Across the world, healthcare workers experience workplace violence, which can differ by gender, seniority, and the type of workplace, according to a recent study.

An analysis found that men were more likely to report physical violence, while women were more likely to face nonphysical violence, such as verbal abuse, sexual harassment, and bullying.

“Our study was sparked by the increasing research on workplace violence in healthcare settings. Yet, there’s less empirical data about workplace violence based on gender, its effects on individuals and the collective workforce, and its subsequent impact on patient care and healthcare organizations,” study author Basnama Ayaz, a PhD candidate in nursing at the University of Toronto, told this news organization.

“Workplace violence in healthcare settings is a critical issue that requires attention and action from all stakeholders, including individual providers, healthcare and other institutions, policymakers, and the community,” she said. “By recognizing the problem and implementing evidence-based solutions, we can create safer work environments that protect healthcare workers and improve quality care for patients and organizational effectiveness.”

The study was published online in PLOS Global Public Health.
 

Widespread and Severe

Although women represent most of the healthcare workforce worldwide, hierarchical structures tend to reflect traditional gender norms, where men hold leadership positions and women serve in front-line care roles, said Ms. Ayaz. Women are often marginalized, and their concerns dismissed, which can exacerbate their vulnerability to gender-based workplace violence, she added.

To better understand these imbalances on a global scale, the investigators conducted a scoping review of the prevalence of and risk factors for gender-based workplace violence in healthcare settings. Participants included physicians, nurses, and midwives, between 2010 and 2024. Although the authors acknowledged that gender-based workplace violence affects the full gender spectrum, only a handful of studies included information about nonbinary personnel, so the review focused on men and women.

Among 226 studies, half focused on physicians, 22% focused on nurses, and 28% included physicians, nurses, midwives, and other medical workers. About 64% of studies reported a higher prevalence of all forms of workplace violence for women, including sexual violence, verbal abuse, discrimination, bullying, and physical violence, while 17% reported a higher prevalence for men.

Overall, across most countries, men experienced more physical violence than did women, and women experienced more verbal abuse, sexual harassment, and bullying. Female nurses were particularly likely to experience violence.

Healthcare workers were also more likely to experience violence if they were younger, less experienced, had a lower professional status, or were part of a minority group based on ethnicity, nationality, culture, or language. These factors were sensitive to gender, “reflecting women’s structural disadvantages in the workplace,” wrote the authors.

As a result of workplace violence, women were more likely to report changes in mental health and social behaviors, as well as dissatisfaction, burnout, and changes in their career goals.

The research team identified various factors linked to violent episodes. In clinical settings where most perpetrators were patients and their relatives, abuse and violence could be related to overcrowding, waiting time, and heavy workloads for healthcare providers. When supervisors or colleagues were the perpetrators, workplace violence appeared to be more likely with long hours, night shifts, and certain clinical settings, such as emergency departments, psychiatric settings, operating rooms, and maternity wards, said Ms. Ayaz. Sexual or gender harassment toward women was more prevalent in male-dominated surgical specialties.

“We were surprised by the extent and severity of workplace violence that healthcare workers face around the globe based on gender,” she said. “One aspect that stood out was the significant role that organizational culture and support systems play either in mitigating or exacerbating these incidents, particularly the power structures between and within professions.”

For instance, trainees in lower hierarchical positions often face a higher risk for violence, especially gender-based harassment, she said. Many times, they feel they can’t report these incidents to trainers or managers, who may also be the perpetrators, she added.
 

Addressing Systemic Issues

In 2002, the World Health Organization, International Council of Nurses, and other major medical and labor groups worldwide launched a program focused on ways to eliminate workplace violence in healthcare settings. Since 2020, the call for a solution has grown louder as clinicians, nurses, and other health professionals faced more physical and verbal violence during the COVID-19 pandemic, often leading to burnout.

“Workplace violence is very important because it is more prevalent in healthcare workers than in many other settings and is on the rise,” said Karen Abrams, MD, assistant professor of psychiatry at the University of Toronto. Dr. Abrams, who wasn’t involved with this study, has researched physicians’ experiences of stalking by patients.

Workplace violence “can affect physical and mental health and lead to burnout, depression, anxiety, and symptoms of PTSD,” said Dr. Abrams. “It can affect one’s sleep and concentration and, therefore, ability to perform one’s job.”

Dr. Ayaz and colleagues suggested recommendations to improve gender-based workplace violence, noting the complex and multifaceted aspects of enhancing current policies, fortifying institutional capacities to respond, and implementing tailored interventions. Changes are needed at various levels, including at the healthcare system and provincial, territorial, and national levels, she said.

In Canada, for instance, lawmakers passed a bill in 2021 that amended the national criminal code to make intimidation or bullying a healthcare worker punishable by as many as 10 years in prison. The changes also required courts to consider more serious penalties for offenders who target healthcare workers aggressively.

But more needs to be done, medical professional groups say. The Canadian Nurses Association and Canadian Federation of Nurses Unions, as well as provincial groups, have called for a pan-Canadian violence-prevention framework, targeted funding for violence prevention infrastructure, and an update to the nation’s health human resources strategy to address severe staffing shortages across the country.

“Canada needs a bold vision for the future of our healthcare. Amid an ongoing staffing crisis, the cracks in our public healthcare systems have only grown deeper and wider, with too many going without the care they need when they need it,” Linda Silas, president of the Canadian Federation of Nurses Unions, told this news organization.

“Access to care relies on safe staffing. Years of unsafe working conditions and insufficient staffing are pushing nurses out of our public healthcare system,” she said. “Working collaboratively, we can make healthcare jobs the best jobs in our communities.”

The authors received no specific funding for the study. Ms. Ayaz, Dr. Abrams, and Ms. Silas reported no relevant financial relationships.

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

Across the world, healthcare workers experience workplace violence, which can differ by gender, seniority, and the type of workplace, according to a recent study.

An analysis found that men were more likely to report physical violence, while women were more likely to face nonphysical violence, such as verbal abuse, sexual harassment, and bullying.

“Our study was sparked by the increasing research on workplace violence in healthcare settings. Yet, there’s less empirical data about workplace violence based on gender, its effects on individuals and the collective workforce, and its subsequent impact on patient care and healthcare organizations,” study author Basnama Ayaz, a PhD candidate in nursing at the University of Toronto, told this news organization.

“Workplace violence in healthcare settings is a critical issue that requires attention and action from all stakeholders, including individual providers, healthcare and other institutions, policymakers, and the community,” she said. “By recognizing the problem and implementing evidence-based solutions, we can create safer work environments that protect healthcare workers and improve quality care for patients and organizational effectiveness.”

The study was published online in PLOS Global Public Health.
 

Widespread and Severe

Although women represent most of the healthcare workforce worldwide, hierarchical structures tend to reflect traditional gender norms, where men hold leadership positions and women serve in front-line care roles, said Ms. Ayaz. Women are often marginalized, and their concerns dismissed, which can exacerbate their vulnerability to gender-based workplace violence, she added.

To better understand these imbalances on a global scale, the investigators conducted a scoping review of the prevalence of and risk factors for gender-based workplace violence in healthcare settings. Participants included physicians, nurses, and midwives, between 2010 and 2024. Although the authors acknowledged that gender-based workplace violence affects the full gender spectrum, only a handful of studies included information about nonbinary personnel, so the review focused on men and women.

Among 226 studies, half focused on physicians, 22% focused on nurses, and 28% included physicians, nurses, midwives, and other medical workers. About 64% of studies reported a higher prevalence of all forms of workplace violence for women, including sexual violence, verbal abuse, discrimination, bullying, and physical violence, while 17% reported a higher prevalence for men.

Overall, across most countries, men experienced more physical violence than did women, and women experienced more verbal abuse, sexual harassment, and bullying. Female nurses were particularly likely to experience violence.

Healthcare workers were also more likely to experience violence if they were younger, less experienced, had a lower professional status, or were part of a minority group based on ethnicity, nationality, culture, or language. These factors were sensitive to gender, “reflecting women’s structural disadvantages in the workplace,” wrote the authors.

As a result of workplace violence, women were more likely to report changes in mental health and social behaviors, as well as dissatisfaction, burnout, and changes in their career goals.

The research team identified various factors linked to violent episodes. In clinical settings where most perpetrators were patients and their relatives, abuse and violence could be related to overcrowding, waiting time, and heavy workloads for healthcare providers. When supervisors or colleagues were the perpetrators, workplace violence appeared to be more likely with long hours, night shifts, and certain clinical settings, such as emergency departments, psychiatric settings, operating rooms, and maternity wards, said Ms. Ayaz. Sexual or gender harassment toward women was more prevalent in male-dominated surgical specialties.

“We were surprised by the extent and severity of workplace violence that healthcare workers face around the globe based on gender,” she said. “One aspect that stood out was the significant role that organizational culture and support systems play either in mitigating or exacerbating these incidents, particularly the power structures between and within professions.”

For instance, trainees in lower hierarchical positions often face a higher risk for violence, especially gender-based harassment, she said. Many times, they feel they can’t report these incidents to trainers or managers, who may also be the perpetrators, she added.
 

Addressing Systemic Issues

In 2002, the World Health Organization, International Council of Nurses, and other major medical and labor groups worldwide launched a program focused on ways to eliminate workplace violence in healthcare settings. Since 2020, the call for a solution has grown louder as clinicians, nurses, and other health professionals faced more physical and verbal violence during the COVID-19 pandemic, often leading to burnout.

“Workplace violence is very important because it is more prevalent in healthcare workers than in many other settings and is on the rise,” said Karen Abrams, MD, assistant professor of psychiatry at the University of Toronto. Dr. Abrams, who wasn’t involved with this study, has researched physicians’ experiences of stalking by patients.

Workplace violence “can affect physical and mental health and lead to burnout, depression, anxiety, and symptoms of PTSD,” said Dr. Abrams. “It can affect one’s sleep and concentration and, therefore, ability to perform one’s job.”

Dr. Ayaz and colleagues suggested recommendations to improve gender-based workplace violence, noting the complex and multifaceted aspects of enhancing current policies, fortifying institutional capacities to respond, and implementing tailored interventions. Changes are needed at various levels, including at the healthcare system and provincial, territorial, and national levels, she said.

In Canada, for instance, lawmakers passed a bill in 2021 that amended the national criminal code to make intimidation or bullying a healthcare worker punishable by as many as 10 years in prison. The changes also required courts to consider more serious penalties for offenders who target healthcare workers aggressively.

But more needs to be done, medical professional groups say. The Canadian Nurses Association and Canadian Federation of Nurses Unions, as well as provincial groups, have called for a pan-Canadian violence-prevention framework, targeted funding for violence prevention infrastructure, and an update to the nation’s health human resources strategy to address severe staffing shortages across the country.

“Canada needs a bold vision for the future of our healthcare. Amid an ongoing staffing crisis, the cracks in our public healthcare systems have only grown deeper and wider, with too many going without the care they need when they need it,” Linda Silas, president of the Canadian Federation of Nurses Unions, told this news organization.

“Access to care relies on safe staffing. Years of unsafe working conditions and insufficient staffing are pushing nurses out of our public healthcare system,” she said. “Working collaboratively, we can make healthcare jobs the best jobs in our communities.”

The authors received no specific funding for the study. Ms. Ayaz, Dr. Abrams, and Ms. Silas reported no relevant financial relationships.

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

Across the world, healthcare workers experience workplace violence, which can differ by gender, seniority, and the type of workplace, according to a recent study.

An analysis found that men were more likely to report physical violence, while women were more likely to face nonphysical violence, such as verbal abuse, sexual harassment, and bullying.

“Our study was sparked by the increasing research on workplace violence in healthcare settings. Yet, there’s less empirical data about workplace violence based on gender, its effects on individuals and the collective workforce, and its subsequent impact on patient care and healthcare organizations,” study author Basnama Ayaz, a PhD candidate in nursing at the University of Toronto, told this news organization.

“Workplace violence in healthcare settings is a critical issue that requires attention and action from all stakeholders, including individual providers, healthcare and other institutions, policymakers, and the community,” she said. “By recognizing the problem and implementing evidence-based solutions, we can create safer work environments that protect healthcare workers and improve quality care for patients and organizational effectiveness.”

The study was published online in PLOS Global Public Health.
 

Widespread and Severe

Although women represent most of the healthcare workforce worldwide, hierarchical structures tend to reflect traditional gender norms, where men hold leadership positions and women serve in front-line care roles, said Ms. Ayaz. Women are often marginalized, and their concerns dismissed, which can exacerbate their vulnerability to gender-based workplace violence, she added.

To better understand these imbalances on a global scale, the investigators conducted a scoping review of the prevalence of and risk factors for gender-based workplace violence in healthcare settings. Participants included physicians, nurses, and midwives, between 2010 and 2024. Although the authors acknowledged that gender-based workplace violence affects the full gender spectrum, only a handful of studies included information about nonbinary personnel, so the review focused on men and women.

Among 226 studies, half focused on physicians, 22% focused on nurses, and 28% included physicians, nurses, midwives, and other medical workers. About 64% of studies reported a higher prevalence of all forms of workplace violence for women, including sexual violence, verbal abuse, discrimination, bullying, and physical violence, while 17% reported a higher prevalence for men.

Overall, across most countries, men experienced more physical violence than did women, and women experienced more verbal abuse, sexual harassment, and bullying. Female nurses were particularly likely to experience violence.

Healthcare workers were also more likely to experience violence if they were younger, less experienced, had a lower professional status, or were part of a minority group based on ethnicity, nationality, culture, or language. These factors were sensitive to gender, “reflecting women’s structural disadvantages in the workplace,” wrote the authors.

As a result of workplace violence, women were more likely to report changes in mental health and social behaviors, as well as dissatisfaction, burnout, and changes in their career goals.

The research team identified various factors linked to violent episodes. In clinical settings where most perpetrators were patients and their relatives, abuse and violence could be related to overcrowding, waiting time, and heavy workloads for healthcare providers. When supervisors or colleagues were the perpetrators, workplace violence appeared to be more likely with long hours, night shifts, and certain clinical settings, such as emergency departments, psychiatric settings, operating rooms, and maternity wards, said Ms. Ayaz. Sexual or gender harassment toward women was more prevalent in male-dominated surgical specialties.

“We were surprised by the extent and severity of workplace violence that healthcare workers face around the globe based on gender,” she said. “One aspect that stood out was the significant role that organizational culture and support systems play either in mitigating or exacerbating these incidents, particularly the power structures between and within professions.”

For instance, trainees in lower hierarchical positions often face a higher risk for violence, especially gender-based harassment, she said. Many times, they feel they can’t report these incidents to trainers or managers, who may also be the perpetrators, she added.
 

Addressing Systemic Issues

In 2002, the World Health Organization, International Council of Nurses, and other major medical and labor groups worldwide launched a program focused on ways to eliminate workplace violence in healthcare settings. Since 2020, the call for a solution has grown louder as clinicians, nurses, and other health professionals faced more physical and verbal violence during the COVID-19 pandemic, often leading to burnout.

“Workplace violence is very important because it is more prevalent in healthcare workers than in many other settings and is on the rise,” said Karen Abrams, MD, assistant professor of psychiatry at the University of Toronto. Dr. Abrams, who wasn’t involved with this study, has researched physicians’ experiences of stalking by patients.

Workplace violence “can affect physical and mental health and lead to burnout, depression, anxiety, and symptoms of PTSD,” said Dr. Abrams. “It can affect one’s sleep and concentration and, therefore, ability to perform one’s job.”

Dr. Ayaz and colleagues suggested recommendations to improve gender-based workplace violence, noting the complex and multifaceted aspects of enhancing current policies, fortifying institutional capacities to respond, and implementing tailored interventions. Changes are needed at various levels, including at the healthcare system and provincial, territorial, and national levels, she said.

In Canada, for instance, lawmakers passed a bill in 2021 that amended the national criminal code to make intimidation or bullying a healthcare worker punishable by as many as 10 years in prison. The changes also required courts to consider more serious penalties for offenders who target healthcare workers aggressively.

But more needs to be done, medical professional groups say. The Canadian Nurses Association and Canadian Federation of Nurses Unions, as well as provincial groups, have called for a pan-Canadian violence-prevention framework, targeted funding for violence prevention infrastructure, and an update to the nation’s health human resources strategy to address severe staffing shortages across the country.

“Canada needs a bold vision for the future of our healthcare. Amid an ongoing staffing crisis, the cracks in our public healthcare systems have only grown deeper and wider, with too many going without the care they need when they need it,” Linda Silas, president of the Canadian Federation of Nurses Unions, told this news organization.

“Access to care relies on safe staffing. Years of unsafe working conditions and insufficient staffing are pushing nurses out of our public healthcare system,” she said. “Working collaboratively, we can make healthcare jobs the best jobs in our communities.”

The authors received no specific funding for the study. Ms. Ayaz, Dr. Abrams, and Ms. Silas reported no relevant financial relationships.

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

In the last 10 years, clinical outcomes have improved for patients with unresectable hepatocellular carcinoma (uHCC). The cancer generally comes with chronic liver inflammation, and liver cirrhosis is present in up to 80% of cases. The level of liver dysfunction helps determine the prognosis, but it also may affect the safety of delivering anticancer treatment.

Clinical trials that have tested systemic immunotherapies have excluded patients who don’t fall into the Child-Pugh class A criteria (CP-A) for liver disease, which is the least severe of the Child-Pugh classes A-C. Therefore, there has been much debate about whether patients who have more liver disease (moderate liver dysfunction) and fit under CP-B criteria, instead of CP-A, should be treated with immune checkpoint inhibitor (ICI) therapy or best supportive care (BSC).

A new study, led by Claudia Angela Maria Fulgenzi, MD, with the Department of Surgery and Cancer at the Imperial College London, England, published in JAMA Oncology on July 18, uses an alternative way to compare outcomes following two different paths of care for uHCC patients with moderate liver dysfunction.
 

How was the study done and what did the investigators find?

Researchers performed a retrospective, multicenter, international clinical case series of patients treated in routine practice in tertiary care centers across Europe, the United States, and Asia. They compared data from uHCC patients with CP-B who were receiving first-line ICI-based treatment regimens (n = 187) with a cohort of matched patients with CP-B receiving BSC (n = 156). The first-line immunotherapies were the monotherapy nivolumab or the combination (atezolizumab plus bevacizumab).

Immunotherapy was linked with significantly lower risk of death, compared with best supportive care.

ICI exposure was associated with a reduction of about 50% in the risk of death (hazard ratio, 0.55; 95% CI, 0.35-0.86; P < .001).
 

Is immunotherapy or best supportive care the superior treatment?

The authors wrote that the results point to “improved survival in association with ICI treatment, compared with BSC in patients with uHCC with CP-B liver dysfunction.”

According to the study’s senior author David Pinato, MD, PhD, “this is the first study to suggest that there might be an advantage [of treatment with immunotherapy] in a proportion of people with Child-Pugh B liver dysfunction and particularly so in those patients with more limited disease and portal vein tumor thrombosis.”
 

Will the findings of this study make treatment allocation for patients with uHCC and moderate liver dysfunction (CP-B) less controversial?

Because it is a retrospective study, Dr. Pinato said in an interview, that the findings are not definitive, but can be used to inform future randomized controlled trials.

Dr. Pinato, who is also with the Imperial College London, added that the findings may also introduce a new question.

Although the study was not powered to look at survival differences across the two immunotherapy options given to the patients, there did not seem to be a striking difference between using one immunotherapy (nivolumab) or a combination (atezolizumab plus bevacizumab), he said.

“This is quite important because we know that combinations are significantly superior to monotherapy in patients with normal liver function but based on our study we might say that this provides preliminary evidence that [superiority of combination therapy] might not be true if the liver function is worse.”
 

What do these findings add to the literature about how best to treat patients with uHCC and suboptimal liver function?

Without evidence of efficacy and safety for the group in previous studies, the widespread recommendation for those with moderate dysfunction has been BSC.

These findings “pave the way to select potential patient subgroups in clinical practice,” Dr. Pinato said. It also suggests that the safety level of immunotherapy treatments is acceptable in this patient population, so they are not necessarily disadvantaged compared to patients with more preserved liver function.

“This is the best level of evidence currently available to guide treatment decisions in patients with Child-Pugh B who have been universally excluded by prospective clinical trials and for whom there is no randomized comparison,” Dr. Pinato said.

Dr. Pinato reported personal fees from Roche, AstraZeneca, Eisai, Mina Therapeutics, Starpharma, Lift Biosciences, Boston Scientific, and Avammune, and grants from GSK, MSD, and BMS outside the submitted work. Dr. Fulgenzi has no disclosures. Other authors of the new research have multiple ties with pharmaceutical companies. Complete disclosures are available with the full text of the journal article.

In the last 10 years, clinical outcomes have improved for patients with unresectable hepatocellular carcinoma (uHCC). The cancer generally comes with chronic liver inflammation, and liver cirrhosis is present in up to 80% of cases. The level of liver dysfunction helps determine the prognosis, but it also may affect the safety of delivering anticancer treatment.

Clinical trials that have tested systemic immunotherapies have excluded patients who don’t fall into the Child-Pugh class A criteria (CP-A) for liver disease, which is the least severe of the Child-Pugh classes A-C. Therefore, there has been much debate about whether patients who have more liver disease (moderate liver dysfunction) and fit under CP-B criteria, instead of CP-A, should be treated with immune checkpoint inhibitor (ICI) therapy or best supportive care (BSC).

A new study, led by Claudia Angela Maria Fulgenzi, MD, with the Department of Surgery and Cancer at the Imperial College London, England, published in JAMA Oncology on July 18, uses an alternative way to compare outcomes following two different paths of care for uHCC patients with moderate liver dysfunction.
 

How was the study done and what did the investigators find?

Researchers performed a retrospective, multicenter, international clinical case series of patients treated in routine practice in tertiary care centers across Europe, the United States, and Asia. They compared data from uHCC patients with CP-B who were receiving first-line ICI-based treatment regimens (n = 187) with a cohort of matched patients with CP-B receiving BSC (n = 156). The first-line immunotherapies were the monotherapy nivolumab or the combination (atezolizumab plus bevacizumab).

Immunotherapy was linked with significantly lower risk of death, compared with best supportive care.

ICI exposure was associated with a reduction of about 50% in the risk of death (hazard ratio, 0.55; 95% CI, 0.35-0.86; P < .001).
 

Is immunotherapy or best supportive care the superior treatment?

The authors wrote that the results point to “improved survival in association with ICI treatment, compared with BSC in patients with uHCC with CP-B liver dysfunction.”

According to the study’s senior author David Pinato, MD, PhD, “this is the first study to suggest that there might be an advantage [of treatment with immunotherapy] in a proportion of people with Child-Pugh B liver dysfunction and particularly so in those patients with more limited disease and portal vein tumor thrombosis.”
 

Will the findings of this study make treatment allocation for patients with uHCC and moderate liver dysfunction (CP-B) less controversial?

Because it is a retrospective study, Dr. Pinato said in an interview, that the findings are not definitive, but can be used to inform future randomized controlled trials.

Dr. Pinato, who is also with the Imperial College London, added that the findings may also introduce a new question.

Although the study was not powered to look at survival differences across the two immunotherapy options given to the patients, there did not seem to be a striking difference between using one immunotherapy (nivolumab) or a combination (atezolizumab plus bevacizumab), he said.

“This is quite important because we know that combinations are significantly superior to monotherapy in patients with normal liver function but based on our study we might say that this provides preliminary evidence that [superiority of combination therapy] might not be true if the liver function is worse.”
 

What do these findings add to the literature about how best to treat patients with uHCC and suboptimal liver function?

Without evidence of efficacy and safety for the group in previous studies, the widespread recommendation for those with moderate dysfunction has been BSC.

These findings “pave the way to select potential patient subgroups in clinical practice,” Dr. Pinato said. It also suggests that the safety level of immunotherapy treatments is acceptable in this patient population, so they are not necessarily disadvantaged compared to patients with more preserved liver function.

“This is the best level of evidence currently available to guide treatment decisions in patients with Child-Pugh B who have been universally excluded by prospective clinical trials and for whom there is no randomized comparison,” Dr. Pinato said.

Dr. Pinato reported personal fees from Roche, AstraZeneca, Eisai, Mina Therapeutics, Starpharma, Lift Biosciences, Boston Scientific, and Avammune, and grants from GSK, MSD, and BMS outside the submitted work. Dr. Fulgenzi has no disclosures. Other authors of the new research have multiple ties with pharmaceutical companies. Complete disclosures are available with the full text of the journal article.

In the last 10 years, clinical outcomes have improved for patients with unresectable hepatocellular carcinoma (uHCC). The cancer generally comes with chronic liver inflammation, and liver cirrhosis is present in up to 80% of cases. The level of liver dysfunction helps determine the prognosis, but it also may affect the safety of delivering anticancer treatment.

Clinical trials that have tested systemic immunotherapies have excluded patients who don’t fall into the Child-Pugh class A criteria (CP-A) for liver disease, which is the least severe of the Child-Pugh classes A-C. Therefore, there has been much debate about whether patients who have more liver disease (moderate liver dysfunction) and fit under CP-B criteria, instead of CP-A, should be treated with immune checkpoint inhibitor (ICI) therapy or best supportive care (BSC).

A new study, led by Claudia Angela Maria Fulgenzi, MD, with the Department of Surgery and Cancer at the Imperial College London, England, published in JAMA Oncology on July 18, uses an alternative way to compare outcomes following two different paths of care for uHCC patients with moderate liver dysfunction.
 

How was the study done and what did the investigators find?

Researchers performed a retrospective, multicenter, international clinical case series of patients treated in routine practice in tertiary care centers across Europe, the United States, and Asia. They compared data from uHCC patients with CP-B who were receiving first-line ICI-based treatment regimens (n = 187) with a cohort of matched patients with CP-B receiving BSC (n = 156). The first-line immunotherapies were the monotherapy nivolumab or the combination (atezolizumab plus bevacizumab).

Immunotherapy was linked with significantly lower risk of death, compared with best supportive care.

ICI exposure was associated with a reduction of about 50% in the risk of death (hazard ratio, 0.55; 95% CI, 0.35-0.86; P < .001).
 

Is immunotherapy or best supportive care the superior treatment?

The authors wrote that the results point to “improved survival in association with ICI treatment, compared with BSC in patients with uHCC with CP-B liver dysfunction.”

According to the study’s senior author David Pinato, MD, PhD, “this is the first study to suggest that there might be an advantage [of treatment with immunotherapy] in a proportion of people with Child-Pugh B liver dysfunction and particularly so in those patients with more limited disease and portal vein tumor thrombosis.”
 

Will the findings of this study make treatment allocation for patients with uHCC and moderate liver dysfunction (CP-B) less controversial?

Because it is a retrospective study, Dr. Pinato said in an interview, that the findings are not definitive, but can be used to inform future randomized controlled trials.

Dr. Pinato, who is also with the Imperial College London, added that the findings may also introduce a new question.

Although the study was not powered to look at survival differences across the two immunotherapy options given to the patients, there did not seem to be a striking difference between using one immunotherapy (nivolumab) or a combination (atezolizumab plus bevacizumab), he said.

“This is quite important because we know that combinations are significantly superior to monotherapy in patients with normal liver function but based on our study we might say that this provides preliminary evidence that [superiority of combination therapy] might not be true if the liver function is worse.”
 

What do these findings add to the literature about how best to treat patients with uHCC and suboptimal liver function?

Without evidence of efficacy and safety for the group in previous studies, the widespread recommendation for those with moderate dysfunction has been BSC.

These findings “pave the way to select potential patient subgroups in clinical practice,” Dr. Pinato said. It also suggests that the safety level of immunotherapy treatments is acceptable in this patient population, so they are not necessarily disadvantaged compared to patients with more preserved liver function.

“This is the best level of evidence currently available to guide treatment decisions in patients with Child-Pugh B who have been universally excluded by prospective clinical trials and for whom there is no randomized comparison,” Dr. Pinato said.

Dr. Pinato reported personal fees from Roche, AstraZeneca, Eisai, Mina Therapeutics, Starpharma, Lift Biosciences, Boston Scientific, and Avammune, and grants from GSK, MSD, and BMS outside the submitted work. Dr. Fulgenzi has no disclosures. Other authors of the new research have multiple ties with pharmaceutical companies. Complete disclosures are available with the full text of the journal article.

For patients with chronic obstructive pulmonary disease (COPD), the Global Initiative on Obstructive Lung Disease recommends long-term term pharmacologic and nonpharmacologic therapies based on each patient’s symptoms and disease severity.

Yet even the most effective drugs work only when patients take them as directed, and according to the World Health Organization, fewer than half of all patients worldwide are fully compliant with long-term COPD drug regimens.

And as a recent cross-sectional study showed, nearly one in six patients in the United States reported missing a COPD drug dose, lowering the dose, or delaying filling a prescription for financial reasons.

“I care for patients with COPD as their pulmonologist, and this is a very common problem that we see in clinical practice,” said Meredith McCormack, MD, a pulmonary and critical care medicine physician and associate director of the Pulmonary & Critical Care Medicine Division at Johns Hopkins University in Baltimore.

Dr. McCormack, a national spokesperson for The American Lung Association, said that she shows new patients the photos of all available inhalers and asks which ones they have and how they take them.

“I would say that a majority of the time people are taking their medicines slightly differently than prescribed, and often, this is due to cost,” she said.
 

Serious Consequences

Cost-related medication nonadherence (CRN), as investigators term it, can have major health effects and can be significantly more costly in the long run due to increased hospitalization rates, higher morbidity, and greater risk for COPD-related death associated with suboptimal care.

“For some patients even a month or two of being off medications increases the risk of having exacerbations, having more symptoms, [and] having a decline in their lung function,” said Douglas M. Beach, MD, a pulmonologist at Beth Israel Deaconess Medical Center in Boston.

In the aforementioned cross-sectional study, published in the open access journal BMC Public Health, Xin Wen, MD, from the Jiamusi (China) University School of Public Health, and colleagues looked at data on a representative sample of US adults who participated in the US National Health Interview Survey from 2013 through 2020.

The sample included 15,928 persons aged 18 years or older with a self-reported history of COPD who completed a CRN survey including the following questions: 

During the past 12 months, have you

• Skipped medication doses to save money?
• Taken less medicine than prescribed to save money?
• Delayed filling a prescription to save money?

The investigators found that a weighted 18.56% of participants representing 2.39 million persons with COPD answered “yes” to one of the questions.

Translated into representative population numbers, that works out to an estimated 1.61 million persons with COPD missing doses, 1.72 million taking lower doses than those prescribed, and 2.03 million delaying filling prescriptions to save money.

A multivariable logistic regression analysis showed that those who were most likely to be nonadherent for financial reasons were patients younger than 65 years, women, persons with low family income, those who lacked health insurance, and patients with multiple comorbidities, the authors found.
 

Financial Barriers

One of the biggest barriers to COPD medication adherence is, somewhat paradoxically, insurance status, particularly Medicare, said Corinne Young, MSN, FNP-C, FCCP, from Colorado Springs Pulmonary Consultants.

“What’s so unfair about Medicare is that patients have to buy a drug plan, so they have to already pay for an extra plan to have access to drugs, and the plans vary because there are so many choices,” she said in an interview.

Elderly patients may be confused about the available options and may choose the Medicare Advantage plan with the lowest monthly premiums, which have the highest annual deductibles, usually in the $5000-and-up range, she said.

In addition, the Medicare Part D prescription coverage gap, commonly known as the “donut hole,” requires patients to pay a percentage of drug costs above a certain limit ($5030 in 2024) until a yearly out-of-pocket limit (currently $8000) is reached, after which the plan will again pick up most of the costs.

Although makers of inhalers have voluntarily agreed to limit monthly co-pays to $35 for uninsured patients, Medicare plans require insured patients to shell out considerably more, with 30 days of Trelegy Ellipta (fluticasone furoate, umeclidinium, and vilanterol) setting patients back nearly $350 per month, according to a recent search of costs for a United Healthcare Medicare Advantage plan.
 

Chasing Lower-Cost Options

“I have a lot of patients who use Canadian pharmacies to try to get around it, and I have a lot of patients who make a trip to Mexico every year and load up. I have patients who don’t take their inhalers as they are supposed to in order to make them last longer, and I have patients who take the inhalers of other family members,” Ms. Young said.

Humayun Anjum, MD, FCCP, from Dallas Pulmonary and Critical Care in Dallas, Texas, said in an interview that when patients claim that a prescribed drug isn’t working as expected for them, financial pressures may be partly to blame.

“When you investigate a little bit more, that’s where things become a bit more clear, and the patient may say ‘yeah, I stopped using this inhaler because it was costing me 200 bucks a month and I’m already on other medications,’ ” he said.

He noted that, when possible, he will steer patients toward discount prescription services such as GoodRx, which offers discounts at local pharmacies, or Mark Cuban Cost Plus Drugs, an online pharmacy that offers generic versions of Advair Diskus (fluticasone propionate/salmeterol) at a 100-50 mcg dose for $94.70, a savings of $307.30 over retail pharmacies, according to the company’s website.

Dr. Beach noted that Beth Israel Deaconess has a pharmacist embedded in the pulmonary clinic who can help eligible patients get financial assistance to pay for their medications.

“The influencing factors of CRN are multifaceted and necessitating more rigorous research. Health policy interventions focusing on reducing drug costs, delaying disease progression, preventing exacerbations, and reducing the risk of comorbidities may improve the economic burden of COPD and its outcomes,” Dr. Wen and colleagues wrote.

The study by Dr. Wen and colleagues was funded by grants from Chinese national and academic sources. Dr. McCormack has served as a consultant to Aridis, Boehringer Ingelheim, GlaxoSmithKline, MCG Diagnostics, ndd Medical Technologies, and UpToDate. Ms. Young, Dr. Anjum, and Dr. Beach reported no conflicts of interest.

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

For patients with chronic obstructive pulmonary disease (COPD), the Global Initiative on Obstructive Lung Disease recommends long-term term pharmacologic and nonpharmacologic therapies based on each patient’s symptoms and disease severity.

Yet even the most effective drugs work only when patients take them as directed, and according to the World Health Organization, fewer than half of all patients worldwide are fully compliant with long-term COPD drug regimens.

And as a recent cross-sectional study showed, nearly one in six patients in the United States reported missing a COPD drug dose, lowering the dose, or delaying filling a prescription for financial reasons.

“I care for patients with COPD as their pulmonologist, and this is a very common problem that we see in clinical practice,” said Meredith McCormack, MD, a pulmonary and critical care medicine physician and associate director of the Pulmonary & Critical Care Medicine Division at Johns Hopkins University in Baltimore.

Dr. McCormack, a national spokesperson for The American Lung Association, said that she shows new patients the photos of all available inhalers and asks which ones they have and how they take them.

“I would say that a majority of the time people are taking their medicines slightly differently than prescribed, and often, this is due to cost,” she said.
 

Serious Consequences

Cost-related medication nonadherence (CRN), as investigators term it, can have major health effects and can be significantly more costly in the long run due to increased hospitalization rates, higher morbidity, and greater risk for COPD-related death associated with suboptimal care.

“For some patients even a month or two of being off medications increases the risk of having exacerbations, having more symptoms, [and] having a decline in their lung function,” said Douglas M. Beach, MD, a pulmonologist at Beth Israel Deaconess Medical Center in Boston.

In the aforementioned cross-sectional study, published in the open access journal BMC Public Health, Xin Wen, MD, from the Jiamusi (China) University School of Public Health, and colleagues looked at data on a representative sample of US adults who participated in the US National Health Interview Survey from 2013 through 2020.

The sample included 15,928 persons aged 18 years or older with a self-reported history of COPD who completed a CRN survey including the following questions: 

During the past 12 months, have you

• Skipped medication doses to save money?
• Taken less medicine than prescribed to save money?
• Delayed filling a prescription to save money?

The investigators found that a weighted 18.56% of participants representing 2.39 million persons with COPD answered “yes” to one of the questions.

Translated into representative population numbers, that works out to an estimated 1.61 million persons with COPD missing doses, 1.72 million taking lower doses than those prescribed, and 2.03 million delaying filling prescriptions to save money.

A multivariable logistic regression analysis showed that those who were most likely to be nonadherent for financial reasons were patients younger than 65 years, women, persons with low family income, those who lacked health insurance, and patients with multiple comorbidities, the authors found.
 

Financial Barriers

One of the biggest barriers to COPD medication adherence is, somewhat paradoxically, insurance status, particularly Medicare, said Corinne Young, MSN, FNP-C, FCCP, from Colorado Springs Pulmonary Consultants.

“What’s so unfair about Medicare is that patients have to buy a drug plan, so they have to already pay for an extra plan to have access to drugs, and the plans vary because there are so many choices,” she said in an interview.

Elderly patients may be confused about the available options and may choose the Medicare Advantage plan with the lowest monthly premiums, which have the highest annual deductibles, usually in the $5000-and-up range, she said.

In addition, the Medicare Part D prescription coverage gap, commonly known as the “donut hole,” requires patients to pay a percentage of drug costs above a certain limit ($5030 in 2024) until a yearly out-of-pocket limit (currently $8000) is reached, after which the plan will again pick up most of the costs.

Although makers of inhalers have voluntarily agreed to limit monthly co-pays to $35 for uninsured patients, Medicare plans require insured patients to shell out considerably more, with 30 days of Trelegy Ellipta (fluticasone furoate, umeclidinium, and vilanterol) setting patients back nearly $350 per month, according to a recent search of costs for a United Healthcare Medicare Advantage plan.
 

Chasing Lower-Cost Options

“I have a lot of patients who use Canadian pharmacies to try to get around it, and I have a lot of patients who make a trip to Mexico every year and load up. I have patients who don’t take their inhalers as they are supposed to in order to make them last longer, and I have patients who take the inhalers of other family members,” Ms. Young said.

Humayun Anjum, MD, FCCP, from Dallas Pulmonary and Critical Care in Dallas, Texas, said in an interview that when patients claim that a prescribed drug isn’t working as expected for them, financial pressures may be partly to blame.

“When you investigate a little bit more, that’s where things become a bit more clear, and the patient may say ‘yeah, I stopped using this inhaler because it was costing me 200 bucks a month and I’m already on other medications,’ ” he said.

He noted that, when possible, he will steer patients toward discount prescription services such as GoodRx, which offers discounts at local pharmacies, or Mark Cuban Cost Plus Drugs, an online pharmacy that offers generic versions of Advair Diskus (fluticasone propionate/salmeterol) at a 100-50 mcg dose for $94.70, a savings of $307.30 over retail pharmacies, according to the company’s website.

Dr. Beach noted that Beth Israel Deaconess has a pharmacist embedded in the pulmonary clinic who can help eligible patients get financial assistance to pay for their medications.

“The influencing factors of CRN are multifaceted and necessitating more rigorous research. Health policy interventions focusing on reducing drug costs, delaying disease progression, preventing exacerbations, and reducing the risk of comorbidities may improve the economic burden of COPD and its outcomes,” Dr. Wen and colleagues wrote.

The study by Dr. Wen and colleagues was funded by grants from Chinese national and academic sources. Dr. McCormack has served as a consultant to Aridis, Boehringer Ingelheim, GlaxoSmithKline, MCG Diagnostics, ndd Medical Technologies, and UpToDate. Ms. Young, Dr. Anjum, and Dr. Beach reported no conflicts of interest.

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

For patients with chronic obstructive pulmonary disease (COPD), the Global Initiative on Obstructive Lung Disease recommends long-term term pharmacologic and nonpharmacologic therapies based on each patient’s symptoms and disease severity.

Yet even the most effective drugs work only when patients take them as directed, and according to the World Health Organization, fewer than half of all patients worldwide are fully compliant with long-term COPD drug regimens.

And as a recent cross-sectional study showed, nearly one in six patients in the United States reported missing a COPD drug dose, lowering the dose, or delaying filling a prescription for financial reasons.

“I care for patients with COPD as their pulmonologist, and this is a very common problem that we see in clinical practice,” said Meredith McCormack, MD, a pulmonary and critical care medicine physician and associate director of the Pulmonary & Critical Care Medicine Division at Johns Hopkins University in Baltimore.

Dr. McCormack, a national spokesperson for The American Lung Association, said that she shows new patients the photos of all available inhalers and asks which ones they have and how they take them.

“I would say that a majority of the time people are taking their medicines slightly differently than prescribed, and often, this is due to cost,” she said.
 

Serious Consequences

Cost-related medication nonadherence (CRN), as investigators term it, can have major health effects and can be significantly more costly in the long run due to increased hospitalization rates, higher morbidity, and greater risk for COPD-related death associated with suboptimal care.

“For some patients even a month or two of being off medications increases the risk of having exacerbations, having more symptoms, [and] having a decline in their lung function,” said Douglas M. Beach, MD, a pulmonologist at Beth Israel Deaconess Medical Center in Boston.

In the aforementioned cross-sectional study, published in the open access journal BMC Public Health, Xin Wen, MD, from the Jiamusi (China) University School of Public Health, and colleagues looked at data on a representative sample of US adults who participated in the US National Health Interview Survey from 2013 through 2020.

The sample included 15,928 persons aged 18 years or older with a self-reported history of COPD who completed a CRN survey including the following questions: 

During the past 12 months, have you

• Skipped medication doses to save money?
• Taken less medicine than prescribed to save money?
• Delayed filling a prescription to save money?

The investigators found that a weighted 18.56% of participants representing 2.39 million persons with COPD answered “yes” to one of the questions.

Translated into representative population numbers, that works out to an estimated 1.61 million persons with COPD missing doses, 1.72 million taking lower doses than those prescribed, and 2.03 million delaying filling prescriptions to save money.

A multivariable logistic regression analysis showed that those who were most likely to be nonadherent for financial reasons were patients younger than 65 years, women, persons with low family income, those who lacked health insurance, and patients with multiple comorbidities, the authors found.
 

Financial Barriers

One of the biggest barriers to COPD medication adherence is, somewhat paradoxically, insurance status, particularly Medicare, said Corinne Young, MSN, FNP-C, FCCP, from Colorado Springs Pulmonary Consultants.

“What’s so unfair about Medicare is that patients have to buy a drug plan, so they have to already pay for an extra plan to have access to drugs, and the plans vary because there are so many choices,” she said in an interview.

Elderly patients may be confused about the available options and may choose the Medicare Advantage plan with the lowest monthly premiums, which have the highest annual deductibles, usually in the $5000-and-up range, she said.

In addition, the Medicare Part D prescription coverage gap, commonly known as the “donut hole,” requires patients to pay a percentage of drug costs above a certain limit ($5030 in 2024) until a yearly out-of-pocket limit (currently $8000) is reached, after which the plan will again pick up most of the costs.

Although makers of inhalers have voluntarily agreed to limit monthly co-pays to $35 for uninsured patients, Medicare plans require insured patients to shell out considerably more, with 30 days of Trelegy Ellipta (fluticasone furoate, umeclidinium, and vilanterol) setting patients back nearly $350 per month, according to a recent search of costs for a United Healthcare Medicare Advantage plan.
 

Chasing Lower-Cost Options

“I have a lot of patients who use Canadian pharmacies to try to get around it, and I have a lot of patients who make a trip to Mexico every year and load up. I have patients who don’t take their inhalers as they are supposed to in order to make them last longer, and I have patients who take the inhalers of other family members,” Ms. Young said.

Humayun Anjum, MD, FCCP, from Dallas Pulmonary and Critical Care in Dallas, Texas, said in an interview that when patients claim that a prescribed drug isn’t working as expected for them, financial pressures may be partly to blame.

“When you investigate a little bit more, that’s where things become a bit more clear, and the patient may say ‘yeah, I stopped using this inhaler because it was costing me 200 bucks a month and I’m already on other medications,’ ” he said.

He noted that, when possible, he will steer patients toward discount prescription services such as GoodRx, which offers discounts at local pharmacies, or Mark Cuban Cost Plus Drugs, an online pharmacy that offers generic versions of Advair Diskus (fluticasone propionate/salmeterol) at a 100-50 mcg dose for $94.70, a savings of $307.30 over retail pharmacies, according to the company’s website.

Dr. Beach noted that Beth Israel Deaconess has a pharmacist embedded in the pulmonary clinic who can help eligible patients get financial assistance to pay for their medications.

“The influencing factors of CRN are multifaceted and necessitating more rigorous research. Health policy interventions focusing on reducing drug costs, delaying disease progression, preventing exacerbations, and reducing the risk of comorbidities may improve the economic burden of COPD and its outcomes,” Dr. Wen and colleagues wrote.

The study by Dr. Wen and colleagues was funded by grants from Chinese national and academic sources. Dr. McCormack has served as a consultant to Aridis, Boehringer Ingelheim, GlaxoSmithKline, MCG Diagnostics, ndd Medical Technologies, and UpToDate. Ms. Young, Dr. Anjum, and Dr. Beach reported no conflicts of interest.

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

Total mesometrial resection (TMMR) is associated with significantly longer recurrence-free survival (RFS) and overall survival (OS) than standard treatment for patients with early-stage cervical cancer, while outcomes were not different among those with locally advanced disease, according to a new study.

These findings suggest that TMMR may be considered a primary treatment option for both early-stage and locally advanced cervical cancer confined to the Müllerian compartment, reported lead author Henrik Falconer, MD, PhD, of Karolinska Institutet, Stockholm, Sweden, and colleagues.
 

What is the rationale behind TMMR?

“Current international guidelines [for cervical cancer] are primarily based on retrospective case series and a small number of outdated randomized controlled trials,” the investigators wrote in EClinicalMedicine, part of The Lancet publication platform. “The stage-dependent treatment recommendations, with surgery advised for early-stage and radiation therapy for locally advanced disease, may be considered too simplistic, suggesting that early stages of cervical cancer cannot be controlled with surgical resection alone or that locally advanced cervical cancer is inoperable.”

This mindset, they noted, overlooks the complexities of cancer spread. In contrast, TMMR and similar surgical approaches based on the cancer field model are mapped along routes of locoregional dissemination, leading to “excellent local control” in more than 600 cases at the University Hospital of Leipzig, Leipzig, Germany.

To date, however, TMMR’s adoption has been limited, and it has not been compared directly with current guideline treatments, prompting the present study.
 

What methods were used to compare TMMR with standard treatment?

The study compared TMMR plus therapeutic lymph node dissection (tLND) without adjuvant radiation versus standard treatment (ST) for early-stage (FIGO 2009 IB1, IIA1) and locally advanced (FIGO 2009 IB2, IIA2, IIB) cervical cancer. Standard treatment for patients with early-stage disease involved radical hysterectomy and pelvic lymphadenectomy, with adjuvant chemoradiation dependent upon final pathology. Those with locally advanced disease received definitive chemoradiation.

Data for the standard treatment group were drawn from population-based registries in Sweden, while those for the TMMR group came from the Leipzig Mesometrial Resection Study Database. The final dataset included 1,007 women treated between 2011 and 2020, with 733 undergoing standard treatment and 274 receiving TMMR.

Outcomes included RFS and OS, adjusted for clinical and tumor-related variables.
 

How did TMMR compare with standard treatment?

TMMR was associated with superior oncologic outcomes compared with standard treatment for early-stage cervical cancer.

Specifically, 5-year RFS was 91.2% for TMMR versus 81.8% for standard therapy (P = .002). In the adjusted analysis, TMMR was associated with a significantly lower hazard of recurrence (hazard ratio [HR], 0.39; 95% CI, 0.22–0.69) and death (HR, 0.42; 95% CI, 0.21-0.86). Also favoring TMMR, absolute difference in the risk of recurrence at 5 years was 9.4% (95% CI 3.2–15.7). In addition, 5-year OS was better in the TMMR group, at 93.3%, compared with 90.3% for standard treatment (P = .034).

Among patients with locally advanced disease, no significant differences in RFS or OS were observed.
 

Are these data strong enough to make TMMR the new standard treatment?

Dr. Falconer and colleagues concluded that TMMR with tLND “may replace the standard treatment approach in early-stage cervical cancer and furthermore be evaluated as an option in locally advanced cervical cancer confined to the Müllerian compartment.”

While the investigators anticipated demands for randomized controlled trials, they questioned the value of such studies, suggesting that any control arm would be “based on inconsistent or flawed concepts.”

How does TMMR fit into the current treatment landscape for cervical cancer?

“This is a very niche surgery that most places don’t do,” Dr. Modesitt said.

She pointed out that “multiple variations” on the standard radical hysterectomy have been proposed in the past, such as the laterally extended endopelvic resection.

“[TMMR] is not a new concept,” she said. “It’s just a question of how radical it is.”

Instead of developing new types of radical surgery, she said, the trend in the United States is toward de-escalation of surgical treatments altogether, with greater reliance upon medical options, such as immunotherapy.

“[This study] is thought provoking, and I applaud them for doing it,” Dr. Modesitt said. “But I’m not going to go out and do that on my next patient.”

This study was supported by grants from Centre for Clinical Research Sörmland (Sweden) and Region Stockholm (Sweden). Dr. Falconer is a board member of Surgical Science.

Total mesometrial resection (TMMR) is associated with significantly longer recurrence-free survival (RFS) and overall survival (OS) than standard treatment for patients with early-stage cervical cancer, while outcomes were not different among those with locally advanced disease, according to a new study.

These findings suggest that TMMR may be considered a primary treatment option for both early-stage and locally advanced cervical cancer confined to the Müllerian compartment, reported lead author Henrik Falconer, MD, PhD, of Karolinska Institutet, Stockholm, Sweden, and colleagues.
 

What is the rationale behind TMMR?

“Current international guidelines [for cervical cancer] are primarily based on retrospective case series and a small number of outdated randomized controlled trials,” the investigators wrote in EClinicalMedicine, part of The Lancet publication platform. “The stage-dependent treatment recommendations, with surgery advised for early-stage and radiation therapy for locally advanced disease, may be considered too simplistic, suggesting that early stages of cervical cancer cannot be controlled with surgical resection alone or that locally advanced cervical cancer is inoperable.”

This mindset, they noted, overlooks the complexities of cancer spread. In contrast, TMMR and similar surgical approaches based on the cancer field model are mapped along routes of locoregional dissemination, leading to “excellent local control” in more than 600 cases at the University Hospital of Leipzig, Leipzig, Germany.

To date, however, TMMR’s adoption has been limited, and it has not been compared directly with current guideline treatments, prompting the present study.
 

What methods were used to compare TMMR with standard treatment?

The study compared TMMR plus therapeutic lymph node dissection (tLND) without adjuvant radiation versus standard treatment (ST) for early-stage (FIGO 2009 IB1, IIA1) and locally advanced (FIGO 2009 IB2, IIA2, IIB) cervical cancer. Standard treatment for patients with early-stage disease involved radical hysterectomy and pelvic lymphadenectomy, with adjuvant chemoradiation dependent upon final pathology. Those with locally advanced disease received definitive chemoradiation.

Data for the standard treatment group were drawn from population-based registries in Sweden, while those for the TMMR group came from the Leipzig Mesometrial Resection Study Database. The final dataset included 1,007 women treated between 2011 and 2020, with 733 undergoing standard treatment and 274 receiving TMMR.

Outcomes included RFS and OS, adjusted for clinical and tumor-related variables.
 

How did TMMR compare with standard treatment?

TMMR was associated with superior oncologic outcomes compared with standard treatment for early-stage cervical cancer.

Specifically, 5-year RFS was 91.2% for TMMR versus 81.8% for standard therapy (P = .002). In the adjusted analysis, TMMR was associated with a significantly lower hazard of recurrence (hazard ratio [HR], 0.39; 95% CI, 0.22–0.69) and death (HR, 0.42; 95% CI, 0.21-0.86). Also favoring TMMR, absolute difference in the risk of recurrence at 5 years was 9.4% (95% CI 3.2–15.7). In addition, 5-year OS was better in the TMMR group, at 93.3%, compared with 90.3% for standard treatment (P = .034).

Among patients with locally advanced disease, no significant differences in RFS or OS were observed.
 

Are these data strong enough to make TMMR the new standard treatment?

Dr. Falconer and colleagues concluded that TMMR with tLND “may replace the standard treatment approach in early-stage cervical cancer and furthermore be evaluated as an option in locally advanced cervical cancer confined to the Müllerian compartment.”

While the investigators anticipated demands for randomized controlled trials, they questioned the value of such studies, suggesting that any control arm would be “based on inconsistent or flawed concepts.”

How does TMMR fit into the current treatment landscape for cervical cancer?

“This is a very niche surgery that most places don’t do,” Dr. Modesitt said.

She pointed out that “multiple variations” on the standard radical hysterectomy have been proposed in the past, such as the laterally extended endopelvic resection.

“[TMMR] is not a new concept,” she said. “It’s just a question of how radical it is.”

Instead of developing new types of radical surgery, she said, the trend in the United States is toward de-escalation of surgical treatments altogether, with greater reliance upon medical options, such as immunotherapy.

“[This study] is thought provoking, and I applaud them for doing it,” Dr. Modesitt said. “But I’m not going to go out and do that on my next patient.”

This study was supported by grants from Centre for Clinical Research Sörmland (Sweden) and Region Stockholm (Sweden). Dr. Falconer is a board member of Surgical Science.

Total mesometrial resection (TMMR) is associated with significantly longer recurrence-free survival (RFS) and overall survival (OS) than standard treatment for patients with early-stage cervical cancer, while outcomes were not different among those with locally advanced disease, according to a new study.

These findings suggest that TMMR may be considered a primary treatment option for both early-stage and locally advanced cervical cancer confined to the Müllerian compartment, reported lead author Henrik Falconer, MD, PhD, of Karolinska Institutet, Stockholm, Sweden, and colleagues.
 

What is the rationale behind TMMR?

“Current international guidelines [for cervical cancer] are primarily based on retrospective case series and a small number of outdated randomized controlled trials,” the investigators wrote in EClinicalMedicine, part of The Lancet publication platform. “The stage-dependent treatment recommendations, with surgery advised for early-stage and radiation therapy for locally advanced disease, may be considered too simplistic, suggesting that early stages of cervical cancer cannot be controlled with surgical resection alone or that locally advanced cervical cancer is inoperable.”

This mindset, they noted, overlooks the complexities of cancer spread. In contrast, TMMR and similar surgical approaches based on the cancer field model are mapped along routes of locoregional dissemination, leading to “excellent local control” in more than 600 cases at the University Hospital of Leipzig, Leipzig, Germany.

To date, however, TMMR’s adoption has been limited, and it has not been compared directly with current guideline treatments, prompting the present study.
 

What methods were used to compare TMMR with standard treatment?

The study compared TMMR plus therapeutic lymph node dissection (tLND) without adjuvant radiation versus standard treatment (ST) for early-stage (FIGO 2009 IB1, IIA1) and locally advanced (FIGO 2009 IB2, IIA2, IIB) cervical cancer. Standard treatment for patients with early-stage disease involved radical hysterectomy and pelvic lymphadenectomy, with adjuvant chemoradiation dependent upon final pathology. Those with locally advanced disease received definitive chemoradiation.

Data for the standard treatment group were drawn from population-based registries in Sweden, while those for the TMMR group came from the Leipzig Mesometrial Resection Study Database. The final dataset included 1,007 women treated between 2011 and 2020, with 733 undergoing standard treatment and 274 receiving TMMR.

Outcomes included RFS and OS, adjusted for clinical and tumor-related variables.
 

How did TMMR compare with standard treatment?

TMMR was associated with superior oncologic outcomes compared with standard treatment for early-stage cervical cancer.

Specifically, 5-year RFS was 91.2% for TMMR versus 81.8% for standard therapy (P = .002). In the adjusted analysis, TMMR was associated with a significantly lower hazard of recurrence (hazard ratio [HR], 0.39; 95% CI, 0.22–0.69) and death (HR, 0.42; 95% CI, 0.21-0.86). Also favoring TMMR, absolute difference in the risk of recurrence at 5 years was 9.4% (95% CI 3.2–15.7). In addition, 5-year OS was better in the TMMR group, at 93.3%, compared with 90.3% for standard treatment (P = .034).

Among patients with locally advanced disease, no significant differences in RFS or OS were observed.
 

Are these data strong enough to make TMMR the new standard treatment?

Dr. Falconer and colleagues concluded that TMMR with tLND “may replace the standard treatment approach in early-stage cervical cancer and furthermore be evaluated as an option in locally advanced cervical cancer confined to the Müllerian compartment.”

While the investigators anticipated demands for randomized controlled trials, they questioned the value of such studies, suggesting that any control arm would be “based on inconsistent or flawed concepts.”

How does TMMR fit into the current treatment landscape for cervical cancer?

“This is a very niche surgery that most places don’t do,” Dr. Modesitt said.

She pointed out that “multiple variations” on the standard radical hysterectomy have been proposed in the past, such as the laterally extended endopelvic resection.

“[TMMR] is not a new concept,” she said. “It’s just a question of how radical it is.”

Instead of developing new types of radical surgery, she said, the trend in the United States is toward de-escalation of surgical treatments altogether, with greater reliance upon medical options, such as immunotherapy.

“[This study] is thought provoking, and I applaud them for doing it,” Dr. Modesitt said. “But I’m not going to go out and do that on my next patient.”

This study was supported by grants from Centre for Clinical Research Sörmland (Sweden) and Region Stockholm (Sweden). Dr. Falconer is a board member of Surgical Science.

Commercial tattoo and permanent makeup inks are too often contaminated with microbes that can lead to infection, warn investigators of a first-of-its-kind study testing the products. 

When US researchers tested 75 unopened and sealed tattoo and permanent makeup inks from 14 different manufacturers, they discovered that about 35% of the products were contaminated with bacteria.

Venerala/gettyimages

New Body Art Culture

Tattoos are more popular than ever, and it is estimated that at least 32% of people in the United States have at least one tattoo. And the rise in popularity has coincided with an increase in ink-related infections.

This new research joins previous studies that have demonstrated that commercial tattoo and permanent makeup inks are often contaminated with pathogenic microorganisms.

Of the 75 ink samples that Dr. Kim and colleagues tested, 26 were contaminated with 34 bacterial isolates classified into 14 genera and 22 species. Among the 34 bacterial isolates, 19 were identified as possibly pathogenic bacterial strains. 

Two species — Cutibacterium acnes (four strains) and Staphylococcus epidermidis (two strains) — were isolated under anaerobic conditions.

Two possibly pathogenic bacterial strains — Staphylococcus saprophyticus and C acnes — were isolated from the same two ink samples, indicating that tattoo and permanent makeup inks can harbor both aerobic (S saprophyticus) and anaerobic (C acnes) bacteria. 

There was no significant association between sterility claims on the ink label and the absence of bacterial contamination.

“The presence of bacteria like Cutibacterium acnes and Staphylococcus epidermidis, which can cause skin infections and other complications, underscores the potential danger to individuals receiving tattoos or permanent makeup,” Dr. Javaid explained.

The results “emphasize the importance of monitoring these products for both aerobic and anaerobic bacteria, including possibly pathogenic microorganisms,” Dr. Kim said in the news release.

The next steps, according to the researchers, include developing more efficient and accurate microbial detection methods for tattoo inks to streamline the monitoring process and examining the occurrence, co-occurrence, and diversity of microbial contaminants in tattoo inks to prevent future contamination.

Counseling Patients

Healthcare professionals play a “crucial role in counseling patients about the risks associated with tattoos. They should inform patients about the potential for infections, allergic reactions, and other complications related to tattooing and permanent ink,” said Dr. Javaid.

Specific advice can include ensuring that the tattoo parlor adheres to strict hygiene practices and verifying that tattoo inks are from reputable sources and, if possible, have undergone sterilization. 

Clinicians should discuss the importance of proper aftercare to minimize the risk for infection, recommend patients with compromised immune systems or skin conditions to reconsider getting a tattoo, and encourage patients to be aware of the signs of infection and to seek medical attention promptly if any symptoms arise.

“Enhanced regulatory measures would help reduce the risk of infections and ensure safer tattooing practices for consumers,” Dr. Javaid said. The findings of Dr. Kim and colleagues “indicate that current manufacturing and sterilization processes are inadequate.” 

Regulations could include stricter manufacturing standards to ensure sterility, the mandatory testing of inks for microbial contamination before they reach the market, clear labeling requirements that accurately reflect the sterility and safety of products, and regular inspections and audits of tattoo ink manufacturers, he said, which could encourage the development of more effective sterilization techniques to eliminate bacterial contamination.

The FDA has created a document — Think Before You Ink: Tattoo Safety — for consumers who are considering getting a tattoo.

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

Commercial tattoo and permanent makeup inks are too often contaminated with microbes that can lead to infection, warn investigators of a first-of-its-kind study testing the products. 

When US researchers tested 75 unopened and sealed tattoo and permanent makeup inks from 14 different manufacturers, they discovered that about 35% of the products were contaminated with bacteria.

Venerala/gettyimages

New Body Art Culture

Tattoos are more popular than ever, and it is estimated that at least 32% of people in the United States have at least one tattoo. And the rise in popularity has coincided with an increase in ink-related infections.

This new research joins previous studies that have demonstrated that commercial tattoo and permanent makeup inks are often contaminated with pathogenic microorganisms.

Of the 75 ink samples that Dr. Kim and colleagues tested, 26 were contaminated with 34 bacterial isolates classified into 14 genera and 22 species. Among the 34 bacterial isolates, 19 were identified as possibly pathogenic bacterial strains. 

Two species — Cutibacterium acnes (four strains) and Staphylococcus epidermidis (two strains) — were isolated under anaerobic conditions.

Two possibly pathogenic bacterial strains — Staphylococcus saprophyticus and C acnes — were isolated from the same two ink samples, indicating that tattoo and permanent makeup inks can harbor both aerobic (S saprophyticus) and anaerobic (C acnes) bacteria. 

There was no significant association between sterility claims on the ink label and the absence of bacterial contamination.

“The presence of bacteria like Cutibacterium acnes and Staphylococcus epidermidis, which can cause skin infections and other complications, underscores the potential danger to individuals receiving tattoos or permanent makeup,” Dr. Javaid explained.

The results “emphasize the importance of monitoring these products for both aerobic and anaerobic bacteria, including possibly pathogenic microorganisms,” Dr. Kim said in the news release.

The next steps, according to the researchers, include developing more efficient and accurate microbial detection methods for tattoo inks to streamline the monitoring process and examining the occurrence, co-occurrence, and diversity of microbial contaminants in tattoo inks to prevent future contamination.

Counseling Patients

Healthcare professionals play a “crucial role in counseling patients about the risks associated with tattoos. They should inform patients about the potential for infections, allergic reactions, and other complications related to tattooing and permanent ink,” said Dr. Javaid.

Specific advice can include ensuring that the tattoo parlor adheres to strict hygiene practices and verifying that tattoo inks are from reputable sources and, if possible, have undergone sterilization. 

Clinicians should discuss the importance of proper aftercare to minimize the risk for infection, recommend patients with compromised immune systems or skin conditions to reconsider getting a tattoo, and encourage patients to be aware of the signs of infection and to seek medical attention promptly if any symptoms arise.

“Enhanced regulatory measures would help reduce the risk of infections and ensure safer tattooing practices for consumers,” Dr. Javaid said. The findings of Dr. Kim and colleagues “indicate that current manufacturing and sterilization processes are inadequate.” 

Regulations could include stricter manufacturing standards to ensure sterility, the mandatory testing of inks for microbial contamination before they reach the market, clear labeling requirements that accurately reflect the sterility and safety of products, and regular inspections and audits of tattoo ink manufacturers, he said, which could encourage the development of more effective sterilization techniques to eliminate bacterial contamination.

The FDA has created a document — Think Before You Ink: Tattoo Safety — for consumers who are considering getting a tattoo.

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

Commercial tattoo and permanent makeup inks are too often contaminated with microbes that can lead to infection, warn investigators of a first-of-its-kind study testing the products. 

When US researchers tested 75 unopened and sealed tattoo and permanent makeup inks from 14 different manufacturers, they discovered that about 35% of the products were contaminated with bacteria.

Venerala/gettyimages

New Body Art Culture

Tattoos are more popular than ever, and it is estimated that at least 32% of people in the United States have at least one tattoo. And the rise in popularity has coincided with an increase in ink-related infections.

This new research joins previous studies that have demonstrated that commercial tattoo and permanent makeup inks are often contaminated with pathogenic microorganisms.

Of the 75 ink samples that Dr. Kim and colleagues tested, 26 were contaminated with 34 bacterial isolates classified into 14 genera and 22 species. Among the 34 bacterial isolates, 19 were identified as possibly pathogenic bacterial strains. 

Two species — Cutibacterium acnes (four strains) and Staphylococcus epidermidis (two strains) — were isolated under anaerobic conditions.

Two possibly pathogenic bacterial strains — Staphylococcus saprophyticus and C acnes — were isolated from the same two ink samples, indicating that tattoo and permanent makeup inks can harbor both aerobic (S saprophyticus) and anaerobic (C acnes) bacteria. 

There was no significant association between sterility claims on the ink label and the absence of bacterial contamination.

“The presence of bacteria like Cutibacterium acnes and Staphylococcus epidermidis, which can cause skin infections and other complications, underscores the potential danger to individuals receiving tattoos or permanent makeup,” Dr. Javaid explained.

The results “emphasize the importance of monitoring these products for both aerobic and anaerobic bacteria, including possibly pathogenic microorganisms,” Dr. Kim said in the news release.

The next steps, according to the researchers, include developing more efficient and accurate microbial detection methods for tattoo inks to streamline the monitoring process and examining the occurrence, co-occurrence, and diversity of microbial contaminants in tattoo inks to prevent future contamination.

Counseling Patients

Healthcare professionals play a “crucial role in counseling patients about the risks associated with tattoos. They should inform patients about the potential for infections, allergic reactions, and other complications related to tattooing and permanent ink,” said Dr. Javaid.

Specific advice can include ensuring that the tattoo parlor adheres to strict hygiene practices and verifying that tattoo inks are from reputable sources and, if possible, have undergone sterilization. 

Clinicians should discuss the importance of proper aftercare to minimize the risk for infection, recommend patients with compromised immune systems or skin conditions to reconsider getting a tattoo, and encourage patients to be aware of the signs of infection and to seek medical attention promptly if any symptoms arise.

“Enhanced regulatory measures would help reduce the risk of infections and ensure safer tattooing practices for consumers,” Dr. Javaid said. The findings of Dr. Kim and colleagues “indicate that current manufacturing and sterilization processes are inadequate.” 

Regulations could include stricter manufacturing standards to ensure sterility, the mandatory testing of inks for microbial contamination before they reach the market, clear labeling requirements that accurately reflect the sterility and safety of products, and regular inspections and audits of tattoo ink manufacturers, he said, which could encourage the development of more effective sterilization techniques to eliminate bacterial contamination.

The FDA has created a document — Think Before You Ink: Tattoo Safety — for consumers who are considering getting a tattoo.

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

In the war against cancer, doctors and patients have long reached for three main weapons to target diseased cells: chemotherapy, radiation, and surgery.

But new research published this month in the journal Nature Materials suggests that manipulating the tissue around those cells — a strategy known as “mechanotherapeutics” — could play a critical role in reducing drug resistance and improving survival rates for hard-to-treat cancers like pancreatic cancer.

“Our study shows the importance of the tumor microenvironment and its properties in dictating how cancer progresses and responds to drug treatment,” said first author Bauer LeSavage, PhD, who conducted the study as a postdoctoral researcher in the Bioengineering Department at Stanford University, Stanford, California. “It also demonstrates that chemoresistance can be reversed.”

Each year, about 66,000 people are diagnosed with pancreatic cancer, and 52,000 die from it. It is a particularly lethal type of cancer, with 5-year survival rates hovering around 7% — a rate that has not improved much since 1996 when the first-line chemotherapy drug gemcitabine was approved.

It looks different from many cancers, said Lynn Matrisian, PhD, chief science officer for the nonprofit Pancreatic Cancer Action Network. Instead of a tumorous mass, it is made of islands of cancer cells surrounded by unusually dense fibrous tissue known as the extracellular matrix, which can collapse blood vessels and prevent drugs from reaching the tumor.

For the study, Dr. LeSavage and his team engineered synthetic but lifelike three-dimensional pancreas tissue with varying degrees of stiffness and different biochemical properties. Then they inserted bits of real tumors from patients with pancreatic cancer, watched them grow, and tried to kill them with drugs.

They found that cells growing in a stiff matrix were more resistant to chemotherapy than those growing in a softer matrix. But the story didn’t end there.

They also found that high amounts of the tissue-strengthening protein hyaluronic acid in stiff tissue seemed to signal the cancer cells to develop tiny pumps on their surface which shuttled out the drugs before they could take effect.

When the researchers moved the cancer cells into either a softer matrix or a stiff matrix in which the hyaluronic acid receptor, called CD44, was blocked, the chemotherapy drugs started working again.

“This suggests that if we can disrupt the stiffness signaling that’s happening through the CD44 receptor, we could make patients’ pancreatic cancer treatable again by normal chemotherapy,” said senior study author Sarah Heilshorn, PhD, a professor of materials science and engineering at Stanford. “These results suggest an exciting new direction for new drug development.”
 

Targeting Nearby Tissue: A Novel Approach to Fighting Chemoresistance

The study is not the first to suggest that chemically targeting the microenvironment surrounding a tumor can influence how patients respond to treatment.

In one recent clinical trial, patients with metastatic pancreatic cancer were given an experimental drug to inhibit a protein called connective tissue growth factor, reduce fibrous tissue, and make pancreatic tumors easier to surgically remove. Results have not been published yet.

Other research suggests that the generic blood pressure drug losartan, when given in combination with chemotherapy and radiation, can boost survival in patients with advanced pancreatic cancer by, in part, improving the health of blood vessels that carry drugs to the tumor.

But other studies of such mechanotherapeutics have yielded inconclusive results, said Dr. Matrisian.

“This paper points to another reason why we should not give up on this approach,” she said.

Ning Wang, PhD, director of the new Institute for Mechanobiology at Northeastern University College of Engineering, Boston, said there is no question that the composition of a tumor’s environment can influence how cancer progresses or responds to drugs. The new paper, he said, adds an important new chapter to the evolving story.

“But it’s very complicated. It’s not as simple as saying make it softer or stiffer and you can change the outcome for the patient,” Dr. Wang said.

In fact, some research has shown that tissue becomes stiffer when cancer arises so it can contain it from spreading.

In one animal study of pancreatic cancer that had spread to the liver, administering drugs to soften the surrounding tissue, or stroma, actually had the opposite effect — accelerating tumor growth and reducing survival rates.

Dr. Wang also noted that any drug designed to influence the extracellular matrix would need to be extremely localized, to prevent damage to other tissues, like bone or heart muscle.

Dr. LeSavage said he sees the paper as a case study in how important the extracellular matrix is and an example of how artificially grown organs or tissues can play a key role in testing how drugs work or don’t work.

He imagines a day when doctors could personalize treatments by taking a bit of a patient’s tumor, growing it in artificial tissue, and seeing how different tissue-altering drugs affect different therapies.

“This isn’t something that is just unique to pancreatic cancer,” he said, noting that the extracellular matrix throughout the body interacts with different cancers. “If we could take someone who has a chemoresistant tumor and convert it into something that is sensitive to existing therapies again, we could give them a second chance.”

A version of this article appeared on Medscape.com.

In the war against cancer, doctors and patients have long reached for three main weapons to target diseased cells: chemotherapy, radiation, and surgery.

But new research published this month in the journal Nature Materials suggests that manipulating the tissue around those cells — a strategy known as “mechanotherapeutics” — could play a critical role in reducing drug resistance and improving survival rates for hard-to-treat cancers like pancreatic cancer.

“Our study shows the importance of the tumor microenvironment and its properties in dictating how cancer progresses and responds to drug treatment,” said first author Bauer LeSavage, PhD, who conducted the study as a postdoctoral researcher in the Bioengineering Department at Stanford University, Stanford, California. “It also demonstrates that chemoresistance can be reversed.”

Each year, about 66,000 people are diagnosed with pancreatic cancer, and 52,000 die from it. It is a particularly lethal type of cancer, with 5-year survival rates hovering around 7% — a rate that has not improved much since 1996 when the first-line chemotherapy drug gemcitabine was approved.

It looks different from many cancers, said Lynn Matrisian, PhD, chief science officer for the nonprofit Pancreatic Cancer Action Network. Instead of a tumorous mass, it is made of islands of cancer cells surrounded by unusually dense fibrous tissue known as the extracellular matrix, which can collapse blood vessels and prevent drugs from reaching the tumor.

For the study, Dr. LeSavage and his team engineered synthetic but lifelike three-dimensional pancreas tissue with varying degrees of stiffness and different biochemical properties. Then they inserted bits of real tumors from patients with pancreatic cancer, watched them grow, and tried to kill them with drugs.

They found that cells growing in a stiff matrix were more resistant to chemotherapy than those growing in a softer matrix. But the story didn’t end there.

They also found that high amounts of the tissue-strengthening protein hyaluronic acid in stiff tissue seemed to signal the cancer cells to develop tiny pumps on their surface which shuttled out the drugs before they could take effect.

When the researchers moved the cancer cells into either a softer matrix or a stiff matrix in which the hyaluronic acid receptor, called CD44, was blocked, the chemotherapy drugs started working again.

“This suggests that if we can disrupt the stiffness signaling that’s happening through the CD44 receptor, we could make patients’ pancreatic cancer treatable again by normal chemotherapy,” said senior study author Sarah Heilshorn, PhD, a professor of materials science and engineering at Stanford. “These results suggest an exciting new direction for new drug development.”
 

Targeting Nearby Tissue: A Novel Approach to Fighting Chemoresistance

The study is not the first to suggest that chemically targeting the microenvironment surrounding a tumor can influence how patients respond to treatment.

In one recent clinical trial, patients with metastatic pancreatic cancer were given an experimental drug to inhibit a protein called connective tissue growth factor, reduce fibrous tissue, and make pancreatic tumors easier to surgically remove. Results have not been published yet.

Other research suggests that the generic blood pressure drug losartan, when given in combination with chemotherapy and radiation, can boost survival in patients with advanced pancreatic cancer by, in part, improving the health of blood vessels that carry drugs to the tumor.

But other studies of such mechanotherapeutics have yielded inconclusive results, said Dr. Matrisian.

“This paper points to another reason why we should not give up on this approach,” she said.

Ning Wang, PhD, director of the new Institute for Mechanobiology at Northeastern University College of Engineering, Boston, said there is no question that the composition of a tumor’s environment can influence how cancer progresses or responds to drugs. The new paper, he said, adds an important new chapter to the evolving story.

“But it’s very complicated. It’s not as simple as saying make it softer or stiffer and you can change the outcome for the patient,” Dr. Wang said.

In fact, some research has shown that tissue becomes stiffer when cancer arises so it can contain it from spreading.

In one animal study of pancreatic cancer that had spread to the liver, administering drugs to soften the surrounding tissue, or stroma, actually had the opposite effect — accelerating tumor growth and reducing survival rates.

Dr. Wang also noted that any drug designed to influence the extracellular matrix would need to be extremely localized, to prevent damage to other tissues, like bone or heart muscle.

Dr. LeSavage said he sees the paper as a case study in how important the extracellular matrix is and an example of how artificially grown organs or tissues can play a key role in testing how drugs work or don’t work.

He imagines a day when doctors could personalize treatments by taking a bit of a patient’s tumor, growing it in artificial tissue, and seeing how different tissue-altering drugs affect different therapies.

“This isn’t something that is just unique to pancreatic cancer,” he said, noting that the extracellular matrix throughout the body interacts with different cancers. “If we could take someone who has a chemoresistant tumor and convert it into something that is sensitive to existing therapies again, we could give them a second chance.”

A version of this article appeared on Medscape.com.

In the war against cancer, doctors and patients have long reached for three main weapons to target diseased cells: chemotherapy, radiation, and surgery.

But new research published this month in the journal Nature Materials suggests that manipulating the tissue around those cells — a strategy known as “mechanotherapeutics” — could play a critical role in reducing drug resistance and improving survival rates for hard-to-treat cancers like pancreatic cancer.

“Our study shows the importance of the tumor microenvironment and its properties in dictating how cancer progresses and responds to drug treatment,” said first author Bauer LeSavage, PhD, who conducted the study as a postdoctoral researcher in the Bioengineering Department at Stanford University, Stanford, California. “It also demonstrates that chemoresistance can be reversed.”

Each year, about 66,000 people are diagnosed with pancreatic cancer, and 52,000 die from it. It is a particularly lethal type of cancer, with 5-year survival rates hovering around 7% — a rate that has not improved much since 1996 when the first-line chemotherapy drug gemcitabine was approved.

It looks different from many cancers, said Lynn Matrisian, PhD, chief science officer for the nonprofit Pancreatic Cancer Action Network. Instead of a tumorous mass, it is made of islands of cancer cells surrounded by unusually dense fibrous tissue known as the extracellular matrix, which can collapse blood vessels and prevent drugs from reaching the tumor.

For the study, Dr. LeSavage and his team engineered synthetic but lifelike three-dimensional pancreas tissue with varying degrees of stiffness and different biochemical properties. Then they inserted bits of real tumors from patients with pancreatic cancer, watched them grow, and tried to kill them with drugs.

They found that cells growing in a stiff matrix were more resistant to chemotherapy than those growing in a softer matrix. But the story didn’t end there.

They also found that high amounts of the tissue-strengthening protein hyaluronic acid in stiff tissue seemed to signal the cancer cells to develop tiny pumps on their surface which shuttled out the drugs before they could take effect.

When the researchers moved the cancer cells into either a softer matrix or a stiff matrix in which the hyaluronic acid receptor, called CD44, was blocked, the chemotherapy drugs started working again.

“This suggests that if we can disrupt the stiffness signaling that’s happening through the CD44 receptor, we could make patients’ pancreatic cancer treatable again by normal chemotherapy,” said senior study author Sarah Heilshorn, PhD, a professor of materials science and engineering at Stanford. “These results suggest an exciting new direction for new drug development.”
 

Targeting Nearby Tissue: A Novel Approach to Fighting Chemoresistance

The study is not the first to suggest that chemically targeting the microenvironment surrounding a tumor can influence how patients respond to treatment.

In one recent clinical trial, patients with metastatic pancreatic cancer were given an experimental drug to inhibit a protein called connective tissue growth factor, reduce fibrous tissue, and make pancreatic tumors easier to surgically remove. Results have not been published yet.

Other research suggests that the generic blood pressure drug losartan, when given in combination with chemotherapy and radiation, can boost survival in patients with advanced pancreatic cancer by, in part, improving the health of blood vessels that carry drugs to the tumor.

But other studies of such mechanotherapeutics have yielded inconclusive results, said Dr. Matrisian.

“This paper points to another reason why we should not give up on this approach,” she said.

Ning Wang, PhD, director of the new Institute for Mechanobiology at Northeastern University College of Engineering, Boston, said there is no question that the composition of a tumor’s environment can influence how cancer progresses or responds to drugs. The new paper, he said, adds an important new chapter to the evolving story.

“But it’s very complicated. It’s not as simple as saying make it softer or stiffer and you can change the outcome for the patient,” Dr. Wang said.

In fact, some research has shown that tissue becomes stiffer when cancer arises so it can contain it from spreading.

In one animal study of pancreatic cancer that had spread to the liver, administering drugs to soften the surrounding tissue, or stroma, actually had the opposite effect — accelerating tumor growth and reducing survival rates.

Dr. Wang also noted that any drug designed to influence the extracellular matrix would need to be extremely localized, to prevent damage to other tissues, like bone or heart muscle.

Dr. LeSavage said he sees the paper as a case study in how important the extracellular matrix is and an example of how artificially grown organs or tissues can play a key role in testing how drugs work or don’t work.

He imagines a day when doctors could personalize treatments by taking a bit of a patient’s tumor, growing it in artificial tissue, and seeing how different tissue-altering drugs affect different therapies.

“This isn’t something that is just unique to pancreatic cancer,” he said, noting that the extracellular matrix throughout the body interacts with different cancers. “If we could take someone who has a chemoresistant tumor and convert it into something that is sensitive to existing therapies again, we could give them a second chance.”

A version of this article appeared on Medscape.com.

The rapid adoption of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) for the treatment of diabetes and weight loss has led to a corresponding interest in their potential side effects. Several recent studies have sought to expound upon what role, if any, GLP-1 RAs may have in increasing the risk for specific gastrointestinal (GI) adverse events. 

Herein is a summary of the most current information on this topic, as well as my best guidance for clinicians on integrating it into the clinical care of their patients. 
 

Aspiration Risks

Albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, and tirzepatide are among the class of medications known as GLP-1 RAs. These medications all work by mimicking the action of hormonal incretins, which are released postprandially. Incretins affect the pancreatic glucose-dependent release of insulin, inhibit release of glucagon, stimulate satiety, and reduce gastric emptying. This last effect has raised concerns that patients taking GLP-1 RAs might be at an elevated risk for endoscopy-related aspiration. 

In June 2023, the American Society of Anesthesiologists released recommendations asking providers to consider holding back GLP-1 RAs in patients with scheduled elective procedures. 

In August 2023, five national GI societies — the American Gastroenterological Association, American Association for the Study of Liver Diseases, American College of Gastroenterology, American Society for Gastrointestinal Endoscopy, and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition — issued their own joint statement on the issue. 

In the absence of sufficient evidence, these groups suggested that healthcare providers “exercise best practices when performing endoscopy on these patients on GLP-1 [RAs].” They called for more data and encouraged key stakeholders to work together to develop the necessary evidence to provide guidance for these patients prior to elective endoscopy. A rapid clinical update issued by the American Gastroenterological Association in 2024 was consistent with these earlier multisociety recommendations. 

Two studies presented at 2024’s Digestive Disease Week provided additional reassurance that concerns about aspiration with these medications were perhaps unwarranted. 

The first (since published in The American Journal of Gastroenterology ) was a case-control study of 16,295 patients undergoing upper endoscopy, among whom 306 were taking GLP-1 RAs. It showed a higher rate of solid gastric residue among those taking GLP-1 RAs compared with controls (14% vs 4%, respectively). Patients who had prolonged fasting and clear liquids for concurrent colonoscopy had lower residue rates (2% vs 11%, respectively). However, there were no recorded incidents of procedural complications or aspiration. 

The second was a retrospective cohort study using TriNetX, a federated cloud-based network pulling millions of data points from multiple US healthcare organizations. It found that the incidence of aspiration pneumonitis and emergent intubation during or immediately after esophagogastroduodenoscopy and colonoscopy among those taking GLP-1 RAs was not increased compared with those not taking these medications. 

These were followed in June 2024 by a systematic review and meta-analysis published by Hiramoto and colleagues, which included 15 studies. The researchers showed a 36-minute prolongation for solid-food emptying and no delay in liquid emptying for patients taking GLP-1 RAs vs controls. The authors concluded that the minimal delay in solid-food emptying would be offset by standard preprocedural fasting periods. 

There is concern that patients with complicated type 2 diabetes may have a bit more of a risk for aspiration. However, this was not supported by an analysis from Barlowe and colleagues, who used a national claims database to identify 15,119 patients with type 2 diabetes on GLP-1 RAs. They found no increased events of pulmonary complications (ie, aspiration, pneumonia, respiratory failure) within 14 days following esophagogastroduodenoscopy. Additional evidence suggests that the risk for aspiration in these patients seems to be offset by prolonged fasting and intake of clear liquids. 

Although physicians clearly need to use clinical judgment when performing endoscopic procedures on these patients, the emerging evidence on safety has been encouraging. 
 

Association With GI Adverse Events

A recent retrospective analysis of real-world data from 10,328 new users of GLP-1 RAs with diabetes/obesity reported that the most common GI adverse events in this cohort were abdominal pain (57.6%), constipation (30.4%), diarrhea (32.7%), nausea and vomiting (23.4%), GI bleeding (15.9%), gastroparesis (5.1%), and pancreatitis (3.4%). 

Notably, dulaglutide and liraglutide had higher rates of abdominal pain, constipation, diarrhea, and nausea and vomiting than did semaglutide and exenatide. Compared with semaglutide, dulaglutide and liraglutide had slightly higher odds of abdominal pain, gastroparesis, and nausea and vomiting. There were no significant differences between the GLP-1 RAs in the risk for GI bleeding or pancreatitis. 

A 2023 report in JAMA observed that the risk for bowel obstruction is also elevated among patients using these agents for weight loss. Possible reasons for this are currently unknown. 

Studies are needed to analyze possible variations in safety profiles between GLP-1 RAs to better guide selection of these drugs, particularly in patients with GI risk factors. Furthermore, the causal relationship between GLP-1 RAs with other concomitant medications requires further investigation. 

Although relatively infrequent, the risk for GI adverse events should be given special consideration by providers when prescribing them for weight loss, because the risk/benefit ratios may be different from those in patients with diabetes. 
 

A Lack of Hepatic Concerns

GLP-1 RAs have demonstrated a significant impact on body weight and glycemic control, as well as beneficial effects on clinical, biochemical, and histologic markers in patients with metabolic dysfunction–associated steatotic liver disease (MASLD). These favorable changes are evident by reductions in the hepatic cytolysis markers (ie, aspartate aminotransferase and alanine aminotransferase). 

GLP-1 RAs may provide a protective function by reducing the accumulation of hepatic triglycerides and expression of several collagen genes. Some preclinical data suggest a risk reduction for progression to hepatocellular carcinoma, and animal studies indicate that complete suppression of hepatic carcinogenesis is achieved with liraglutide.

The most recent assessment of risk reduction for MASLD progression comes from a Scandinavian cohort analysis of national registries. In looking at 91,479 patients using GLP-1 RAs, investigators demonstrated this treatment was associated with a significant reduction in the composite primary endpoint of hepatocellular carcinoma, as well as both compensated and decompensated cirrhosis. 

Given the various favorable hepatic effects of GLP-1 RAs, it is likely that the composite benefit on MASLD is multifactorial. The current literature is clear that it is safe to use these agents across the spectrum of MASLD with or without fibrosis, although it must be noted that GLP-1 RAs are not approved by the Food and Drug Administration for this indication. 
 

Dr. Johnson is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. He disclosed ties with ISOTHRIVE and Johnson & Johnson.

A version of this article appeared on Medscape.com.

The rapid adoption of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) for the treatment of diabetes and weight loss has led to a corresponding interest in their potential side effects. Several recent studies have sought to expound upon what role, if any, GLP-1 RAs may have in increasing the risk for specific gastrointestinal (GI) adverse events. 

Herein is a summary of the most current information on this topic, as well as my best guidance for clinicians on integrating it into the clinical care of their patients. 
 

Aspiration Risks

Albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, and tirzepatide are among the class of medications known as GLP-1 RAs. These medications all work by mimicking the action of hormonal incretins, which are released postprandially. Incretins affect the pancreatic glucose-dependent release of insulin, inhibit release of glucagon, stimulate satiety, and reduce gastric emptying. This last effect has raised concerns that patients taking GLP-1 RAs might be at an elevated risk for endoscopy-related aspiration. 

In June 2023, the American Society of Anesthesiologists released recommendations asking providers to consider holding back GLP-1 RAs in patients with scheduled elective procedures. 

In August 2023, five national GI societies — the American Gastroenterological Association, American Association for the Study of Liver Diseases, American College of Gastroenterology, American Society for Gastrointestinal Endoscopy, and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition — issued their own joint statement on the issue. 

In the absence of sufficient evidence, these groups suggested that healthcare providers “exercise best practices when performing endoscopy on these patients on GLP-1 [RAs].” They called for more data and encouraged key stakeholders to work together to develop the necessary evidence to provide guidance for these patients prior to elective endoscopy. A rapid clinical update issued by the American Gastroenterological Association in 2024 was consistent with these earlier multisociety recommendations. 

Two studies presented at 2024’s Digestive Disease Week provided additional reassurance that concerns about aspiration with these medications were perhaps unwarranted. 

The first (since published in The American Journal of Gastroenterology ) was a case-control study of 16,295 patients undergoing upper endoscopy, among whom 306 were taking GLP-1 RAs. It showed a higher rate of solid gastric residue among those taking GLP-1 RAs compared with controls (14% vs 4%, respectively). Patients who had prolonged fasting and clear liquids for concurrent colonoscopy had lower residue rates (2% vs 11%, respectively). However, there were no recorded incidents of procedural complications or aspiration. 

The second was a retrospective cohort study using TriNetX, a federated cloud-based network pulling millions of data points from multiple US healthcare organizations. It found that the incidence of aspiration pneumonitis and emergent intubation during or immediately after esophagogastroduodenoscopy and colonoscopy among those taking GLP-1 RAs was not increased compared with those not taking these medications. 

These were followed in June 2024 by a systematic review and meta-analysis published by Hiramoto and colleagues, which included 15 studies. The researchers showed a 36-minute prolongation for solid-food emptying and no delay in liquid emptying for patients taking GLP-1 RAs vs controls. The authors concluded that the minimal delay in solid-food emptying would be offset by standard preprocedural fasting periods. 

There is concern that patients with complicated type 2 diabetes may have a bit more of a risk for aspiration. However, this was not supported by an analysis from Barlowe and colleagues, who used a national claims database to identify 15,119 patients with type 2 diabetes on GLP-1 RAs. They found no increased events of pulmonary complications (ie, aspiration, pneumonia, respiratory failure) within 14 days following esophagogastroduodenoscopy. Additional evidence suggests that the risk for aspiration in these patients seems to be offset by prolonged fasting and intake of clear liquids. 

Although physicians clearly need to use clinical judgment when performing endoscopic procedures on these patients, the emerging evidence on safety has been encouraging. 
 

Association With GI Adverse Events

A recent retrospective analysis of real-world data from 10,328 new users of GLP-1 RAs with diabetes/obesity reported that the most common GI adverse events in this cohort were abdominal pain (57.6%), constipation (30.4%), diarrhea (32.7%), nausea and vomiting (23.4%), GI bleeding (15.9%), gastroparesis (5.1%), and pancreatitis (3.4%). 

Notably, dulaglutide and liraglutide had higher rates of abdominal pain, constipation, diarrhea, and nausea and vomiting than did semaglutide and exenatide. Compared with semaglutide, dulaglutide and liraglutide had slightly higher odds of abdominal pain, gastroparesis, and nausea and vomiting. There were no significant differences between the GLP-1 RAs in the risk for GI bleeding or pancreatitis. 

A 2023 report in JAMA observed that the risk for bowel obstruction is also elevated among patients using these agents for weight loss. Possible reasons for this are currently unknown. 

Studies are needed to analyze possible variations in safety profiles between GLP-1 RAs to better guide selection of these drugs, particularly in patients with GI risk factors. Furthermore, the causal relationship between GLP-1 RAs with other concomitant medications requires further investigation. 

Although relatively infrequent, the risk for GI adverse events should be given special consideration by providers when prescribing them for weight loss, because the risk/benefit ratios may be different from those in patients with diabetes. 
 

A Lack of Hepatic Concerns

GLP-1 RAs have demonstrated a significant impact on body weight and glycemic control, as well as beneficial effects on clinical, biochemical, and histologic markers in patients with metabolic dysfunction–associated steatotic liver disease (MASLD). These favorable changes are evident by reductions in the hepatic cytolysis markers (ie, aspartate aminotransferase and alanine aminotransferase). 

GLP-1 RAs may provide a protective function by reducing the accumulation of hepatic triglycerides and expression of several collagen genes. Some preclinical data suggest a risk reduction for progression to hepatocellular carcinoma, and animal studies indicate that complete suppression of hepatic carcinogenesis is achieved with liraglutide.

The most recent assessment of risk reduction for MASLD progression comes from a Scandinavian cohort analysis of national registries. In looking at 91,479 patients using GLP-1 RAs, investigators demonstrated this treatment was associated with a significant reduction in the composite primary endpoint of hepatocellular carcinoma, as well as both compensated and decompensated cirrhosis. 

Given the various favorable hepatic effects of GLP-1 RAs, it is likely that the composite benefit on MASLD is multifactorial. The current literature is clear that it is safe to use these agents across the spectrum of MASLD with or without fibrosis, although it must be noted that GLP-1 RAs are not approved by the Food and Drug Administration for this indication. 
 

Dr. Johnson is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. He disclosed ties with ISOTHRIVE and Johnson & Johnson.

A version of this article appeared on Medscape.com.

The rapid adoption of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) for the treatment of diabetes and weight loss has led to a corresponding interest in their potential side effects. Several recent studies have sought to expound upon what role, if any, GLP-1 RAs may have in increasing the risk for specific gastrointestinal (GI) adverse events. 

Herein is a summary of the most current information on this topic, as well as my best guidance for clinicians on integrating it into the clinical care of their patients. 
 

Aspiration Risks

Albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide, and tirzepatide are among the class of medications known as GLP-1 RAs. These medications all work by mimicking the action of hormonal incretins, which are released postprandially. Incretins affect the pancreatic glucose-dependent release of insulin, inhibit release of glucagon, stimulate satiety, and reduce gastric emptying. This last effect has raised concerns that patients taking GLP-1 RAs might be at an elevated risk for endoscopy-related aspiration. 

In June 2023, the American Society of Anesthesiologists released recommendations asking providers to consider holding back GLP-1 RAs in patients with scheduled elective procedures. 

In August 2023, five national GI societies — the American Gastroenterological Association, American Association for the Study of Liver Diseases, American College of Gastroenterology, American Society for Gastrointestinal Endoscopy, and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition — issued their own joint statement on the issue. 

In the absence of sufficient evidence, these groups suggested that healthcare providers “exercise best practices when performing endoscopy on these patients on GLP-1 [RAs].” They called for more data and encouraged key stakeholders to work together to develop the necessary evidence to provide guidance for these patients prior to elective endoscopy. A rapid clinical update issued by the American Gastroenterological Association in 2024 was consistent with these earlier multisociety recommendations. 

Two studies presented at 2024’s Digestive Disease Week provided additional reassurance that concerns about aspiration with these medications were perhaps unwarranted. 

The first (since published in The American Journal of Gastroenterology ) was a case-control study of 16,295 patients undergoing upper endoscopy, among whom 306 were taking GLP-1 RAs. It showed a higher rate of solid gastric residue among those taking GLP-1 RAs compared with controls (14% vs 4%, respectively). Patients who had prolonged fasting and clear liquids for concurrent colonoscopy had lower residue rates (2% vs 11%, respectively). However, there were no recorded incidents of procedural complications or aspiration. 

The second was a retrospective cohort study using TriNetX, a federated cloud-based network pulling millions of data points from multiple US healthcare organizations. It found that the incidence of aspiration pneumonitis and emergent intubation during or immediately after esophagogastroduodenoscopy and colonoscopy among those taking GLP-1 RAs was not increased compared with those not taking these medications. 

These were followed in June 2024 by a systematic review and meta-analysis published by Hiramoto and colleagues, which included 15 studies. The researchers showed a 36-minute prolongation for solid-food emptying and no delay in liquid emptying for patients taking GLP-1 RAs vs controls. The authors concluded that the minimal delay in solid-food emptying would be offset by standard preprocedural fasting periods. 

There is concern that patients with complicated type 2 diabetes may have a bit more of a risk for aspiration. However, this was not supported by an analysis from Barlowe and colleagues, who used a national claims database to identify 15,119 patients with type 2 diabetes on GLP-1 RAs. They found no increased events of pulmonary complications (ie, aspiration, pneumonia, respiratory failure) within 14 days following esophagogastroduodenoscopy. Additional evidence suggests that the risk for aspiration in these patients seems to be offset by prolonged fasting and intake of clear liquids. 

Although physicians clearly need to use clinical judgment when performing endoscopic procedures on these patients, the emerging evidence on safety has been encouraging. 
 

Association With GI Adverse Events

A recent retrospective analysis of real-world data from 10,328 new users of GLP-1 RAs with diabetes/obesity reported that the most common GI adverse events in this cohort were abdominal pain (57.6%), constipation (30.4%), diarrhea (32.7%), nausea and vomiting (23.4%), GI bleeding (15.9%), gastroparesis (5.1%), and pancreatitis (3.4%). 

Notably, dulaglutide and liraglutide had higher rates of abdominal pain, constipation, diarrhea, and nausea and vomiting than did semaglutide and exenatide. Compared with semaglutide, dulaglutide and liraglutide had slightly higher odds of abdominal pain, gastroparesis, and nausea and vomiting. There were no significant differences between the GLP-1 RAs in the risk for GI bleeding or pancreatitis. 

A 2023 report in JAMA observed that the risk for bowel obstruction is also elevated among patients using these agents for weight loss. Possible reasons for this are currently unknown. 

Studies are needed to analyze possible variations in safety profiles between GLP-1 RAs to better guide selection of these drugs, particularly in patients with GI risk factors. Furthermore, the causal relationship between GLP-1 RAs with other concomitant medications requires further investigation. 

Although relatively infrequent, the risk for GI adverse events should be given special consideration by providers when prescribing them for weight loss, because the risk/benefit ratios may be different from those in patients with diabetes. 
 

A Lack of Hepatic Concerns

GLP-1 RAs have demonstrated a significant impact on body weight and glycemic control, as well as beneficial effects on clinical, biochemical, and histologic markers in patients with metabolic dysfunction–associated steatotic liver disease (MASLD). These favorable changes are evident by reductions in the hepatic cytolysis markers (ie, aspartate aminotransferase and alanine aminotransferase). 

GLP-1 RAs may provide a protective function by reducing the accumulation of hepatic triglycerides and expression of several collagen genes. Some preclinical data suggest a risk reduction for progression to hepatocellular carcinoma, and animal studies indicate that complete suppression of hepatic carcinogenesis is achieved with liraglutide.

The most recent assessment of risk reduction for MASLD progression comes from a Scandinavian cohort analysis of national registries. In looking at 91,479 patients using GLP-1 RAs, investigators demonstrated this treatment was associated with a significant reduction in the composite primary endpoint of hepatocellular carcinoma, as well as both compensated and decompensated cirrhosis. 

Given the various favorable hepatic effects of GLP-1 RAs, it is likely that the composite benefit on MASLD is multifactorial. The current literature is clear that it is safe to use these agents across the spectrum of MASLD with or without fibrosis, although it must be noted that GLP-1 RAs are not approved by the Food and Drug Administration for this indication. 
 

Dr. Johnson is professor of medicine and chief of gastroenterology at Eastern Virginia Medical School in Norfolk, Virginia, and a past president of the American College of Gastroenterology. He disclosed ties with ISOTHRIVE and Johnson & Johnson.

A version of this article appeared on Medscape.com.

For 3 years, Ajala Efem’s type 2 diabetes was so poorly controlled that her blood sugar often soared northward of 500 mg/dL despite insulin shots three to five times a day. She would experience dizziness, vomiting, severe headaches, and the neuropathy in her feet made walking painful. She was also — literally — frothing at the mouth. The 47-year-old single mother of two adult children with mental disabilities feared that she would die.

Ms. Efem lives in the South Bronx, which is among the poorest areas of New York City, where the combined rate of prediabetes and diabetes is close to 30%, the highest rate of any borough in the city.

She had to wait 8 months for an appointment with an endocrinologist, but that visit proved to be life-changing. She lost 28 pounds and got off 15 medications in a single month. She did not join a gym or count calories; she simply changed the food she ate and adopted a low-carb diet.

“I went from being sick to feeling so great,” she told her endocrinologist recently: “My feet aren’t hurting; I’m not in pain; I’m eating as much as I want, and I really enjoy my food so much.” 

Ms. Efem’s life-changing visit was with Mariela Glandt, MD, at the offices of Essen Health Care. One month earlier, Dr. Glandt’s company, OwnaHealth, was contracted by Essen to conduct a 100-person pilot program for endocrinology patients. Essen is the largest Medicaid provider in New York City, and “they were desperate for an endocrinologist,” said Dr. Glandt, who trained at Columbia University in New York. So she came — all the way from Madrid, Spain. She commutes monthly, staying for a week each visit.

Dr. Glandt keeps up this punishing schedule because, as she explains, “it’s such a high for me to see these incredible transformations.” Her mostly Black and Hispanic patients are poor and lack resources, yet they lose significant amounts of weight, and their health issues resolve.

“Food is medicine” is an idea very much in vogue. The concept was central to the landmark White House Conference on Hunger, Nutrition, and Health in 2022 and is now the focus of a number of a wide range of government programs. Recently, the Senate held a hearing aimed at further expanding food as medicine programs.

Still, only a single randomized controlled clinical trial has been conducted on this nutritional approach, with unexpectedly disappointing results. In the mid-Atlantic region, 456 food-insecure adults with type 2 diabetes were randomly assigned to usual care or the provision of weekly groceries for their entire families for about 1 year. Provisions for a Mediterranean-style diet included whole grains, fruits and vegetables, lean protein, low-fat dairy products, cereal, brown rice, and bread. In addition, participants received dietary consultations. Yet, those who got free food and coaching did not see improvements in their average blood sugar (the study’s primary outcome), and their low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels appeared to have worsened. 

“To be honest, I was surprised,” the study’s lead author, Joseph Doyle, PhD, professor at the Sloan School of Management at MIT in Cambridge, Massachusetts, told me. “I was hoping we would show improved outcomes, but the way to make progress is to do well-randomized trials to find out what works.”

I was not surprised by these results because a recent rigorous systematic review and meta-analysis in The BMJ did not show a Mediterranean-style diet to be the most effective for glycemic control. And Ms. Efem was not in fact following a Mediterranean-style diet.

Ms. Efem’s low-carb success story is anecdotal, but Dr. Glandt has an established track record from her 9 years’ experience as the medical director of the eponymous diabetes center she founded in Tel Aviv. A recent audit of 344 patients from the center found that after 6 months of following a very low–carbohydrate diet, 96.3% of those with diabetes saw their A1c fall from a median 7.6% to 6.3%. Weight loss was significant, with a median drop of 6.5 kg (14 pounds) for patients with diabetes and 5.7 kg for those with prediabetes. The diet comprises 5%-10% of calories from carbs, but Dr. Glandt does not use numeric targets with her patients.

Blood pressure, triglycerides, and liver enzymes also improved. And though LDL cholesterol went up by 8%, this result may have been offset by an accompanying 13% rise in HDL cholesterol. Of the 78 patients initially on insulin, 62 were able to stop this medication entirely.

Although these results aren’t from a clinical trial, they’re still highly meaningful because the current dietary standard of care for type 2 diabetes can only slow the progression of the disease, not cause remission. Indeed, the idea that type 2 diabetes could be put into remission was not seriously considered by the American Diabetes Association (ADA) until 2009. By 2019, an ADA report concluded that “[r]educing overall carbohydrate intake for individuals with diabetes has demonstrated the most evidence for improving glycemia.” In other words, the best way to improve the key factor in diabetes is to reduce total carbohydrates. Yet, the ADA still advocates filling one quarter of one’s plate with carbohydrate-based foods, an amount that will prevent remission. Given that the ADA’s vision statement is “a life free of diabetes,” it seems negligent not to tell people with a deadly condition that they can reverse this diagnosis. 

A 2023 meta-analysis of 42 controlled clinical trials on 4809 patients showed that a very low–carbohydrate ketogenic diet (keto) was “superior” to alternatives for glycemic control. A more recent review of 11 clinical trials found that this diet was equal but not superior to other nutritional approaches in terms of blood sugar control, but this review also concluded that keto led to greater increases in HDL cholesterol and lower triglycerides. 

Dr. Glandt’s patients in the Bronx might not seem like obvious low-carb candidates. The diet is considered expensive and difficult to sustain. My interviews with a half dozen patients revealed some of these difficulties, but even for a woman living in a homeless shelter, the obstacles are not insurmountable.

Jerrilyn, who preferred that I use only her first name, lives in a shelter in Queens. While we strolled through a nearby park, she told me about her desire to lose weight and recover from polycystic ovary syndrome, which terrified her because it had caused dramatic hair loss. When she landed in Dr. Glandt’s office at age 28, she weighed 180 pounds. 

Less than 5 months later, Jerrilyn had lost 25 pounds, and her period had returned with some regularity. She said she used “food stamps,” known as the Supplemental Nutrition Assistance Program (SNAP), to buy most of her food at local delis because the meals served at the shelter were too heavy in starches. She starts her day with eggs, turkey bacon, and avocado. 

“It was hard to give up carbohydrates because in my culture [Latina], we have nothing but carbs: rice, potatoes, yuca,” Jerrilyn shared. She noticed that carbs make her hungrier, but after 3 days of going low-carb, her cravings diminished. “It was like getting over an addiction,” she said.

Jerrilyn told me she’d seen many doctors but none as involved as Dr. Glandt. “It feels awesome to know that I have a lot of really useful information coming from her all the time.” The OwnaHealth app tracks weight, blood pressure, blood sugar, ketones, meals, mood, and cravings. Patients wear continuous glucose monitors and enter other information manually. Ketone bodies are used to measure dietary adherence and are obtained through finger pricks and test strips provided by OwnaHealth. Dr. Glandt gives patients her own food plan, along with free visual guides to low-carbohydrate foods by dietdoctor.com. 

Dr. Glandt also sends her patients for regular blood work. She says she does not frequently see a rise in LDL cholesterol, which can sometimes occur on a low-carbohydrate diet. This effect is most common among people who are lean and fit. She says she doesn’t discontinue statins unless cholesterol levels improve significantly.

Samuel Gonzalez, age 56, weighed 275 pounds when he walked into Dr. Glandt’s office this past November. His A1c was 9.2%, but none of his previous doctors had diagnosed him with diabetes. “I was like a walking bag of sugar!” he joked. 

A low-carbohydrate diet seemed absurd to a Puerto Rican like himself: “Having coffee without sugar? That’s like sacrilegious in my culture!” exclaimed Mr. Gonzalez. Still, he managed, with SNAP, to cook eggs and bacon for breakfast and some kind of protein for dinner. He keeps lunch light, “like tuna fish,” and finds checking in with the OwnaHealth app to be very helpful. “Every day, I’m on it,” he said. In the past 7 months, he’s lost 50 pounds, normalized his cholesterol and blood pressure levels, and lowered his A1c to 5.5%.

Mr. Gonzalez gets disability payments due to a back injury, and Ms. Efem receives government payments because her husband died serving in the military. Ms. Efem says her new diet challenges her budget, but Mr. Gonzalez says he manages easily.

Mélissa Cruz, a 28-year-old studying to be a nail technician while also doing back office work at a physical therapy practice, says she’s stretched thin. “I end up sad because I can’t put energy into looking up recipes and cooking for me and my boyfriend,” she told me. She’ll often cook rice and plantains for him and meat for herself, but “it’s frustrating when I’m low on funds and can’t figure out what to eat.” 

Low-carbohydrate diets have a reputation for being expensive because people often start eating pricier foods, like meat and cheese, to replace cheaper starchy foods such as pasta and rice. Eggs and ground beef are less expensive low-carb meal options, and meat, unlike fruits and vegetables, is easy to freeze and doesn’t spoil quickly. These advantages can add up.

A 2019 cost analysis published in Nutrition & Dietetics compared a low-carbohydrate dietary pattern with the New Zealand government’s recommended guidelines (which are almost identical to those in the United States) and found that it cost only an extra $1.27 in US dollars per person per day. One explanation is that protein and fat are more satiating than carbohydrates, so people who mostly consume these macronutrients often cut back on snacks like packaged chips, crackers, and even fruits. Also, those on a ketogenic diet usually cut down on medications, so the additional $1.27 daily is likely offset by reduced spending at the pharmacy.

It’s not just Bronx residents with low socioeconomic status (SES) who adapt well to low-carbohydrate diets. Among Alabama state employees with diabetes enrolled in a low-carbohydrate dietary program provided by a company called Virta, the low SES population had the best outcomes. Virta also published survey data in 2023 showing that participants in a program with the Veteran’s Administration did not find additional costs to be an obstacle to dietary adherence. In fact, some participants saw cost reductions due to decreased spending on processed snacks and fast foods.

Ms. Cruz told me she struggles financially, yet she’s still lost nearly 30 pounds in 5 months, and her A1c went from 7.1% down to 5.9%, putting her diabetes into remission. Equally motivating for her are the improvements she’s seen in other hormonal issues. Since childhood, she’s had acanthosis, a condition that causes the skin to darken in velvety patches, and more recently, she developed severe hirsutism to the point of growing sideburns. “I had tried going vegan and fasting, but these just weren’t sustainable for me, and I was so overwhelmed with counting calories all the time.” Now, on a low-carbohydrate diet, which doesn’t require calorie counting, she’s finally seeing both these conditions improve significantly.

When I last checked in with Ms. Cruz, she said she had “kind of ghosted” Dr. Glandt due to her work and school constraints, but she hadn’t abandoned the diet. She appreciated, too, that Dr. Glandt had not given up on her and kept calling and messaging. “She’s not at all like a typical doctor who would just tell me to lose weight and shake their head at me,” Ms. Cruz said. 

Because Dr. Glandt’s approach is time-intensive and high-touch, it might seem impractical to scale up, but Dr. Glandt’s app uses artificial intelligence to help with communications thus allowing her, with help from part-time health coaches, to care for patients. 

This early success in one of the United States’ poorest and sickest neighborhoods should give us hope that type 2 diabetes need not to be a progressive irreversible disease, even among the disadvantaged. 

OwnaHealth’s track record, along with that of Virta and other similar low-carbohydrate medical practices also give hope to the food-is-medicine idea. Diabetes can go into remission, and people can be healed, provided that health practitioners prescribe the right foods. And in truth, it’s not a diet. It’s a way of eating that must be maintained. The sustainability of low-carbohydrate diets has been a point of contention, but the Virta trial, with 38% of patients sustaining remission at 2 years, showed that it’s possible. (OwnaHealth, for its part, offers long-term maintenance plans to help patients stay very low-carb permanently.) 

Given the tremendous costs and health burden of diabetes, this approach should no doubt be the first line of treatment for doctors and the ADA. The past two decades of clinical trial research have demonstrated that remission of type 2 diabetes is possible through diet alone. It turns out that for metabolic diseases, only certain foods are truly medicine. 
 

Tools and Tips for Clinicians: 

• Free two-page keto starter’s guide by OwnaHealth; Dr. Glandt uses this guide with her patients.
• Illustrated low-carb guides by dietdoctor.com
• Free low-carbohydrate starter guide by the Michigan Collaborative for Type 2 Diabetes
• Low-Carb for Any Budget, a free digital booklet by Mark Cucuzzella, MD, and Kristie Sullivan, PhD
• Recipe and meal ideas from Ruled.me, Keto-Mojo.com, and 

Dr. Teicholz is the founder of Nutrition Coalition, an independent nonprofit dedicated to ensuring that US dietary guidelines align with current science. She disclosed receiving book royalties from The Big Fat Surprise, and received honorarium not exceeding $2000 for speeches from various sources.

A version of this article appeared on Medscape.com.

For 3 years, Ajala Efem’s type 2 diabetes was so poorly controlled that her blood sugar often soared northward of 500 mg/dL despite insulin shots three to five times a day. She would experience dizziness, vomiting, severe headaches, and the neuropathy in her feet made walking painful. She was also — literally — frothing at the mouth. The 47-year-old single mother of two adult children with mental disabilities feared that she would die.

Ms. Efem lives in the South Bronx, which is among the poorest areas of New York City, where the combined rate of prediabetes and diabetes is close to 30%, the highest rate of any borough in the city.

She had to wait 8 months for an appointment with an endocrinologist, but that visit proved to be life-changing. She lost 28 pounds and got off 15 medications in a single month. She did not join a gym or count calories; she simply changed the food she ate and adopted a low-carb diet.

“I went from being sick to feeling so great,” she told her endocrinologist recently: “My feet aren’t hurting; I’m not in pain; I’m eating as much as I want, and I really enjoy my food so much.” 

Ms. Efem’s life-changing visit was with Mariela Glandt, MD, at the offices of Essen Health Care. One month earlier, Dr. Glandt’s company, OwnaHealth, was contracted by Essen to conduct a 100-person pilot program for endocrinology patients. Essen is the largest Medicaid provider in New York City, and “they were desperate for an endocrinologist,” said Dr. Glandt, who trained at Columbia University in New York. So she came — all the way from Madrid, Spain. She commutes monthly, staying for a week each visit.

Dr. Glandt keeps up this punishing schedule because, as she explains, “it’s such a high for me to see these incredible transformations.” Her mostly Black and Hispanic patients are poor and lack resources, yet they lose significant amounts of weight, and their health issues resolve.

“Food is medicine” is an idea very much in vogue. The concept was central to the landmark White House Conference on Hunger, Nutrition, and Health in 2022 and is now the focus of a number of a wide range of government programs. Recently, the Senate held a hearing aimed at further expanding food as medicine programs.

Still, only a single randomized controlled clinical trial has been conducted on this nutritional approach, with unexpectedly disappointing results. In the mid-Atlantic region, 456 food-insecure adults with type 2 diabetes were randomly assigned to usual care or the provision of weekly groceries for their entire families for about 1 year. Provisions for a Mediterranean-style diet included whole grains, fruits and vegetables, lean protein, low-fat dairy products, cereal, brown rice, and bread. In addition, participants received dietary consultations. Yet, those who got free food and coaching did not see improvements in their average blood sugar (the study’s primary outcome), and their low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels appeared to have worsened. 

“To be honest, I was surprised,” the study’s lead author, Joseph Doyle, PhD, professor at the Sloan School of Management at MIT in Cambridge, Massachusetts, told me. “I was hoping we would show improved outcomes, but the way to make progress is to do well-randomized trials to find out what works.”

I was not surprised by these results because a recent rigorous systematic review and meta-analysis in The BMJ did not show a Mediterranean-style diet to be the most effective for glycemic control. And Ms. Efem was not in fact following a Mediterranean-style diet.

Ms. Efem’s low-carb success story is anecdotal, but Dr. Glandt has an established track record from her 9 years’ experience as the medical director of the eponymous diabetes center she founded in Tel Aviv. A recent audit of 344 patients from the center found that after 6 months of following a very low–carbohydrate diet, 96.3% of those with diabetes saw their A1c fall from a median 7.6% to 6.3%. Weight loss was significant, with a median drop of 6.5 kg (14 pounds) for patients with diabetes and 5.7 kg for those with prediabetes. The diet comprises 5%-10% of calories from carbs, but Dr. Glandt does not use numeric targets with her patients.

Blood pressure, triglycerides, and liver enzymes also improved. And though LDL cholesterol went up by 8%, this result may have been offset by an accompanying 13% rise in HDL cholesterol. Of the 78 patients initially on insulin, 62 were able to stop this medication entirely.

Although these results aren’t from a clinical trial, they’re still highly meaningful because the current dietary standard of care for type 2 diabetes can only slow the progression of the disease, not cause remission. Indeed, the idea that type 2 diabetes could be put into remission was not seriously considered by the American Diabetes Association (ADA) until 2009. By 2019, an ADA report concluded that “[r]educing overall carbohydrate intake for individuals with diabetes has demonstrated the most evidence for improving glycemia.” In other words, the best way to improve the key factor in diabetes is to reduce total carbohydrates. Yet, the ADA still advocates filling one quarter of one’s plate with carbohydrate-based foods, an amount that will prevent remission. Given that the ADA’s vision statement is “a life free of diabetes,” it seems negligent not to tell people with a deadly condition that they can reverse this diagnosis. 

A 2023 meta-analysis of 42 controlled clinical trials on 4809 patients showed that a very low–carbohydrate ketogenic diet (keto) was “superior” to alternatives for glycemic control. A more recent review of 11 clinical trials found that this diet was equal but not superior to other nutritional approaches in terms of blood sugar control, but this review also concluded that keto led to greater increases in HDL cholesterol and lower triglycerides. 

Dr. Glandt’s patients in the Bronx might not seem like obvious low-carb candidates. The diet is considered expensive and difficult to sustain. My interviews with a half dozen patients revealed some of these difficulties, but even for a woman living in a homeless shelter, the obstacles are not insurmountable.

Jerrilyn, who preferred that I use only her first name, lives in a shelter in Queens. While we strolled through a nearby park, she told me about her desire to lose weight and recover from polycystic ovary syndrome, which terrified her because it had caused dramatic hair loss. When she landed in Dr. Glandt’s office at age 28, she weighed 180 pounds. 

Less than 5 months later, Jerrilyn had lost 25 pounds, and her period had returned with some regularity. She said she used “food stamps,” known as the Supplemental Nutrition Assistance Program (SNAP), to buy most of her food at local delis because the meals served at the shelter were too heavy in starches. She starts her day with eggs, turkey bacon, and avocado. 

“It was hard to give up carbohydrates because in my culture [Latina], we have nothing but carbs: rice, potatoes, yuca,” Jerrilyn shared. She noticed that carbs make her hungrier, but after 3 days of going low-carb, her cravings diminished. “It was like getting over an addiction,” she said.

Jerrilyn told me she’d seen many doctors but none as involved as Dr. Glandt. “It feels awesome to know that I have a lot of really useful information coming from her all the time.” The OwnaHealth app tracks weight, blood pressure, blood sugar, ketones, meals, mood, and cravings. Patients wear continuous glucose monitors and enter other information manually. Ketone bodies are used to measure dietary adherence and are obtained through finger pricks and test strips provided by OwnaHealth. Dr. Glandt gives patients her own food plan, along with free visual guides to low-carbohydrate foods by dietdoctor.com. 

Dr. Glandt also sends her patients for regular blood work. She says she does not frequently see a rise in LDL cholesterol, which can sometimes occur on a low-carbohydrate diet. This effect is most common among people who are lean and fit. She says she doesn’t discontinue statins unless cholesterol levels improve significantly.

Samuel Gonzalez, age 56, weighed 275 pounds when he walked into Dr. Glandt’s office this past November. His A1c was 9.2%, but none of his previous doctors had diagnosed him with diabetes. “I was like a walking bag of sugar!” he joked. 

A low-carbohydrate diet seemed absurd to a Puerto Rican like himself: “Having coffee without sugar? That’s like sacrilegious in my culture!” exclaimed Mr. Gonzalez. Still, he managed, with SNAP, to cook eggs and bacon for breakfast and some kind of protein for dinner. He keeps lunch light, “like tuna fish,” and finds checking in with the OwnaHealth app to be very helpful. “Every day, I’m on it,” he said. In the past 7 months, he’s lost 50 pounds, normalized his cholesterol and blood pressure levels, and lowered his A1c to 5.5%.

Mr. Gonzalez gets disability payments due to a back injury, and Ms. Efem receives government payments because her husband died serving in the military. Ms. Efem says her new diet challenges her budget, but Mr. Gonzalez says he manages easily.

Mélissa Cruz, a 28-year-old studying to be a nail technician while also doing back office work at a physical therapy practice, says she’s stretched thin. “I end up sad because I can’t put energy into looking up recipes and cooking for me and my boyfriend,” she told me. She’ll often cook rice and plantains for him and meat for herself, but “it’s frustrating when I’m low on funds and can’t figure out what to eat.” 

Low-carbohydrate diets have a reputation for being expensive because people often start eating pricier foods, like meat and cheese, to replace cheaper starchy foods such as pasta and rice. Eggs and ground beef are less expensive low-carb meal options, and meat, unlike fruits and vegetables, is easy to freeze and doesn’t spoil quickly. These advantages can add up.

A 2019 cost analysis published in Nutrition & Dietetics compared a low-carbohydrate dietary pattern with the New Zealand government’s recommended guidelines (which are almost identical to those in the United States) and found that it cost only an extra $1.27 in US dollars per person per day. One explanation is that protein and fat are more satiating than carbohydrates, so people who mostly consume these macronutrients often cut back on snacks like packaged chips, crackers, and even fruits. Also, those on a ketogenic diet usually cut down on medications, so the additional $1.27 daily is likely offset by reduced spending at the pharmacy.

It’s not just Bronx residents with low socioeconomic status (SES) who adapt well to low-carbohydrate diets. Among Alabama state employees with diabetes enrolled in a low-carbohydrate dietary program provided by a company called Virta, the low SES population had the best outcomes. Virta also published survey data in 2023 showing that participants in a program with the Veteran’s Administration did not find additional costs to be an obstacle to dietary adherence. In fact, some participants saw cost reductions due to decreased spending on processed snacks and fast foods.

Ms. Cruz told me she struggles financially, yet she’s still lost nearly 30 pounds in 5 months, and her A1c went from 7.1% down to 5.9%, putting her diabetes into remission. Equally motivating for her are the improvements she’s seen in other hormonal issues. Since childhood, she’s had acanthosis, a condition that causes the skin to darken in velvety patches, and more recently, she developed severe hirsutism to the point of growing sideburns. “I had tried going vegan and fasting, but these just weren’t sustainable for me, and I was so overwhelmed with counting calories all the time.” Now, on a low-carbohydrate diet, which doesn’t require calorie counting, she’s finally seeing both these conditions improve significantly.

When I last checked in with Ms. Cruz, she said she had “kind of ghosted” Dr. Glandt due to her work and school constraints, but she hadn’t abandoned the diet. She appreciated, too, that Dr. Glandt had not given up on her and kept calling and messaging. “She’s not at all like a typical doctor who would just tell me to lose weight and shake their head at me,” Ms. Cruz said. 

Because Dr. Glandt’s approach is time-intensive and high-touch, it might seem impractical to scale up, but Dr. Glandt’s app uses artificial intelligence to help with communications thus allowing her, with help from part-time health coaches, to care for patients. 

This early success in one of the United States’ poorest and sickest neighborhoods should give us hope that type 2 diabetes need not to be a progressive irreversible disease, even among the disadvantaged. 

OwnaHealth’s track record, along with that of Virta and other similar low-carbohydrate medical practices also give hope to the food-is-medicine idea. Diabetes can go into remission, and people can be healed, provided that health practitioners prescribe the right foods. And in truth, it’s not a diet. It’s a way of eating that must be maintained. The sustainability of low-carbohydrate diets has been a point of contention, but the Virta trial, with 38% of patients sustaining remission at 2 years, showed that it’s possible. (OwnaHealth, for its part, offers long-term maintenance plans to help patients stay very low-carb permanently.) 

Given the tremendous costs and health burden of diabetes, this approach should no doubt be the first line of treatment for doctors and the ADA. The past two decades of clinical trial research have demonstrated that remission of type 2 diabetes is possible through diet alone. It turns out that for metabolic diseases, only certain foods are truly medicine. 
 

Tools and Tips for Clinicians: 

• Free two-page keto starter’s guide by OwnaHealth; Dr. Glandt uses this guide with her patients.
• Illustrated low-carb guides by dietdoctor.com
• Free low-carbohydrate starter guide by the Michigan Collaborative for Type 2 Diabetes
• Low-Carb for Any Budget, a free digital booklet by Mark Cucuzzella, MD, and Kristie Sullivan, PhD
• Recipe and meal ideas from Ruled.me, Keto-Mojo.com, and 

Dr. Teicholz is the founder of Nutrition Coalition, an independent nonprofit dedicated to ensuring that US dietary guidelines align with current science. She disclosed receiving book royalties from The Big Fat Surprise, and received honorarium not exceeding $2000 for speeches from various sources.

A version of this article appeared on Medscape.com.

For 3 years, Ajala Efem’s type 2 diabetes was so poorly controlled that her blood sugar often soared northward of 500 mg/dL despite insulin shots three to five times a day. She would experience dizziness, vomiting, severe headaches, and the neuropathy in her feet made walking painful. She was also — literally — frothing at the mouth. The 47-year-old single mother of two adult children with mental disabilities feared that she would die.

Ms. Efem lives in the South Bronx, which is among the poorest areas of New York City, where the combined rate of prediabetes and diabetes is close to 30%, the highest rate of any borough in the city.

She had to wait 8 months for an appointment with an endocrinologist, but that visit proved to be life-changing. She lost 28 pounds and got off 15 medications in a single month. She did not join a gym or count calories; she simply changed the food she ate and adopted a low-carb diet.

“I went from being sick to feeling so great,” she told her endocrinologist recently: “My feet aren’t hurting; I’m not in pain; I’m eating as much as I want, and I really enjoy my food so much.” 

Ms. Efem’s life-changing visit was with Mariela Glandt, MD, at the offices of Essen Health Care. One month earlier, Dr. Glandt’s company, OwnaHealth, was contracted by Essen to conduct a 100-person pilot program for endocrinology patients. Essen is the largest Medicaid provider in New York City, and “they were desperate for an endocrinologist,” said Dr. Glandt, who trained at Columbia University in New York. So she came — all the way from Madrid, Spain. She commutes monthly, staying for a week each visit.

Dr. Glandt keeps up this punishing schedule because, as she explains, “it’s such a high for me to see these incredible transformations.” Her mostly Black and Hispanic patients are poor and lack resources, yet they lose significant amounts of weight, and their health issues resolve.

“Food is medicine” is an idea very much in vogue. The concept was central to the landmark White House Conference on Hunger, Nutrition, and Health in 2022 and is now the focus of a number of a wide range of government programs. Recently, the Senate held a hearing aimed at further expanding food as medicine programs.

Still, only a single randomized controlled clinical trial has been conducted on this nutritional approach, with unexpectedly disappointing results. In the mid-Atlantic region, 456 food-insecure adults with type 2 diabetes were randomly assigned to usual care or the provision of weekly groceries for their entire families for about 1 year. Provisions for a Mediterranean-style diet included whole grains, fruits and vegetables, lean protein, low-fat dairy products, cereal, brown rice, and bread. In addition, participants received dietary consultations. Yet, those who got free food and coaching did not see improvements in their average blood sugar (the study’s primary outcome), and their low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol levels appeared to have worsened. 

“To be honest, I was surprised,” the study’s lead author, Joseph Doyle, PhD, professor at the Sloan School of Management at MIT in Cambridge, Massachusetts, told me. “I was hoping we would show improved outcomes, but the way to make progress is to do well-randomized trials to find out what works.”

I was not surprised by these results because a recent rigorous systematic review and meta-analysis in The BMJ did not show a Mediterranean-style diet to be the most effective for glycemic control. And Ms. Efem was not in fact following a Mediterranean-style diet.

Ms. Efem’s low-carb success story is anecdotal, but Dr. Glandt has an established track record from her 9 years’ experience as the medical director of the eponymous diabetes center she founded in Tel Aviv. A recent audit of 344 patients from the center found that after 6 months of following a very low–carbohydrate diet, 96.3% of those with diabetes saw their A1c fall from a median 7.6% to 6.3%. Weight loss was significant, with a median drop of 6.5 kg (14 pounds) for patients with diabetes and 5.7 kg for those with prediabetes. The diet comprises 5%-10% of calories from carbs, but Dr. Glandt does not use numeric targets with her patients.

Blood pressure, triglycerides, and liver enzymes also improved. And though LDL cholesterol went up by 8%, this result may have been offset by an accompanying 13% rise in HDL cholesterol. Of the 78 patients initially on insulin, 62 were able to stop this medication entirely.

Although these results aren’t from a clinical trial, they’re still highly meaningful because the current dietary standard of care for type 2 diabetes can only slow the progression of the disease, not cause remission. Indeed, the idea that type 2 diabetes could be put into remission was not seriously considered by the American Diabetes Association (ADA) until 2009. By 2019, an ADA report concluded that “[r]educing overall carbohydrate intake for individuals with diabetes has demonstrated the most evidence for improving glycemia.” In other words, the best way to improve the key factor in diabetes is to reduce total carbohydrates. Yet, the ADA still advocates filling one quarter of one’s plate with carbohydrate-based foods, an amount that will prevent remission. Given that the ADA’s vision statement is “a life free of diabetes,” it seems negligent not to tell people with a deadly condition that they can reverse this diagnosis. 

A 2023 meta-analysis of 42 controlled clinical trials on 4809 patients showed that a very low–carbohydrate ketogenic diet (keto) was “superior” to alternatives for glycemic control. A more recent review of 11 clinical trials found that this diet was equal but not superior to other nutritional approaches in terms of blood sugar control, but this review also concluded that keto led to greater increases in HDL cholesterol and lower triglycerides. 

Dr. Glandt’s patients in the Bronx might not seem like obvious low-carb candidates. The diet is considered expensive and difficult to sustain. My interviews with a half dozen patients revealed some of these difficulties, but even for a woman living in a homeless shelter, the obstacles are not insurmountable.

Jerrilyn, who preferred that I use only her first name, lives in a shelter in Queens. While we strolled through a nearby park, she told me about her desire to lose weight and recover from polycystic ovary syndrome, which terrified her because it had caused dramatic hair loss. When she landed in Dr. Glandt’s office at age 28, she weighed 180 pounds. 

Less than 5 months later, Jerrilyn had lost 25 pounds, and her period had returned with some regularity. She said she used “food stamps,” known as the Supplemental Nutrition Assistance Program (SNAP), to buy most of her food at local delis because the meals served at the shelter were too heavy in starches. She starts her day with eggs, turkey bacon, and avocado. 

“It was hard to give up carbohydrates because in my culture [Latina], we have nothing but carbs: rice, potatoes, yuca,” Jerrilyn shared. She noticed that carbs make her hungrier, but after 3 days of going low-carb, her cravings diminished. “It was like getting over an addiction,” she said.

Jerrilyn told me she’d seen many doctors but none as involved as Dr. Glandt. “It feels awesome to know that I have a lot of really useful information coming from her all the time.” The OwnaHealth app tracks weight, blood pressure, blood sugar, ketones, meals, mood, and cravings. Patients wear continuous glucose monitors and enter other information manually. Ketone bodies are used to measure dietary adherence and are obtained through finger pricks and test strips provided by OwnaHealth. Dr. Glandt gives patients her own food plan, along with free visual guides to low-carbohydrate foods by dietdoctor.com. 

Dr. Glandt also sends her patients for regular blood work. She says she does not frequently see a rise in LDL cholesterol, which can sometimes occur on a low-carbohydrate diet. This effect is most common among people who are lean and fit. She says she doesn’t discontinue statins unless cholesterol levels improve significantly.

Samuel Gonzalez, age 56, weighed 275 pounds when he walked into Dr. Glandt’s office this past November. His A1c was 9.2%, but none of his previous doctors had diagnosed him with diabetes. “I was like a walking bag of sugar!” he joked. 

A low-carbohydrate diet seemed absurd to a Puerto Rican like himself: “Having coffee without sugar? That’s like sacrilegious in my culture!” exclaimed Mr. Gonzalez. Still, he managed, with SNAP, to cook eggs and bacon for breakfast and some kind of protein for dinner. He keeps lunch light, “like tuna fish,” and finds checking in with the OwnaHealth app to be very helpful. “Every day, I’m on it,” he said. In the past 7 months, he’s lost 50 pounds, normalized his cholesterol and blood pressure levels, and lowered his A1c to 5.5%.

Mr. Gonzalez gets disability payments due to a back injury, and Ms. Efem receives government payments because her husband died serving in the military. Ms. Efem says her new diet challenges her budget, but Mr. Gonzalez says he manages easily.

Mélissa Cruz, a 28-year-old studying to be a nail technician while also doing back office work at a physical therapy practice, says she’s stretched thin. “I end up sad because I can’t put energy into looking up recipes and cooking for me and my boyfriend,” she told me. She’ll often cook rice and plantains for him and meat for herself, but “it’s frustrating when I’m low on funds and can’t figure out what to eat.” 

Low-carbohydrate diets have a reputation for being expensive because people often start eating pricier foods, like meat and cheese, to replace cheaper starchy foods such as pasta and rice. Eggs and ground beef are less expensive low-carb meal options, and meat, unlike fruits and vegetables, is easy to freeze and doesn’t spoil quickly. These advantages can add up.

A 2019 cost analysis published in Nutrition & Dietetics compared a low-carbohydrate dietary pattern with the New Zealand government’s recommended guidelines (which are almost identical to those in the United States) and found that it cost only an extra $1.27 in US dollars per person per day. One explanation is that protein and fat are more satiating than carbohydrates, so people who mostly consume these macronutrients often cut back on snacks like packaged chips, crackers, and even fruits. Also, those on a ketogenic diet usually cut down on medications, so the additional $1.27 daily is likely offset by reduced spending at the pharmacy.

It’s not just Bronx residents with low socioeconomic status (SES) who adapt well to low-carbohydrate diets. Among Alabama state employees with diabetes enrolled in a low-carbohydrate dietary program provided by a company called Virta, the low SES population had the best outcomes. Virta also published survey data in 2023 showing that participants in a program with the Veteran’s Administration did not find additional costs to be an obstacle to dietary adherence. In fact, some participants saw cost reductions due to decreased spending on processed snacks and fast foods.

Ms. Cruz told me she struggles financially, yet she’s still lost nearly 30 pounds in 5 months, and her A1c went from 7.1% down to 5.9%, putting her diabetes into remission. Equally motivating for her are the improvements she’s seen in other hormonal issues. Since childhood, she’s had acanthosis, a condition that causes the skin to darken in velvety patches, and more recently, she developed severe hirsutism to the point of growing sideburns. “I had tried going vegan and fasting, but these just weren’t sustainable for me, and I was so overwhelmed with counting calories all the time.” Now, on a low-carbohydrate diet, which doesn’t require calorie counting, she’s finally seeing both these conditions improve significantly.

When I last checked in with Ms. Cruz, she said she had “kind of ghosted” Dr. Glandt due to her work and school constraints, but she hadn’t abandoned the diet. She appreciated, too, that Dr. Glandt had not given up on her and kept calling and messaging. “She’s not at all like a typical doctor who would just tell me to lose weight and shake their head at me,” Ms. Cruz said. 

Because Dr. Glandt’s approach is time-intensive and high-touch, it might seem impractical to scale up, but Dr. Glandt’s app uses artificial intelligence to help with communications thus allowing her, with help from part-time health coaches, to care for patients. 

This early success in one of the United States’ poorest and sickest neighborhoods should give us hope that type 2 diabetes need not to be a progressive irreversible disease, even among the disadvantaged. 

OwnaHealth’s track record, along with that of Virta and other similar low-carbohydrate medical practices also give hope to the food-is-medicine idea. Diabetes can go into remission, and people can be healed, provided that health practitioners prescribe the right foods. And in truth, it’s not a diet. It’s a way of eating that must be maintained. The sustainability of low-carbohydrate diets has been a point of contention, but the Virta trial, with 38% of patients sustaining remission at 2 years, showed that it’s possible. (OwnaHealth, for its part, offers long-term maintenance plans to help patients stay very low-carb permanently.) 

Given the tremendous costs and health burden of diabetes, this approach should no doubt be the first line of treatment for doctors and the ADA. The past two decades of clinical trial research have demonstrated that remission of type 2 diabetes is possible through diet alone. It turns out that for metabolic diseases, only certain foods are truly medicine. 
 

Tools and Tips for Clinicians: 

• Free two-page keto starter’s guide by OwnaHealth; Dr. Glandt uses this guide with her patients.
• Illustrated low-carb guides by dietdoctor.com
• Free low-carbohydrate starter guide by the Michigan Collaborative for Type 2 Diabetes
• Low-Carb for Any Budget, a free digital booklet by Mark Cucuzzella, MD, and Kristie Sullivan, PhD
• Recipe and meal ideas from Ruled.me, Keto-Mojo.com, and 

Dr. Teicholz is the founder of Nutrition Coalition, an independent nonprofit dedicated to ensuring that US dietary guidelines align with current science. She disclosed receiving book royalties from The Big Fat Surprise, and received honorarium not exceeding $2000 for speeches from various sources.

A version of this article appeared on Medscape.com.

My field of electrophysiology is abuzz with excitement over the new technology of pulsed field ablation (PFA). It dominated 2024’s heart rhythm meetings, and it dominates my private electrophysiologist chat groups. My Google alert for “AF ablation” most often includes notices on PFA and the expansion of the atrial fibrillation ablation market. 

Yet, the excitement does not match the empirical data. 

Despite having strong brains, electrophysiologists adopt new things as if we were emotional shoppers. Our neighbor buys a sports car and we think we need the same car. Left atrial appendage occlusion and subcutaneous defibrillators were past examples. 

The most recent example of soft thinking (especially in the United States) is the enthusiasm and early adoption of first-generation PFA systems for the treatment of AF. 

Readers of cardiac news (including some of my patients) might think PFA has solved the AF puzzle. It has not.

A true breakthrough in AF would be to find its cause. PFA is simply another way to destroy (ablate) cardiac myocytes. PFA uses electrical energy (think shocks) to create pores in the cell membranes of myocytes. It’s delivered through various types of catheters. 

The main theoretical advantage of PFA is cardioselectivity, which is possible because myocytes have lower thresholds for irreversible electroporation than surrounding tissues. The dose of electrical energy that ablates cardiac tissue does not affect surrounding tissues. Cardioselectivity decreases the chance of the most feared complication of standard AF ablation, thermal damage to the esophagus, which is often fatal. The esophagus lies immediately behind the posterior wall of the left atrium and can be inadvertently injured during thermal ablation. 

The challenge in assessing this potential advantage is that thermal esophageal damage is, thankfully, exceedingly rare. Its incidence is in the range of 1 in 10,000 AF ablations. But it might be even lower than that in contemporary practice, because knowledge of esophageal injury has led to innovations that probably have reduced its incidence even further. 

Proponents of PFA would rightly point to the fact that not having to worry about esophageal injury allows operators to add posterior wall ablation to the normal pulmonary vein isolation lesion set. This ability, they would argue, is likely to improve AF ablation outcomes. The problem is that the strongest and most recent trial of posterior wall isolation (with radiofrequency ablation) did not show better outcomes. A more recent observational analysis also showed no benefit to posterior wall isolation (using PFA) over pulmonary vein isolation alone. 
 

What About PFA Efficacy?

I’ve long spoken and written about the lack of progress in AF ablation. In 1998, the first report on ablation of AF showed a 62% arrhythmia-free rate. Two decades later, in the carefully chosen labs treating patients in the CABANA trial, arrhythmia-free rates after AF ablation remain unchanged. We have improved our speed and ability to isolate pulmonary veins, but this has not increased our success in eliminating AF. The reason, I believe, is that we have made little to no progress in understanding the pathophysiology of AF. 

The Food and Drug Administration regulatory trial called ADVENT randomly assigned more than 600 patients to thermal ablation or PFA, and the primary endpoint of ablation success was nearly identical. Single-center studies, observational registries, and single-arm studies have all shown similar efficacy of PFA and thermal ablation. 

Proponents of PFA might argue that these early studies used first-generation PFA systems, and iteration will lead to better efficacy. Perhaps, but we’ve had 20 years of iteration of thermal ablation, and its efficacy has not budged. 
 

What About PFA Safety?

In the ADVENT randomized trial, safety results were similar, though the one death, caused by cardiac perforation and tamponade, occurred in the PFA arm. In the MANIFEST-17K multinational survey of PFA ablation, safety events were in the range reported with thermal ablation. PFA still involves placing catheters in the heart, and complications such as tamponade, stroke, and vascular damage occur. 

The large MANIFEST-17K survey also exposed two PFA-specific complications: coronary artery spasm, which can occur when PFA is delivered close to coronary arteries; and hemolysis-related kidney failure — severe enough to require dialysis in five patients. Supporters of PFA speculate that hemolysis occurs because electrical energy within the atrium can shred red blood cells. Their solution is to strive for good contact and use hydration. The irony of this latter fix is that one of the best advances in thermal ablation has been catheters that deliver less fluid and less need for diuresis after the procedure. 

No PFA study has shown a decreased incidence of thermal damage to the esophagus with PFA ablation. Of course, this is because it is such a low-incidence event. 

One of my concerns with PFA is brain safety. PFA creates substantial microbubbles in the left atrium, which can then travel north to the brain. In a small series from ADVENT, three patients had brain lesions after PFA vs none with thermal ablation. PFA proponents wrote that brain safety was important to study, but few patients have been systematically studied with brain MRI scans. Asymptomatic brain lesions have been noted after many arterial procedures. The clinical significance of these is not known. As a new technology, and one that creates substantial microbubbles in the left atrium, I agree with the PFA proponents that brain safety should be thoroughly studied — before widespread adoption. 
 

What About Speed and Cost? 

Observational studies from European labs report fast procedure times. I have seen PFA procedures in Europe; they’re fast — typically under an hour. A standard thermal ablation takes me about 60-70 minutes.

I am not sure that US operators can duplicate European procedural times. In the ADVENT regulatory trial, the mean procedure time was 105 minutes and that was in experienced US centers. While this still represents early experience with PFA, the culture of US AF ablation entails far more mapping and extra catheters than I have seen used in European labs. 

Cost is a major issue. It’s hard to sort out exact costs in the United States, but a PFA catheter costs approximately threefold more than a standard ablation catheter. A recent study from Liverpool, England, found that PFA ablation was faster but more expensive than standard thermal ablation because of higher PFA equipment prices. For better or worse, US patients are not directly affected by the higher procedural costs. But the fact remains that PFA adds more costs to the healthcare system. 
 

What Drives the Enthusiasm for First-Generation PFA? 

So why all the enthusiasm? It’s surely not the empirical data. Evidence thus far shows no obvious advantage in safety or efficacy. European use of PFA does seem to reduce procedure time. But in many electrophysiology labs in the United States, the rate-limiting step for AF ablation is not time in the lab but having enough staff to turn rooms around.

The main factor driving early acceptance of PFA relates to basic human nature. It is the fear of missing out. Marketing works on consumers, and it surely works on doctors. Companies that make PFA systems sponsor key opinion leaders to discuss PFA. These companies have beautiful booths in the expo of our meetings; they host dinners and talks. When a hospital in a city does PFA, the other hospitals feel the urge to keep up. It’s hard to be a Top Person in electrophysiology and not be a PFA user. 

One of my favorite comments came from a key opinion leader. He told me that he advised his administration to buy a PFA system, promote that they have it, and keep it in the closet until better systems are released. 

Iteration in the medical device field is tricky. There are negatives to being too harsh on first-generation systems. Early cardiac resynchronization tools, for instance, were horrible. Now CRT is transformative in selected patients with heart failure. 

It’s possible (but not certain) that electrical ablative therapy will iterate and surpass thermal ablation in the future. Maybe. 

But for now, the enthusiasm for PFA far outstrips its evidence. Until better evidence emerges, I will be a slow adopter. And I hope that our field gathers evidence before widespread adoption makes it impossible to do proper studies. 
 

Dr. Mandrola, clinical electrophysiologist, Baptist Medical Associates, Louisville, Kentucky, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

My field of electrophysiology is abuzz with excitement over the new technology of pulsed field ablation (PFA). It dominated 2024’s heart rhythm meetings, and it dominates my private electrophysiologist chat groups. My Google alert for “AF ablation” most often includes notices on PFA and the expansion of the atrial fibrillation ablation market. 

Yet, the excitement does not match the empirical data. 

Despite having strong brains, electrophysiologists adopt new things as if we were emotional shoppers. Our neighbor buys a sports car and we think we need the same car. Left atrial appendage occlusion and subcutaneous defibrillators were past examples. 

The most recent example of soft thinking (especially in the United States) is the enthusiasm and early adoption of first-generation PFA systems for the treatment of AF. 

Readers of cardiac news (including some of my patients) might think PFA has solved the AF puzzle. It has not.

A true breakthrough in AF would be to find its cause. PFA is simply another way to destroy (ablate) cardiac myocytes. PFA uses electrical energy (think shocks) to create pores in the cell membranes of myocytes. It’s delivered through various types of catheters. 

The main theoretical advantage of PFA is cardioselectivity, which is possible because myocytes have lower thresholds for irreversible electroporation than surrounding tissues. The dose of electrical energy that ablates cardiac tissue does not affect surrounding tissues. Cardioselectivity decreases the chance of the most feared complication of standard AF ablation, thermal damage to the esophagus, which is often fatal. The esophagus lies immediately behind the posterior wall of the left atrium and can be inadvertently injured during thermal ablation. 

The challenge in assessing this potential advantage is that thermal esophageal damage is, thankfully, exceedingly rare. Its incidence is in the range of 1 in 10,000 AF ablations. But it might be even lower than that in contemporary practice, because knowledge of esophageal injury has led to innovations that probably have reduced its incidence even further. 

Proponents of PFA would rightly point to the fact that not having to worry about esophageal injury allows operators to add posterior wall ablation to the normal pulmonary vein isolation lesion set. This ability, they would argue, is likely to improve AF ablation outcomes. The problem is that the strongest and most recent trial of posterior wall isolation (with radiofrequency ablation) did not show better outcomes. A more recent observational analysis also showed no benefit to posterior wall isolation (using PFA) over pulmonary vein isolation alone. 
 

What About PFA Efficacy?

I’ve long spoken and written about the lack of progress in AF ablation. In 1998, the first report on ablation of AF showed a 62% arrhythmia-free rate. Two decades later, in the carefully chosen labs treating patients in the CABANA trial, arrhythmia-free rates after AF ablation remain unchanged. We have improved our speed and ability to isolate pulmonary veins, but this has not increased our success in eliminating AF. The reason, I believe, is that we have made little to no progress in understanding the pathophysiology of AF. 

The Food and Drug Administration regulatory trial called ADVENT randomly assigned more than 600 patients to thermal ablation or PFA, and the primary endpoint of ablation success was nearly identical. Single-center studies, observational registries, and single-arm studies have all shown similar efficacy of PFA and thermal ablation. 

Proponents of PFA might argue that these early studies used first-generation PFA systems, and iteration will lead to better efficacy. Perhaps, but we’ve had 20 years of iteration of thermal ablation, and its efficacy has not budged. 
 

What About PFA Safety?

In the ADVENT randomized trial, safety results were similar, though the one death, caused by cardiac perforation and tamponade, occurred in the PFA arm. In the MANIFEST-17K multinational survey of PFA ablation, safety events were in the range reported with thermal ablation. PFA still involves placing catheters in the heart, and complications such as tamponade, stroke, and vascular damage occur. 

The large MANIFEST-17K survey also exposed two PFA-specific complications: coronary artery spasm, which can occur when PFA is delivered close to coronary arteries; and hemolysis-related kidney failure — severe enough to require dialysis in five patients. Supporters of PFA speculate that hemolysis occurs because electrical energy within the atrium can shred red blood cells. Their solution is to strive for good contact and use hydration. The irony of this latter fix is that one of the best advances in thermal ablation has been catheters that deliver less fluid and less need for diuresis after the procedure. 

No PFA study has shown a decreased incidence of thermal damage to the esophagus with PFA ablation. Of course, this is because it is such a low-incidence event. 

One of my concerns with PFA is brain safety. PFA creates substantial microbubbles in the left atrium, which can then travel north to the brain. In a small series from ADVENT, three patients had brain lesions after PFA vs none with thermal ablation. PFA proponents wrote that brain safety was important to study, but few patients have been systematically studied with brain MRI scans. Asymptomatic brain lesions have been noted after many arterial procedures. The clinical significance of these is not known. As a new technology, and one that creates substantial microbubbles in the left atrium, I agree with the PFA proponents that brain safety should be thoroughly studied — before widespread adoption. 
 

What About Speed and Cost? 

Observational studies from European labs report fast procedure times. I have seen PFA procedures in Europe; they’re fast — typically under an hour. A standard thermal ablation takes me about 60-70 minutes.

I am not sure that US operators can duplicate European procedural times. In the ADVENT regulatory trial, the mean procedure time was 105 minutes and that was in experienced US centers. While this still represents early experience with PFA, the culture of US AF ablation entails far more mapping and extra catheters than I have seen used in European labs. 

Cost is a major issue. It’s hard to sort out exact costs in the United States, but a PFA catheter costs approximately threefold more than a standard ablation catheter. A recent study from Liverpool, England, found that PFA ablation was faster but more expensive than standard thermal ablation because of higher PFA equipment prices. For better or worse, US patients are not directly affected by the higher procedural costs. But the fact remains that PFA adds more costs to the healthcare system. 
 

What Drives the Enthusiasm for First-Generation PFA? 

So why all the enthusiasm? It’s surely not the empirical data. Evidence thus far shows no obvious advantage in safety or efficacy. European use of PFA does seem to reduce procedure time. But in many electrophysiology labs in the United States, the rate-limiting step for AF ablation is not time in the lab but having enough staff to turn rooms around.

The main factor driving early acceptance of PFA relates to basic human nature. It is the fear of missing out. Marketing works on consumers, and it surely works on doctors. Companies that make PFA systems sponsor key opinion leaders to discuss PFA. These companies have beautiful booths in the expo of our meetings; they host dinners and talks. When a hospital in a city does PFA, the other hospitals feel the urge to keep up. It’s hard to be a Top Person in electrophysiology and not be a PFA user. 

One of my favorite comments came from a key opinion leader. He told me that he advised his administration to buy a PFA system, promote that they have it, and keep it in the closet until better systems are released. 

Iteration in the medical device field is tricky. There are negatives to being too harsh on first-generation systems. Early cardiac resynchronization tools, for instance, were horrible. Now CRT is transformative in selected patients with heart failure. 

It’s possible (but not certain) that electrical ablative therapy will iterate and surpass thermal ablation in the future. Maybe. 

But for now, the enthusiasm for PFA far outstrips its evidence. Until better evidence emerges, I will be a slow adopter. And I hope that our field gathers evidence before widespread adoption makes it impossible to do proper studies. 
 

Dr. Mandrola, clinical electrophysiologist, Baptist Medical Associates, Louisville, Kentucky, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

My field of electrophysiology is abuzz with excitement over the new technology of pulsed field ablation (PFA). It dominated 2024’s heart rhythm meetings, and it dominates my private electrophysiologist chat groups. My Google alert for “AF ablation” most often includes notices on PFA and the expansion of the atrial fibrillation ablation market. 

Yet, the excitement does not match the empirical data. 

Despite having strong brains, electrophysiologists adopt new things as if we were emotional shoppers. Our neighbor buys a sports car and we think we need the same car. Left atrial appendage occlusion and subcutaneous defibrillators were past examples. 

The most recent example of soft thinking (especially in the United States) is the enthusiasm and early adoption of first-generation PFA systems for the treatment of AF. 

Readers of cardiac news (including some of my patients) might think PFA has solved the AF puzzle. It has not.

A true breakthrough in AF would be to find its cause. PFA is simply another way to destroy (ablate) cardiac myocytes. PFA uses electrical energy (think shocks) to create pores in the cell membranes of myocytes. It’s delivered through various types of catheters. 

The main theoretical advantage of PFA is cardioselectivity, which is possible because myocytes have lower thresholds for irreversible electroporation than surrounding tissues. The dose of electrical energy that ablates cardiac tissue does not affect surrounding tissues. Cardioselectivity decreases the chance of the most feared complication of standard AF ablation, thermal damage to the esophagus, which is often fatal. The esophagus lies immediately behind the posterior wall of the left atrium and can be inadvertently injured during thermal ablation. 

The challenge in assessing this potential advantage is that thermal esophageal damage is, thankfully, exceedingly rare. Its incidence is in the range of 1 in 10,000 AF ablations. But it might be even lower than that in contemporary practice, because knowledge of esophageal injury has led to innovations that probably have reduced its incidence even further. 

Proponents of PFA would rightly point to the fact that not having to worry about esophageal injury allows operators to add posterior wall ablation to the normal pulmonary vein isolation lesion set. This ability, they would argue, is likely to improve AF ablation outcomes. The problem is that the strongest and most recent trial of posterior wall isolation (with radiofrequency ablation) did not show better outcomes. A more recent observational analysis also showed no benefit to posterior wall isolation (using PFA) over pulmonary vein isolation alone. 
 

What About PFA Efficacy?

I’ve long spoken and written about the lack of progress in AF ablation. In 1998, the first report on ablation of AF showed a 62% arrhythmia-free rate. Two decades later, in the carefully chosen labs treating patients in the CABANA trial, arrhythmia-free rates after AF ablation remain unchanged. We have improved our speed and ability to isolate pulmonary veins, but this has not increased our success in eliminating AF. The reason, I believe, is that we have made little to no progress in understanding the pathophysiology of AF. 

The Food and Drug Administration regulatory trial called ADVENT randomly assigned more than 600 patients to thermal ablation or PFA, and the primary endpoint of ablation success was nearly identical. Single-center studies, observational registries, and single-arm studies have all shown similar efficacy of PFA and thermal ablation. 

Proponents of PFA might argue that these early studies used first-generation PFA systems, and iteration will lead to better efficacy. Perhaps, but we’ve had 20 years of iteration of thermal ablation, and its efficacy has not budged. 
 

What About PFA Safety?

In the ADVENT randomized trial, safety results were similar, though the one death, caused by cardiac perforation and tamponade, occurred in the PFA arm. In the MANIFEST-17K multinational survey of PFA ablation, safety events were in the range reported with thermal ablation. PFA still involves placing catheters in the heart, and complications such as tamponade, stroke, and vascular damage occur. 

The large MANIFEST-17K survey also exposed two PFA-specific complications: coronary artery spasm, which can occur when PFA is delivered close to coronary arteries; and hemolysis-related kidney failure — severe enough to require dialysis in five patients. Supporters of PFA speculate that hemolysis occurs because electrical energy within the atrium can shred red blood cells. Their solution is to strive for good contact and use hydration. The irony of this latter fix is that one of the best advances in thermal ablation has been catheters that deliver less fluid and less need for diuresis after the procedure. 

No PFA study has shown a decreased incidence of thermal damage to the esophagus with PFA ablation. Of course, this is because it is such a low-incidence event. 

One of my concerns with PFA is brain safety. PFA creates substantial microbubbles in the left atrium, which can then travel north to the brain. In a small series from ADVENT, three patients had brain lesions after PFA vs none with thermal ablation. PFA proponents wrote that brain safety was important to study, but few patients have been systematically studied with brain MRI scans. Asymptomatic brain lesions have been noted after many arterial procedures. The clinical significance of these is not known. As a new technology, and one that creates substantial microbubbles in the left atrium, I agree with the PFA proponents that brain safety should be thoroughly studied — before widespread adoption. 
 

What About Speed and Cost? 

Observational studies from European labs report fast procedure times. I have seen PFA procedures in Europe; they’re fast — typically under an hour. A standard thermal ablation takes me about 60-70 minutes.

I am not sure that US operators can duplicate European procedural times. In the ADVENT regulatory trial, the mean procedure time was 105 minutes and that was in experienced US centers. While this still represents early experience with PFA, the culture of US AF ablation entails far more mapping and extra catheters than I have seen used in European labs. 

Cost is a major issue. It’s hard to sort out exact costs in the United States, but a PFA catheter costs approximately threefold more than a standard ablation catheter. A recent study from Liverpool, England, found that PFA ablation was faster but more expensive than standard thermal ablation because of higher PFA equipment prices. For better or worse, US patients are not directly affected by the higher procedural costs. But the fact remains that PFA adds more costs to the healthcare system. 
 

What Drives the Enthusiasm for First-Generation PFA? 

So why all the enthusiasm? It’s surely not the empirical data. Evidence thus far shows no obvious advantage in safety or efficacy. European use of PFA does seem to reduce procedure time. But in many electrophysiology labs in the United States, the rate-limiting step for AF ablation is not time in the lab but having enough staff to turn rooms around.

The main factor driving early acceptance of PFA relates to basic human nature. It is the fear of missing out. Marketing works on consumers, and it surely works on doctors. Companies that make PFA systems sponsor key opinion leaders to discuss PFA. These companies have beautiful booths in the expo of our meetings; they host dinners and talks. When a hospital in a city does PFA, the other hospitals feel the urge to keep up. It’s hard to be a Top Person in electrophysiology and not be a PFA user. 

One of my favorite comments came from a key opinion leader. He told me that he advised his administration to buy a PFA system, promote that they have it, and keep it in the closet until better systems are released. 

Iteration in the medical device field is tricky. There are negatives to being too harsh on first-generation systems. Early cardiac resynchronization tools, for instance, were horrible. Now CRT is transformative in selected patients with heart failure. 

It’s possible (but not certain) that electrical ablative therapy will iterate and surpass thermal ablation in the future. Maybe. 

But for now, the enthusiasm for PFA far outstrips its evidence. Until better evidence emerges, I will be a slow adopter. And I hope that our field gathers evidence before widespread adoption makes it impossible to do proper studies. 
 

Dr. Mandrola, clinical electrophysiologist, Baptist Medical Associates, Louisville, Kentucky, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

TOPLINE:

Surveillance of high-risk individuals may detect pancreatic ductal adenocarcinoma at an earlier stage, when the tumor is smaller and easier to treat, and could help improve survival in this population.

METHODOLOGY:

• Pancreatic ductal adenocarcinoma has poor 5-year survival rates and is often detected at later stages. General population screening is not recommended, but high-risk individuals, such as those with familial or genetic predispositions, may benefit from regular surveillance.
• The Cancer of the Pancreas Screening (CAPS) program, initiated in 1998, has been evaluating the effectiveness of such targeted surveillance for over two decades, but whether targeted surveillance confers a survival benefit remains unclear.
• The current study evaluated 26 high-risk individuals in the CAPS program who were ultimately diagnosed with pancreatic ductal adenocarcinoma. These high-risk individuals had undergone surveillance with annual endoscopic ultrasonography or MRI prior to diagnosis.
• The researchers compared these 26 individuals with 1504 matched control patients with pancreatic ductal adenocarcinoma from the Surveillance, Epidemiology, and End Results (SEER) database. The high-risk individuals and SEER control patients were matched on age, sex, and year of diagnosis.
• The primary outcomes were tumor stage at diagnosis, overall survival, and pancreatic cancer-specific mortality.

TAKEAWAY:

• High-risk individuals were significantly more likely to be diagnosed with early-stage pancreatic cancer: 38.5% were diagnosed at stage I vs 10.3% in the general US population, and 30.8% were diagnosed at stage II vs 25.1% in the general US population (P < .001).
• The median tumor size at diagnosis was smaller in high-risk individuals than in control patients (2.5 vs 3.6 cm; P < .001), and significantly fewer high-risk individuals had distant metastases at diagnosis (M1 stage) vs control patients (26.9% vs 53.8%; P = .01).
• Overall, high-risk individuals lived about 4.5 years longer — median of 61.7 months vs 8 months for control patients (hazard ratio [HR], 4.19; P < .001). In the 20 high-risk patients with screen-detected cancer, median overall survival was even higher at 144 months.
• The probability of surviving 5 years was significantly better in the high-risk group (50%) than in the control group (9%). And at 5 years, high-risk individuals had a significantly lower probability of dying from pancreatic cancer (HR, 3.58; P < .001).

IN PRACTICE:

Surveillance of high-risk individuals led to detection of “smaller pancreatic cancers, a greater number of patients with stage I disease,” as well as “a much higher likelihood of long-term survival than unscreened patients in the general population,” the authors concluded. “These findings suggest that selective surveillance of individuals at high risk for pancreatic cancer may improve clinical outcomes.”

SOURCE:

This study, with first author Amanda L. Blackford, from Johns Hopkins Medical Institutions, Baltimore, was published online July 3 in JAMA Oncology.

LIMITATIONS:

The findings might have limited generalizability due to enrollment at academic referral centers, limited racial and ethnic diversity, and a small number of high-risk individuals progressing to pancreatic cancer. The study also lacked a control group of unscreened high-risk individuals.

DISCLOSURES:

This study was supported by the National Institutes of Health, Susan Wojcicki and Dennis Troper, and others. Several authors reported financial ties outside this work.

A version of this article appeared on Medscape.com.

TOPLINE:

Surveillance of high-risk individuals may detect pancreatic ductal adenocarcinoma at an earlier stage, when the tumor is smaller and easier to treat, and could help improve survival in this population.

METHODOLOGY:

• Pancreatic ductal adenocarcinoma has poor 5-year survival rates and is often detected at later stages. General population screening is not recommended, but high-risk individuals, such as those with familial or genetic predispositions, may benefit from regular surveillance.
• The Cancer of the Pancreas Screening (CAPS) program, initiated in 1998, has been evaluating the effectiveness of such targeted surveillance for over two decades, but whether targeted surveillance confers a survival benefit remains unclear.
• The current study evaluated 26 high-risk individuals in the CAPS program who were ultimately diagnosed with pancreatic ductal adenocarcinoma. These high-risk individuals had undergone surveillance with annual endoscopic ultrasonography or MRI prior to diagnosis.
• The researchers compared these 26 individuals with 1504 matched control patients with pancreatic ductal adenocarcinoma from the Surveillance, Epidemiology, and End Results (SEER) database. The high-risk individuals and SEER control patients were matched on age, sex, and year of diagnosis.
• The primary outcomes were tumor stage at diagnosis, overall survival, and pancreatic cancer-specific mortality.

TAKEAWAY:

• High-risk individuals were significantly more likely to be diagnosed with early-stage pancreatic cancer: 38.5% were diagnosed at stage I vs 10.3% in the general US population, and 30.8% were diagnosed at stage II vs 25.1% in the general US population (P < .001).
• The median tumor size at diagnosis was smaller in high-risk individuals than in control patients (2.5 vs 3.6 cm; P < .001), and significantly fewer high-risk individuals had distant metastases at diagnosis (M1 stage) vs control patients (26.9% vs 53.8%; P = .01).
• Overall, high-risk individuals lived about 4.5 years longer — median of 61.7 months vs 8 months for control patients (hazard ratio [HR], 4.19; P < .001). In the 20 high-risk patients with screen-detected cancer, median overall survival was even higher at 144 months.
• The probability of surviving 5 years was significantly better in the high-risk group (50%) than in the control group (9%). And at 5 years, high-risk individuals had a significantly lower probability of dying from pancreatic cancer (HR, 3.58; P < .001).

IN PRACTICE:

Surveillance of high-risk individuals led to detection of “smaller pancreatic cancers, a greater number of patients with stage I disease,” as well as “a much higher likelihood of long-term survival than unscreened patients in the general population,” the authors concluded. “These findings suggest that selective surveillance of individuals at high risk for pancreatic cancer may improve clinical outcomes.”

SOURCE:

This study, with first author Amanda L. Blackford, from Johns Hopkins Medical Institutions, Baltimore, was published online July 3 in JAMA Oncology.

LIMITATIONS:

The findings might have limited generalizability due to enrollment at academic referral centers, limited racial and ethnic diversity, and a small number of high-risk individuals progressing to pancreatic cancer. The study also lacked a control group of unscreened high-risk individuals.

DISCLOSURES:

This study was supported by the National Institutes of Health, Susan Wojcicki and Dennis Troper, and others. Several authors reported financial ties outside this work.

A version of this article appeared on Medscape.com.

TOPLINE:

Surveillance of high-risk individuals may detect pancreatic ductal adenocarcinoma at an earlier stage, when the tumor is smaller and easier to treat, and could help improve survival in this population.

METHODOLOGY:

• Pancreatic ductal adenocarcinoma has poor 5-year survival rates and is often detected at later stages. General population screening is not recommended, but high-risk individuals, such as those with familial or genetic predispositions, may benefit from regular surveillance.
• The Cancer of the Pancreas Screening (CAPS) program, initiated in 1998, has been evaluating the effectiveness of such targeted surveillance for over two decades, but whether targeted surveillance confers a survival benefit remains unclear.
• The current study evaluated 26 high-risk individuals in the CAPS program who were ultimately diagnosed with pancreatic ductal adenocarcinoma. These high-risk individuals had undergone surveillance with annual endoscopic ultrasonography or MRI prior to diagnosis.
• The researchers compared these 26 individuals with 1504 matched control patients with pancreatic ductal adenocarcinoma from the Surveillance, Epidemiology, and End Results (SEER) database. The high-risk individuals and SEER control patients were matched on age, sex, and year of diagnosis.
• The primary outcomes were tumor stage at diagnosis, overall survival, and pancreatic cancer-specific mortality.

TAKEAWAY:

• High-risk individuals were significantly more likely to be diagnosed with early-stage pancreatic cancer: 38.5% were diagnosed at stage I vs 10.3% in the general US population, and 30.8% were diagnosed at stage II vs 25.1% in the general US population (P < .001).
• The median tumor size at diagnosis was smaller in high-risk individuals than in control patients (2.5 vs 3.6 cm; P < .001), and significantly fewer high-risk individuals had distant metastases at diagnosis (M1 stage) vs control patients (26.9% vs 53.8%; P = .01).
• Overall, high-risk individuals lived about 4.5 years longer — median of 61.7 months vs 8 months for control patients (hazard ratio [HR], 4.19; P < .001). In the 20 high-risk patients with screen-detected cancer, median overall survival was even higher at 144 months.
• The probability of surviving 5 years was significantly better in the high-risk group (50%) than in the control group (9%). And at 5 years, high-risk individuals had a significantly lower probability of dying from pancreatic cancer (HR, 3.58; P < .001).

IN PRACTICE:

Surveillance of high-risk individuals led to detection of “smaller pancreatic cancers, a greater number of patients with stage I disease,” as well as “a much higher likelihood of long-term survival than unscreened patients in the general population,” the authors concluded. “These findings suggest that selective surveillance of individuals at high risk for pancreatic cancer may improve clinical outcomes.”

SOURCE:

This study, with first author Amanda L. Blackford, from Johns Hopkins Medical Institutions, Baltimore, was published online July 3 in JAMA Oncology.

LIMITATIONS:

The findings might have limited generalizability due to enrollment at academic referral centers, limited racial and ethnic diversity, and a small number of high-risk individuals progressing to pancreatic cancer. The study also lacked a control group of unscreened high-risk individuals.

DISCLOSURES:

This study was supported by the National Institutes of Health, Susan Wojcicki and Dennis Troper, and others. Several authors reported financial ties outside this work.

A version of this article appeared on Medscape.com.