at the edges of the graft within 8 months, and the patient elected for a BKA. In addition, this patient also presented with a verrucous carcinoma of the contralateral great toe. The tumor presented as a warty ulcer of 4 months’ duration in the setting of osteomyelitis and was resected by great toe amputation that was performed concurrently with the opposite leg BKA; there has been no recurrence. Of note, this was the only patient to have right inguinal sentinel lymph node tissue sampled and HPV testing conducted, which were negative for verrucous carcinoma and high or low strains of HPV.

Another recurrent case (patient 14) presented with a large warty lesion on the dorsal great toe positive for verrucous carcinoma. He underwent a complete great toe amputation with skin graft placement. Verrucous carcinoma recurred on the edges of the graft within 6 months, and the patient was lost to follow-up when a BKA was suggested.

The fourth recurrent case (patient 15) initially had been treated for 1 year as a viral verruca of the dorsal aspect of the great toe. He had an exophytic mass positive for verrucous carcinoma growing on the dorsal aspect of the great toe around the prior excision site. After primary wide excision with negative 1-cm margins and graft placement, the tumor was re-excised twice within the next 2 years with pathologic negative margins. The patient underwent a foot amputation due to a severe osteomyelitis infection at the reconstruction site.

The final recurrent case (patient 16) presented with a mass on the lateral great toe that initially was treated as a viral verruca (for unknown duration) that had begun to ulcerate. The patient underwent wide excision with 1-cm margins and graft placement. Final pathology was consistent with verrucous carcinoma with negative margins. Recurrence occurred within 11 months on the edge of the graft, and a great toe amputation through the metatarsal phalangeal joint was performed.

Comment

Our series of 19 cases of verrucous carcinoma adds to the limited number of reported cases in the literature. We sought to evaluate the potential risk factors for early recurrence. Consistent with prior studies, our series found verrucous carcinoma of the foot to occur most frequently in patients aged 50 to 70 years, predominantly in White men.¹ These tumors grew in the setting of chronic inflammation, tissue regeneration, multiple comorbidities, and poor wound hygiene. Misdiagnosis of verrucous carcinoma often leads to ineffective treatments and local invasion of nerves, muscle, and bone tissue.^9,15,16 Our case series also clearly demonstrated the diagnostic challenge verrucous carcinoma presents, with an average delay in diagnosis of 5 years; correct diagnosis often did not occur until the tumor was 4 cm in size (average) and more than 50% had chronic ulceration. Tissue collection of the raised ulcer borders and the deep dermis layer of warty lesions is imperative for diagnosis. Clinicians should have a high suspicion for verrucous carcinoma in the setting of a chronic ulceration or warty lesion that is resistant to traditional treatment.

The histologic features of the tumors showed striking uniformity. Within the literature, there is confusion regarding the use of the terms verrucous carcinoma and carcinoma (epithelioma) cuniculatum and the possible pathologic differences between the two. The World Health Organization’s classification of skin tumors describes epithelioma cuniculatum as verrucous carcinoma located on the sole of the foot.⁷ Kubik and Rhatigan⁶ pointed out that carcinoma cuniculatum does not have a warty or verrucous surface, which is a defining feature of verrucous carcinoma. Multiple authors have further surmised that the deep burrowing sinus tracts of epithelioma cuniculatum are different than those seen in verrucous carcinoma formed by the undulations extending from the papillomatous and verrucous surface.^1,6 We did not observe these notable pathologic differences in recurrent or nonrecurrent primary tumors or differences between primary and recurrent cases. Although our cohort was small, the findings suggest that standard histologic features do not predict aggressive behavior in verrucous carcinomas. Furthermore, our observations support a model wherein recurrence is an inherent property of certain verrucous carcinomas rather than a consequence of histologic progression to conventional squamous cell carcinoma. The lack of overt malignant features in such cases underscores the need for distinction of verrucous carcinoma from benign mimics such as viral verruca or reactive epidermal hyperplasia.

Our recurrent cases showed a greater predilection for nonplantar surfaces and the great toe (P=.002). Five of 6 cases on the nonplantar surface—1 on the ankle and 5 on the great toe—recurred despite negative pathologic margins. There was no significant difference in demographics, pathogenesis, tumor size, chronicity, phenotype, or metastatic spread in recurrent and nonrecurrent cases in our cohort.

The tumor has only been described in rare instances at extrapedal cutaneous sites including the hand, scalp, and abdomen.^14,17,18 Our series did include a case of synchronous presentation with a verrucous carcinoma on the thumb. Given the rarity of this presentation, thus far there are no data supporting any atypical locations of verrucous carcinoma having greater instances of recurrence. Our recurrent cases displaying atypical location on nonglabrous skin could suggest an underlying pathologic mechanism distinct from tumors on glabrous skin and relevant to increased recurrence risk. Such a mechanism might relate to distinct genetic insults, tumor-microenvironment interactions, or field effects. There are few studies regarding physiologic differences between the plantar surface and the nonglabrous surface and how that influences cancer genesis. Within acral melanoma studies, nonglabrous skin of more sun-exposed surfaces has a higher burden of genetic insults including BRAF mutations.¹⁹ Genetic testing of verrucous carcinoma is highly limited, with abnormal expression of the p53 tumor suppressor protein and possible association with several types of HPV. Verrucous carcinoma in general has been found to contain HPV types 6 and 11, nononcogenic forms, and higher risk from HPV types 16 and 18.^9,20 However, only a few cases of HPV type 16 as well as 1 case each of HPV type 2 and type 11 have been found within verrucous carcinoma of the foot.^21,22 In squamous cell carcinoma of the head and neck, HPV-positive tumors have shown better response to treatment. Further investigation of HPV and genetic contributors in verrucous carcinoma is warranted.

There is notable evidence that surgical resection is the best mode of treatment of verrucous carcinoma.^2,3,10,11 Our case series was treated with wide local excision, with partial metatarsal amputation or great toe amputation, in cases with bone invasion or osteomyelitis. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm with no significant differences between the recurrent and nonrecurrent groups. After excision, closure was conducted by incorporating primary, secondary, and delayed closure techniques, along with skin grafts for larger defects. Lymph node biopsy traditionally has not been recommended due to reported low metastatic potential. In all 5 recurrent cases, the tumors recurred after multiple attempts at wide excision and greater resection of bone and tissue, with negative margins. The tumors regrew quickly, within months, on the edges of the new graft or in the middle of the graft. The sites of recurrent tumor growth would suggest regrowth in the areas of greatest tissue stress and proliferation. We recommend a low threshold for biopsy and aggressive retreatment in the setting of exophytic growth at reconstruction sites.

Recurrence is uncommon in the setting of verrucous carcinoma, with our series being the first to analyze prognostic factors.^3,9,14 Our findings indicate that tumors of the nonglabrous surface of the foot should have a higher suspicion for possible local recurrence. Recurrence occurs within months of treatment, deserves early biopsy, and and warrants aggressive treatment. Our series and review highlight the continual diagnostic challenge of this tumor and the pathologic ambiguity that exists. We encourage earlier detection of verrucous carcinoma by appropriate deep tissue biopsy. Future directions should include more comprehensive examination of pathologic features and genetic markers to improve prognostication and management of recurrent and nonrecurrent verrucous carcinoma of the foot.

Verrucous carcinoma is a rare cancer with the greatest predilection for the foot. Multiple case reports with only a few large case series have been published. ^1-3 Plantar verrucous carcinoma is characterized as a slowly but relentlessly enlarging warty tumor with low metastatic potential and high risk for local invasion. The tumor occurs most frequently in patients aged 60 to 70 years, predominantly in White males. ¹ It often is misdiagnosed for years as an ulcer or wart that is highly resistant to therapy. Size typically ranges from 1 to 12 cm in greatest dimension. ¹

The pathogenesis of plantar verrucous carcinoma remains unclear, but some contributing factors have been proposed, including trauma, chronic irritation, infection, and poor local hygiene.² This tumor has been reported to occur in chronic foot ulcerations, particularly in the diabetic population.⁴ It has been proposed that abnormal expression of the p53 tumor suppressor protein and several types of human papillomavirus (HPV) may have a role in the pathogenesis of verrucous carcinoma.⁵

The pathologic hallmarks of this tumor include a verrucous/hyperkeratotic surface with a deeply endophytic, broad, pushing base. Tumor cells are well differentiated, and atypia is either absent or confined to 1 or 2 layers at the base of the tumor. Overt invasion at the base is lacking, except in cases with a component of conventional invasive squamous cell carcinoma. Human papillomavirus viropathic changes are classically absent.^1,3 Studies of the histopathology of verrucous carcinoma have been complicated by similar entities, nomenclatural uncertainty, and variable diagnostic criteria. For example, epithelioma cuniculatum variously has been defined as being synonymous with verrucous carcinoma, a distinct clinical verrucous carcinoma subtype occurring on the soles, a histologic subtype (characterized by prominent burrowing sinuses), or a separate entity entirely.^1,2,6,7 Furthermore, in the genital area, several different types of carcinomas have verruciform features but display distinct microscopic findings and outcomes from verrucous carcinoma.⁸

Verrucous carcinoma represents an unusual variant of squamous cell carcinoma and is treated as such. Treatments have included laser surgery; immunotherapy; retinoid therapy; and chemotherapy by oral, intralesional, or iontophoretic routes in select patients.⁹ Radiotherapy presents another option, though reports have described progression to aggressive squamous cell carcinoma in some cases.⁹ Surgery is the best course of treatment, and as more case reports have been published, a transition from radical resection to wide excision with tumor-free margins is the treatment of choice.^2,3,10,11 To minimize soft-tissue deficits, Mohs micrographic surgery has been discussed as a treatment option for verrucous carcinoma.^11-13

Few studies have described verrucous carcinoma recurrence, and none have systematically examined recurrence rate, risk factors, or prognosis.^3,9,14 In our retrospective review of 19 new cases of verrucous carcinoma of the foot, we examined 5 recurrent tumors despite negative margin surgical resection and report risk factors and surgical management of these lesions.

Methods

Patient cases were identified through the University of Michigan (Ann Arbor, Michigan) pathology database from 1995 to 2019 based on the primary diagnosis of verrucous carcinoma located on the foot. Nineteen cases were identified and were included in demographic and clinical presentation analyses. Medical records were reviewed to abstract selected clinical data and outcomes of analysis.

Of the 19 cases, 16 were treated at the University of Michigan and are included in the treatment analyses. Specific attention was then paid to the cases with a clinical recurrence despite negative surgical margins. We compared the clinical and surgical differences between recurrent cases and nonrecurrent cases.

Pathology was rereviewed for selected cases, including 2 cases with recurrence and matched primary, 2 cases with recurrence (for which the matched primary was unavailable for review), and 5 representative primary cases that were not complicated by recurrence. Pathology review was conducted in a blinded manner by one of the authors (P.W.H) who is a board-certified dermatopathologist for approximate depth of invasion from the granular layer, perineural invasion, bone invasion, infiltrative growth, presence of conventional squamous cell carcinoma, and margin status.

Statistical analysis was performed when appropriate using an N1 χ² test or Student t test.

Results

Demographics and Comorbidities—The median age of the patients at the time of diagnosis was 55 years (range, 34–77 years). There were 12 males and 7 females (Table 1). Two patients were Black and 17 were White. Almost all patients had additional comorbidities including tobacco use (68%), alcohol use (47%), and diabetes (47%). Only 1 patient had an autoimmune disease and was on chronic steroids. No significant difference was found between the demographics of patients with recurrent lesions and those without recurrence.

Tumor Location and Clinical Presentation—The most common clinical presentation included a nonhealing ulceration with warty edges, pain, bleeding, and lowered mobility. In most cases, there was history of prior treatment over a duration ranging from 1 to 8 years, with a median of 5 years prior to biopsy-based diagnosis (Table 1). Six patients had a history of osteomyelitis, diagnosed by imaging or biopsy, within a year before tumor diagnosis. The size of the primary tumor ranged from 2.4 to 6 cm, with a mean of 4 cm (P=.20). The clinical presentation, time before diagnosis, and size of the tumors did not differ significantly between recurrent and nonrecurrent cases.

The tumor location for the recurrent cases differed significantly compared to nonrecurrent cases. All 5 of the patients with a recurrence presented with a tumor on the nonglabrous part of the foot. Four patients (80%) had lesions on the dorsal or lateral aspect of the great toe (P=.002), and 1 patient (20%) had a lesion on the low ankle (P=.09)(Table 1). Of the nonrecurrent cases, 1 patient (7%) presented with a tumor on the plantar surface of the great toe (P=.002), 13 patients (93%) presented with tumors on the distal plantar surface of the foot (P=.0002), and 1 patient with a plantar foot tumor (Figure 1) also had verrucous carcinoma on the thumb (Table 1 and Figure 2).

Histopathology—Available pathology slides for recurrent cases of verrucous carcinoma were reviewed alongside representative cases of verrucous carcinomas that did not progress to recurrence. The diagnosis of verrucous carcinoma was confirmed in all cases, with no evidence of conventional squamous cell carcinoma, perineural invasion, extension beyond the dermis, or bone invasion in any case. The median size of the tumors was 4.2 cm and 4 cm for nonrecurrent and recurrent specimens, respectively. Recurrences displayed a trend toward increased depth compared to primary tumors without recurrence (average depth, 5.5 mm vs 3.7 mm); however, this did not reach statistical significance (P=.24). Primary tumors that progressed to recurrence (n=2) displayed similar findings to the other cases, with invasive depths of 3.5 and 5.5 mm, and there was no evidence of conventional squamous cell carcinoma, perineural invasion, or extension beyond the dermis.

Treatment of Nonrecurrent Cases—Of the 16 total cases treated at the University of Michigan, surgery was the primary mode of therapy in every case (Tables 2 and 3). Of the 11 nonrecurrent cases, 7 patients had wide local excision with a dermal regeneration template, and delayed split-thickness graft reconstruction. Three cases had wide local excision with metatarsal resection, dermal regeneration template, and delayed skin grafting. One case had a great toe amputation. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (8/11 [73%] reported). Three cases had positive margins at the time of primary resection; 2 were treated with further resection, and 1 had a below the knee amputation (BKA). Follow-up on average was 12 months, with a range of 3 to 36 months.

Treatment of Recurrent Cases—For the 5 patients with recurrence, surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (4/5 [80%] reported). On average, follow-up for this group of patients was 29 months, with a range of 12 to 60 months (Table 3).

Another patient with recurrence (patient 13) presented with a chronic great toe ulcer of 5 years’ duration that formed on the dorsal aspect of the great toe after a previously excised wart (Figure 4A). This patient underwent mid-proximal metatarsal amputation with 2-cm margins and subsequent skin graft. Pathologic margins were negative. Within 6 months, there was hyperkeratosis and a draining wound (Figure 4B). Biopsy results confirmed recurrent disease that was treated with re-resection, including complete metatarsal amputation with negative margins and skin graft placement. Verrucous carcinoma recurred at the edges of the graft within 8 months, and the patient elected for a BKA. In addition, this patient also presented with a verrucous carcinoma of the contralateral great toe. The tumor presented as a warty ulcer of 4 months’ duration in the setting of osteomyelitis and was resected by great toe amputation that was performed concurrently with the opposite leg BKA; there has been no recurrence. Of note, this was the only patient to have right inguinal sentinel lymph node tissue sampled and HPV testing conducted, which were negative for verrucous carcinoma and high or low strains of HPV.

Another recurrent case (patient 14) presented with a large warty lesion on the dorsal great toe positive for verrucous carcinoma. He underwent a complete great toe amputation with skin graft placement. Verrucous carcinoma recurred on the edges of the graft within 6 months, and the patient was lost to follow-up when a BKA was suggested.

The fourth recurrent case (patient 15) initially had been treated for 1 year as a viral verruca of the dorsal aspect of the great toe. He had an exophytic mass positive for verrucous carcinoma growing on the dorsal aspect of the great toe around the prior excision site. After primary wide excision with negative 1-cm margins and graft placement, the tumor was re-excised twice within the next 2 years with pathologic negative margins. The patient underwent a foot amputation due to a severe osteomyelitis infection at the reconstruction site.

The final recurrent case (patient 16) presented with a mass on the lateral great toe that initially was treated as a viral verruca (for unknown duration) that had begun to ulcerate. The patient underwent wide excision with 1-cm margins and graft placement. Final pathology was consistent with verrucous carcinoma with negative margins. Recurrence occurred within 11 months on the edge of the graft, and a great toe amputation through the metatarsal phalangeal joint was performed.

Comment

Our series of 19 cases of verrucous carcinoma adds to the limited number of reported cases in the literature. We sought to evaluate the potential risk factors for early recurrence. Consistent with prior studies, our series found verrucous carcinoma of the foot to occur most frequently in patients aged 50 to 70 years, predominantly in White men.¹ These tumors grew in the setting of chronic inflammation, tissue regeneration, multiple comorbidities, and poor wound hygiene. Misdiagnosis of verrucous carcinoma often leads to ineffective treatments and local invasion of nerves, muscle, and bone tissue.^9,15,16 Our case series also clearly demonstrated the diagnostic challenge verrucous carcinoma presents, with an average delay in diagnosis of 5 years; correct diagnosis often did not occur until the tumor was 4 cm in size (average) and more than 50% had chronic ulceration. Tissue collection of the raised ulcer borders and the deep dermis layer of warty lesions is imperative for diagnosis. Clinicians should have a high suspicion for verrucous carcinoma in the setting of a chronic ulceration or warty lesion that is resistant to traditional treatment.

The histologic features of the tumors showed striking uniformity. Within the literature, there is confusion regarding the use of the terms verrucous carcinoma and carcinoma (epithelioma) cuniculatum and the possible pathologic differences between the two. The World Health Organization’s classification of skin tumors describes epithelioma cuniculatum as verrucous carcinoma located on the sole of the foot.⁷ Kubik and Rhatigan⁶ pointed out that carcinoma cuniculatum does not have a warty or verrucous surface, which is a defining feature of verrucous carcinoma. Multiple authors have further surmised that the deep burrowing sinus tracts of epithelioma cuniculatum are different than those seen in verrucous carcinoma formed by the undulations extending from the papillomatous and verrucous surface.^1,6 We did not observe these notable pathologic differences in recurrent or nonrecurrent primary tumors or differences between primary and recurrent cases. Although our cohort was small, the findings suggest that standard histologic features do not predict aggressive behavior in verrucous carcinomas. Furthermore, our observations support a model wherein recurrence is an inherent property of certain verrucous carcinomas rather than a consequence of histologic progression to conventional squamous cell carcinoma. The lack of overt malignant features in such cases underscores the need for distinction of verrucous carcinoma from benign mimics such as viral verruca or reactive epidermal hyperplasia.

Our recurrent cases showed a greater predilection for nonplantar surfaces and the great toe (P=.002). Five of 6 cases on the nonplantar surface—1 on the ankle and 5 on the great toe—recurred despite negative pathologic margins. There was no significant difference in demographics, pathogenesis, tumor size, chronicity, phenotype, or metastatic spread in recurrent and nonrecurrent cases in our cohort.

The tumor has only been described in rare instances at extrapedal cutaneous sites including the hand, scalp, and abdomen.^14,17,18 Our series did include a case of synchronous presentation with a verrucous carcinoma on the thumb. Given the rarity of this presentation, thus far there are no data supporting any atypical locations of verrucous carcinoma having greater instances of recurrence. Our recurrent cases displaying atypical location on nonglabrous skin could suggest an underlying pathologic mechanism distinct from tumors on glabrous skin and relevant to increased recurrence risk. Such a mechanism might relate to distinct genetic insults, tumor-microenvironment interactions, or field effects. There are few studies regarding physiologic differences between the plantar surface and the nonglabrous surface and how that influences cancer genesis. Within acral melanoma studies, nonglabrous skin of more sun-exposed surfaces has a higher burden of genetic insults including BRAF mutations.¹⁹ Genetic testing of verrucous carcinoma is highly limited, with abnormal expression of the p53 tumor suppressor protein and possible association with several types of HPV. Verrucous carcinoma in general has been found to contain HPV types 6 and 11, nononcogenic forms, and higher risk from HPV types 16 and 18.^9,20 However, only a few cases of HPV type 16 as well as 1 case each of HPV type 2 and type 11 have been found within verrucous carcinoma of the foot.^21,22 In squamous cell carcinoma of the head and neck, HPV-positive tumors have shown better response to treatment. Further investigation of HPV and genetic contributors in verrucous carcinoma is warranted.

There is notable evidence that surgical resection is the best mode of treatment of verrucous carcinoma.^2,3,10,11 Our case series was treated with wide local excision, with partial metatarsal amputation or great toe amputation, in cases with bone invasion or osteomyelitis. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm with no significant differences between the recurrent and nonrecurrent groups. After excision, closure was conducted by incorporating primary, secondary, and delayed closure techniques, along with skin grafts for larger defects. Lymph node biopsy traditionally has not been recommended due to reported low metastatic potential. In all 5 recurrent cases, the tumors recurred after multiple attempts at wide excision and greater resection of bone and tissue, with negative margins. The tumors regrew quickly, within months, on the edges of the new graft or in the middle of the graft. The sites of recurrent tumor growth would suggest regrowth in the areas of greatest tissue stress and proliferation. We recommend a low threshold for biopsy and aggressive retreatment in the setting of exophytic growth at reconstruction sites.

Recurrence is uncommon in the setting of verrucous carcinoma, with our series being the first to analyze prognostic factors.^3,9,14 Our findings indicate that tumors of the nonglabrous surface of the foot should have a higher suspicion for possible local recurrence. Recurrence occurs within months of treatment, deserves early biopsy, and and warrants aggressive treatment. Our series and review highlight the continual diagnostic challenge of this tumor and the pathologic ambiguity that exists. We encourage earlier detection of verrucous carcinoma by appropriate deep tissue biopsy. Future directions should include more comprehensive examination of pathologic features and genetic markers to improve prognostication and management of recurrent and nonrecurrent verrucous carcinoma of the foot.

Verrucous carcinoma is a rare cancer with the greatest predilection for the foot. Multiple case reports with only a few large case series have been published. ^1-3 Plantar verrucous carcinoma is characterized as a slowly but relentlessly enlarging warty tumor with low metastatic potential and high risk for local invasion. The tumor occurs most frequently in patients aged 60 to 70 years, predominantly in White males. ¹ It often is misdiagnosed for years as an ulcer or wart that is highly resistant to therapy. Size typically ranges from 1 to 12 cm in greatest dimension. ¹

The pathogenesis of plantar verrucous carcinoma remains unclear, but some contributing factors have been proposed, including trauma, chronic irritation, infection, and poor local hygiene.² This tumor has been reported to occur in chronic foot ulcerations, particularly in the diabetic population.⁴ It has been proposed that abnormal expression of the p53 tumor suppressor protein and several types of human papillomavirus (HPV) may have a role in the pathogenesis of verrucous carcinoma.⁵

The pathologic hallmarks of this tumor include a verrucous/hyperkeratotic surface with a deeply endophytic, broad, pushing base. Tumor cells are well differentiated, and atypia is either absent or confined to 1 or 2 layers at the base of the tumor. Overt invasion at the base is lacking, except in cases with a component of conventional invasive squamous cell carcinoma. Human papillomavirus viropathic changes are classically absent.^1,3 Studies of the histopathology of verrucous carcinoma have been complicated by similar entities, nomenclatural uncertainty, and variable diagnostic criteria. For example, epithelioma cuniculatum variously has been defined as being synonymous with verrucous carcinoma, a distinct clinical verrucous carcinoma subtype occurring on the soles, a histologic subtype (characterized by prominent burrowing sinuses), or a separate entity entirely.^1,2,6,7 Furthermore, in the genital area, several different types of carcinomas have verruciform features but display distinct microscopic findings and outcomes from verrucous carcinoma.⁸

Verrucous carcinoma represents an unusual variant of squamous cell carcinoma and is treated as such. Treatments have included laser surgery; immunotherapy; retinoid therapy; and chemotherapy by oral, intralesional, or iontophoretic routes in select patients.⁹ Radiotherapy presents another option, though reports have described progression to aggressive squamous cell carcinoma in some cases.⁹ Surgery is the best course of treatment, and as more case reports have been published, a transition from radical resection to wide excision with tumor-free margins is the treatment of choice.^2,3,10,11 To minimize soft-tissue deficits, Mohs micrographic surgery has been discussed as a treatment option for verrucous carcinoma.^11-13

Few studies have described verrucous carcinoma recurrence, and none have systematically examined recurrence rate, risk factors, or prognosis.^3,9,14 In our retrospective review of 19 new cases of verrucous carcinoma of the foot, we examined 5 recurrent tumors despite negative margin surgical resection and report risk factors and surgical management of these lesions.

Methods

Patient cases were identified through the University of Michigan (Ann Arbor, Michigan) pathology database from 1995 to 2019 based on the primary diagnosis of verrucous carcinoma located on the foot. Nineteen cases were identified and were included in demographic and clinical presentation analyses. Medical records were reviewed to abstract selected clinical data and outcomes of analysis.

Of the 19 cases, 16 were treated at the University of Michigan and are included in the treatment analyses. Specific attention was then paid to the cases with a clinical recurrence despite negative surgical margins. We compared the clinical and surgical differences between recurrent cases and nonrecurrent cases.

Pathology was rereviewed for selected cases, including 2 cases with recurrence and matched primary, 2 cases with recurrence (for which the matched primary was unavailable for review), and 5 representative primary cases that were not complicated by recurrence. Pathology review was conducted in a blinded manner by one of the authors (P.W.H) who is a board-certified dermatopathologist for approximate depth of invasion from the granular layer, perineural invasion, bone invasion, infiltrative growth, presence of conventional squamous cell carcinoma, and margin status.

Statistical analysis was performed when appropriate using an N1 χ² test or Student t test.

Results

Demographics and Comorbidities—The median age of the patients at the time of diagnosis was 55 years (range, 34–77 years). There were 12 males and 7 females (Table 1). Two patients were Black and 17 were White. Almost all patients had additional comorbidities including tobacco use (68%), alcohol use (47%), and diabetes (47%). Only 1 patient had an autoimmune disease and was on chronic steroids. No significant difference was found between the demographics of patients with recurrent lesions and those without recurrence.

Tumor Location and Clinical Presentation—The most common clinical presentation included a nonhealing ulceration with warty edges, pain, bleeding, and lowered mobility. In most cases, there was history of prior treatment over a duration ranging from 1 to 8 years, with a median of 5 years prior to biopsy-based diagnosis (Table 1). Six patients had a history of osteomyelitis, diagnosed by imaging or biopsy, within a year before tumor diagnosis. The size of the primary tumor ranged from 2.4 to 6 cm, with a mean of 4 cm (P=.20). The clinical presentation, time before diagnosis, and size of the tumors did not differ significantly between recurrent and nonrecurrent cases.

The tumor location for the recurrent cases differed significantly compared to nonrecurrent cases. All 5 of the patients with a recurrence presented with a tumor on the nonglabrous part of the foot. Four patients (80%) had lesions on the dorsal or lateral aspect of the great toe (P=.002), and 1 patient (20%) had a lesion on the low ankle (P=.09)(Table 1). Of the nonrecurrent cases, 1 patient (7%) presented with a tumor on the plantar surface of the great toe (P=.002), 13 patients (93%) presented with tumors on the distal plantar surface of the foot (P=.0002), and 1 patient with a plantar foot tumor (Figure 1) also had verrucous carcinoma on the thumb (Table 1 and Figure 2).

Histopathology—Available pathology slides for recurrent cases of verrucous carcinoma were reviewed alongside representative cases of verrucous carcinomas that did not progress to recurrence. The diagnosis of verrucous carcinoma was confirmed in all cases, with no evidence of conventional squamous cell carcinoma, perineural invasion, extension beyond the dermis, or bone invasion in any case. The median size of the tumors was 4.2 cm and 4 cm for nonrecurrent and recurrent specimens, respectively. Recurrences displayed a trend toward increased depth compared to primary tumors without recurrence (average depth, 5.5 mm vs 3.7 mm); however, this did not reach statistical significance (P=.24). Primary tumors that progressed to recurrence (n=2) displayed similar findings to the other cases, with invasive depths of 3.5 and 5.5 mm, and there was no evidence of conventional squamous cell carcinoma, perineural invasion, or extension beyond the dermis.

Treatment of Nonrecurrent Cases—Of the 16 total cases treated at the University of Michigan, surgery was the primary mode of therapy in every case (Tables 2 and 3). Of the 11 nonrecurrent cases, 7 patients had wide local excision with a dermal regeneration template, and delayed split-thickness graft reconstruction. Three cases had wide local excision with metatarsal resection, dermal regeneration template, and delayed skin grafting. One case had a great toe amputation. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (8/11 [73%] reported). Three cases had positive margins at the time of primary resection; 2 were treated with further resection, and 1 had a below the knee amputation (BKA). Follow-up on average was 12 months, with a range of 3 to 36 months.

Treatment of Recurrent Cases—For the 5 patients with recurrence, surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm (4/5 [80%] reported). On average, follow-up for this group of patients was 29 months, with a range of 12 to 60 months (Table 3).

Another patient with recurrence (patient 13) presented with a chronic great toe ulcer of 5 years’ duration that formed on the dorsal aspect of the great toe after a previously excised wart (Figure 4A). This patient underwent mid-proximal metatarsal amputation with 2-cm margins and subsequent skin graft. Pathologic margins were negative. Within 6 months, there was hyperkeratosis and a draining wound (Figure 4B). Biopsy results confirmed recurrent disease that was treated with re-resection, including complete metatarsal amputation with negative margins and skin graft placement. Verrucous carcinoma recurred at the edges of the graft within 8 months, and the patient elected for a BKA. In addition, this patient also presented with a verrucous carcinoma of the contralateral great toe. The tumor presented as a warty ulcer of 4 months’ duration in the setting of osteomyelitis and was resected by great toe amputation that was performed concurrently with the opposite leg BKA; there has been no recurrence. Of note, this was the only patient to have right inguinal sentinel lymph node tissue sampled and HPV testing conducted, which were negative for verrucous carcinoma and high or low strains of HPV.

Another recurrent case (patient 14) presented with a large warty lesion on the dorsal great toe positive for verrucous carcinoma. He underwent a complete great toe amputation with skin graft placement. Verrucous carcinoma recurred on the edges of the graft within 6 months, and the patient was lost to follow-up when a BKA was suggested.

The fourth recurrent case (patient 15) initially had been treated for 1 year as a viral verruca of the dorsal aspect of the great toe. He had an exophytic mass positive for verrucous carcinoma growing on the dorsal aspect of the great toe around the prior excision site. After primary wide excision with negative 1-cm margins and graft placement, the tumor was re-excised twice within the next 2 years with pathologic negative margins. The patient underwent a foot amputation due to a severe osteomyelitis infection at the reconstruction site.

The final recurrent case (patient 16) presented with a mass on the lateral great toe that initially was treated as a viral verruca (for unknown duration) that had begun to ulcerate. The patient underwent wide excision with 1-cm margins and graft placement. Final pathology was consistent with verrucous carcinoma with negative margins. Recurrence occurred within 11 months on the edge of the graft, and a great toe amputation through the metatarsal phalangeal joint was performed.

Comment

Our series of 19 cases of verrucous carcinoma adds to the limited number of reported cases in the literature. We sought to evaluate the potential risk factors for early recurrence. Consistent with prior studies, our series found verrucous carcinoma of the foot to occur most frequently in patients aged 50 to 70 years, predominantly in White men.¹ These tumors grew in the setting of chronic inflammation, tissue regeneration, multiple comorbidities, and poor wound hygiene. Misdiagnosis of verrucous carcinoma often leads to ineffective treatments and local invasion of nerves, muscle, and bone tissue.^9,15,16 Our case series also clearly demonstrated the diagnostic challenge verrucous carcinoma presents, with an average delay in diagnosis of 5 years; correct diagnosis often did not occur until the tumor was 4 cm in size (average) and more than 50% had chronic ulceration. Tissue collection of the raised ulcer borders and the deep dermis layer of warty lesions is imperative for diagnosis. Clinicians should have a high suspicion for verrucous carcinoma in the setting of a chronic ulceration or warty lesion that is resistant to traditional treatment.

The histologic features of the tumors showed striking uniformity. Within the literature, there is confusion regarding the use of the terms verrucous carcinoma and carcinoma (epithelioma) cuniculatum and the possible pathologic differences between the two. The World Health Organization’s classification of skin tumors describes epithelioma cuniculatum as verrucous carcinoma located on the sole of the foot.⁷ Kubik and Rhatigan⁶ pointed out that carcinoma cuniculatum does not have a warty or verrucous surface, which is a defining feature of verrucous carcinoma. Multiple authors have further surmised that the deep burrowing sinus tracts of epithelioma cuniculatum are different than those seen in verrucous carcinoma formed by the undulations extending from the papillomatous and verrucous surface.^1,6 We did not observe these notable pathologic differences in recurrent or nonrecurrent primary tumors or differences between primary and recurrent cases. Although our cohort was small, the findings suggest that standard histologic features do not predict aggressive behavior in verrucous carcinomas. Furthermore, our observations support a model wherein recurrence is an inherent property of certain verrucous carcinomas rather than a consequence of histologic progression to conventional squamous cell carcinoma. The lack of overt malignant features in such cases underscores the need for distinction of verrucous carcinoma from benign mimics such as viral verruca or reactive epidermal hyperplasia.

Our recurrent cases showed a greater predilection for nonplantar surfaces and the great toe (P=.002). Five of 6 cases on the nonplantar surface—1 on the ankle and 5 on the great toe—recurred despite negative pathologic margins. There was no significant difference in demographics, pathogenesis, tumor size, chronicity, phenotype, or metastatic spread in recurrent and nonrecurrent cases in our cohort.

The tumor has only been described in rare instances at extrapedal cutaneous sites including the hand, scalp, and abdomen.^14,17,18 Our series did include a case of synchronous presentation with a verrucous carcinoma on the thumb. Given the rarity of this presentation, thus far there are no data supporting any atypical locations of verrucous carcinoma having greater instances of recurrence. Our recurrent cases displaying atypical location on nonglabrous skin could suggest an underlying pathologic mechanism distinct from tumors on glabrous skin and relevant to increased recurrence risk. Such a mechanism might relate to distinct genetic insults, tumor-microenvironment interactions, or field effects. There are few studies regarding physiologic differences between the plantar surface and the nonglabrous surface and how that influences cancer genesis. Within acral melanoma studies, nonglabrous skin of more sun-exposed surfaces has a higher burden of genetic insults including BRAF mutations.¹⁹ Genetic testing of verrucous carcinoma is highly limited, with abnormal expression of the p53 tumor suppressor protein and possible association with several types of HPV. Verrucous carcinoma in general has been found to contain HPV types 6 and 11, nononcogenic forms, and higher risk from HPV types 16 and 18.^9,20 However, only a few cases of HPV type 16 as well as 1 case each of HPV type 2 and type 11 have been found within verrucous carcinoma of the foot.^21,22 In squamous cell carcinoma of the head and neck, HPV-positive tumors have shown better response to treatment. Further investigation of HPV and genetic contributors in verrucous carcinoma is warranted.

There is notable evidence that surgical resection is the best mode of treatment of verrucous carcinoma.^2,3,10,11 Our case series was treated with wide local excision, with partial metatarsal amputation or great toe amputation, in cases with bone invasion or osteomyelitis. Surgical margins were not reported in all the cases but ranged from 0.5 to 2 cm with no significant differences between the recurrent and nonrecurrent groups. After excision, closure was conducted by incorporating primary, secondary, and delayed closure techniques, along with skin grafts for larger defects. Lymph node biopsy traditionally has not been recommended due to reported low metastatic potential. In all 5 recurrent cases, the tumors recurred after multiple attempts at wide excision and greater resection of bone and tissue, with negative margins. The tumors regrew quickly, within months, on the edges of the new graft or in the middle of the graft. The sites of recurrent tumor growth would suggest regrowth in the areas of greatest tissue stress and proliferation. We recommend a low threshold for biopsy and aggressive retreatment in the setting of exophytic growth at reconstruction sites.

Recurrence is uncommon in the setting of verrucous carcinoma, with our series being the first to analyze prognostic factors.^3,9,14 Our findings indicate that tumors of the nonglabrous surface of the foot should have a higher suspicion for possible local recurrence. Recurrence occurs within months of treatment, deserves early biopsy, and and warrants aggressive treatment. Our series and review highlight the continual diagnostic challenge of this tumor and the pathologic ambiguity that exists. We encourage earlier detection of verrucous carcinoma by appropriate deep tissue biopsy. Future directions should include more comprehensive examination of pathologic features and genetic markers to improve prognostication and management of recurrent and nonrecurrent verrucous carcinoma of the foot.

The link between obesity and cancer has increasingly been emphasized in public health messages, but is the current message correct?

“Being overweight or having obesity increases your risk of getting cancer,” warns the U.S. Centers for Disease Control and Prevention. It warns that overweight/obesity is “linked with a higher risk of getting 13 types of cancer ... [which] make up 40% of all cancers diagnosed in the United States each year.”

But that message, which is also promulgated by many cancer organizations, is based on data from observational studies, which have many limitations.

A new study based on Mendelian randomization studies has come to a slightly different conclusion and has found a potential causal association with just six cancers.

In addition, it found an inverse relationship for breast cancer, in which early-life obesity was associated with a reduced risk of breast cancer, and the relationship with obesity was “complicated” for lung and prostate cancer.

The study, headed by Zhe Fang, MBBS, Harvard T. H. Chan School of Public Health, Boston, Mass., was published in the Journal of the National Cancer Institute

“For a seemingly straightforward question of whether excessive body fatness causes cancer, the answer may not be straightforward after all,” writes Song Yao, PhD, professor of oncology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., in an accompanying editorial

“How to craft a simple public health message to convey the complexity and nuances of the relationships may be a challenge to be grappled with going forward,” he added.

In an interview, Dr. Yao said that it “really depends on what kind of message you want to get out.”

“If you want to talk about cancer overall, as one disease, we all know that a clear association with obesity does not exist,” he said. “It’s not that simple.”

“You really cannot say that obesity increases cancer risk overall,” he said.

For some cancers included in the study, Dr. Yao continued, it was “very clear that obesity increased the risk ... but for some other cancer types, we either don’t have enough data yet or the association is not as consistent.”

This, he said, is especially the case for prostate and lung cancer.

All of this indicates that there is a complex relationship between obesity and cancer risk, he maintains.

“We always think obesity is bad, not only for cancer but also for more common conditions, like hypertension, diabetes, and cardiovascular disease,” Dr. Yao noted. This points to the link between obesity and chronic inflammation, he added.

However, there are also other hypotheses, including synthesis of estrogen in adipose tissue, which may explain the link between obesity and breast cancer risk in older women.

However, in younger women, obesity protects against breast cancer, and “we really don’t know why,” Dr. Yao said.

The new study used Mendelian randomization to examine these relationships. This is a “new tool that we have developed over the past 20 years or so, largely because there is so much data coming from genome-wide association studies,” Dr. Yao explained.

It has “advantages” over other methods, including observational studies. One of its strengths is that it is “not impacted by reverse causality,” because genetic risk does not change over time.

However, he said, it is “quite straightforward to think that the genetics do not change, but at the same time, the environment we live in throughout our life course changes,” and the impact of genetic variants may be “washed out.”

How genetics influences cancer risk may therefore change over time, and it is a “dynamic process,” Dr. Yao commented.

In addition, this approach has its own limitations, he said, because it depends on how much of the variation in a given measure can be attributed to genetic factors.
 

New conclusions

In their study, Dr. Fang and colleagues reviewed 204 meta-analyses of 2,179 individual estimates from 507 cohort or case-control studies. They found “strong evidence” that supports the association between obesity and 11 cancers.

These are esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney.

They note, however, that the associations “may be causal for some malignancies” but that the co-occurrence of obesity with various cancer risk factors means that others may be “susceptible to potential confounding bias.”

To overcome some of these limitations, the team looked to Mendelian randomization studies that examined the association between genetic variants linked to body mass index (BMI), indicating lifetime risk of high BMI, and cancer risk for a range of cancer types.

These Mendelian randomization studies were then compared with the results of large-scale conventional observational studies, as well as with evidence in reports from the International Agency for Research on Cancer and the World Cancer Research Fund–American Institute of Cancer Research, which also include experimental studies.

The researchers say that, overall, the Mendelian randomization studies “further establish the causality of obesity” with six cancer types: colorectal, endometrial, ovarian, kidney, and pancreatic cancer, and esophageal adenocarcinoma.

In addition, these studies further establish the inverse relationship of early-life obesity with breast cancer.

However, the approach could not confirm a positive association between obesity and gallbladder and gastric cardia cancer, as well as multiple myeloma.

“This could be due to low power,” the team suggests, “and larger studies are required.”

With respect to lung cancer, the Mendelian randomization identified a positive association with obesity that supports the inverse association identified in observational studies, that is, that obesity may reduce the risk for lung cancer.

The researchers suggest this may reflect reverse causality related to the loss of lean body mass before diagnosis, as well as confounding by smoking.

For prostate cancer, the evidence was “conflicting” and “implies a complicated role of obesity,” Dr. Zhang and colleagues comment.

The link between obesity and lower prostate-specific antigen levels, they suggest, may result in a detection bias by masking the presence of prostate cancer, or it “could be biological” in origin, owing to reduced androgen levels.

For six cancer types for which a causal relationship with obesity could be established, the effect estimates from the Mendelian randomization studies were stronger than those seen in conventional studies, with the magnitude of risk ranging from 1.14-fold for early-life obesity and breast cancer to 1.37-fold for adult obesity and esophageal adenocarcinoma.

In another editorial accompanying the new study, Graham A. Colditz, MD, DrPH, from Washington University School of Medicine, St. Louis, underlined that childhood and adolescent obesity and their contribution to cancer risk need further attention.

“To reap the reward from past research, we must act to implement effective strategies to reduce childhood and adolescent adiposity, reduce excess weight gain in adult years, and maintain a healthy weight,” he writes.

“This will require us to change the way we live, but COVID-19 has shown we can make changes to how we live and work. Let us keep the changes we have already made, or take on new ones, that will cut our collective cancer toll,” he implores.

No funding for the study was described. Dr. Colditz is supported by the Breast Cancer Research Foundation. No other relevant financial relationships were described.

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

The link between obesity and cancer has increasingly been emphasized in public health messages, but is the current message correct?

“Being overweight or having obesity increases your risk of getting cancer,” warns the U.S. Centers for Disease Control and Prevention. It warns that overweight/obesity is “linked with a higher risk of getting 13 types of cancer ... [which] make up 40% of all cancers diagnosed in the United States each year.”

But that message, which is also promulgated by many cancer organizations, is based on data from observational studies, which have many limitations.

A new study based on Mendelian randomization studies has come to a slightly different conclusion and has found a potential causal association with just six cancers.

In addition, it found an inverse relationship for breast cancer, in which early-life obesity was associated with a reduced risk of breast cancer, and the relationship with obesity was “complicated” for lung and prostate cancer.

The study, headed by Zhe Fang, MBBS, Harvard T. H. Chan School of Public Health, Boston, Mass., was published in the Journal of the National Cancer Institute

“For a seemingly straightforward question of whether excessive body fatness causes cancer, the answer may not be straightforward after all,” writes Song Yao, PhD, professor of oncology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., in an accompanying editorial

“How to craft a simple public health message to convey the complexity and nuances of the relationships may be a challenge to be grappled with going forward,” he added.

In an interview, Dr. Yao said that it “really depends on what kind of message you want to get out.”

“If you want to talk about cancer overall, as one disease, we all know that a clear association with obesity does not exist,” he said. “It’s not that simple.”

“You really cannot say that obesity increases cancer risk overall,” he said.

For some cancers included in the study, Dr. Yao continued, it was “very clear that obesity increased the risk ... but for some other cancer types, we either don’t have enough data yet or the association is not as consistent.”

This, he said, is especially the case for prostate and lung cancer.

All of this indicates that there is a complex relationship between obesity and cancer risk, he maintains.

“We always think obesity is bad, not only for cancer but also for more common conditions, like hypertension, diabetes, and cardiovascular disease,” Dr. Yao noted. This points to the link between obesity and chronic inflammation, he added.

However, there are also other hypotheses, including synthesis of estrogen in adipose tissue, which may explain the link between obesity and breast cancer risk in older women.

However, in younger women, obesity protects against breast cancer, and “we really don’t know why,” Dr. Yao said.

The new study used Mendelian randomization to examine these relationships. This is a “new tool that we have developed over the past 20 years or so, largely because there is so much data coming from genome-wide association studies,” Dr. Yao explained.

It has “advantages” over other methods, including observational studies. One of its strengths is that it is “not impacted by reverse causality,” because genetic risk does not change over time.

However, he said, it is “quite straightforward to think that the genetics do not change, but at the same time, the environment we live in throughout our life course changes,” and the impact of genetic variants may be “washed out.”

How genetics influences cancer risk may therefore change over time, and it is a “dynamic process,” Dr. Yao commented.

In addition, this approach has its own limitations, he said, because it depends on how much of the variation in a given measure can be attributed to genetic factors.
 

New conclusions

In their study, Dr. Fang and colleagues reviewed 204 meta-analyses of 2,179 individual estimates from 507 cohort or case-control studies. They found “strong evidence” that supports the association between obesity and 11 cancers.

These are esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney.

They note, however, that the associations “may be causal for some malignancies” but that the co-occurrence of obesity with various cancer risk factors means that others may be “susceptible to potential confounding bias.”

To overcome some of these limitations, the team looked to Mendelian randomization studies that examined the association between genetic variants linked to body mass index (BMI), indicating lifetime risk of high BMI, and cancer risk for a range of cancer types.

These Mendelian randomization studies were then compared with the results of large-scale conventional observational studies, as well as with evidence in reports from the International Agency for Research on Cancer and the World Cancer Research Fund–American Institute of Cancer Research, which also include experimental studies.

The researchers say that, overall, the Mendelian randomization studies “further establish the causality of obesity” with six cancer types: colorectal, endometrial, ovarian, kidney, and pancreatic cancer, and esophageal adenocarcinoma.

In addition, these studies further establish the inverse relationship of early-life obesity with breast cancer.

However, the approach could not confirm a positive association between obesity and gallbladder and gastric cardia cancer, as well as multiple myeloma.

“This could be due to low power,” the team suggests, “and larger studies are required.”

With respect to lung cancer, the Mendelian randomization identified a positive association with obesity that supports the inverse association identified in observational studies, that is, that obesity may reduce the risk for lung cancer.

The researchers suggest this may reflect reverse causality related to the loss of lean body mass before diagnosis, as well as confounding by smoking.

For prostate cancer, the evidence was “conflicting” and “implies a complicated role of obesity,” Dr. Zhang and colleagues comment.

The link between obesity and lower prostate-specific antigen levels, they suggest, may result in a detection bias by masking the presence of prostate cancer, or it “could be biological” in origin, owing to reduced androgen levels.

For six cancer types for which a causal relationship with obesity could be established, the effect estimates from the Mendelian randomization studies were stronger than those seen in conventional studies, with the magnitude of risk ranging from 1.14-fold for early-life obesity and breast cancer to 1.37-fold for adult obesity and esophageal adenocarcinoma.

In another editorial accompanying the new study, Graham A. Colditz, MD, DrPH, from Washington University School of Medicine, St. Louis, underlined that childhood and adolescent obesity and their contribution to cancer risk need further attention.

“To reap the reward from past research, we must act to implement effective strategies to reduce childhood and adolescent adiposity, reduce excess weight gain in adult years, and maintain a healthy weight,” he writes.

“This will require us to change the way we live, but COVID-19 has shown we can make changes to how we live and work. Let us keep the changes we have already made, or take on new ones, that will cut our collective cancer toll,” he implores.

No funding for the study was described. Dr. Colditz is supported by the Breast Cancer Research Foundation. No other relevant financial relationships were described.

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

The link between obesity and cancer has increasingly been emphasized in public health messages, but is the current message correct?

“Being overweight or having obesity increases your risk of getting cancer,” warns the U.S. Centers for Disease Control and Prevention. It warns that overweight/obesity is “linked with a higher risk of getting 13 types of cancer ... [which] make up 40% of all cancers diagnosed in the United States each year.”

But that message, which is also promulgated by many cancer organizations, is based on data from observational studies, which have many limitations.

A new study based on Mendelian randomization studies has come to a slightly different conclusion and has found a potential causal association with just six cancers.

In addition, it found an inverse relationship for breast cancer, in which early-life obesity was associated with a reduced risk of breast cancer, and the relationship with obesity was “complicated” for lung and prostate cancer.

The study, headed by Zhe Fang, MBBS, Harvard T. H. Chan School of Public Health, Boston, Mass., was published in the Journal of the National Cancer Institute

“For a seemingly straightforward question of whether excessive body fatness causes cancer, the answer may not be straightforward after all,” writes Song Yao, PhD, professor of oncology, Roswell Park Comprehensive Cancer Center, Buffalo, N.Y., in an accompanying editorial

“How to craft a simple public health message to convey the complexity and nuances of the relationships may be a challenge to be grappled with going forward,” he added.

In an interview, Dr. Yao said that it “really depends on what kind of message you want to get out.”

“If you want to talk about cancer overall, as one disease, we all know that a clear association with obesity does not exist,” he said. “It’s not that simple.”

“You really cannot say that obesity increases cancer risk overall,” he said.

For some cancers included in the study, Dr. Yao continued, it was “very clear that obesity increased the risk ... but for some other cancer types, we either don’t have enough data yet or the association is not as consistent.”

This, he said, is especially the case for prostate and lung cancer.

All of this indicates that there is a complex relationship between obesity and cancer risk, he maintains.

“We always think obesity is bad, not only for cancer but also for more common conditions, like hypertension, diabetes, and cardiovascular disease,” Dr. Yao noted. This points to the link between obesity and chronic inflammation, he added.

However, there are also other hypotheses, including synthesis of estrogen in adipose tissue, which may explain the link between obesity and breast cancer risk in older women.

However, in younger women, obesity protects against breast cancer, and “we really don’t know why,” Dr. Yao said.

The new study used Mendelian randomization to examine these relationships. This is a “new tool that we have developed over the past 20 years or so, largely because there is so much data coming from genome-wide association studies,” Dr. Yao explained.

It has “advantages” over other methods, including observational studies. One of its strengths is that it is “not impacted by reverse causality,” because genetic risk does not change over time.

However, he said, it is “quite straightforward to think that the genetics do not change, but at the same time, the environment we live in throughout our life course changes,” and the impact of genetic variants may be “washed out.”

How genetics influences cancer risk may therefore change over time, and it is a “dynamic process,” Dr. Yao commented.

In addition, this approach has its own limitations, he said, because it depends on how much of the variation in a given measure can be attributed to genetic factors.
 

New conclusions

In their study, Dr. Fang and colleagues reviewed 204 meta-analyses of 2,179 individual estimates from 507 cohort or case-control studies. They found “strong evidence” that supports the association between obesity and 11 cancers.

These are esophageal adenocarcinoma, multiple myeloma, and cancers of the gastric cardia, colon, rectum, biliary tract system, pancreas, breast, endometrium, ovary, and kidney.

They note, however, that the associations “may be causal for some malignancies” but that the co-occurrence of obesity with various cancer risk factors means that others may be “susceptible to potential confounding bias.”

To overcome some of these limitations, the team looked to Mendelian randomization studies that examined the association between genetic variants linked to body mass index (BMI), indicating lifetime risk of high BMI, and cancer risk for a range of cancer types.

These Mendelian randomization studies were then compared with the results of large-scale conventional observational studies, as well as with evidence in reports from the International Agency for Research on Cancer and the World Cancer Research Fund–American Institute of Cancer Research, which also include experimental studies.

The researchers say that, overall, the Mendelian randomization studies “further establish the causality of obesity” with six cancer types: colorectal, endometrial, ovarian, kidney, and pancreatic cancer, and esophageal adenocarcinoma.

In addition, these studies further establish the inverse relationship of early-life obesity with breast cancer.

However, the approach could not confirm a positive association between obesity and gallbladder and gastric cardia cancer, as well as multiple myeloma.

“This could be due to low power,” the team suggests, “and larger studies are required.”

With respect to lung cancer, the Mendelian randomization identified a positive association with obesity that supports the inverse association identified in observational studies, that is, that obesity may reduce the risk for lung cancer.

The researchers suggest this may reflect reverse causality related to the loss of lean body mass before diagnosis, as well as confounding by smoking.

For prostate cancer, the evidence was “conflicting” and “implies a complicated role of obesity,” Dr. Zhang and colleagues comment.

The link between obesity and lower prostate-specific antigen levels, they suggest, may result in a detection bias by masking the presence of prostate cancer, or it “could be biological” in origin, owing to reduced androgen levels.

For six cancer types for which a causal relationship with obesity could be established, the effect estimates from the Mendelian randomization studies were stronger than those seen in conventional studies, with the magnitude of risk ranging from 1.14-fold for early-life obesity and breast cancer to 1.37-fold for adult obesity and esophageal adenocarcinoma.

In another editorial accompanying the new study, Graham A. Colditz, MD, DrPH, from Washington University School of Medicine, St. Louis, underlined that childhood and adolescent obesity and their contribution to cancer risk need further attention.

“To reap the reward from past research, we must act to implement effective strategies to reduce childhood and adolescent adiposity, reduce excess weight gain in adult years, and maintain a healthy weight,” he writes.

“This will require us to change the way we live, but COVID-19 has shown we can make changes to how we live and work. Let us keep the changes we have already made, or take on new ones, that will cut our collective cancer toll,” he implores.

No funding for the study was described. Dr. Colditz is supported by the Breast Cancer Research Foundation. No other relevant financial relationships were described.

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

WASHINGTON – Dietary fiber impacts not only the composition of the gut microbiome, but the production of a broad spectrum of microbiota-produced metabolites – including amino acid metabolites – that may modify health, said Gary D. Wu, MD, of the University of Pennsylvania, Philadelphia.

During the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility, Dr. Wu led a plenary session in which the impact of diet on the microbiome was characterized as important, rapid, personalized, likely modest relative to other contributing ecological factors, influenced by the process of cooking, and exceedingly difficult to tease apart and characterize in human studies.

In a human study published in 2021, Dr. Wu and coinvestigators performed a controlled feeding experiment with 30 healthy volunteers, randomizing them to several weeks of a vegan diet, an omnivore diet (a typical American diet), and an exclusive enteral nutrition diet (EEN) devoid of dietary fiber.

They compared the composition and metabolic function of the gut microbiome during three phases: an initial dietary phase (days 1-5), a purge phase in which antibiotics and polyethylene glycol were administered to transiently reduce bacterial load in the gut (days 6-8), and a recovery phase (days 9-15).

Diversity of the gut microbiota recovered from the purge phase in both vegans and omnivores, but not in those receiving EEN. “The EEN diet was having a profound effect on the [short-term] recovery of microbiota,” said Dr. Wu, the Ferdinand G. Weisbrod Professor in Gastroenterology, in describing the Food And Resulting Microbial Metabolites study.

Using genetic sequencing, microbial culturing, and bioinformatics processing, the researchers also determined that EEN subsequently led to metabolites that were distinct from omnivores and vegans. Unexpectedly, bacterial metabolites of amino acid origin – not only carbohydrate origin – were altered in the EEN group, suggesting a broad impact of dietary fiber on the bacterial metabolome. EEN-induced alterations in the microbiome and metabolome resolved after the study period, he noted.

In other words, “depriving or supplying the gut microbiome with one dietary component (i.e., fiber) can directly impact metabolites of an unrelated portion of the diet (i.e., amino acids) via the induction of specific gut bacterial taxa,” Dr. Wu and colleagues wrote.

Clinically, the results as a whole suggest that the combination of antibiotics with EEN may be less effective in patients with Crohn’s disease than EEN alone, and can be potentially harmful, they said.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Wu said that, for patients in the ICU on EEN treatment and antibiotics, “we do need to think carefully about microbiota reconstitution because it could have a very significant effect not only on short-chain fatty acid metabolites but on amino acid metabolites that may be good or bad in the setting of disease.”

The scientific rationale for the effectiveness of EEN for IBD is still not well understood, he noted. “All I can say is that EEN works in IBD, but there are aspects about the microbiota and diet and IBD that we don’t understand.”


 

Dietary impact through the immigration lens

In another presentation, Dan Knights, PhD, of the University of Minnesota, Minneapolis, described his lab’s findings on the association of U.S. immigration with loss of gut microbiome diversity, and the role of diet.

As part of the Immigration Microbiome Project reported several years ago, his team collected stool, dietary recalls, and anthropometrics from 550 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants, as well as some U.S.-born European American individuals. They found that the gut microbiome of immigrants changed within months of arriving in the United States, and that immigration status had a stronger effect on the microbiome than obesity status.

“By the time people were in their second generation, their microbiomes were roughly on the same order of diversity as U.S. controls,” said Dr. Knights, associate professor in the Biotechnology Institute and the department of computer science and engineering.

Dietary changes only partly explained microbiome variation, however. “By the second generation, the microbiome tended to be fully Westernized, but the diet was only partly Westernized,” he said. “Diet is only part of the story.”

Other research from his lab, including one study that performed daily fecal shotgun sequencing on 34 people, has found that effects of diet on the microbiome are likely to be observable within days, and that microbial responses to food are highly personalized. Diet appears to explain about 6% of the daily microbiome variation within an individual, and “an average diet explains about 4% of microbiome variation between people,” Dr. Knights said.
 

The impact of cooking

“The gut microbiota responds to food and to its form,” said Rachel N. Carmody, PhD, of the department of human evolutionary biology at Harvard University, Cambridge, during the plenary session. Her research has shown that, in mice, a plant diet served raw versus cooked quickly reshaped the gut microbiome and disrupted gut microbial physiology. Notably, shifts in gut microbiota modulated host energy status – one of the many areas that begs further research.

The effects of cooking have also been detectable in human pilot studies. “We saw different changes in the microbiome when [study participants] were eating the same plant items either raw or cooked,” she said. “Some microbes were affected only on the raw diet, other were affected only on the cooked diet.”

Other research in animal models and humans has demonstrated a significant amount of plasticity in the microbiome in response to diet. “In mice you get the microbiome signatures to shift within 24 hours by feeding them a new diet,” Dr. Carmody said.

In an interview about the plenary session, Eugene B. Chang, MD, the Martin Boyer Distinguished Professor of Medicine at the University of Chicago, said that he was struck both by the resiliency of individual gut microbiomes overall and by findings that, “in animal models where conditions and diets can be carefully controlled, diet and environment are major drivers of gut microbial membership and function.”

Dr. Chang co-led a separate workshop on “defining a healthy gut microbiome” – a task that he said remains “a challenge [and is not yet] resolved, at least with general consensus.”

Dr. Chang, Dr. Wu, and Dr. Carmody reported no relevant disclosures. Dr. Knights disclosed that he is a paid adviser to Diversigen, a company involved with the commercialization of microbiome analysis.

The 2022 Gut Microbiota for Health World Summit was supported by sponsorships from Danone, Ferring Pharmaceuticals, Aimmune Therapeutics and Seres Therapeutics, Sanofi, and Intrinsic Medicine Inc. with additional support from educational grants provided by Ferring Pharmaceuticals and Salix Pharmaceuticals.

This article was updated 4/5/22.

WASHINGTON – Dietary fiber impacts not only the composition of the gut microbiome, but the production of a broad spectrum of microbiota-produced metabolites – including amino acid metabolites – that may modify health, said Gary D. Wu, MD, of the University of Pennsylvania, Philadelphia.

During the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility, Dr. Wu led a plenary session in which the impact of diet on the microbiome was characterized as important, rapid, personalized, likely modest relative to other contributing ecological factors, influenced by the process of cooking, and exceedingly difficult to tease apart and characterize in human studies.

In a human study published in 2021, Dr. Wu and coinvestigators performed a controlled feeding experiment with 30 healthy volunteers, randomizing them to several weeks of a vegan diet, an omnivore diet (a typical American diet), and an exclusive enteral nutrition diet (EEN) devoid of dietary fiber.

They compared the composition and metabolic function of the gut microbiome during three phases: an initial dietary phase (days 1-5), a purge phase in which antibiotics and polyethylene glycol were administered to transiently reduce bacterial load in the gut (days 6-8), and a recovery phase (days 9-15).

Diversity of the gut microbiota recovered from the purge phase in both vegans and omnivores, but not in those receiving EEN. “The EEN diet was having a profound effect on the [short-term] recovery of microbiota,” said Dr. Wu, the Ferdinand G. Weisbrod Professor in Gastroenterology, in describing the Food And Resulting Microbial Metabolites study.

Using genetic sequencing, microbial culturing, and bioinformatics processing, the researchers also determined that EEN subsequently led to metabolites that were distinct from omnivores and vegans. Unexpectedly, bacterial metabolites of amino acid origin – not only carbohydrate origin – were altered in the EEN group, suggesting a broad impact of dietary fiber on the bacterial metabolome. EEN-induced alterations in the microbiome and metabolome resolved after the study period, he noted.

In other words, “depriving or supplying the gut microbiome with one dietary component (i.e., fiber) can directly impact metabolites of an unrelated portion of the diet (i.e., amino acids) via the induction of specific gut bacterial taxa,” Dr. Wu and colleagues wrote.

Clinically, the results as a whole suggest that the combination of antibiotics with EEN may be less effective in patients with Crohn’s disease than EEN alone, and can be potentially harmful, they said.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Wu said that, for patients in the ICU on EEN treatment and antibiotics, “we do need to think carefully about microbiota reconstitution because it could have a very significant effect not only on short-chain fatty acid metabolites but on amino acid metabolites that may be good or bad in the setting of disease.”

The scientific rationale for the effectiveness of EEN for IBD is still not well understood, he noted. “All I can say is that EEN works in IBD, but there are aspects about the microbiota and diet and IBD that we don’t understand.”


 

Dietary impact through the immigration lens

In another presentation, Dan Knights, PhD, of the University of Minnesota, Minneapolis, described his lab’s findings on the association of U.S. immigration with loss of gut microbiome diversity, and the role of diet.

As part of the Immigration Microbiome Project reported several years ago, his team collected stool, dietary recalls, and anthropometrics from 550 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants, as well as some U.S.-born European American individuals. They found that the gut microbiome of immigrants changed within months of arriving in the United States, and that immigration status had a stronger effect on the microbiome than obesity status.

“By the time people were in their second generation, their microbiomes were roughly on the same order of diversity as U.S. controls,” said Dr. Knights, associate professor in the Biotechnology Institute and the department of computer science and engineering.

Dietary changes only partly explained microbiome variation, however. “By the second generation, the microbiome tended to be fully Westernized, but the diet was only partly Westernized,” he said. “Diet is only part of the story.”

Other research from his lab, including one study that performed daily fecal shotgun sequencing on 34 people, has found that effects of diet on the microbiome are likely to be observable within days, and that microbial responses to food are highly personalized. Diet appears to explain about 6% of the daily microbiome variation within an individual, and “an average diet explains about 4% of microbiome variation between people,” Dr. Knights said.
 

The impact of cooking

“The gut microbiota responds to food and to its form,” said Rachel N. Carmody, PhD, of the department of human evolutionary biology at Harvard University, Cambridge, during the plenary session. Her research has shown that, in mice, a plant diet served raw versus cooked quickly reshaped the gut microbiome and disrupted gut microbial physiology. Notably, shifts in gut microbiota modulated host energy status – one of the many areas that begs further research.

The effects of cooking have also been detectable in human pilot studies. “We saw different changes in the microbiome when [study participants] were eating the same plant items either raw or cooked,” she said. “Some microbes were affected only on the raw diet, other were affected only on the cooked diet.”

Other research in animal models and humans has demonstrated a significant amount of plasticity in the microbiome in response to diet. “In mice you get the microbiome signatures to shift within 24 hours by feeding them a new diet,” Dr. Carmody said.

In an interview about the plenary session, Eugene B. Chang, MD, the Martin Boyer Distinguished Professor of Medicine at the University of Chicago, said that he was struck both by the resiliency of individual gut microbiomes overall and by findings that, “in animal models where conditions and diets can be carefully controlled, diet and environment are major drivers of gut microbial membership and function.”

Dr. Chang co-led a separate workshop on “defining a healthy gut microbiome” – a task that he said remains “a challenge [and is not yet] resolved, at least with general consensus.”

Dr. Chang, Dr. Wu, and Dr. Carmody reported no relevant disclosures. Dr. Knights disclosed that he is a paid adviser to Diversigen, a company involved with the commercialization of microbiome analysis.

The 2022 Gut Microbiota for Health World Summit was supported by sponsorships from Danone, Ferring Pharmaceuticals, Aimmune Therapeutics and Seres Therapeutics, Sanofi, and Intrinsic Medicine Inc. with additional support from educational grants provided by Ferring Pharmaceuticals and Salix Pharmaceuticals.

This article was updated 4/5/22.

WASHINGTON – Dietary fiber impacts not only the composition of the gut microbiome, but the production of a broad spectrum of microbiota-produced metabolites – including amino acid metabolites – that may modify health, said Gary D. Wu, MD, of the University of Pennsylvania, Philadelphia.

During the 2022 Gut Microbiota for Health World Summit, organized by the American Gastroenterological Association and the European Society of Neurogastroenterology and Motility, Dr. Wu led a plenary session in which the impact of diet on the microbiome was characterized as important, rapid, personalized, likely modest relative to other contributing ecological factors, influenced by the process of cooking, and exceedingly difficult to tease apart and characterize in human studies.

In a human study published in 2021, Dr. Wu and coinvestigators performed a controlled feeding experiment with 30 healthy volunteers, randomizing them to several weeks of a vegan diet, an omnivore diet (a typical American diet), and an exclusive enteral nutrition diet (EEN) devoid of dietary fiber.

They compared the composition and metabolic function of the gut microbiome during three phases: an initial dietary phase (days 1-5), a purge phase in which antibiotics and polyethylene glycol were administered to transiently reduce bacterial load in the gut (days 6-8), and a recovery phase (days 9-15).

Diversity of the gut microbiota recovered from the purge phase in both vegans and omnivores, but not in those receiving EEN. “The EEN diet was having a profound effect on the [short-term] recovery of microbiota,” said Dr. Wu, the Ferdinand G. Weisbrod Professor in Gastroenterology, in describing the Food And Resulting Microbial Metabolites study.

Using genetic sequencing, microbial culturing, and bioinformatics processing, the researchers also determined that EEN subsequently led to metabolites that were distinct from omnivores and vegans. Unexpectedly, bacterial metabolites of amino acid origin – not only carbohydrate origin – were altered in the EEN group, suggesting a broad impact of dietary fiber on the bacterial metabolome. EEN-induced alterations in the microbiome and metabolome resolved after the study period, he noted.

In other words, “depriving or supplying the gut microbiome with one dietary component (i.e., fiber) can directly impact metabolites of an unrelated portion of the diet (i.e., amino acids) via the induction of specific gut bacterial taxa,” Dr. Wu and colleagues wrote.

Clinically, the results as a whole suggest that the combination of antibiotics with EEN may be less effective in patients with Crohn’s disease than EEN alone, and can be potentially harmful, they said.

At the meeting, sponsored by the American Gastroenterological Association and the European Society for Neurogastroenterology and Motility, Dr. Wu said that, for patients in the ICU on EEN treatment and antibiotics, “we do need to think carefully about microbiota reconstitution because it could have a very significant effect not only on short-chain fatty acid metabolites but on amino acid metabolites that may be good or bad in the setting of disease.”

The scientific rationale for the effectiveness of EEN for IBD is still not well understood, he noted. “All I can say is that EEN works in IBD, but there are aspects about the microbiota and diet and IBD that we don’t understand.”


 

Dietary impact through the immigration lens

In another presentation, Dan Knights, PhD, of the University of Minnesota, Minneapolis, described his lab’s findings on the association of U.S. immigration with loss of gut microbiome diversity, and the role of diet.

As part of the Immigration Microbiome Project reported several years ago, his team collected stool, dietary recalls, and anthropometrics from 550 Hmong and Karen individuals living in Thailand and the United States, including first- and second-generation immigrants, as well as some U.S.-born European American individuals. They found that the gut microbiome of immigrants changed within months of arriving in the United States, and that immigration status had a stronger effect on the microbiome than obesity status.

“By the time people were in their second generation, their microbiomes were roughly on the same order of diversity as U.S. controls,” said Dr. Knights, associate professor in the Biotechnology Institute and the department of computer science and engineering.

Dietary changes only partly explained microbiome variation, however. “By the second generation, the microbiome tended to be fully Westernized, but the diet was only partly Westernized,” he said. “Diet is only part of the story.”

Other research from his lab, including one study that performed daily fecal shotgun sequencing on 34 people, has found that effects of diet on the microbiome are likely to be observable within days, and that microbial responses to food are highly personalized. Diet appears to explain about 6% of the daily microbiome variation within an individual, and “an average diet explains about 4% of microbiome variation between people,” Dr. Knights said.
 

The impact of cooking

“The gut microbiota responds to food and to its form,” said Rachel N. Carmody, PhD, of the department of human evolutionary biology at Harvard University, Cambridge, during the plenary session. Her research has shown that, in mice, a plant diet served raw versus cooked quickly reshaped the gut microbiome and disrupted gut microbial physiology. Notably, shifts in gut microbiota modulated host energy status – one of the many areas that begs further research.

The effects of cooking have also been detectable in human pilot studies. “We saw different changes in the microbiome when [study participants] were eating the same plant items either raw or cooked,” she said. “Some microbes were affected only on the raw diet, other were affected only on the cooked diet.”

Other research in animal models and humans has demonstrated a significant amount of plasticity in the microbiome in response to diet. “In mice you get the microbiome signatures to shift within 24 hours by feeding them a new diet,” Dr. Carmody said.

In an interview about the plenary session, Eugene B. Chang, MD, the Martin Boyer Distinguished Professor of Medicine at the University of Chicago, said that he was struck both by the resiliency of individual gut microbiomes overall and by findings that, “in animal models where conditions and diets can be carefully controlled, diet and environment are major drivers of gut microbial membership and function.”

Dr. Chang co-led a separate workshop on “defining a healthy gut microbiome” – a task that he said remains “a challenge [and is not yet] resolved, at least with general consensus.”

Dr. Chang, Dr. Wu, and Dr. Carmody reported no relevant disclosures. Dr. Knights disclosed that he is a paid adviser to Diversigen, a company involved with the commercialization of microbiome analysis.

The 2022 Gut Microbiota for Health World Summit was supported by sponsorships from Danone, Ferring Pharmaceuticals, Aimmune Therapeutics and Seres Therapeutics, Sanofi, and Intrinsic Medicine Inc. with additional support from educational grants provided by Ferring Pharmaceuticals and Salix Pharmaceuticals.

This article was updated 4/5/22.