Feature

The University of Virginia (UVA) is defending the CEO of its health system and its medical school dean in the wake of a very public call for their removal.

At least 128 members of the University of Virginia faculty who are employed by both the medical school and the UVA Physicians Group wrote to the UVA Board of Visitors and its peer-elected faculty leaders, expressing no confidence in K. Craig Kent, MD, CEO of UVA Health and executive vice president for health affairs, and Melina Kibbe, MD, dean of the medical school and chief health affairs officer.

Dr. Kibbe, a vascular surgeon and researcher, is also the editor in chief of JAMA Surgery.

“We call for the immediate removal of Craig Kent and Melina Kibbe,” wrote the physicians.

The letter alleged that patient safety was compromised because doctors, nurses, and other staff were pressured to abstain from reporting safety concerns and that physicians had been hired “despite concerns regarding integrity and quality.” Those who raised safety concerns faced “explicit and implicit threats and retaliation,” including delays and denials of promotion and tenure, said the letter.

The September 5 letter did not include signatures. The authors said that names were being protected, but that they would share the names with a limited audience.

UVA President Jim Ryan took issue with the notion that the signees were anonymous. He said in his own letter to medical school faculty that some of the accusations were about matters that had already been addressed or that were being worked on. As far as allegations that he was not previously aware of, “we will do our best to investigate,” he said.

The faculty who signed the letter “have besmirched the reputations of not just Melina and Craig,” wrote Mr. Ryan. “They have unfairly — and I trust unwittingly — cast a shadow over the great work of the entire health system and medical school.”

The authors claimed that reports about bullying and harassment of trainees had been “suppressed, minimized, and subsequently altered.”

And they said that spending on leadership was prioritized over addressing clinical and technical staff shortages. Whistleblowers who reported fraud were not protected, and clinicians were pressured to modify patient records to “obfuscate adverse outcomes and boost productivity metrics,” they wrote.

The 128 members of the UVA Physicians Group who signed the letter represent about 10% of the 1400 medical school faculty members.

It is not the first time that Dr. Kent has been given a vote of no confidence. In 2017, when he was the dean of the College of Medicine at the Ohio State University, Dr. Kent was accused in a “no confidence” letter from 25 physicians and faculty of helping to undermine the school’s mission and taking actions that led to resignations and early retirements of many staff, the Columbus Dispatch reported.

William G. Crutchfield Jr., a member of the UVA Health System Board, defended Dr. Kent and Dr. Kibbe in a lengthy statement shared with this news organization. He said that UVA Health’s four hospitals had received “A” ratings for safety, and that the system has a 5.1% turnover rate compared with a national average of 8.3%.

Dr. Kent and Dr. Kibbe have recruited faculty from top academic medical centers, Mr. Crutchfield wrote.

“If our work environment were so toxic, these people would not have joined our faculty,” he wrote.

Mr. Crutchfield credited Dr. Kent and Dr. Kibbe with crafting a new 10-year strategic plan and for hiring a chief strategy officer to lead the plan — a move that replaced “expensive outside consultants.”

Mr. Ryan said in his letter that his inbox “is overflowing with testimonials from some of the 1200-plus faculty who did not sign the letter, who attest that the health system today — under Melina and Craig’s leadership — is in the best shape it has ever been in, and that they have addressed changes that have needed to be made for more than two decades.”

A request to see some of these positive testimonials was not answered by press time.

Mr. Crutchfield, like Mr. Ryan, said that the letter writers were doing more harm than good.

“If a small cabal of people hiding behind anonymity can force outstanding leaders out of UVA, it will make it extremely difficult to recruit outstanding new physicians, nurses, technicians, and administrators,” he wrote.

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

The University of Virginia (UVA) is defending the CEO of its health system and its medical school dean in the wake of a very public call for their removal.

At least 128 members of the University of Virginia faculty who are employed by both the medical school and the UVA Physicians Group wrote to the UVA Board of Visitors and its peer-elected faculty leaders, expressing no confidence in K. Craig Kent, MD, CEO of UVA Health and executive vice president for health affairs, and Melina Kibbe, MD, dean of the medical school and chief health affairs officer.

Dr. Kibbe, a vascular surgeon and researcher, is also the editor in chief of JAMA Surgery.

“We call for the immediate removal of Craig Kent and Melina Kibbe,” wrote the physicians.

The letter alleged that patient safety was compromised because doctors, nurses, and other staff were pressured to abstain from reporting safety concerns and that physicians had been hired “despite concerns regarding integrity and quality.” Those who raised safety concerns faced “explicit and implicit threats and retaliation,” including delays and denials of promotion and tenure, said the letter.

The September 5 letter did not include signatures. The authors said that names were being protected, but that they would share the names with a limited audience.

UVA President Jim Ryan took issue with the notion that the signees were anonymous. He said in his own letter to medical school faculty that some of the accusations were about matters that had already been addressed or that were being worked on. As far as allegations that he was not previously aware of, “we will do our best to investigate,” he said.

The faculty who signed the letter “have besmirched the reputations of not just Melina and Craig,” wrote Mr. Ryan. “They have unfairly — and I trust unwittingly — cast a shadow over the great work of the entire health system and medical school.”

The authors claimed that reports about bullying and harassment of trainees had been “suppressed, minimized, and subsequently altered.”

And they said that spending on leadership was prioritized over addressing clinical and technical staff shortages. Whistleblowers who reported fraud were not protected, and clinicians were pressured to modify patient records to “obfuscate adverse outcomes and boost productivity metrics,” they wrote.

The 128 members of the UVA Physicians Group who signed the letter represent about 10% of the 1400 medical school faculty members.

It is not the first time that Dr. Kent has been given a vote of no confidence. In 2017, when he was the dean of the College of Medicine at the Ohio State University, Dr. Kent was accused in a “no confidence” letter from 25 physicians and faculty of helping to undermine the school’s mission and taking actions that led to resignations and early retirements of many staff, the Columbus Dispatch reported.

William G. Crutchfield Jr., a member of the UVA Health System Board, defended Dr. Kent and Dr. Kibbe in a lengthy statement shared with this news organization. He said that UVA Health’s four hospitals had received “A” ratings for safety, and that the system has a 5.1% turnover rate compared with a national average of 8.3%.

Dr. Kent and Dr. Kibbe have recruited faculty from top academic medical centers, Mr. Crutchfield wrote.

“If our work environment were so toxic, these people would not have joined our faculty,” he wrote.

Mr. Crutchfield credited Dr. Kent and Dr. Kibbe with crafting a new 10-year strategic plan and for hiring a chief strategy officer to lead the plan — a move that replaced “expensive outside consultants.”

Mr. Ryan said in his letter that his inbox “is overflowing with testimonials from some of the 1200-plus faculty who did not sign the letter, who attest that the health system today — under Melina and Craig’s leadership — is in the best shape it has ever been in, and that they have addressed changes that have needed to be made for more than two decades.”

A request to see some of these positive testimonials was not answered by press time.

Mr. Crutchfield, like Mr. Ryan, said that the letter writers were doing more harm than good.

“If a small cabal of people hiding behind anonymity can force outstanding leaders out of UVA, it will make it extremely difficult to recruit outstanding new physicians, nurses, technicians, and administrators,” he wrote.

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

The University of Virginia (UVA) is defending the CEO of its health system and its medical school dean in the wake of a very public call for their removal.

At least 128 members of the University of Virginia faculty who are employed by both the medical school and the UVA Physicians Group wrote to the UVA Board of Visitors and its peer-elected faculty leaders, expressing no confidence in K. Craig Kent, MD, CEO of UVA Health and executive vice president for health affairs, and Melina Kibbe, MD, dean of the medical school and chief health affairs officer.

Dr. Kibbe, a vascular surgeon and researcher, is also the editor in chief of JAMA Surgery.

“We call for the immediate removal of Craig Kent and Melina Kibbe,” wrote the physicians.

The letter alleged that patient safety was compromised because doctors, nurses, and other staff were pressured to abstain from reporting safety concerns and that physicians had been hired “despite concerns regarding integrity and quality.” Those who raised safety concerns faced “explicit and implicit threats and retaliation,” including delays and denials of promotion and tenure, said the letter.

The September 5 letter did not include signatures. The authors said that names were being protected, but that they would share the names with a limited audience.

UVA President Jim Ryan took issue with the notion that the signees were anonymous. He said in his own letter to medical school faculty that some of the accusations were about matters that had already been addressed or that were being worked on. As far as allegations that he was not previously aware of, “we will do our best to investigate,” he said.

The faculty who signed the letter “have besmirched the reputations of not just Melina and Craig,” wrote Mr. Ryan. “They have unfairly — and I trust unwittingly — cast a shadow over the great work of the entire health system and medical school.”

The authors claimed that reports about bullying and harassment of trainees had been “suppressed, minimized, and subsequently altered.”

And they said that spending on leadership was prioritized over addressing clinical and technical staff shortages. Whistleblowers who reported fraud were not protected, and clinicians were pressured to modify patient records to “obfuscate adverse outcomes and boost productivity metrics,” they wrote.

The 128 members of the UVA Physicians Group who signed the letter represent about 10% of the 1400 medical school faculty members.

It is not the first time that Dr. Kent has been given a vote of no confidence. In 2017, when he was the dean of the College of Medicine at the Ohio State University, Dr. Kent was accused in a “no confidence” letter from 25 physicians and faculty of helping to undermine the school’s mission and taking actions that led to resignations and early retirements of many staff, the Columbus Dispatch reported.

William G. Crutchfield Jr., a member of the UVA Health System Board, defended Dr. Kent and Dr. Kibbe in a lengthy statement shared with this news organization. He said that UVA Health’s four hospitals had received “A” ratings for safety, and that the system has a 5.1% turnover rate compared with a national average of 8.3%.

Dr. Kent and Dr. Kibbe have recruited faculty from top academic medical centers, Mr. Crutchfield wrote.

“If our work environment were so toxic, these people would not have joined our faculty,” he wrote.

Mr. Crutchfield credited Dr. Kent and Dr. Kibbe with crafting a new 10-year strategic plan and for hiring a chief strategy officer to lead the plan — a move that replaced “expensive outside consultants.”

Mr. Ryan said in his letter that his inbox “is overflowing with testimonials from some of the 1200-plus faculty who did not sign the letter, who attest that the health system today — under Melina and Craig’s leadership — is in the best shape it has ever been in, and that they have addressed changes that have needed to be made for more than two decades.”

A request to see some of these positive testimonials was not answered by press time.

Mr. Crutchfield, like Mr. Ryan, said that the letter writers were doing more harm than good.

“If a small cabal of people hiding behind anonymity can force outstanding leaders out of UVA, it will make it extremely difficult to recruit outstanding new physicians, nurses, technicians, and administrators,” he wrote.

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

Postoperative cognitive dysfunction (POCD) is a form of cognitive decline that involves a functional deterioration of activities of the nervous system, such as selective attention, vigilance, perception, learning, memory, executive function, verbal and language abilities, emotion, visuospatial and visuomotor skills. It occurs in the absence of cranial trauma or other brain injuries, and prevalence rates range from 36.6% in young adults to 42.4% in older adults, as a consequence of significant invasive procedures such as cardiac, noncardiac, and carotid surgeries that are lengthy and intensive.

Alzheimer’s disease (AD), the most common form of dementia, accounts for about two thirds of all cases of dementia globally. It is estimated that 41 million patients with dementia remain undiagnosed worldwide, and 25% of patients are diagnosed only when they are fully symptomatic. AD is a neurodegenerative disorder defined by neuropathologic changes, including beta-amyloid (Abeta) plaques composed of aggregated Abeta and neurofibrillary tangles containing aggregated tau proteins.

Patients with AD are unaware of their condition. Dementia, especially in its early stages, is often a hidden disease. Even when suspected, patients and families may believe that the symptoms are part of normal aging and may not report them to the doctor. In these patients, surgery may unmask subclinical dementia.

The complex correlation between POCD and AD has sparked debate following numerous anecdotal reports of how older adults undergoing surgical procedures may experience long-term cognitive decline with clinical characteristics such as those of patients with dementia. Despite advances in knowledge, it is still difficult to establish a priori how much surgery and anesthesia can increase the risk or accelerate the progression of a prodromal and asymptomatic AD condition (stages I-II) to clinically evident stage III AD. The current trend of an aging population poses a challenge for anesthesiology surgery because as the age of patients undergoing surgery increases, so does the likelihood of developing POCD.

Recent research in these fields has improved knowledge of the characteristics, epidemiology, risk factors, pathogenesis, and potential prevention strategies associated with POCD. It has improved the perspectives of future prevention and treatment.
 

Definition and Diagnostic Criteria

POCD, according to the cognitive impairment classification in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, is characterized by mild neurologic disturbance resulting from routine surgical procedures, excluding conditions such as deafness, dementia, or amnesia. The definition of POCD involves prolonged cognitive decline that can last for weeks, months, or even years. POCD may be confused with postoperative delirium, an acute and fluctuating disorder of consciousness that typically occurs within 3 days of surgery.

The diagnosis of POCD is based primarily on neurocognitive function scales. Widely used assessments include the Montreal Cognitive Assessment, the Wechsler Memory Scale, and the Mini-Mental State Examination.
 

Epidemiology

POCD is prevalent among patients undergoing cardiac or orthopedic surgery. In patients undergoing aortic-coronary bypass and cardiopulmonary bypass, 50%-70% develop POCD 1 week after surgery. In addition, 10%-30% experience long-term effects on cognitive function at 6 months after the procedure. In patients undergoing hip arthroplasty, 20%-50% exhibit POCD within 1 week of surgery, with 10%-14% still presenting it after 3 months.

Risk Factors

Age

POCD is typically observed in patients older than 65 years. However, after surgery, around 30% of younger patients and about 40% of older patients develop POCD at the time of hospital discharge. Specifically, 12.7% of older patients continue to have POCD 3 months after surgery, compared with 5% of younger patients.

Type of Surgery 

Hip and knee arthroplasty procedures entail a higher risk for POCD than general surgery. The same is true of cardiac surgery, especially aortic-coronary bypass and cardiopulmonary bypass.

Types of Anesthesia 

Initial assessments of postoperative cognitive function in cardiac surgery did not provide significant correlations between observed changes and the type of anesthesia because of the high number of confounding factors involved. A more recent meta-analysis of 28 randomized clinical trials concluded that the incidence of POCD is lower in surgeries using intravenous anesthesia with propofol than in those using inhalation anesthesia with isoflurane or sevoflurane.

Pain

Postoperative pain is a common issue, mainly resulting from substantial surgical trauma or potential wound infection. Patient-controlled postoperative analgesia independently increases the risk for POCD, compared with oral postoperative analgesia. Meta-analyses indicate that persistent pain can lead to a decline in patients’ cognitive abilities, attention, memory, and information processing.

Evolving Scenarios

Current research on POCD has deepened our understanding of its pathogenesis, implicating factors such as central nervous system inflammation, neuronal apoptosis, synaptic plasticity damage, abnormal tau protein modification, chronic pain, and mitochondrial metabolic disorders. Several neuroprotective drugs are currently under study, but none have shown consistent benefits for the prevention and treatment of POCD. The available evidence on the subject does not unambiguously guide the practicing physician. But neither does it exclude the importance of a careful assessment of POCD risk factors and the cognitive status of an older patient before surgery to provide useful information to the patient, family, and doctors when deciding on appropriate and shared procedures.

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Postoperative cognitive dysfunction (POCD) is a form of cognitive decline that involves a functional deterioration of activities of the nervous system, such as selective attention, vigilance, perception, learning, memory, executive function, verbal and language abilities, emotion, visuospatial and visuomotor skills. It occurs in the absence of cranial trauma or other brain injuries, and prevalence rates range from 36.6% in young adults to 42.4% in older adults, as a consequence of significant invasive procedures such as cardiac, noncardiac, and carotid surgeries that are lengthy and intensive.

Alzheimer’s disease (AD), the most common form of dementia, accounts for about two thirds of all cases of dementia globally. It is estimated that 41 million patients with dementia remain undiagnosed worldwide, and 25% of patients are diagnosed only when they are fully symptomatic. AD is a neurodegenerative disorder defined by neuropathologic changes, including beta-amyloid (Abeta) plaques composed of aggregated Abeta and neurofibrillary tangles containing aggregated tau proteins.

Patients with AD are unaware of their condition. Dementia, especially in its early stages, is often a hidden disease. Even when suspected, patients and families may believe that the symptoms are part of normal aging and may not report them to the doctor. In these patients, surgery may unmask subclinical dementia.

The complex correlation between POCD and AD has sparked debate following numerous anecdotal reports of how older adults undergoing surgical procedures may experience long-term cognitive decline with clinical characteristics such as those of patients with dementia. Despite advances in knowledge, it is still difficult to establish a priori how much surgery and anesthesia can increase the risk or accelerate the progression of a prodromal and asymptomatic AD condition (stages I-II) to clinically evident stage III AD. The current trend of an aging population poses a challenge for anesthesiology surgery because as the age of patients undergoing surgery increases, so does the likelihood of developing POCD.

Recent research in these fields has improved knowledge of the characteristics, epidemiology, risk factors, pathogenesis, and potential prevention strategies associated with POCD. It has improved the perspectives of future prevention and treatment.
 

Definition and Diagnostic Criteria

POCD, according to the cognitive impairment classification in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, is characterized by mild neurologic disturbance resulting from routine surgical procedures, excluding conditions such as deafness, dementia, or amnesia. The definition of POCD involves prolonged cognitive decline that can last for weeks, months, or even years. POCD may be confused with postoperative delirium, an acute and fluctuating disorder of consciousness that typically occurs within 3 days of surgery.

The diagnosis of POCD is based primarily on neurocognitive function scales. Widely used assessments include the Montreal Cognitive Assessment, the Wechsler Memory Scale, and the Mini-Mental State Examination.
 

Epidemiology

POCD is prevalent among patients undergoing cardiac or orthopedic surgery. In patients undergoing aortic-coronary bypass and cardiopulmonary bypass, 50%-70% develop POCD 1 week after surgery. In addition, 10%-30% experience long-term effects on cognitive function at 6 months after the procedure. In patients undergoing hip arthroplasty, 20%-50% exhibit POCD within 1 week of surgery, with 10%-14% still presenting it after 3 months.

Risk Factors

Age

POCD is typically observed in patients older than 65 years. However, after surgery, around 30% of younger patients and about 40% of older patients develop POCD at the time of hospital discharge. Specifically, 12.7% of older patients continue to have POCD 3 months after surgery, compared with 5% of younger patients.

Type of Surgery 

Hip and knee arthroplasty procedures entail a higher risk for POCD than general surgery. The same is true of cardiac surgery, especially aortic-coronary bypass and cardiopulmonary bypass.

Types of Anesthesia 

Initial assessments of postoperative cognitive function in cardiac surgery did not provide significant correlations between observed changes and the type of anesthesia because of the high number of confounding factors involved. A more recent meta-analysis of 28 randomized clinical trials concluded that the incidence of POCD is lower in surgeries using intravenous anesthesia with propofol than in those using inhalation anesthesia with isoflurane or sevoflurane.

Pain

Postoperative pain is a common issue, mainly resulting from substantial surgical trauma or potential wound infection. Patient-controlled postoperative analgesia independently increases the risk for POCD, compared with oral postoperative analgesia. Meta-analyses indicate that persistent pain can lead to a decline in patients’ cognitive abilities, attention, memory, and information processing.

Evolving Scenarios

Current research on POCD has deepened our understanding of its pathogenesis, implicating factors such as central nervous system inflammation, neuronal apoptosis, synaptic plasticity damage, abnormal tau protein modification, chronic pain, and mitochondrial metabolic disorders. Several neuroprotective drugs are currently under study, but none have shown consistent benefits for the prevention and treatment of POCD. The available evidence on the subject does not unambiguously guide the practicing physician. But neither does it exclude the importance of a careful assessment of POCD risk factors and the cognitive status of an older patient before surgery to provide useful information to the patient, family, and doctors when deciding on appropriate and shared procedures.

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

Postoperative cognitive dysfunction (POCD) is a form of cognitive decline that involves a functional deterioration of activities of the nervous system, such as selective attention, vigilance, perception, learning, memory, executive function, verbal and language abilities, emotion, visuospatial and visuomotor skills. It occurs in the absence of cranial trauma or other brain injuries, and prevalence rates range from 36.6% in young adults to 42.4% in older adults, as a consequence of significant invasive procedures such as cardiac, noncardiac, and carotid surgeries that are lengthy and intensive.

Alzheimer’s disease (AD), the most common form of dementia, accounts for about two thirds of all cases of dementia globally. It is estimated that 41 million patients with dementia remain undiagnosed worldwide, and 25% of patients are diagnosed only when they are fully symptomatic. AD is a neurodegenerative disorder defined by neuropathologic changes, including beta-amyloid (Abeta) plaques composed of aggregated Abeta and neurofibrillary tangles containing aggregated tau proteins.

Patients with AD are unaware of their condition. Dementia, especially in its early stages, is often a hidden disease. Even when suspected, patients and families may believe that the symptoms are part of normal aging and may not report them to the doctor. In these patients, surgery may unmask subclinical dementia.

The complex correlation between POCD and AD has sparked debate following numerous anecdotal reports of how older adults undergoing surgical procedures may experience long-term cognitive decline with clinical characteristics such as those of patients with dementia. Despite advances in knowledge, it is still difficult to establish a priori how much surgery and anesthesia can increase the risk or accelerate the progression of a prodromal and asymptomatic AD condition (stages I-II) to clinically evident stage III AD. The current trend of an aging population poses a challenge for anesthesiology surgery because as the age of patients undergoing surgery increases, so does the likelihood of developing POCD.

Recent research in these fields has improved knowledge of the characteristics, epidemiology, risk factors, pathogenesis, and potential prevention strategies associated with POCD. It has improved the perspectives of future prevention and treatment.
 

Definition and Diagnostic Criteria

POCD, according to the cognitive impairment classification in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, is characterized by mild neurologic disturbance resulting from routine surgical procedures, excluding conditions such as deafness, dementia, or amnesia. The definition of POCD involves prolonged cognitive decline that can last for weeks, months, or even years. POCD may be confused with postoperative delirium, an acute and fluctuating disorder of consciousness that typically occurs within 3 days of surgery.

The diagnosis of POCD is based primarily on neurocognitive function scales. Widely used assessments include the Montreal Cognitive Assessment, the Wechsler Memory Scale, and the Mini-Mental State Examination.
 

Epidemiology

POCD is prevalent among patients undergoing cardiac or orthopedic surgery. In patients undergoing aortic-coronary bypass and cardiopulmonary bypass, 50%-70% develop POCD 1 week after surgery. In addition, 10%-30% experience long-term effects on cognitive function at 6 months after the procedure. In patients undergoing hip arthroplasty, 20%-50% exhibit POCD within 1 week of surgery, with 10%-14% still presenting it after 3 months.

Risk Factors

Age

POCD is typically observed in patients older than 65 years. However, after surgery, around 30% of younger patients and about 40% of older patients develop POCD at the time of hospital discharge. Specifically, 12.7% of older patients continue to have POCD 3 months after surgery, compared with 5% of younger patients.

Type of Surgery 

Hip and knee arthroplasty procedures entail a higher risk for POCD than general surgery. The same is true of cardiac surgery, especially aortic-coronary bypass and cardiopulmonary bypass.

Types of Anesthesia 

Initial assessments of postoperative cognitive function in cardiac surgery did not provide significant correlations between observed changes and the type of anesthesia because of the high number of confounding factors involved. A more recent meta-analysis of 28 randomized clinical trials concluded that the incidence of POCD is lower in surgeries using intravenous anesthesia with propofol than in those using inhalation anesthesia with isoflurane or sevoflurane.

Pain

Postoperative pain is a common issue, mainly resulting from substantial surgical trauma or potential wound infection. Patient-controlled postoperative analgesia independently increases the risk for POCD, compared with oral postoperative analgesia. Meta-analyses indicate that persistent pain can lead to a decline in patients’ cognitive abilities, attention, memory, and information processing.

Evolving Scenarios

Current research on POCD has deepened our understanding of its pathogenesis, implicating factors such as central nervous system inflammation, neuronal apoptosis, synaptic plasticity damage, abnormal tau protein modification, chronic pain, and mitochondrial metabolic disorders. Several neuroprotective drugs are currently under study, but none have shown consistent benefits for the prevention and treatment of POCD. The available evidence on the subject does not unambiguously guide the practicing physician. But neither does it exclude the importance of a careful assessment of POCD risk factors and the cognitive status of an older patient before surgery to provide useful information to the patient, family, and doctors when deciding on appropriate and shared procedures.

This story was translated from Univadis Italy, which is part of the Medscape professional network, using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

While she cared deeply about her work, Melissa Adams*, a family nurse practitioner (NP) in Madison, Alabama, was being frequently triple-booked, didn’t feel respected by her office manager, and started to worry about becoming burned out. When she sought help, “the administration was tone-deaf,” she said. “When I asked about what I could do to prevent burnout, they sent me an article about it. It was clear to me that asking for respite from triple-booking and asking to be respected by my office manager wasn’t being heard ... so I thought, ‘how do I fly under the radar and get by with what I can?’ ” That meant focusing on patient care and refusing to take on additional responsibilities, like training new hires or working with students.

“You’re overworked and underpaid, and you start giving less and less of yourself,” Ms. Adams said in an interview.

Quiet quitting, defined as performing only the assigned tasks of the job without making any extra effort or going the proverbial extra mile, has gained attention in the press in recent years. A Gallup poll found that about 50% of the workforce were “quiet quitters” or disengaged.

It may be even more prevalent in healthcare, where a recent survey found that 57% of frontline medical staff, including NPs and physician assistants (PAs), report being disengaged at work.
 

The Causes of Quiet Quitting

Potential causes of quiet quitting among PAs and NPs include:

• Unrealistic care expectations. They ask you to give your all to patients, handle everything, and do it all in under 15 minutes since that’s how much time the appointment allows, Ms. Adams said.
• Lack of trust or respect. Physicians don’t always respect the role that PAs and NPs play in a practice.
• Dissatisfaction with leadership or administration. There’s often a feeling that the PA or NP isn’t “heard” or appreciated.
• Dissatisfaction with pay or working conditions.
• Moral injury. “There’s no way to escape being morally injured when you work with an at-risk population,” said Ms. Adams. “You may see someone who has 20-24 determinants of health, and you’re expected to schlep them through in 8 minutes — you know you’re not able to do what they need.”

What Quiet Quitting Looks Like

Terri Smith*, an NP at an academic medical center outpatient clinic in rural Vermont, said that, while she feels appreciated by her patients and her team, there’s poor communication from the administration, which has caused her to quietly quit.

“I stopped saying ‘yes’ to all the normal committee work and the extra stuff that used to add a lot to my professional enjoyment,” she said. “The last couple of years, my whole motto is to nod and smile when administration says to do something — to put your head down and take care of your patients.”

While the term “quiet quitting” may be new, the issue is not, said Bridget Roberts, PhD, a healthcare executive who ran a large physician’s group of 100 healthcare providers in Jacksonville, Florida, for a decade. “Quiet quitting is a fancy title for employees who are completely disengaged,” said Dr. Roberts. “When they’re on the way out, they ‘check the box’. That’s not a new thing.”

“Typically, the first thing you see is a lot of frustration in that they aren’t able to complete the tasks they have at hand,” said Rebecca Day, PMNHP, a doctoral-educated NP and director of nursing practice at a Federally Qualified Health Center in Corbin, Kentucky. “Staff may be overworked and not have enough time to do what’s required of them with patient care as well as the paperwork required behind the scenes. It [quiet quitting] is doing just enough to get by, but shortcutting as much as they can to try to save some time.”
 

Addressing Quiet Quitting

Those kinds of shortcuts may affect patients, admits Ms. Smith. “I do think it starts to seep into patient care,” she said. “And that really doesn’t feel good ... at our institution, I’m not just an NP — I’m the nurse, the doctor, the secretary — I’m everybody, and for the last year, almost every single day in clinic, I’m apologizing [to a patient] because we can’t do something.”

Watching for this frustration can help alert administrators to NPs and PAs who may be “checking out” at work. Open lines of communication can help you address the issue. “Ask questions like ‘What could we do differently to make your day easier?’” said Dr. Roberts. Understanding the day-to-day issues NPs and PAs face at work can help in developing a plan to address disengagement.

When Dr. Day sees quiet quitting at her practice, she talks with the advance practice provider about what’s causing the issue. “’Are you overworked? Are you understaffed? Are there problems at home? Do you feel you’re receiving inadequate pay?’ ” she said. “The first thing to do is address that and find mutual ground on the issues…deal with the person as a person and then go back and deal with the person as an employee. If your staff isn’t happy, your clinic isn’t going to be productive.”

Finally, while reasons for quiet quitting may vary, cultivating a collaborative atmosphere where NPs and PAs feel appreciated and valued can help reduce the risk for quiet quitting. “Get to know your advanced practice providers,” said Ms. Adams. “Understand their strengths and what they’re about. It’s not an ‘us vs them’ ... there is a lot more commonality when we approach it that way.” Respect for the integral role that NPs and PAs play in your practice can help reduce the risk for quiet quitting — and help provide better patient care.

*Names have been changed.

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

While she cared deeply about her work, Melissa Adams*, a family nurse practitioner (NP) in Madison, Alabama, was being frequently triple-booked, didn’t feel respected by her office manager, and started to worry about becoming burned out. When she sought help, “the administration was tone-deaf,” she said. “When I asked about what I could do to prevent burnout, they sent me an article about it. It was clear to me that asking for respite from triple-booking and asking to be respected by my office manager wasn’t being heard ... so I thought, ‘how do I fly under the radar and get by with what I can?’ ” That meant focusing on patient care and refusing to take on additional responsibilities, like training new hires or working with students.

“You’re overworked and underpaid, and you start giving less and less of yourself,” Ms. Adams said in an interview.

Quiet quitting, defined as performing only the assigned tasks of the job without making any extra effort or going the proverbial extra mile, has gained attention in the press in recent years. A Gallup poll found that about 50% of the workforce were “quiet quitters” or disengaged.

It may be even more prevalent in healthcare, where a recent survey found that 57% of frontline medical staff, including NPs and physician assistants (PAs), report being disengaged at work.
 

The Causes of Quiet Quitting

Potential causes of quiet quitting among PAs and NPs include:

• Unrealistic care expectations. They ask you to give your all to patients, handle everything, and do it all in under 15 minutes since that’s how much time the appointment allows, Ms. Adams said.
• Lack of trust or respect. Physicians don’t always respect the role that PAs and NPs play in a practice.
• Dissatisfaction with leadership or administration. There’s often a feeling that the PA or NP isn’t “heard” or appreciated.
• Dissatisfaction with pay or working conditions.
• Moral injury. “There’s no way to escape being morally injured when you work with an at-risk population,” said Ms. Adams. “You may see someone who has 20-24 determinants of health, and you’re expected to schlep them through in 8 minutes — you know you’re not able to do what they need.”

What Quiet Quitting Looks Like

Terri Smith*, an NP at an academic medical center outpatient clinic in rural Vermont, said that, while she feels appreciated by her patients and her team, there’s poor communication from the administration, which has caused her to quietly quit.

“I stopped saying ‘yes’ to all the normal committee work and the extra stuff that used to add a lot to my professional enjoyment,” she said. “The last couple of years, my whole motto is to nod and smile when administration says to do something — to put your head down and take care of your patients.”

While the term “quiet quitting” may be new, the issue is not, said Bridget Roberts, PhD, a healthcare executive who ran a large physician’s group of 100 healthcare providers in Jacksonville, Florida, for a decade. “Quiet quitting is a fancy title for employees who are completely disengaged,” said Dr. Roberts. “When they’re on the way out, they ‘check the box’. That’s not a new thing.”

“Typically, the first thing you see is a lot of frustration in that they aren’t able to complete the tasks they have at hand,” said Rebecca Day, PMNHP, a doctoral-educated NP and director of nursing practice at a Federally Qualified Health Center in Corbin, Kentucky. “Staff may be overworked and not have enough time to do what’s required of them with patient care as well as the paperwork required behind the scenes. It [quiet quitting] is doing just enough to get by, but shortcutting as much as they can to try to save some time.”
 

Addressing Quiet Quitting

Those kinds of shortcuts may affect patients, admits Ms. Smith. “I do think it starts to seep into patient care,” she said. “And that really doesn’t feel good ... at our institution, I’m not just an NP — I’m the nurse, the doctor, the secretary — I’m everybody, and for the last year, almost every single day in clinic, I’m apologizing [to a patient] because we can’t do something.”

Watching for this frustration can help alert administrators to NPs and PAs who may be “checking out” at work. Open lines of communication can help you address the issue. “Ask questions like ‘What could we do differently to make your day easier?’” said Dr. Roberts. Understanding the day-to-day issues NPs and PAs face at work can help in developing a plan to address disengagement.

When Dr. Day sees quiet quitting at her practice, she talks with the advance practice provider about what’s causing the issue. “’Are you overworked? Are you understaffed? Are there problems at home? Do you feel you’re receiving inadequate pay?’ ” she said. “The first thing to do is address that and find mutual ground on the issues…deal with the person as a person and then go back and deal with the person as an employee. If your staff isn’t happy, your clinic isn’t going to be productive.”

Finally, while reasons for quiet quitting may vary, cultivating a collaborative atmosphere where NPs and PAs feel appreciated and valued can help reduce the risk for quiet quitting. “Get to know your advanced practice providers,” said Ms. Adams. “Understand their strengths and what they’re about. It’s not an ‘us vs them’ ... there is a lot more commonality when we approach it that way.” Respect for the integral role that NPs and PAs play in your practice can help reduce the risk for quiet quitting — and help provide better patient care.

*Names have been changed.

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

While she cared deeply about her work, Melissa Adams*, a family nurse practitioner (NP) in Madison, Alabama, was being frequently triple-booked, didn’t feel respected by her office manager, and started to worry about becoming burned out. When she sought help, “the administration was tone-deaf,” she said. “When I asked about what I could do to prevent burnout, they sent me an article about it. It was clear to me that asking for respite from triple-booking and asking to be respected by my office manager wasn’t being heard ... so I thought, ‘how do I fly under the radar and get by with what I can?’ ” That meant focusing on patient care and refusing to take on additional responsibilities, like training new hires or working with students.

“You’re overworked and underpaid, and you start giving less and less of yourself,” Ms. Adams said in an interview.

Quiet quitting, defined as performing only the assigned tasks of the job without making any extra effort or going the proverbial extra mile, has gained attention in the press in recent years. A Gallup poll found that about 50% of the workforce were “quiet quitters” or disengaged.

It may be even more prevalent in healthcare, where a recent survey found that 57% of frontline medical staff, including NPs and physician assistants (PAs), report being disengaged at work.
 

The Causes of Quiet Quitting

Potential causes of quiet quitting among PAs and NPs include:

• Unrealistic care expectations. They ask you to give your all to patients, handle everything, and do it all in under 15 minutes since that’s how much time the appointment allows, Ms. Adams said.
• Lack of trust or respect. Physicians don’t always respect the role that PAs and NPs play in a practice.
• Dissatisfaction with leadership or administration. There’s often a feeling that the PA or NP isn’t “heard” or appreciated.
• Dissatisfaction with pay or working conditions.
• Moral injury. “There’s no way to escape being morally injured when you work with an at-risk population,” said Ms. Adams. “You may see someone who has 20-24 determinants of health, and you’re expected to schlep them through in 8 minutes — you know you’re not able to do what they need.”

What Quiet Quitting Looks Like

Terri Smith*, an NP at an academic medical center outpatient clinic in rural Vermont, said that, while she feels appreciated by her patients and her team, there’s poor communication from the administration, which has caused her to quietly quit.

“I stopped saying ‘yes’ to all the normal committee work and the extra stuff that used to add a lot to my professional enjoyment,” she said. “The last couple of years, my whole motto is to nod and smile when administration says to do something — to put your head down and take care of your patients.”

While the term “quiet quitting” may be new, the issue is not, said Bridget Roberts, PhD, a healthcare executive who ran a large physician’s group of 100 healthcare providers in Jacksonville, Florida, for a decade. “Quiet quitting is a fancy title for employees who are completely disengaged,” said Dr. Roberts. “When they’re on the way out, they ‘check the box’. That’s not a new thing.”

“Typically, the first thing you see is a lot of frustration in that they aren’t able to complete the tasks they have at hand,” said Rebecca Day, PMNHP, a doctoral-educated NP and director of nursing practice at a Federally Qualified Health Center in Corbin, Kentucky. “Staff may be overworked and not have enough time to do what’s required of them with patient care as well as the paperwork required behind the scenes. It [quiet quitting] is doing just enough to get by, but shortcutting as much as they can to try to save some time.”
 

Addressing Quiet Quitting

Those kinds of shortcuts may affect patients, admits Ms. Smith. “I do think it starts to seep into patient care,” she said. “And that really doesn’t feel good ... at our institution, I’m not just an NP — I’m the nurse, the doctor, the secretary — I’m everybody, and for the last year, almost every single day in clinic, I’m apologizing [to a patient] because we can’t do something.”

Watching for this frustration can help alert administrators to NPs and PAs who may be “checking out” at work. Open lines of communication can help you address the issue. “Ask questions like ‘What could we do differently to make your day easier?’” said Dr. Roberts. Understanding the day-to-day issues NPs and PAs face at work can help in developing a plan to address disengagement.

When Dr. Day sees quiet quitting at her practice, she talks with the advance practice provider about what’s causing the issue. “’Are you overworked? Are you understaffed? Are there problems at home? Do you feel you’re receiving inadequate pay?’ ” she said. “The first thing to do is address that and find mutual ground on the issues…deal with the person as a person and then go back and deal with the person as an employee. If your staff isn’t happy, your clinic isn’t going to be productive.”

Finally, while reasons for quiet quitting may vary, cultivating a collaborative atmosphere where NPs and PAs feel appreciated and valued can help reduce the risk for quiet quitting. “Get to know your advanced practice providers,” said Ms. Adams. “Understand their strengths and what they’re about. It’s not an ‘us vs them’ ... there is a lot more commonality when we approach it that way.” Respect for the integral role that NPs and PAs play in your practice can help reduce the risk for quiet quitting — and help provide better patient care.

*Names have been changed.

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

A more definitive picture of how some hormones and moisturizers can offer relief to women experiencing vaginal dryness or painful intercourse during menopause was published in a recent systematic review in Annals of Internal Medicine. However, researchers noted scant long-term data on the safety of these products.

Vaginal dryness and challenges with intercourse and urination are among the symptoms of genitourinary syndrome of menopause (GSM). Hormones such as vaginal estrogen, vaginal dehydroepiandrosterone (DHEA), or oral ospemifene are common treatments, along with moisturizers.

“The main finding is that commonly used therapies are likely to be effective for the common symptoms people have for GSM,” particularly vaginal dryness and painful intercourse, said Elisheva Danan, MD, MPH, a primary care physician and health services researcher at the Minneapolis VA Health Care System and assistant professor of medicine at the University of Minnesota Medical School in Minneapolis, who was the lead study author.

Many women might recognize hot flashes as connected to menopause, Dr. Danan said, as these tend to occur with the cessation of the menstrual cycle. However, genitourinary effects may not manifest until a few years later and worsen over time, when the connection to menopause is less clear.

“Women might not bring it up or think there’s a treatment that can work,” Dr. Danan said.

The systematic review may provide clinicians with more evidence of specific treatments to recommend. However, most of the trials included in the analysis studied treatment periods of 12 weeks or less, so the safety of long-term use is unclear.

“One question that hasn’t been answered yet in clinical trials is whether there could be a risk of uterine cancer with extended use of any of these treatments,” Dr. Danan said, because vaginal estrogen or ospemifene could stimulate growth of the uterine lining.

The studies Dr. Danan and colleagues found showed no increased risk for uterine cancer, but Dr, Danan noted that the maximum follow-up was 1 year, and study participants had a low risk for cancer to begin with. She advised that clinicians closely monitor women with risk factors if they use hormones to treat GSM indefinitely.
 

Forty-Six Randomized Controlled Trials, Many Open Questions

Dr. Danan and her colleagues conducted a systematic review of 46 randomized controlled trials, meant to inform an upcoming clinical practice guideline from the American Urological Association on treatment of GSM. Dr. Danan’s work was funded by the Patient-Centered Outcomes Research Institute.

Studies evaluated vaginal estrogen (22), other hormones such as vaginal oxytocin or vaginal testosterone (16), vaginal moisturizers (4), and multiple interventions (4).

Included trials lasted at least 8 weeks and included at least 20 postmenopausal women; most treatments lasted 12 weeks or less. Studies used varying definitions of GSM, and no head-to-head trials of different treatments were found.

Researchers used the Core Outcomes in Menopause (COMMA) framework, developed in 2021 to standardize outcomes research in menopause care and to understand treatment effectiveness. They applied this framework retroactively, as almost all the studies in the review were written before the COMMA framework existed.

Hormonal treatments were associated with reduced pain during intercourse and decreased vaginal dryness; moisturizers were linked to reduced dryness.

Vaginal estrogen did not reduce pain during intercourse as consistently as DHEA or oral ospemifene, per the review. Dr. Danan and her coauthors said this could be because the DHEA and ospemifene trials were larger and more uniformly conducted than those for vaginal estrogen. Even so, vaginal estrogen outperformed placebo at reducing painful intercourse.

But given the short timeframe of most studies and the differing definitions of GSM symptoms, Dr. Danan cautioned that all their conclusions have low certainty.

Few studies examined whether these treatments reduced vaginal itchiness or difficulties with urination. And the authors found no evidence for the benefit of oral DHEA, raloxifene, bazedoxifene, vaginal oxytocin, or vaginal testosterone for GSM treatment.

In an accompanying report, the researchers found no evidence for the benefits of treatments such as vaginal testosterone or vaginal laser therapy.

Stephanie Faubion, MD, MBA, medical director for the North American Menopause Society and director of the Mayo Clinic Center for Women’s Health, Rochester, Minnesota, wrote an accompanying editorial noting that the patients represented in the GSM treatment clinical trials were not diverse and that the exclusion criteria generally meant that women with cardiovascular challenges or cancer were not included.

“That’s one of the biggest questions — what is the safety in women with cardiovascular risk factors or history of a blood clot or history of a cancer? The data is just completely absent there,” Dr. Faubion said.
 

The Connection Between GSM and Urinary Tract Infections (UTIs)

“Genitourinary syndrome of menopause is not just a little bit of vaginal dryness that can be cured with moisturizers and lubricants, but the syndrome can lead to recurrent urinary tract infections, which are extremely harmful and dangerous to our patients and cost the healthcare system a lot of money,” said Rachel Rubin, MD, a urologist and sexual medicine specialist in Bethesda, Maryland.

Lubricants and moisturizers can all help with the symptoms of GSM, at least in the short term, Dr. Rubin noted. But only hormones can get to the root of the problem and reduce the risk for a recurrent UTI (rUTI), Dr. Rubin added, noting that the American Urological Association recommends the use of vaginal estrogen to reduce the risk for rUTIs and is developing the clinical practice guidelines for GSM.

Dr. Danan’s review did not address the association between UTIs and GSM, but Dr. Rubin said she sees the link in clinical practice.

“Recurrent urinary tract infections occur because of GSM, because of the lack of hormones to the tissue,” sometimes when a woman is in her 60s or 70s and thinks menopause is long over, Dr. Rubin said.

The reality is that women may need to take hormones for decades to reduce the risk for UTIs, another reason longer-term safety data are needed, Dr. Rubin said.

Dr. Danan, Dr. Faubion, and Dr. Rubin reported no relevant financial relationships.

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

A more definitive picture of how some hormones and moisturizers can offer relief to women experiencing vaginal dryness or painful intercourse during menopause was published in a recent systematic review in Annals of Internal Medicine. However, researchers noted scant long-term data on the safety of these products.

Vaginal dryness and challenges with intercourse and urination are among the symptoms of genitourinary syndrome of menopause (GSM). Hormones such as vaginal estrogen, vaginal dehydroepiandrosterone (DHEA), or oral ospemifene are common treatments, along with moisturizers.

“The main finding is that commonly used therapies are likely to be effective for the common symptoms people have for GSM,” particularly vaginal dryness and painful intercourse, said Elisheva Danan, MD, MPH, a primary care physician and health services researcher at the Minneapolis VA Health Care System and assistant professor of medicine at the University of Minnesota Medical School in Minneapolis, who was the lead study author.

Many women might recognize hot flashes as connected to menopause, Dr. Danan said, as these tend to occur with the cessation of the menstrual cycle. However, genitourinary effects may not manifest until a few years later and worsen over time, when the connection to menopause is less clear.

“Women might not bring it up or think there’s a treatment that can work,” Dr. Danan said.

The systematic review may provide clinicians with more evidence of specific treatments to recommend. However, most of the trials included in the analysis studied treatment periods of 12 weeks or less, so the safety of long-term use is unclear.

“One question that hasn’t been answered yet in clinical trials is whether there could be a risk of uterine cancer with extended use of any of these treatments,” Dr. Danan said, because vaginal estrogen or ospemifene could stimulate growth of the uterine lining.

The studies Dr. Danan and colleagues found showed no increased risk for uterine cancer, but Dr, Danan noted that the maximum follow-up was 1 year, and study participants had a low risk for cancer to begin with. She advised that clinicians closely monitor women with risk factors if they use hormones to treat GSM indefinitely.
 

Forty-Six Randomized Controlled Trials, Many Open Questions

Dr. Danan and her colleagues conducted a systematic review of 46 randomized controlled trials, meant to inform an upcoming clinical practice guideline from the American Urological Association on treatment of GSM. Dr. Danan’s work was funded by the Patient-Centered Outcomes Research Institute.

Studies evaluated vaginal estrogen (22), other hormones such as vaginal oxytocin or vaginal testosterone (16), vaginal moisturizers (4), and multiple interventions (4).

Included trials lasted at least 8 weeks and included at least 20 postmenopausal women; most treatments lasted 12 weeks or less. Studies used varying definitions of GSM, and no head-to-head trials of different treatments were found.

Researchers used the Core Outcomes in Menopause (COMMA) framework, developed in 2021 to standardize outcomes research in menopause care and to understand treatment effectiveness. They applied this framework retroactively, as almost all the studies in the review were written before the COMMA framework existed.

Hormonal treatments were associated with reduced pain during intercourse and decreased vaginal dryness; moisturizers were linked to reduced dryness.

Vaginal estrogen did not reduce pain during intercourse as consistently as DHEA or oral ospemifene, per the review. Dr. Danan and her coauthors said this could be because the DHEA and ospemifene trials were larger and more uniformly conducted than those for vaginal estrogen. Even so, vaginal estrogen outperformed placebo at reducing painful intercourse.

But given the short timeframe of most studies and the differing definitions of GSM symptoms, Dr. Danan cautioned that all their conclusions have low certainty.

Few studies examined whether these treatments reduced vaginal itchiness or difficulties with urination. And the authors found no evidence for the benefit of oral DHEA, raloxifene, bazedoxifene, vaginal oxytocin, or vaginal testosterone for GSM treatment.

In an accompanying report, the researchers found no evidence for the benefits of treatments such as vaginal testosterone or vaginal laser therapy.

Stephanie Faubion, MD, MBA, medical director for the North American Menopause Society and director of the Mayo Clinic Center for Women’s Health, Rochester, Minnesota, wrote an accompanying editorial noting that the patients represented in the GSM treatment clinical trials were not diverse and that the exclusion criteria generally meant that women with cardiovascular challenges or cancer were not included.

“That’s one of the biggest questions — what is the safety in women with cardiovascular risk factors or history of a blood clot or history of a cancer? The data is just completely absent there,” Dr. Faubion said.
 

The Connection Between GSM and Urinary Tract Infections (UTIs)

“Genitourinary syndrome of menopause is not just a little bit of vaginal dryness that can be cured with moisturizers and lubricants, but the syndrome can lead to recurrent urinary tract infections, which are extremely harmful and dangerous to our patients and cost the healthcare system a lot of money,” said Rachel Rubin, MD, a urologist and sexual medicine specialist in Bethesda, Maryland.

Lubricants and moisturizers can all help with the symptoms of GSM, at least in the short term, Dr. Rubin noted. But only hormones can get to the root of the problem and reduce the risk for a recurrent UTI (rUTI), Dr. Rubin added, noting that the American Urological Association recommends the use of vaginal estrogen to reduce the risk for rUTIs and is developing the clinical practice guidelines for GSM.

Dr. Danan’s review did not address the association between UTIs and GSM, but Dr. Rubin said she sees the link in clinical practice.

“Recurrent urinary tract infections occur because of GSM, because of the lack of hormones to the tissue,” sometimes when a woman is in her 60s or 70s and thinks menopause is long over, Dr. Rubin said.

The reality is that women may need to take hormones for decades to reduce the risk for UTIs, another reason longer-term safety data are needed, Dr. Rubin said.

Dr. Danan, Dr. Faubion, and Dr. Rubin reported no relevant financial relationships.

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

A more definitive picture of how some hormones and moisturizers can offer relief to women experiencing vaginal dryness or painful intercourse during menopause was published in a recent systematic review in Annals of Internal Medicine. However, researchers noted scant long-term data on the safety of these products.

Vaginal dryness and challenges with intercourse and urination are among the symptoms of genitourinary syndrome of menopause (GSM). Hormones such as vaginal estrogen, vaginal dehydroepiandrosterone (DHEA), or oral ospemifene are common treatments, along with moisturizers.

“The main finding is that commonly used therapies are likely to be effective for the common symptoms people have for GSM,” particularly vaginal dryness and painful intercourse, said Elisheva Danan, MD, MPH, a primary care physician and health services researcher at the Minneapolis VA Health Care System and assistant professor of medicine at the University of Minnesota Medical School in Minneapolis, who was the lead study author.

Many women might recognize hot flashes as connected to menopause, Dr. Danan said, as these tend to occur with the cessation of the menstrual cycle. However, genitourinary effects may not manifest until a few years later and worsen over time, when the connection to menopause is less clear.

“Women might not bring it up or think there’s a treatment that can work,” Dr. Danan said.

The systematic review may provide clinicians with more evidence of specific treatments to recommend. However, most of the trials included in the analysis studied treatment periods of 12 weeks or less, so the safety of long-term use is unclear.

“One question that hasn’t been answered yet in clinical trials is whether there could be a risk of uterine cancer with extended use of any of these treatments,” Dr. Danan said, because vaginal estrogen or ospemifene could stimulate growth of the uterine lining.

The studies Dr. Danan and colleagues found showed no increased risk for uterine cancer, but Dr, Danan noted that the maximum follow-up was 1 year, and study participants had a low risk for cancer to begin with. She advised that clinicians closely monitor women with risk factors if they use hormones to treat GSM indefinitely.
 

Forty-Six Randomized Controlled Trials, Many Open Questions

Dr. Danan and her colleagues conducted a systematic review of 46 randomized controlled trials, meant to inform an upcoming clinical practice guideline from the American Urological Association on treatment of GSM. Dr. Danan’s work was funded by the Patient-Centered Outcomes Research Institute.

Studies evaluated vaginal estrogen (22), other hormones such as vaginal oxytocin or vaginal testosterone (16), vaginal moisturizers (4), and multiple interventions (4).

Included trials lasted at least 8 weeks and included at least 20 postmenopausal women; most treatments lasted 12 weeks or less. Studies used varying definitions of GSM, and no head-to-head trials of different treatments were found.

Researchers used the Core Outcomes in Menopause (COMMA) framework, developed in 2021 to standardize outcomes research in menopause care and to understand treatment effectiveness. They applied this framework retroactively, as almost all the studies in the review were written before the COMMA framework existed.

Hormonal treatments were associated with reduced pain during intercourse and decreased vaginal dryness; moisturizers were linked to reduced dryness.

Vaginal estrogen did not reduce pain during intercourse as consistently as DHEA or oral ospemifene, per the review. Dr. Danan and her coauthors said this could be because the DHEA and ospemifene trials were larger and more uniformly conducted than those for vaginal estrogen. Even so, vaginal estrogen outperformed placebo at reducing painful intercourse.

But given the short timeframe of most studies and the differing definitions of GSM symptoms, Dr. Danan cautioned that all their conclusions have low certainty.

Few studies examined whether these treatments reduced vaginal itchiness or difficulties with urination. And the authors found no evidence for the benefit of oral DHEA, raloxifene, bazedoxifene, vaginal oxytocin, or vaginal testosterone for GSM treatment.

In an accompanying report, the researchers found no evidence for the benefits of treatments such as vaginal testosterone or vaginal laser therapy.

Stephanie Faubion, MD, MBA, medical director for the North American Menopause Society and director of the Mayo Clinic Center for Women’s Health, Rochester, Minnesota, wrote an accompanying editorial noting that the patients represented in the GSM treatment clinical trials were not diverse and that the exclusion criteria generally meant that women with cardiovascular challenges or cancer were not included.

“That’s one of the biggest questions — what is the safety in women with cardiovascular risk factors or history of a blood clot or history of a cancer? The data is just completely absent there,” Dr. Faubion said.
 

The Connection Between GSM and Urinary Tract Infections (UTIs)

“Genitourinary syndrome of menopause is not just a little bit of vaginal dryness that can be cured with moisturizers and lubricants, but the syndrome can lead to recurrent urinary tract infections, which are extremely harmful and dangerous to our patients and cost the healthcare system a lot of money,” said Rachel Rubin, MD, a urologist and sexual medicine specialist in Bethesda, Maryland.

Lubricants and moisturizers can all help with the symptoms of GSM, at least in the short term, Dr. Rubin noted. But only hormones can get to the root of the problem and reduce the risk for a recurrent UTI (rUTI), Dr. Rubin added, noting that the American Urological Association recommends the use of vaginal estrogen to reduce the risk for rUTIs and is developing the clinical practice guidelines for GSM.

Dr. Danan’s review did not address the association between UTIs and GSM, but Dr. Rubin said she sees the link in clinical practice.

“Recurrent urinary tract infections occur because of GSM, because of the lack of hormones to the tissue,” sometimes when a woman is in her 60s or 70s and thinks menopause is long over, Dr. Rubin said.

The reality is that women may need to take hormones for decades to reduce the risk for UTIs, another reason longer-term safety data are needed, Dr. Rubin said.

Dr. Danan, Dr. Faubion, and Dr. Rubin reported no relevant financial relationships.

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

In a video posted to Reddit, Lucie Rosenthal’s face starts focused and uncertain, looking intently into the camera, before it happens.

She releases a succinct, croak-like belch.

Then, it’s wide-eyed surprise, followed by rollicking laughter. “I got it!” the Denver resident says after what was her second burp ever.

“It’s really rocking my mind that I am fully introducing a new bodily function at 26 years old,” Ms. Rosenthal later told KFF Health News while working remotely, because, as great as the burping was, it was now happening uncontrollably. “Sorry, excuse me. Oh, my god. That was a burp. Did you hear it?”

Ms. Rosenthal is among more than a thousand people who have received a procedure to help them burp since 2019 when an Illinois doctor first reported the steps of the intervention in a medical journal.

The inability to belch can cause bloating, pain, gurgling in the neck and chest, and excessive flatulence as built-up air seeks an alternate exit route. One Reddit user described the gurgling sound as an “alien trying to escape me,” and pain like a heart attack that goes away with a fart.

The procedure has spread, primarily thanks to increasingly loud rumblings in the bowels of Reddit. Membership in a subreddit for people with or interested in the condition has ballooned to about 31,000 people, to become one of the platform’s larger groups.

Since 2019, the condition has had an official name: retrograde cricopharyngeus dysfunction, also known as “abelchia” or “no-burp syndrome.” The syndrome is caused by a quirk in the muscle that acts as the gatekeeper to the esophagus, the roughly 10-inch-long muscular tube that moves food between the throat and the stomach.

The procedure to fix it involves a doctor injecting 50 to 100 units of Botox — more than twice the amount often used to smooth forehead wrinkles — into the upper cricopharyngeal muscle.

Michael King, MD, the physician who treated Rosenthal, said he hadn’t heard of the disorder until 2020, when a teenager, armed with a list of academic papers found on Reddit, asked him to do the procedure.

It wasn’t a stretch. Dr. King, a laryngologist with Peak ENT and Voice Center, had been injecting Botox in the same muscle to treat people having a hard time swallowing after a stroke.

Now he’s among doctors from Norway to Thailand listed on the subreddit, r/noburp, as offering the procedure. Other doctors, commenters have noted, have occasionally laughed at them or made them feel they were being melodramatic.

To be fair, doctors and researchers don’t understand why the same muscle that lets food move down won’t let air move up.

“It’s very odd,” Dr. King said.

Doctors also aren’t sure why many patients keep burping long after the Botox wears off after a few months. Robert Bastian, MD, a laryngologist outside of Chicago, named the condition and came up with the procedure. He estimates he and his colleagues have treated about 1,800 people, charging about $4,000 a pop.

“We hear that in Southern California it’s $25,000, in Seattle $16,000, in New York City $25,000,” Dr. Bastian said.

Because insurance companies viewed Botox charges as a “red flag,” he said, his patients now pay $650 to cover the medication so it can be excluded from the insurance claims.

The pioneering patient is Daryl Moody, a car technician who has worked at the same Toyota dealership in Houston for half his life. The 34-year-old said that by 2015 he had become “desperate” for relief. The bloating and gurgling wasn’t just a painful shadow over his day; it was cramping his new hobby: skydiving.

“I hadn’t done anything fun or interesting with my life,” he said.

That is, until he tried skydiving. But as he gained altitude on the way up, his stomach would inflate like a bag of chips on a flight.

“I went to 10 doctors,” he said. “Nobody seemed to believe me that this problem even existed.”

Then he stumbled upon a YouTube video by Bastian describing how Botox injections can fix some throat conditions. Moody asked if Bastian could try it to cure his burping problem. Dr. Bastian agreed.

Mr. Moody’s insurance considered it “experimental and unnecessary,” he recalled, so he had to pay about $2,700 out of pocket.

“This is honestly going to change everything,” he posted on his Facebook page in December 2015, about his trip to Illinois.

The year after his procedure, Mr. Moody helped break a national record for participating in the largest group of people to skydive together while wearing wingsuits, those getups that turn people into flying squirrels. He has jumped about 400 times now.

People have been plagued by this issue for at least a few millennia. Two thousand years ago, the Roman philosopher Pliny the Elder described a man named Pomponius who could not belch. And 840 years ago, Johannes de Hauvilla included the tidbit in a poem, writing, “The steaming face of Pomponius could find no relief by belching.”

It took a few more centuries for clinical examples to pop up. In the 1980s, a few case reports in the United States described people who couldn’t burp and had no memory of vomiting. One woman, doctors wrote, was “unable to voluntarily belch along with her childhood friends when this was a popular game.”

The patients were in a great deal of pain, though doctors couldn’t find anything wrong with their anatomy. But the doctors confirmed using a method called manometry that patients’ upper esophageal sphincters simply would not relax — not after a meal of a sandwich, glass of milk, and candy bar, nor after doctors used a catheter to squirt several ounces of air beneath the stubborn valve.

André Smout, MD, PhD, a gastroenterologist at the University of Amsterdam in the Netherlands, said he read those reports when they came out.

“But we never saw the condition, so we didn’t believe that it existed in real life,” he said.

Dr. Smout’s doubts persisted until he and colleagues studied a small group of patients a few years ago. The researchers gave eight patients with a reported inability to burp a “belch provocation” in the form of carbonated water, and used pressure sensors to observe how their throats moved. Indeed, the air stayed trapped. A Botox injection resolved their problems by giving them the ability to burp, or, to use an academic term, eructate.

“We had to admit that it really existed,” Dr. Smout said.

He wrote in Current Opinion in Gastroenterology that the syndrome “may not be as rare as thought hitherto.” He credits Reddit with alerting patients and medical professionals to its existence.

But he wonders how often the treatment might cause a placebo effect. He pointed to studies finding that with conditions such as irritable bowel syndrome, 40% or more of patients who receive placebo treatment feel their symptoms improve. Awareness is also growing about “cyberchondria,” when people search desperately online for answers to their ailments — putting them at risk of unnecessary treatment or further distress.

In Denver, Ms. Rosenthal, the new burper, is open to the idea that the placebo effect could be at play for her. But even if that’s the case, she feels much better.

“I felt perpetual nausea, and that has subsided a lot since I got the procedure done,” she said. So has the bloating and stomach pain. She can drink a beer at happy hour and not feel ill.

She’s pleased insurance covered the procedure, and she’s getting a handle on the involuntary burping. She cannot, however, burp the alphabet.

“Not yet,” she said.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

In a video posted to Reddit, Lucie Rosenthal’s face starts focused and uncertain, looking intently into the camera, before it happens.

She releases a succinct, croak-like belch.

Then, it’s wide-eyed surprise, followed by rollicking laughter. “I got it!” the Denver resident says after what was her second burp ever.

“It’s really rocking my mind that I am fully introducing a new bodily function at 26 years old,” Ms. Rosenthal later told KFF Health News while working remotely, because, as great as the burping was, it was now happening uncontrollably. “Sorry, excuse me. Oh, my god. That was a burp. Did you hear it?”

Ms. Rosenthal is among more than a thousand people who have received a procedure to help them burp since 2019 when an Illinois doctor first reported the steps of the intervention in a medical journal.

The inability to belch can cause bloating, pain, gurgling in the neck and chest, and excessive flatulence as built-up air seeks an alternate exit route. One Reddit user described the gurgling sound as an “alien trying to escape me,” and pain like a heart attack that goes away with a fart.

The procedure has spread, primarily thanks to increasingly loud rumblings in the bowels of Reddit. Membership in a subreddit for people with or interested in the condition has ballooned to about 31,000 people, to become one of the platform’s larger groups.

Since 2019, the condition has had an official name: retrograde cricopharyngeus dysfunction, also known as “abelchia” or “no-burp syndrome.” The syndrome is caused by a quirk in the muscle that acts as the gatekeeper to the esophagus, the roughly 10-inch-long muscular tube that moves food between the throat and the stomach.

The procedure to fix it involves a doctor injecting 50 to 100 units of Botox — more than twice the amount often used to smooth forehead wrinkles — into the upper cricopharyngeal muscle.

Michael King, MD, the physician who treated Rosenthal, said he hadn’t heard of the disorder until 2020, when a teenager, armed with a list of academic papers found on Reddit, asked him to do the procedure.

It wasn’t a stretch. Dr. King, a laryngologist with Peak ENT and Voice Center, had been injecting Botox in the same muscle to treat people having a hard time swallowing after a stroke.

Now he’s among doctors from Norway to Thailand listed on the subreddit, r/noburp, as offering the procedure. Other doctors, commenters have noted, have occasionally laughed at them or made them feel they were being melodramatic.

To be fair, doctors and researchers don’t understand why the same muscle that lets food move down won’t let air move up.

“It’s very odd,” Dr. King said.

Doctors also aren’t sure why many patients keep burping long after the Botox wears off after a few months. Robert Bastian, MD, a laryngologist outside of Chicago, named the condition and came up with the procedure. He estimates he and his colleagues have treated about 1,800 people, charging about $4,000 a pop.

“We hear that in Southern California it’s $25,000, in Seattle $16,000, in New York City $25,000,” Dr. Bastian said.

Because insurance companies viewed Botox charges as a “red flag,” he said, his patients now pay $650 to cover the medication so it can be excluded from the insurance claims.

The pioneering patient is Daryl Moody, a car technician who has worked at the same Toyota dealership in Houston for half his life. The 34-year-old said that by 2015 he had become “desperate” for relief. The bloating and gurgling wasn’t just a painful shadow over his day; it was cramping his new hobby: skydiving.

“I hadn’t done anything fun or interesting with my life,” he said.

That is, until he tried skydiving. But as he gained altitude on the way up, his stomach would inflate like a bag of chips on a flight.

“I went to 10 doctors,” he said. “Nobody seemed to believe me that this problem even existed.”

Then he stumbled upon a YouTube video by Bastian describing how Botox injections can fix some throat conditions. Moody asked if Bastian could try it to cure his burping problem. Dr. Bastian agreed.

Mr. Moody’s insurance considered it “experimental and unnecessary,” he recalled, so he had to pay about $2,700 out of pocket.

“This is honestly going to change everything,” he posted on his Facebook page in December 2015, about his trip to Illinois.

The year after his procedure, Mr. Moody helped break a national record for participating in the largest group of people to skydive together while wearing wingsuits, those getups that turn people into flying squirrels. He has jumped about 400 times now.

People have been plagued by this issue for at least a few millennia. Two thousand years ago, the Roman philosopher Pliny the Elder described a man named Pomponius who could not belch. And 840 years ago, Johannes de Hauvilla included the tidbit in a poem, writing, “The steaming face of Pomponius could find no relief by belching.”

It took a few more centuries for clinical examples to pop up. In the 1980s, a few case reports in the United States described people who couldn’t burp and had no memory of vomiting. One woman, doctors wrote, was “unable to voluntarily belch along with her childhood friends when this was a popular game.”

The patients were in a great deal of pain, though doctors couldn’t find anything wrong with their anatomy. But the doctors confirmed using a method called manometry that patients’ upper esophageal sphincters simply would not relax — not after a meal of a sandwich, glass of milk, and candy bar, nor after doctors used a catheter to squirt several ounces of air beneath the stubborn valve.

André Smout, MD, PhD, a gastroenterologist at the University of Amsterdam in the Netherlands, said he read those reports when they came out.

“But we never saw the condition, so we didn’t believe that it existed in real life,” he said.

Dr. Smout’s doubts persisted until he and colleagues studied a small group of patients a few years ago. The researchers gave eight patients with a reported inability to burp a “belch provocation” in the form of carbonated water, and used pressure sensors to observe how their throats moved. Indeed, the air stayed trapped. A Botox injection resolved their problems by giving them the ability to burp, or, to use an academic term, eructate.

“We had to admit that it really existed,” Dr. Smout said.

He wrote in Current Opinion in Gastroenterology that the syndrome “may not be as rare as thought hitherto.” He credits Reddit with alerting patients and medical professionals to its existence.

But he wonders how often the treatment might cause a placebo effect. He pointed to studies finding that with conditions such as irritable bowel syndrome, 40% or more of patients who receive placebo treatment feel their symptoms improve. Awareness is also growing about “cyberchondria,” when people search desperately online for answers to their ailments — putting them at risk of unnecessary treatment or further distress.

In Denver, Ms. Rosenthal, the new burper, is open to the idea that the placebo effect could be at play for her. But even if that’s the case, she feels much better.

“I felt perpetual nausea, and that has subsided a lot since I got the procedure done,” she said. So has the bloating and stomach pain. She can drink a beer at happy hour and not feel ill.

She’s pleased insurance covered the procedure, and she’s getting a handle on the involuntary burping. She cannot, however, burp the alphabet.

“Not yet,” she said.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

In a video posted to Reddit, Lucie Rosenthal’s face starts focused and uncertain, looking intently into the camera, before it happens.

She releases a succinct, croak-like belch.

Then, it’s wide-eyed surprise, followed by rollicking laughter. “I got it!” the Denver resident says after what was her second burp ever.

“It’s really rocking my mind that I am fully introducing a new bodily function at 26 years old,” Ms. Rosenthal later told KFF Health News while working remotely, because, as great as the burping was, it was now happening uncontrollably. “Sorry, excuse me. Oh, my god. That was a burp. Did you hear it?”

Ms. Rosenthal is among more than a thousand people who have received a procedure to help them burp since 2019 when an Illinois doctor first reported the steps of the intervention in a medical journal.

The inability to belch can cause bloating, pain, gurgling in the neck and chest, and excessive flatulence as built-up air seeks an alternate exit route. One Reddit user described the gurgling sound as an “alien trying to escape me,” and pain like a heart attack that goes away with a fart.

The procedure has spread, primarily thanks to increasingly loud rumblings in the bowels of Reddit. Membership in a subreddit for people with or interested in the condition has ballooned to about 31,000 people, to become one of the platform’s larger groups.

Since 2019, the condition has had an official name: retrograde cricopharyngeus dysfunction, also known as “abelchia” or “no-burp syndrome.” The syndrome is caused by a quirk in the muscle that acts as the gatekeeper to the esophagus, the roughly 10-inch-long muscular tube that moves food between the throat and the stomach.

The procedure to fix it involves a doctor injecting 50 to 100 units of Botox — more than twice the amount often used to smooth forehead wrinkles — into the upper cricopharyngeal muscle.

Michael King, MD, the physician who treated Rosenthal, said he hadn’t heard of the disorder until 2020, when a teenager, armed with a list of academic papers found on Reddit, asked him to do the procedure.

It wasn’t a stretch. Dr. King, a laryngologist with Peak ENT and Voice Center, had been injecting Botox in the same muscle to treat people having a hard time swallowing after a stroke.

Now he’s among doctors from Norway to Thailand listed on the subreddit, r/noburp, as offering the procedure. Other doctors, commenters have noted, have occasionally laughed at them or made them feel they were being melodramatic.

To be fair, doctors and researchers don’t understand why the same muscle that lets food move down won’t let air move up.

“It’s very odd,” Dr. King said.

Doctors also aren’t sure why many patients keep burping long after the Botox wears off after a few months. Robert Bastian, MD, a laryngologist outside of Chicago, named the condition and came up with the procedure. He estimates he and his colleagues have treated about 1,800 people, charging about $4,000 a pop.

“We hear that in Southern California it’s $25,000, in Seattle $16,000, in New York City $25,000,” Dr. Bastian said.

Because insurance companies viewed Botox charges as a “red flag,” he said, his patients now pay $650 to cover the medication so it can be excluded from the insurance claims.

The pioneering patient is Daryl Moody, a car technician who has worked at the same Toyota dealership in Houston for half his life. The 34-year-old said that by 2015 he had become “desperate” for relief. The bloating and gurgling wasn’t just a painful shadow over his day; it was cramping his new hobby: skydiving.

“I hadn’t done anything fun or interesting with my life,” he said.

That is, until he tried skydiving. But as he gained altitude on the way up, his stomach would inflate like a bag of chips on a flight.

“I went to 10 doctors,” he said. “Nobody seemed to believe me that this problem even existed.”

Then he stumbled upon a YouTube video by Bastian describing how Botox injections can fix some throat conditions. Moody asked if Bastian could try it to cure his burping problem. Dr. Bastian agreed.

Mr. Moody’s insurance considered it “experimental and unnecessary,” he recalled, so he had to pay about $2,700 out of pocket.

“This is honestly going to change everything,” he posted on his Facebook page in December 2015, about his trip to Illinois.

The year after his procedure, Mr. Moody helped break a national record for participating in the largest group of people to skydive together while wearing wingsuits, those getups that turn people into flying squirrels. He has jumped about 400 times now.

People have been plagued by this issue for at least a few millennia. Two thousand years ago, the Roman philosopher Pliny the Elder described a man named Pomponius who could not belch. And 840 years ago, Johannes de Hauvilla included the tidbit in a poem, writing, “The steaming face of Pomponius could find no relief by belching.”

It took a few more centuries for clinical examples to pop up. In the 1980s, a few case reports in the United States described people who couldn’t burp and had no memory of vomiting. One woman, doctors wrote, was “unable to voluntarily belch along with her childhood friends when this was a popular game.”

The patients were in a great deal of pain, though doctors couldn’t find anything wrong with their anatomy. But the doctors confirmed using a method called manometry that patients’ upper esophageal sphincters simply would not relax — not after a meal of a sandwich, glass of milk, and candy bar, nor after doctors used a catheter to squirt several ounces of air beneath the stubborn valve.

André Smout, MD, PhD, a gastroenterologist at the University of Amsterdam in the Netherlands, said he read those reports when they came out.

“But we never saw the condition, so we didn’t believe that it existed in real life,” he said.

Dr. Smout’s doubts persisted until he and colleagues studied a small group of patients a few years ago. The researchers gave eight patients with a reported inability to burp a “belch provocation” in the form of carbonated water, and used pressure sensors to observe how their throats moved. Indeed, the air stayed trapped. A Botox injection resolved their problems by giving them the ability to burp, or, to use an academic term, eructate.

“We had to admit that it really existed,” Dr. Smout said.

He wrote in Current Opinion in Gastroenterology that the syndrome “may not be as rare as thought hitherto.” He credits Reddit with alerting patients and medical professionals to its existence.

But he wonders how often the treatment might cause a placebo effect. He pointed to studies finding that with conditions such as irritable bowel syndrome, 40% or more of patients who receive placebo treatment feel their symptoms improve. Awareness is also growing about “cyberchondria,” when people search desperately online for answers to their ailments — putting them at risk of unnecessary treatment or further distress.

In Denver, Ms. Rosenthal, the new burper, is open to the idea that the placebo effect could be at play for her. But even if that’s the case, she feels much better.

“I felt perpetual nausea, and that has subsided a lot since I got the procedure done,” she said. So has the bloating and stomach pain. She can drink a beer at happy hour and not feel ill.

She’s pleased insurance covered the procedure, and she’s getting a handle on the involuntary burping. She cannot, however, burp the alphabet.

“Not yet,” she said.

KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF—an independent source of health policy research, polling, and journalism. Learn more about KFF.

Tirzepatide (Zepbound) is not in shortage for now, but the weight loss drug has remained inaccessible to people without insurance coverage who can’t afford to pay out of pocket. Now, its manufacturer, Eli Lilly, has introduced a new formulation it says will “significantly expand” the supply. But not all endocrinologists are enthusiastic.

As of August 27, LillyDirect made 2.5-mg and 5-mg single-dose vials of tirzepatide available to self-pay patients with an on-label electronic prescription. Lilly’s announcement said the single-dose vials “are priced at a 50% or greater discount compared to the list price of all other incretin (glucagon-like peptide 1 receptor agonists or GLP-1) medicines for obesity.”

For a 4-week supply of the weekly injections, the discount at LillyDirect translates to $399 for a 2.5-mg single-dose vial ($99.75 per vial) and $549 for the 5-mg dose ($137.25 per vial), which the company noted was “in line with the Zepbound savings program for noncovered individuals.” (The new direct single-dose prescriptions cannot be filled at community or retail pharmacies.)

“In a clinical study, the 5-mg maintenance dose helped patients achieve an average of 15% weight loss after 72 weeks of treatment and has been a powerful tool for millions of people with obesity looking to lose weight and keep it off,” according to the announcement.

The clinical study, which is not named or referenced in the announcement, is SURMOUNT-1, a Lilly spokesperson said in an interview. Yet, that study also found that patients achieved an average weight loss of 19.5% with 10-mg doses and 20.9% with 15-mg doses of tirzepatide. Furthermore, the percentage of participants achieving body weight reductions of ≥ 5% was 85% (5 mg), 89% (10 mg), and 91% (15 mg), showing the benefits of higher doses.

And there’s the rub.
 

‘Only Two Different Doses’

Anne Peters, MD, a professor of clinical medicine and a clinical scholar at the University of Southern California, Los Angeles, said in an interview: “My concern is, they’re only providing two different doses, 2.5 mg and 5 mg. You get somebody on it, and then they still have to go back to the traditional pens. I’m very opposed to getting patients connected to a medication they can’t then continue to take.

“Now we have starter doses that are easy to come by,” she said. “But the problem isn’t starting. The problem for all of these patients is chronic continuation of the right dose of the drug, and out-of-pocket costs become exorbitantly higher when they have to self-purchase the pens for the higher doses.

“Yes, the 5-mg dose has benefits, but not the same as higher doses,” she continued. “I have nobody for whom 5 mg is the right dose. They have to take more, sometimes within a month or 2 of starting, in order to achieve the kind of weight loss they need.”

If their insurance doesn’t cover the drug, “what are they going to do to stay on 5 mg? Or pay a crapload of money to buy three of the 5-mg doses to reach a higher dose?”

Michael Weintraub, MD, clinical assistant professor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism at New York University Grossman School of Medicine in New York City, said that, “for many, this lower monthly cost is attainable and is a significant advancement in increasing access. For others, however, an out-of-pocket monthly cost of $349-549 for a chronic medication is still unaffordable.”

And like Dr. Peters, he said, “some patients do not lose a clinically significant amount of weight with 2.5 mg or 5 mg and require higher doses. There is no way of prescribing a higher dose of Zepbound vials, so patients would have to resort to the higher-dose auto-injector pens that are still double the price.”

A Lilly spokesperson countered in a comment: “Offering Zepbound single-dose vials in higher dosage strengths could increase the potential for dose splitting, which is not contemplated by the FDA [Food and Drug Adminstration]–approved label and may pose patient safety risks.”

But Dr. Peters wondered: “Wouldn’t dose splitting of a known-to-be-pure compound be better than getting it at a compounding pharmacy that lacks purity/safety? The one message from all of this is that patients need to know what they’re getting into. They’re starting a drug that can help with weight loss, but they’re going to be on a sub-max dose. And a higher dose is going to be double the price.”

In addition, said Robert F. Kushner, MD, a professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois, “for the lower-dose vials, instead of administering the drug with a self-auto-injection pen, patients will need to use a needle and syringe and draw up the dose from a vial. This will take a higher skill level and health literacy that may be challenging for some patients. Patients may need additional training on how to use this new formulation. That will take additional time and resources, such as a demonstration in the office or referral to video.”

The Lilly news release noted that “patients can also purchase ancillary supplies, like syringes and needles, and will have access to important patient-friendly instructional materials on correctly administering the medicine via needle and syringe.”
 

Protection From Compounders?

According to the Lilly spokesperson, the launch of Zepbound vials “furthers our commitment to helping patients avoid the risks associated with compounded products by providing patients another option for access to genuine Lilly medicine.”

Indeed, said Jaime Almandoz, MD, medical director of the Weight Wellness Program and associate professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas, “The introduction of Zepbound/tirzepatide in single-dose vials should improve access to evidence-based obesity treatments, reducing potential risks associated with compounded additives and eliminating the need for patients to calculate correct medication doses,” which have led to accidental overdoses of compounded semaglutide.

Lilly’s spokesperson added: “We have taken multiple steps — including publishing an open letter and launching lilly.com/real-medicine — to warn the public about the risks posed by the proliferation of counterfeit, fake, unsafe, or untested knockoffs of Lilly’s genuine medicines.”

But whether these steps are strong enough to overcome the realities of cost and the need for affordable higher doses remains to be seen.

Scott Brunner, CEO of the Alliance for Pharmacy Compounding, said in a statement that the new version of Zepbound “is great news for patients. It’s a much more rational and care-focused response to the remarkable demand for their drug than the lawsuits and cease-and-desist letters Lilly has been raining down on compounding pharmacies.”

“For 20 months now,” he continued, “compounders have been a lifeline for many patients, filling prescriptions for compounded tirzepatide injection at a time when the FDA-approved drug has been in shortage. We’ll be eager to see whether Lilly’s direct-to-patient approach actually works.”

Dr. Almandoz affirmed: “Everyone wants to see improved access to evidence-based obesity care. It’s crucial to ensure patients receive the most appropriate interventions, whether it is lifestyle changes, medications, or bariatric surgery,” he said. “There are resources available, [including his recent paper], for nutrition and lifestyle modifications specifically for patients taking obesity medications, which can help clinicians guide their patients toward better health.”

Dr. Almandoz is a member of advisory boards and consults for: Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. Dr. Kushner is an adviser to Eli Lilly and Novo Nordisk. Dr. Peters and Dr. Weintraub declared no competing interests.

A version of this article appeared on Medscape.com.

Tirzepatide (Zepbound) is not in shortage for now, but the weight loss drug has remained inaccessible to people without insurance coverage who can’t afford to pay out of pocket. Now, its manufacturer, Eli Lilly, has introduced a new formulation it says will “significantly expand” the supply. But not all endocrinologists are enthusiastic.

As of August 27, LillyDirect made 2.5-mg and 5-mg single-dose vials of tirzepatide available to self-pay patients with an on-label electronic prescription. Lilly’s announcement said the single-dose vials “are priced at a 50% or greater discount compared to the list price of all other incretin (glucagon-like peptide 1 receptor agonists or GLP-1) medicines for obesity.”

For a 4-week supply of the weekly injections, the discount at LillyDirect translates to $399 for a 2.5-mg single-dose vial ($99.75 per vial) and $549 for the 5-mg dose ($137.25 per vial), which the company noted was “in line with the Zepbound savings program for noncovered individuals.” (The new direct single-dose prescriptions cannot be filled at community or retail pharmacies.)

“In a clinical study, the 5-mg maintenance dose helped patients achieve an average of 15% weight loss after 72 weeks of treatment and has been a powerful tool for millions of people with obesity looking to lose weight and keep it off,” according to the announcement.

The clinical study, which is not named or referenced in the announcement, is SURMOUNT-1, a Lilly spokesperson said in an interview. Yet, that study also found that patients achieved an average weight loss of 19.5% with 10-mg doses and 20.9% with 15-mg doses of tirzepatide. Furthermore, the percentage of participants achieving body weight reductions of ≥ 5% was 85% (5 mg), 89% (10 mg), and 91% (15 mg), showing the benefits of higher doses.

And there’s the rub.
 

‘Only Two Different Doses’

Anne Peters, MD, a professor of clinical medicine and a clinical scholar at the University of Southern California, Los Angeles, said in an interview: “My concern is, they’re only providing two different doses, 2.5 mg and 5 mg. You get somebody on it, and then they still have to go back to the traditional pens. I’m very opposed to getting patients connected to a medication they can’t then continue to take.

“Now we have starter doses that are easy to come by,” she said. “But the problem isn’t starting. The problem for all of these patients is chronic continuation of the right dose of the drug, and out-of-pocket costs become exorbitantly higher when they have to self-purchase the pens for the higher doses.

“Yes, the 5-mg dose has benefits, but not the same as higher doses,” she continued. “I have nobody for whom 5 mg is the right dose. They have to take more, sometimes within a month or 2 of starting, in order to achieve the kind of weight loss they need.”

If their insurance doesn’t cover the drug, “what are they going to do to stay on 5 mg? Or pay a crapload of money to buy three of the 5-mg doses to reach a higher dose?”

Michael Weintraub, MD, clinical assistant professor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism at New York University Grossman School of Medicine in New York City, said that, “for many, this lower monthly cost is attainable and is a significant advancement in increasing access. For others, however, an out-of-pocket monthly cost of $349-549 for a chronic medication is still unaffordable.”

And like Dr. Peters, he said, “some patients do not lose a clinically significant amount of weight with 2.5 mg or 5 mg and require higher doses. There is no way of prescribing a higher dose of Zepbound vials, so patients would have to resort to the higher-dose auto-injector pens that are still double the price.”

A Lilly spokesperson countered in a comment: “Offering Zepbound single-dose vials in higher dosage strengths could increase the potential for dose splitting, which is not contemplated by the FDA [Food and Drug Adminstration]–approved label and may pose patient safety risks.”

But Dr. Peters wondered: “Wouldn’t dose splitting of a known-to-be-pure compound be better than getting it at a compounding pharmacy that lacks purity/safety? The one message from all of this is that patients need to know what they’re getting into. They’re starting a drug that can help with weight loss, but they’re going to be on a sub-max dose. And a higher dose is going to be double the price.”

In addition, said Robert F. Kushner, MD, a professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois, “for the lower-dose vials, instead of administering the drug with a self-auto-injection pen, patients will need to use a needle and syringe and draw up the dose from a vial. This will take a higher skill level and health literacy that may be challenging for some patients. Patients may need additional training on how to use this new formulation. That will take additional time and resources, such as a demonstration in the office or referral to video.”

The Lilly news release noted that “patients can also purchase ancillary supplies, like syringes and needles, and will have access to important patient-friendly instructional materials on correctly administering the medicine via needle and syringe.”
 

Protection From Compounders?

According to the Lilly spokesperson, the launch of Zepbound vials “furthers our commitment to helping patients avoid the risks associated with compounded products by providing patients another option for access to genuine Lilly medicine.”

Indeed, said Jaime Almandoz, MD, medical director of the Weight Wellness Program and associate professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas, “The introduction of Zepbound/tirzepatide in single-dose vials should improve access to evidence-based obesity treatments, reducing potential risks associated with compounded additives and eliminating the need for patients to calculate correct medication doses,” which have led to accidental overdoses of compounded semaglutide.

Lilly’s spokesperson added: “We have taken multiple steps — including publishing an open letter and launching lilly.com/real-medicine — to warn the public about the risks posed by the proliferation of counterfeit, fake, unsafe, or untested knockoffs of Lilly’s genuine medicines.”

But whether these steps are strong enough to overcome the realities of cost and the need for affordable higher doses remains to be seen.

Scott Brunner, CEO of the Alliance for Pharmacy Compounding, said in a statement that the new version of Zepbound “is great news for patients. It’s a much more rational and care-focused response to the remarkable demand for their drug than the lawsuits and cease-and-desist letters Lilly has been raining down on compounding pharmacies.”

“For 20 months now,” he continued, “compounders have been a lifeline for many patients, filling prescriptions for compounded tirzepatide injection at a time when the FDA-approved drug has been in shortage. We’ll be eager to see whether Lilly’s direct-to-patient approach actually works.”

Dr. Almandoz affirmed: “Everyone wants to see improved access to evidence-based obesity care. It’s crucial to ensure patients receive the most appropriate interventions, whether it is lifestyle changes, medications, or bariatric surgery,” he said. “There are resources available, [including his recent paper], for nutrition and lifestyle modifications specifically for patients taking obesity medications, which can help clinicians guide their patients toward better health.”

Dr. Almandoz is a member of advisory boards and consults for: Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. Dr. Kushner is an adviser to Eli Lilly and Novo Nordisk. Dr. Peters and Dr. Weintraub declared no competing interests.

A version of this article appeared on Medscape.com.

Tirzepatide (Zepbound) is not in shortage for now, but the weight loss drug has remained inaccessible to people without insurance coverage who can’t afford to pay out of pocket. Now, its manufacturer, Eli Lilly, has introduced a new formulation it says will “significantly expand” the supply. But not all endocrinologists are enthusiastic.

As of August 27, LillyDirect made 2.5-mg and 5-mg single-dose vials of tirzepatide available to self-pay patients with an on-label electronic prescription. Lilly’s announcement said the single-dose vials “are priced at a 50% or greater discount compared to the list price of all other incretin (glucagon-like peptide 1 receptor agonists or GLP-1) medicines for obesity.”

For a 4-week supply of the weekly injections, the discount at LillyDirect translates to $399 for a 2.5-mg single-dose vial ($99.75 per vial) and $549 for the 5-mg dose ($137.25 per vial), which the company noted was “in line with the Zepbound savings program for noncovered individuals.” (The new direct single-dose prescriptions cannot be filled at community or retail pharmacies.)

“In a clinical study, the 5-mg maintenance dose helped patients achieve an average of 15% weight loss after 72 weeks of treatment and has been a powerful tool for millions of people with obesity looking to lose weight and keep it off,” according to the announcement.

The clinical study, which is not named or referenced in the announcement, is SURMOUNT-1, a Lilly spokesperson said in an interview. Yet, that study also found that patients achieved an average weight loss of 19.5% with 10-mg doses and 20.9% with 15-mg doses of tirzepatide. Furthermore, the percentage of participants achieving body weight reductions of ≥ 5% was 85% (5 mg), 89% (10 mg), and 91% (15 mg), showing the benefits of higher doses.

And there’s the rub.
 

‘Only Two Different Doses’

Anne Peters, MD, a professor of clinical medicine and a clinical scholar at the University of Southern California, Los Angeles, said in an interview: “My concern is, they’re only providing two different doses, 2.5 mg and 5 mg. You get somebody on it, and then they still have to go back to the traditional pens. I’m very opposed to getting patients connected to a medication they can’t then continue to take.

“Now we have starter doses that are easy to come by,” she said. “But the problem isn’t starting. The problem for all of these patients is chronic continuation of the right dose of the drug, and out-of-pocket costs become exorbitantly higher when they have to self-purchase the pens for the higher doses.

“Yes, the 5-mg dose has benefits, but not the same as higher doses,” she continued. “I have nobody for whom 5 mg is the right dose. They have to take more, sometimes within a month or 2 of starting, in order to achieve the kind of weight loss they need.”

If their insurance doesn’t cover the drug, “what are they going to do to stay on 5 mg? Or pay a crapload of money to buy three of the 5-mg doses to reach a higher dose?”

Michael Weintraub, MD, clinical assistant professor in the Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism at New York University Grossman School of Medicine in New York City, said that, “for many, this lower monthly cost is attainable and is a significant advancement in increasing access. For others, however, an out-of-pocket monthly cost of $349-549 for a chronic medication is still unaffordable.”

And like Dr. Peters, he said, “some patients do not lose a clinically significant amount of weight with 2.5 mg or 5 mg and require higher doses. There is no way of prescribing a higher dose of Zepbound vials, so patients would have to resort to the higher-dose auto-injector pens that are still double the price.”

A Lilly spokesperson countered in a comment: “Offering Zepbound single-dose vials in higher dosage strengths could increase the potential for dose splitting, which is not contemplated by the FDA [Food and Drug Adminstration]–approved label and may pose patient safety risks.”

But Dr. Peters wondered: “Wouldn’t dose splitting of a known-to-be-pure compound be better than getting it at a compounding pharmacy that lacks purity/safety? The one message from all of this is that patients need to know what they’re getting into. They’re starting a drug that can help with weight loss, but they’re going to be on a sub-max dose. And a higher dose is going to be double the price.”

In addition, said Robert F. Kushner, MD, a professor at Northwestern University Feinberg School of Medicine in Chicago, Illinois, “for the lower-dose vials, instead of administering the drug with a self-auto-injection pen, patients will need to use a needle and syringe and draw up the dose from a vial. This will take a higher skill level and health literacy that may be challenging for some patients. Patients may need additional training on how to use this new formulation. That will take additional time and resources, such as a demonstration in the office or referral to video.”

The Lilly news release noted that “patients can also purchase ancillary supplies, like syringes and needles, and will have access to important patient-friendly instructional materials on correctly administering the medicine via needle and syringe.”
 

Protection From Compounders?

According to the Lilly spokesperson, the launch of Zepbound vials “furthers our commitment to helping patients avoid the risks associated with compounded products by providing patients another option for access to genuine Lilly medicine.”

Indeed, said Jaime Almandoz, MD, medical director of the Weight Wellness Program and associate professor of internal medicine at the University of Texas Southwestern Medical Center in Dallas, “The introduction of Zepbound/tirzepatide in single-dose vials should improve access to evidence-based obesity treatments, reducing potential risks associated with compounded additives and eliminating the need for patients to calculate correct medication doses,” which have led to accidental overdoses of compounded semaglutide.

Lilly’s spokesperson added: “We have taken multiple steps — including publishing an open letter and launching lilly.com/real-medicine — to warn the public about the risks posed by the proliferation of counterfeit, fake, unsafe, or untested knockoffs of Lilly’s genuine medicines.”

But whether these steps are strong enough to overcome the realities of cost and the need for affordable higher doses remains to be seen.

Scott Brunner, CEO of the Alliance for Pharmacy Compounding, said in a statement that the new version of Zepbound “is great news for patients. It’s a much more rational and care-focused response to the remarkable demand for their drug than the lawsuits and cease-and-desist letters Lilly has been raining down on compounding pharmacies.”

“For 20 months now,” he continued, “compounders have been a lifeline for many patients, filling prescriptions for compounded tirzepatide injection at a time when the FDA-approved drug has been in shortage. We’ll be eager to see whether Lilly’s direct-to-patient approach actually works.”

Dr. Almandoz affirmed: “Everyone wants to see improved access to evidence-based obesity care. It’s crucial to ensure patients receive the most appropriate interventions, whether it is lifestyle changes, medications, or bariatric surgery,” he said. “There are resources available, [including his recent paper], for nutrition and lifestyle modifications specifically for patients taking obesity medications, which can help clinicians guide their patients toward better health.”

Dr. Almandoz is a member of advisory boards and consults for: Novo Nordisk, Eli Lilly, and Boehringer Ingelheim. Dr. Kushner is an adviser to Eli Lilly and Novo Nordisk. Dr. Peters and Dr. Weintraub declared no competing interests.

A version of this article appeared on Medscape.com.

Pancreatic cancer remains one of the deadliest cancers. 

When the disease is caught earlier, the 5-year survival rates hover around 44%, but once the cancer metastasizes, only about 3% of patients live that long.

Finding effective treatments for the disease continues to be a challenge. 

No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.

Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.” 

Until recently. 

In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers. 

A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.

“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Dr. Aguirre said.
 

A Challenging Cancer

Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.

But it’s still early days on the evidence front.

The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far. 

The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.

Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.

And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.

For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.

In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations. 

At this year’s American Society of Clinical Oncology meeting, Dr. Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.

Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks. 

Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%. 

Revolution Medicines is now planning a phase 3 trial.

Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.

While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Dr. Aguirre said. 

Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Dr. Aguirre explained. 

In his own lab, Dr. Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.

Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Dr. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes. 

Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing. 

“We tend to get excited about preliminary data,” said Dr. Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.” 

Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.

But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Dr. Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?” 

Dr. Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy. 

Still, “I think there’s tremendous reason for optimism right now,” Dr. Aguirre said.

Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Dr. Marshall said. And that’s because “we need a new game.”

Dr. Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Dr. Venook did not have any disclosures. Dr. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor.

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

Pancreatic cancer remains one of the deadliest cancers. 

When the disease is caught earlier, the 5-year survival rates hover around 44%, but once the cancer metastasizes, only about 3% of patients live that long.

Finding effective treatments for the disease continues to be a challenge. 

No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.

Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.” 

Until recently. 

In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers. 

A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.

“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Dr. Aguirre said.
 

A Challenging Cancer

Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.

But it’s still early days on the evidence front.

The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far. 

The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.

Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.

And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.

For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.

In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations. 

At this year’s American Society of Clinical Oncology meeting, Dr. Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.

Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks. 

Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%. 

Revolution Medicines is now planning a phase 3 trial.

Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.

While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Dr. Aguirre said. 

Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Dr. Aguirre explained. 

In his own lab, Dr. Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.

Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Dr. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes. 

Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing. 

“We tend to get excited about preliminary data,” said Dr. Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.” 

Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.

But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Dr. Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?” 

Dr. Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy. 

Still, “I think there’s tremendous reason for optimism right now,” Dr. Aguirre said.

Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Dr. Marshall said. And that’s because “we need a new game.”

Dr. Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Dr. Venook did not have any disclosures. Dr. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor.

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

Pancreatic cancer remains one of the deadliest cancers. 

When the disease is caught earlier, the 5-year survival rates hover around 44%, but once the cancer metastasizes, only about 3% of patients live that long.

Finding effective treatments for the disease continues to be a challenge. 

No significant new therapies in pancreatic cancer have emerged in the past 20 years, explained John Marshall, MD, a gastrointestinal medical oncologist at Georgetown University in Washington, DC.

Oncology researchers have long eyed a potential holy grail target: the KRAS oncogene. Present in about 90% of patients with pancreatic cancer, KRAS mutations are considered a key driver of the disease. But for decades, KRAS was considered “undruggable.” 

Until recently. 

In the past 2 years, the US Food and Drug Administration has approved two KRAS inhibitors — sotorasib and adagrasib — to treat certain colorectal and lung cancers. 

A pipeline of KRAS inhibitors targeting pancreatic cancer has now emerged, leaving some oncologists feeling optimistic about the future of treating the disease.

“I think KRAS inhibitors — [maybe not alone] but as a foundational agent for combinations — are really poised to transform how we care for patients,” said Andrew Aguirre, MD, PhD, a gastrointestinal medical oncologist at the Dana-Farber Cancer Institute, Boston, who heads a lab focused on RAS signaling and pancreatic cancer. These agents won’t necessarily cure pancreatic cancer but will be “part of the solution” to improve outcomes, Dr. Aguirre said.
 

A Challenging Cancer

Pharmaceutical companies currently have at least eight agents in development and are conducting dozens of KRAS/RAS studies that focus on or include pancreatic cancer.

But it’s still early days on the evidence front.

The investigational drugs are only in phase 1/2 testing, and the reported outcomes have been limited so far. 

The current mainstay frontline options in pancreatic cancer largely center on chemotherapy combinations. These include FOLFIRINOX (irinotecan, fluorouracil, leucovorin, and oxaliplatin), gemcitabine, nab-paclitaxel, and capecitabine. The four-drug chemotherapy combination NALIRIFOX — a slight tweak on FOLFIRINOX — was also recently approved in the first-line setting.

Patient outcomes on these chemotherapy combinations have been modest, with median overall survival in the metastatic setting ranging from 6.7 months to 11.1 months.

And although two KRAS inhibitors, sotorasib and adagrasib, are currently on the US market, neither is approved for pancreatic cancer, and use of these agents to treat pancreatic cancer would be limited. Only about 1%-2% of tumors have the specific KRAS G12C mutation that these drugs target. These KRAS inhibitors have shown limited efficacy in pancreatic cancer.

For instance, a small study evaluating sotorasib in pancreatic cancer found that only 21% of 38 patients with metastatic disease who carried the G12C mutation achieved an objective response, and no patients had a complete response. In the overall population, median progression-free survival was 4 months and median overall survival was 6.9 months, with 19.6% of patients alive at 12 months.

In pancreatic cancer, better targets for KRAS inhibitors include the G12D mutation, carried by about 44% of tumors; G12V, present in 29% of tumors; G12R, present in 20%; and pan-RAS inhibitors, which cover all mutations. 

At this year’s American Society of Clinical Oncology meeting, Dr. Aguirre discussed the pipeline of investigational KRAS agents targeting some of these more relevant mutations.

Results from a recent phase 1 study, evaluating the investigational pan-RAS inhibitor RMC-6236 from Revolution Medicines, showed initial promise. The study revealed an objective response rate at 14 weeks of 20% in 76 patients with metastatic pancreatic ductal adenocarcinoma treated in the second line. The disease control rate reached almost 90% at 14 weeks. 

Median progression-free survival was 8.1 months, an improvement over the 2-3.5 months expected with additional chemotherapy. Overall survival was not reached but started at 8.5 months. The rate of grade 3 or higher adverse events — most commonly rash, diarrhea, and thrombocytopenia — was 22%. 

Revolution Medicines is now planning a phase 3 trial.

Other investigational KRAS inhibitors, outside of KRAS G12C agents, are entering or are in early trials, but without results reported yet.

While there’s “room for improvement,” such studies only offer “proof of concept” that KRAS inhibition has potential, Dr. Aguirre said. 

Oncologists may ultimately see better outcomes by expanding when and how patients receive these drugs. The research to date has been limited to monotherapy in previously treated patients with metastatic disease, which leaves the door open to explore the inhibitors in earlier lines of treatment; in patients with resectable disease; and in combination with chemotherapy, immunotherapy, or other targeted approaches, Dr. Aguirre explained. 

In his own lab, Dr. Aguirre and colleagues have data suggesting that combining KRAS inhibitors and chemotherapy may bring more benefit than either treatment alone.

Pancreatic tumors generally comprise a mix of both basal-like and classical cell subtypes, and basal-like cells have shown more resistance to chemotherapy. Dr. Aguirre’s team has found that basal-like cells may be more sensitive to KRAS inhibitors, which suggests that combining these inhibitors with chemotherapy could improve patient outcomes. 

Alan Venook, MD, said he “remains to be convinced” about the benefit of KRAS inhibition because he’s seen many other promising approaches, such as pegylated hyaluronidase, show initial potential but then fall flat in phase 3 testing. 

“We tend to get excited about preliminary data,” said Dr. Venook, a gastrointestinal medical oncologist at the University of California, San Francisco. “At the moment, there’s no data that suggests [KRAS inhibition] is going to be a game changer.” 

Mutation testing in patients with pancreatic cancer will be critical to identify who might benefit from different KRAS agents, and a subset of patients may do very well.

But with many patients presenting with advanced disease, “I just don’t see how turning off the disease [process] can happen adequately enough to stop it from progressing,” Dr. Venook said. And “is it a big advance to keep disease from progressing over 3 or 6 months?” 

Dr. Aguirre said he respects the caution. Much work remains to be done, including how to improve response rates and durability and to overcome the resistance that sets in with monotherapy. 

Still, “I think there’s tremendous reason for optimism right now,” Dr. Aguirre said.

Although the benefits of these agents may be limited, any improvement in pancreatic cancer treatment would still be a “game changer,” Dr. Marshall said. And that’s because “we need a new game.”

Dr. Aguirre is an advisor and/or disclosed research funding from companies developing KRAS/RAS inhibitors, including Revolution Medicines, Boehringer Ingelheim, Novartis, and Mirati. Dr. Venook did not have any disclosures. Dr. Marshall has ties to numerous companies, including Caris Life Sciences, Bayer, Merck, and Pfizer. He is also a Medscape Oncology editorial advisor.

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

The Food and Drug Administration’s (FDA) decision not to approve midomafetamine-assisted therapy (MDMA-AT) for posttraumatic stress disorder (PTSD) puts the therapy’s near-term future in doubt, but officials say the rejection may not knock it out of contention as an eventual therapeutic tool for a variety of conditions.

In August the agency declined to approve the drug with currently available study data and requested that the company conduct an additional phase 3 trial. The agency’s action had potentially devastating consequences for MDMA-AT’s sponsor, Lykos Therapeutics, and was a huge disappointment for researchers, clinicians, and patients who were optimistic that it would be a new option for a condition that affects 13-17 million Americans.

For now, no other company is poised to imminently seek FDA approval for MDMA.

Despite the setback, research into MDMA that combines different psychotherapeutic approaches continues. Currently, there are seven US studies actively recruiting participants, and another 13 are registered with an eye toward starting recruitment, as reported on ClinicalTrials.gov.

The lack of FDA approval “actually increases the opportunity now for us to do trials,” said Michael Ostacher, MD, professor of psychiatry and behavioral sciences at Stanford Medicine in California. Researchers won’t have to be sponsored by Lykos to get access to MDMA.

“There’s a lot of energy and interest in doing these studies,” he said in an interview, adding that philanthropic organizations and Veterans Affairs (VA) are contributing funds to support such studies.

The VA provided a statement saying that it “intends to gather rigorous scientific evidence on the potential efficacy and safety of psychedelic compounds when used in conjunction with psychotherapy.” It also noted that “these studies will be conducted under stringent safety protocols and will mark the first time since the 1960’s that VA is funding research on such compounds.”

Rachel Yehuda, PhD, director of the Center for Psychedelic Therapy Research at Icahn School of Medicine at Mount Sinai in New York City, said in an interview that the FDA rejection “raises questions about how to keep the work going.”

Without the FDA’s imprimatur, MDMA remains a schedule 1 drug, which means it has no valid medical use.

“It’s a lot more complicated and expensive to work with a scheduled compound than to work with a compound that has been approved,” Dr. Yehuda said.

Also, without Lykos or another drug company sponsor, investigators have to find an acceptable MDMA source on their own, said Dr. Yehuda, who was an investigator on a study in which Lykos provided MDMA but was not involved in study design, data collection, analysis, or manuscript preparation.
 

Lykos in Disarray

Within a week of the FDA’s decision, Lykos announced it was cutting its staff by 75% and that Rick Doblin, PhD, the founder and president of the Multidisciplinary Association for Psychedelic Studies (MAPS) that gave rise to Lykos, had resigned from the Lykos board.

A frequently controversial figure, Doblin has been attempting to legitimize MDMA as a therapy since the mid-1980s. He formed a public benefit corporation (PBC) in 2014 with an eye toward FDA approval. The PBC fully separated from MAPS in 2024 and became Lykos.

Although the FDA has left the door open to approval, Lykos has not released the agency’s complete response letter, so it’s not clear exactly what the FDA is seeking. In a statement, the company said it believes the issues “can be addressed with existing data, postapproval requirements, or through reference to the scientific literature.”

Lykos said in an email that it is working on “securing the meeting with the FDA” and that it “will work with the agency to determine what needs to be done to fulfill their requests.”

Soon after the FDA decision, Lykos was hit with another blow. The journal Psychopharmacology retracted an article that pooled six Lykos phase 2 studies, claiming the paper’s authors knew about unethical conduct before submission but did not inform the publisher.

Lykos said the issues could have been addressed through a correction and that it has filed a complaint with the Committee on Publication Ethics. It also noted that the misconduct at issue was reported to the FDA and Health Canada.

“However, we did not disclose the violations to the journal itself, an additional step we should have taken and regret not doing,” the company said. It added that the efficacy data in the paper were not part of the FDA submission.

Author Allison A. Feduccia, PhD, cofounder of Psychedelic Support, agreed with the retraction but disagreed with the wording. In a post on LinkedIn, she said she and other authors were not informed about the misconduct until years after the study’s submission.

Four authors — including Dr. Doblin — disagreed with the retraction.

Dr. Doblin said in a statement that he’d resigned from Lykos to escape the restrictions that came with being a fiduciary. “Now I can advocate and speak freely,” he said, adding that he could also return to his activist roots.

He predicted that Lykos would eventually gain FDA approval. But if Lykos can’t convince the agency, it have the necessary data already in hand; “potential FDA approval is now at least 2 years away, possibly more,” Dr. Doblin said in his statement.
 

Research Continues

Lykos is not the only company hoping to commercialize MDMA. Toronto-based Awakn Life Sciences has an MDMA preclinical development program for addiction. In addition, some companies are offering MDMA therapy through clinics, such as Numinus in Utah and Sunstone Therapies in Rockville, Maryland.

But Lykos was the closest to bringing a product to market. The company is still a sponsor of four MDMA-related clinical trials, three of which appear to be on hold. One study at the VA San Diego Healthcare System, San Diego, that is actively recruiting is an open-label trial to assess MDMA-AT in combination with brief Cognitive-Behavioral Conjoint Therapy for PTSD.

Those studies are among 13 US trials listed in ClinicalTrials.gov that have not yet begun recruiting and 7 that are actively recruiting.

Among them is a study of MDMA plus exposure therapy, funded by and conducted at Emory University in Atlanta. One of the Emory principal investigators, Barbara Rothbaum, MD, has also been named to a Lykos’ panel that would help ensure oversight of MDMA-AT post FDA approval.

Dr. Ostacher is an investigator in a study planned at VA Palo Alto Health Care System in California, that will compare MDMA-AT with cognitive processing therapy in veterans with severe PTSD. He said it will be open label in an effort to minimize expectation bias and issues with blinding — both problems that tripped up the Lykos application. Although placebo-controlled trials are the gold standard, it’s not ideal when “the purpose of the drug is for it to change how you see the world and yourself,” Dr. Ostacher said.

The study aims to see whether MDMA-AT is better than “a much shorter, less onerous, but quite evidence-based psychotherapy for PTSD,” he said.

The FDA’s decision is not the end of the road, said Dr. Ostacher. “Even though I think this makes for an obvious delay, I don’t think that it’s a permanent one,” he said.

Dr. Yehuda also said she is not ready to give up.

“We don’t plan on stopping — we plan on finding a way,” she said.

“In our experience, this is a very powerful approach that helps a lot of people that haven’t found help using other approaches, and when it’s in the hands of really trusted, experienced, ethical clinicians in a trusted environment, this could be a real game changer for people who have not been able to find belief by traditional methods,” she said.

Dr. Ostacher reported no relevant financial relationships. Dr. Yahuda is the principal investigator on clinical trials for the Center for Psychedelic Psychotherapy and Trauma Research that are sponsored by the Multidisciplinary Association for Psychedelic Studies and COMPASS Pathways.

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

The Food and Drug Administration’s (FDA) decision not to approve midomafetamine-assisted therapy (MDMA-AT) for posttraumatic stress disorder (PTSD) puts the therapy’s near-term future in doubt, but officials say the rejection may not knock it out of contention as an eventual therapeutic tool for a variety of conditions.

In August the agency declined to approve the drug with currently available study data and requested that the company conduct an additional phase 3 trial. The agency’s action had potentially devastating consequences for MDMA-AT’s sponsor, Lykos Therapeutics, and was a huge disappointment for researchers, clinicians, and patients who were optimistic that it would be a new option for a condition that affects 13-17 million Americans.

For now, no other company is poised to imminently seek FDA approval for MDMA.

Despite the setback, research into MDMA that combines different psychotherapeutic approaches continues. Currently, there are seven US studies actively recruiting participants, and another 13 are registered with an eye toward starting recruitment, as reported on ClinicalTrials.gov.

The lack of FDA approval “actually increases the opportunity now for us to do trials,” said Michael Ostacher, MD, professor of psychiatry and behavioral sciences at Stanford Medicine in California. Researchers won’t have to be sponsored by Lykos to get access to MDMA.

“There’s a lot of energy and interest in doing these studies,” he said in an interview, adding that philanthropic organizations and Veterans Affairs (VA) are contributing funds to support such studies.

The VA provided a statement saying that it “intends to gather rigorous scientific evidence on the potential efficacy and safety of psychedelic compounds when used in conjunction with psychotherapy.” It also noted that “these studies will be conducted under stringent safety protocols and will mark the first time since the 1960’s that VA is funding research on such compounds.”

Rachel Yehuda, PhD, director of the Center for Psychedelic Therapy Research at Icahn School of Medicine at Mount Sinai in New York City, said in an interview that the FDA rejection “raises questions about how to keep the work going.”

Without the FDA’s imprimatur, MDMA remains a schedule 1 drug, which means it has no valid medical use.

“It’s a lot more complicated and expensive to work with a scheduled compound than to work with a compound that has been approved,” Dr. Yehuda said.

Also, without Lykos or another drug company sponsor, investigators have to find an acceptable MDMA source on their own, said Dr. Yehuda, who was an investigator on a study in which Lykos provided MDMA but was not involved in study design, data collection, analysis, or manuscript preparation.
 

Lykos in Disarray

Within a week of the FDA’s decision, Lykos announced it was cutting its staff by 75% and that Rick Doblin, PhD, the founder and president of the Multidisciplinary Association for Psychedelic Studies (MAPS) that gave rise to Lykos, had resigned from the Lykos board.

A frequently controversial figure, Doblin has been attempting to legitimize MDMA as a therapy since the mid-1980s. He formed a public benefit corporation (PBC) in 2014 with an eye toward FDA approval. The PBC fully separated from MAPS in 2024 and became Lykos.

Although the FDA has left the door open to approval, Lykos has not released the agency’s complete response letter, so it’s not clear exactly what the FDA is seeking. In a statement, the company said it believes the issues “can be addressed with existing data, postapproval requirements, or through reference to the scientific literature.”

Lykos said in an email that it is working on “securing the meeting with the FDA” and that it “will work with the agency to determine what needs to be done to fulfill their requests.”

Soon after the FDA decision, Lykos was hit with another blow. The journal Psychopharmacology retracted an article that pooled six Lykos phase 2 studies, claiming the paper’s authors knew about unethical conduct before submission but did not inform the publisher.

Lykos said the issues could have been addressed through a correction and that it has filed a complaint with the Committee on Publication Ethics. It also noted that the misconduct at issue was reported to the FDA and Health Canada.

“However, we did not disclose the violations to the journal itself, an additional step we should have taken and regret not doing,” the company said. It added that the efficacy data in the paper were not part of the FDA submission.

Author Allison A. Feduccia, PhD, cofounder of Psychedelic Support, agreed with the retraction but disagreed with the wording. In a post on LinkedIn, she said she and other authors were not informed about the misconduct until years after the study’s submission.

Four authors — including Dr. Doblin — disagreed with the retraction.

Dr. Doblin said in a statement that he’d resigned from Lykos to escape the restrictions that came with being a fiduciary. “Now I can advocate and speak freely,” he said, adding that he could also return to his activist roots.

He predicted that Lykos would eventually gain FDA approval. But if Lykos can’t convince the agency, it have the necessary data already in hand; “potential FDA approval is now at least 2 years away, possibly more,” Dr. Doblin said in his statement.
 

Research Continues

Lykos is not the only company hoping to commercialize MDMA. Toronto-based Awakn Life Sciences has an MDMA preclinical development program for addiction. In addition, some companies are offering MDMA therapy through clinics, such as Numinus in Utah and Sunstone Therapies in Rockville, Maryland.

But Lykos was the closest to bringing a product to market. The company is still a sponsor of four MDMA-related clinical trials, three of which appear to be on hold. One study at the VA San Diego Healthcare System, San Diego, that is actively recruiting is an open-label trial to assess MDMA-AT in combination with brief Cognitive-Behavioral Conjoint Therapy for PTSD.

Those studies are among 13 US trials listed in ClinicalTrials.gov that have not yet begun recruiting and 7 that are actively recruiting.

Among them is a study of MDMA plus exposure therapy, funded by and conducted at Emory University in Atlanta. One of the Emory principal investigators, Barbara Rothbaum, MD, has also been named to a Lykos’ panel that would help ensure oversight of MDMA-AT post FDA approval.

Dr. Ostacher is an investigator in a study planned at VA Palo Alto Health Care System in California, that will compare MDMA-AT with cognitive processing therapy in veterans with severe PTSD. He said it will be open label in an effort to minimize expectation bias and issues with blinding — both problems that tripped up the Lykos application. Although placebo-controlled trials are the gold standard, it’s not ideal when “the purpose of the drug is for it to change how you see the world and yourself,” Dr. Ostacher said.

The study aims to see whether MDMA-AT is better than “a much shorter, less onerous, but quite evidence-based psychotherapy for PTSD,” he said.

The FDA’s decision is not the end of the road, said Dr. Ostacher. “Even though I think this makes for an obvious delay, I don’t think that it’s a permanent one,” he said.

Dr. Yehuda also said she is not ready to give up.

“We don’t plan on stopping — we plan on finding a way,” she said.

“In our experience, this is a very powerful approach that helps a lot of people that haven’t found help using other approaches, and when it’s in the hands of really trusted, experienced, ethical clinicians in a trusted environment, this could be a real game changer for people who have not been able to find belief by traditional methods,” she said.

Dr. Ostacher reported no relevant financial relationships. Dr. Yahuda is the principal investigator on clinical trials for the Center for Psychedelic Psychotherapy and Trauma Research that are sponsored by the Multidisciplinary Association for Psychedelic Studies and COMPASS Pathways.

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

The Food and Drug Administration’s (FDA) decision not to approve midomafetamine-assisted therapy (MDMA-AT) for posttraumatic stress disorder (PTSD) puts the therapy’s near-term future in doubt, but officials say the rejection may not knock it out of contention as an eventual therapeutic tool for a variety of conditions.

In August the agency declined to approve the drug with currently available study data and requested that the company conduct an additional phase 3 trial. The agency’s action had potentially devastating consequences for MDMA-AT’s sponsor, Lykos Therapeutics, and was a huge disappointment for researchers, clinicians, and patients who were optimistic that it would be a new option for a condition that affects 13-17 million Americans.

For now, no other company is poised to imminently seek FDA approval for MDMA.

Despite the setback, research into MDMA that combines different psychotherapeutic approaches continues. Currently, there are seven US studies actively recruiting participants, and another 13 are registered with an eye toward starting recruitment, as reported on ClinicalTrials.gov.

The lack of FDA approval “actually increases the opportunity now for us to do trials,” said Michael Ostacher, MD, professor of psychiatry and behavioral sciences at Stanford Medicine in California. Researchers won’t have to be sponsored by Lykos to get access to MDMA.

“There’s a lot of energy and interest in doing these studies,” he said in an interview, adding that philanthropic organizations and Veterans Affairs (VA) are contributing funds to support such studies.

The VA provided a statement saying that it “intends to gather rigorous scientific evidence on the potential efficacy and safety of psychedelic compounds when used in conjunction with psychotherapy.” It also noted that “these studies will be conducted under stringent safety protocols and will mark the first time since the 1960’s that VA is funding research on such compounds.”

Rachel Yehuda, PhD, director of the Center for Psychedelic Therapy Research at Icahn School of Medicine at Mount Sinai in New York City, said in an interview that the FDA rejection “raises questions about how to keep the work going.”

Without the FDA’s imprimatur, MDMA remains a schedule 1 drug, which means it has no valid medical use.

“It’s a lot more complicated and expensive to work with a scheduled compound than to work with a compound that has been approved,” Dr. Yehuda said.

Also, without Lykos or another drug company sponsor, investigators have to find an acceptable MDMA source on their own, said Dr. Yehuda, who was an investigator on a study in which Lykos provided MDMA but was not involved in study design, data collection, analysis, or manuscript preparation.
 

Lykos in Disarray

Within a week of the FDA’s decision, Lykos announced it was cutting its staff by 75% and that Rick Doblin, PhD, the founder and president of the Multidisciplinary Association for Psychedelic Studies (MAPS) that gave rise to Lykos, had resigned from the Lykos board.

A frequently controversial figure, Doblin has been attempting to legitimize MDMA as a therapy since the mid-1980s. He formed a public benefit corporation (PBC) in 2014 with an eye toward FDA approval. The PBC fully separated from MAPS in 2024 and became Lykos.

Although the FDA has left the door open to approval, Lykos has not released the agency’s complete response letter, so it’s not clear exactly what the FDA is seeking. In a statement, the company said it believes the issues “can be addressed with existing data, postapproval requirements, or through reference to the scientific literature.”

Lykos said in an email that it is working on “securing the meeting with the FDA” and that it “will work with the agency to determine what needs to be done to fulfill their requests.”

Soon after the FDA decision, Lykos was hit with another blow. The journal Psychopharmacology retracted an article that pooled six Lykos phase 2 studies, claiming the paper’s authors knew about unethical conduct before submission but did not inform the publisher.

Lykos said the issues could have been addressed through a correction and that it has filed a complaint with the Committee on Publication Ethics. It also noted that the misconduct at issue was reported to the FDA and Health Canada.

“However, we did not disclose the violations to the journal itself, an additional step we should have taken and regret not doing,” the company said. It added that the efficacy data in the paper were not part of the FDA submission.

Author Allison A. Feduccia, PhD, cofounder of Psychedelic Support, agreed with the retraction but disagreed with the wording. In a post on LinkedIn, she said she and other authors were not informed about the misconduct until years after the study’s submission.

Four authors — including Dr. Doblin — disagreed with the retraction.

Dr. Doblin said in a statement that he’d resigned from Lykos to escape the restrictions that came with being a fiduciary. “Now I can advocate and speak freely,” he said, adding that he could also return to his activist roots.

He predicted that Lykos would eventually gain FDA approval. But if Lykos can’t convince the agency, it have the necessary data already in hand; “potential FDA approval is now at least 2 years away, possibly more,” Dr. Doblin said in his statement.
 

Research Continues

Lykos is not the only company hoping to commercialize MDMA. Toronto-based Awakn Life Sciences has an MDMA preclinical development program for addiction. In addition, some companies are offering MDMA therapy through clinics, such as Numinus in Utah and Sunstone Therapies in Rockville, Maryland.

But Lykos was the closest to bringing a product to market. The company is still a sponsor of four MDMA-related clinical trials, three of which appear to be on hold. One study at the VA San Diego Healthcare System, San Diego, that is actively recruiting is an open-label trial to assess MDMA-AT in combination with brief Cognitive-Behavioral Conjoint Therapy for PTSD.

Those studies are among 13 US trials listed in ClinicalTrials.gov that have not yet begun recruiting and 7 that are actively recruiting.

Among them is a study of MDMA plus exposure therapy, funded by and conducted at Emory University in Atlanta. One of the Emory principal investigators, Barbara Rothbaum, MD, has also been named to a Lykos’ panel that would help ensure oversight of MDMA-AT post FDA approval.

Dr. Ostacher is an investigator in a study planned at VA Palo Alto Health Care System in California, that will compare MDMA-AT with cognitive processing therapy in veterans with severe PTSD. He said it will be open label in an effort to minimize expectation bias and issues with blinding — both problems that tripped up the Lykos application. Although placebo-controlled trials are the gold standard, it’s not ideal when “the purpose of the drug is for it to change how you see the world and yourself,” Dr. Ostacher said.

The study aims to see whether MDMA-AT is better than “a much shorter, less onerous, but quite evidence-based psychotherapy for PTSD,” he said.

The FDA’s decision is not the end of the road, said Dr. Ostacher. “Even though I think this makes for an obvious delay, I don’t think that it’s a permanent one,” he said.

Dr. Yehuda also said she is not ready to give up.

“We don’t plan on stopping — we plan on finding a way,” she said.

“In our experience, this is a very powerful approach that helps a lot of people that haven’t found help using other approaches, and when it’s in the hands of really trusted, experienced, ethical clinicians in a trusted environment, this could be a real game changer for people who have not been able to find belief by traditional methods,” she said.

Dr. Ostacher reported no relevant financial relationships. Dr. Yahuda is the principal investigator on clinical trials for the Center for Psychedelic Psychotherapy and Trauma Research that are sponsored by the Multidisciplinary Association for Psychedelic Studies and COMPASS Pathways.

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

Adjuvant radiotherapy reduces the risk for short-term recurrence in patients with early breast cancer, but it may have no impact on long-term recurrence or overall survival, based on a 30-year follow-up of the Scottish Breast Conservation Trial.

These findings suggest that patients with biology predicting late relapse may receive little benefit from adjuvant radiotherapy, lead author Linda J. Williams, PhD, of the University of Edinburgh in Scotland, and colleagues, reported.

“During the past 30 years, several randomized controlled trials have investigated the role of postoperative radiotherapy after breast-conserving surgery for early breast cancer,” the investigators wrote in The Lancet Oncology. “These trials showed that radiotherapy reduces the risk of local recurrence but were underpowered individually to detect a difference in overall survival.”
 

How Did the Present Study Increase Our Understanding of the Benefits of Adjuvant Radiotherapy in Early Breast Cancer?

The present analysis included data from a trial that began in 1985, when 589 patients with early breast cancer (tumors ≤ 4 cm [T1 or T2 and N0 or N1]) were randomized to receive either high-dose or no radiotherapy, with final cohorts including 291 patients and 294 patients, respectively. The radiotherapy was given 50 Gy in 20-25 fractions, either locally or locoregionally.

Estrogen receptor (ER)–positive patients (≥ 20 fmol/mg protein) received 5 years of daily oral tamoxifen. ER-poor patients (< 20 fmol/mg protein) received a chemotherapy combination of cyclophosphamide, methotrexate, and fluorouracil on a 21-day cycle for eight cycles.

Considering all data across a median follow-up of 17.5 years, adjuvant radiotherapy appeared to offer benefit, as it was associated with significantly lower ipsilateral breast tumor recurrence (16% vs 36%; hazard ratio [HR], 0.39; P < .0001).

But that tells only part of the story.

The positive impact of radiotherapy persisted for 1 decade (HR, 0.24; P < .0001), but risk beyond this point was no different between groups (HR, 0.98; P = .95).

“[The] benefit of radiotherapy was time dependent,” the investigators noted.

What’s more, median overall survival was no different between those who received radiotherapy and those who did not (18.7 vs 19.2 years; HR, 1.08; log-rank P = .43), and “reassuringly,” omitting radiotherapy did not increase the rate of distant metastasis.
 

How Might These Findings Influence Treatment Planning for Patients With Early Breast Cancer?

“The results can help clinicians to advise patients better about their choice to have radiotherapy or not if they better understand what benefits it does and does not bring,” the investigators wrote. “These results might provide clues perhaps to the biology of radiotherapy benefit, given that it does not prevent late recurrences, suggesting that patients whose biology predicts a late relapse only might not gain a benefit from radiotherapy.”

Gary M. Freedman, MD, chief of Women’s Health Service, Radiation Oncology, at Penn Medicine, Philadelphia, offered a different perspective.

“The study lumps together a local recurrence of breast cancer — that is relapse of the cancer years after treatment with lumpectomy and radiation — with the development of an entirely new breast cancer in the same breast,” Dr. Freedman said in a written comment. “When something comes back between years 0-5 and 0-8, we usually think of it as a true local recurrence arbitrarily, but beyond that they are new cancers.”

He went on to emphasize the clinical importance of reducing local recurrence within the first decade, noting that “this leads to much less morbidity and better quality of life for the patients.”

Dr. Freedman also shared his perspective on the survival data.

“Radiation did reduce breast cancer mortality very significantly — death from breast cancers went down from 46% to 37%,” he wrote (P = .054). “This is on the same level as chemo or hormone therapy. The study was not powered to detect significant differences in survival by radiation, but that has been shown with other meta-analyses.”
 

Are Findings From a Trial Started 30 Years Ago Still Relevant Today?

“Clearly the treatment of early breast cancer has advanced since the 1980s when the Scottish Conservation trial was launched,” study coauthor Ian Kunkler, MB, FRCR, of the University of Edinburgh, said in a written comment. “There is more breast screening, attention to clearing surgical margins of residual disease, more effective and longer periods of adjuvant hormonal therapy, reduced radiotherapy toxicity from more precise delivery. However, most anticancer treatments lose their effectiveness over time.”

He suggested that more trials are needed to confirm the present findings and reiterated that the lack of long-term recurrence benefit is most relevant for patients with disease features that predict late relapse, who “seem to gain little from adjuvant radiotherapy given as part of primary treatment.”

Dr. Kunkler noted that the observed benefit in the first decade supports the continued use of radiotherapy alongside anticancer drug treatment.

When asked the same question, Freedman emphasized the differences in treatment today vs the 1980s.

“The results of modern multidisciplinary cancer care are much, much better than these 30-year results,” Dr. Freedman said. “The risk for local recurrence in the breast after radiation is now about 2%-3% at 10 years in most studies.”

He also noted that modern radiotherapy techniques have “significantly lowered dose and risks to heart and lung,” compared with techniques used 30 years ago.

“A take-home point for the study is after breast conservation, whether or not you have radiation, you have to continue long-term screening mammograms for new breast cancers that may occur even decades later,” Dr. Freedman concluded.
 

How Might These Findings Impact Future Research Design and Funding?

“The findings should encourage trial funders to consider funding long-term follow-up beyond 10 years to assess benefits and risks of anticancer therapies,” Dr. Kunkler said. “The importance of long-term follow-up cannot be understated.”

This study was funded by Breast Cancer Institute (part of Edinburgh and Lothians Health Foundation), PFS Genomics (now part of Exact Sciences), the University of Edinburgh, and NHS Lothian. The investigators reported no conflicts of interest.

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

Adjuvant radiotherapy reduces the risk for short-term recurrence in patients with early breast cancer, but it may have no impact on long-term recurrence or overall survival, based on a 30-year follow-up of the Scottish Breast Conservation Trial.

These findings suggest that patients with biology predicting late relapse may receive little benefit from adjuvant radiotherapy, lead author Linda J. Williams, PhD, of the University of Edinburgh in Scotland, and colleagues, reported.

“During the past 30 years, several randomized controlled trials have investigated the role of postoperative radiotherapy after breast-conserving surgery for early breast cancer,” the investigators wrote in The Lancet Oncology. “These trials showed that radiotherapy reduces the risk of local recurrence but were underpowered individually to detect a difference in overall survival.”
 

How Did the Present Study Increase Our Understanding of the Benefits of Adjuvant Radiotherapy in Early Breast Cancer?

The present analysis included data from a trial that began in 1985, when 589 patients with early breast cancer (tumors ≤ 4 cm [T1 or T2 and N0 or N1]) were randomized to receive either high-dose or no radiotherapy, with final cohorts including 291 patients and 294 patients, respectively. The radiotherapy was given 50 Gy in 20-25 fractions, either locally or locoregionally.

Estrogen receptor (ER)–positive patients (≥ 20 fmol/mg protein) received 5 years of daily oral tamoxifen. ER-poor patients (< 20 fmol/mg protein) received a chemotherapy combination of cyclophosphamide, methotrexate, and fluorouracil on a 21-day cycle for eight cycles.

Considering all data across a median follow-up of 17.5 years, adjuvant radiotherapy appeared to offer benefit, as it was associated with significantly lower ipsilateral breast tumor recurrence (16% vs 36%; hazard ratio [HR], 0.39; P < .0001).

But that tells only part of the story.

The positive impact of radiotherapy persisted for 1 decade (HR, 0.24; P < .0001), but risk beyond this point was no different between groups (HR, 0.98; P = .95).

“[The] benefit of radiotherapy was time dependent,” the investigators noted.

What’s more, median overall survival was no different between those who received radiotherapy and those who did not (18.7 vs 19.2 years; HR, 1.08; log-rank P = .43), and “reassuringly,” omitting radiotherapy did not increase the rate of distant metastasis.
 

How Might These Findings Influence Treatment Planning for Patients With Early Breast Cancer?

“The results can help clinicians to advise patients better about their choice to have radiotherapy or not if they better understand what benefits it does and does not bring,” the investigators wrote. “These results might provide clues perhaps to the biology of radiotherapy benefit, given that it does not prevent late recurrences, suggesting that patients whose biology predicts a late relapse only might not gain a benefit from radiotherapy.”

Gary M. Freedman, MD, chief of Women’s Health Service, Radiation Oncology, at Penn Medicine, Philadelphia, offered a different perspective.

“The study lumps together a local recurrence of breast cancer — that is relapse of the cancer years after treatment with lumpectomy and radiation — with the development of an entirely new breast cancer in the same breast,” Dr. Freedman said in a written comment. “When something comes back between years 0-5 and 0-8, we usually think of it as a true local recurrence arbitrarily, but beyond that they are new cancers.”

He went on to emphasize the clinical importance of reducing local recurrence within the first decade, noting that “this leads to much less morbidity and better quality of life for the patients.”

Dr. Freedman also shared his perspective on the survival data.

“Radiation did reduce breast cancer mortality very significantly — death from breast cancers went down from 46% to 37%,” he wrote (P = .054). “This is on the same level as chemo or hormone therapy. The study was not powered to detect significant differences in survival by radiation, but that has been shown with other meta-analyses.”
 

Are Findings From a Trial Started 30 Years Ago Still Relevant Today?

“Clearly the treatment of early breast cancer has advanced since the 1980s when the Scottish Conservation trial was launched,” study coauthor Ian Kunkler, MB, FRCR, of the University of Edinburgh, said in a written comment. “There is more breast screening, attention to clearing surgical margins of residual disease, more effective and longer periods of adjuvant hormonal therapy, reduced radiotherapy toxicity from more precise delivery. However, most anticancer treatments lose their effectiveness over time.”

He suggested that more trials are needed to confirm the present findings and reiterated that the lack of long-term recurrence benefit is most relevant for patients with disease features that predict late relapse, who “seem to gain little from adjuvant radiotherapy given as part of primary treatment.”

Dr. Kunkler noted that the observed benefit in the first decade supports the continued use of radiotherapy alongside anticancer drug treatment.

When asked the same question, Freedman emphasized the differences in treatment today vs the 1980s.

“The results of modern multidisciplinary cancer care are much, much better than these 30-year results,” Dr. Freedman said. “The risk for local recurrence in the breast after radiation is now about 2%-3% at 10 years in most studies.”

He also noted that modern radiotherapy techniques have “significantly lowered dose and risks to heart and lung,” compared with techniques used 30 years ago.

“A take-home point for the study is after breast conservation, whether or not you have radiation, you have to continue long-term screening mammograms for new breast cancers that may occur even decades later,” Dr. Freedman concluded.
 

How Might These Findings Impact Future Research Design and Funding?

“The findings should encourage trial funders to consider funding long-term follow-up beyond 10 years to assess benefits and risks of anticancer therapies,” Dr. Kunkler said. “The importance of long-term follow-up cannot be understated.”

This study was funded by Breast Cancer Institute (part of Edinburgh and Lothians Health Foundation), PFS Genomics (now part of Exact Sciences), the University of Edinburgh, and NHS Lothian. The investigators reported no conflicts of interest.

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

Adjuvant radiotherapy reduces the risk for short-term recurrence in patients with early breast cancer, but it may have no impact on long-term recurrence or overall survival, based on a 30-year follow-up of the Scottish Breast Conservation Trial.

These findings suggest that patients with biology predicting late relapse may receive little benefit from adjuvant radiotherapy, lead author Linda J. Williams, PhD, of the University of Edinburgh in Scotland, and colleagues, reported.

“During the past 30 years, several randomized controlled trials have investigated the role of postoperative radiotherapy after breast-conserving surgery for early breast cancer,” the investigators wrote in The Lancet Oncology. “These trials showed that radiotherapy reduces the risk of local recurrence but were underpowered individually to detect a difference in overall survival.”
 

How Did the Present Study Increase Our Understanding of the Benefits of Adjuvant Radiotherapy in Early Breast Cancer?

The present analysis included data from a trial that began in 1985, when 589 patients with early breast cancer (tumors ≤ 4 cm [T1 or T2 and N0 or N1]) were randomized to receive either high-dose or no radiotherapy, with final cohorts including 291 patients and 294 patients, respectively. The radiotherapy was given 50 Gy in 20-25 fractions, either locally or locoregionally.

Estrogen receptor (ER)–positive patients (≥ 20 fmol/mg protein) received 5 years of daily oral tamoxifen. ER-poor patients (< 20 fmol/mg protein) received a chemotherapy combination of cyclophosphamide, methotrexate, and fluorouracil on a 21-day cycle for eight cycles.

Considering all data across a median follow-up of 17.5 years, adjuvant radiotherapy appeared to offer benefit, as it was associated with significantly lower ipsilateral breast tumor recurrence (16% vs 36%; hazard ratio [HR], 0.39; P < .0001).

But that tells only part of the story.

The positive impact of radiotherapy persisted for 1 decade (HR, 0.24; P < .0001), but risk beyond this point was no different between groups (HR, 0.98; P = .95).

“[The] benefit of radiotherapy was time dependent,” the investigators noted.

What’s more, median overall survival was no different between those who received radiotherapy and those who did not (18.7 vs 19.2 years; HR, 1.08; log-rank P = .43), and “reassuringly,” omitting radiotherapy did not increase the rate of distant metastasis.
 

How Might These Findings Influence Treatment Planning for Patients With Early Breast Cancer?

“The results can help clinicians to advise patients better about their choice to have radiotherapy or not if they better understand what benefits it does and does not bring,” the investigators wrote. “These results might provide clues perhaps to the biology of radiotherapy benefit, given that it does not prevent late recurrences, suggesting that patients whose biology predicts a late relapse only might not gain a benefit from radiotherapy.”

Gary M. Freedman, MD, chief of Women’s Health Service, Radiation Oncology, at Penn Medicine, Philadelphia, offered a different perspective.

“The study lumps together a local recurrence of breast cancer — that is relapse of the cancer years after treatment with lumpectomy and radiation — with the development of an entirely new breast cancer in the same breast,” Dr. Freedman said in a written comment. “When something comes back between years 0-5 and 0-8, we usually think of it as a true local recurrence arbitrarily, but beyond that they are new cancers.”

He went on to emphasize the clinical importance of reducing local recurrence within the first decade, noting that “this leads to much less morbidity and better quality of life for the patients.”

Dr. Freedman also shared his perspective on the survival data.

“Radiation did reduce breast cancer mortality very significantly — death from breast cancers went down from 46% to 37%,” he wrote (P = .054). “This is on the same level as chemo or hormone therapy. The study was not powered to detect significant differences in survival by radiation, but that has been shown with other meta-analyses.”
 

Are Findings From a Trial Started 30 Years Ago Still Relevant Today?

“Clearly the treatment of early breast cancer has advanced since the 1980s when the Scottish Conservation trial was launched,” study coauthor Ian Kunkler, MB, FRCR, of the University of Edinburgh, said in a written comment. “There is more breast screening, attention to clearing surgical margins of residual disease, more effective and longer periods of adjuvant hormonal therapy, reduced radiotherapy toxicity from more precise delivery. However, most anticancer treatments lose their effectiveness over time.”

He suggested that more trials are needed to confirm the present findings and reiterated that the lack of long-term recurrence benefit is most relevant for patients with disease features that predict late relapse, who “seem to gain little from adjuvant radiotherapy given as part of primary treatment.”

Dr. Kunkler noted that the observed benefit in the first decade supports the continued use of radiotherapy alongside anticancer drug treatment.

When asked the same question, Freedman emphasized the differences in treatment today vs the 1980s.

“The results of modern multidisciplinary cancer care are much, much better than these 30-year results,” Dr. Freedman said. “The risk for local recurrence in the breast after radiation is now about 2%-3% at 10 years in most studies.”

He also noted that modern radiotherapy techniques have “significantly lowered dose and risks to heart and lung,” compared with techniques used 30 years ago.

“A take-home point for the study is after breast conservation, whether or not you have radiation, you have to continue long-term screening mammograms for new breast cancers that may occur even decades later,” Dr. Freedman concluded.
 

How Might These Findings Impact Future Research Design and Funding?

“The findings should encourage trial funders to consider funding long-term follow-up beyond 10 years to assess benefits and risks of anticancer therapies,” Dr. Kunkler said. “The importance of long-term follow-up cannot be understated.”

This study was funded by Breast Cancer Institute (part of Edinburgh and Lothians Health Foundation), PFS Genomics (now part of Exact Sciences), the University of Edinburgh, and NHS Lothian. The investigators reported no conflicts of interest.

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

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are associated with an increased risk for breast cancer, and CHIP is associated with increased mortality in patients with colon cancer, according to the authors of new research.

These findings, drawn from almost 11,000 patients in the Women’s Health Initiative (WHI) study, add further evidence that CHIP and mCA drive solid tumor risk, alongside known associations with hematologic malignancies, reported lead author Pinkal Desai, MD, associate professor of medicine and clinical director of molecular aging at Englander Institute for Precision Medicine, Weill Cornell Medical College, New York City, and colleagues.
 

How This Study Differs From Others of Breast Cancer Risk Factors

“The independent effect of CHIP and mCA on risk and mortality from solid tumors has not been elucidated due to lack of detailed data on mortality outcomes and risk factors,” the investigators wrote in Cancer, although some previous studies have suggested a link.

In particular, the investigators highlighted a 2022 UK Biobank study, which reported an association between CHIP and lung cancer and a borderline association with breast cancer that did not quite reach statistical significance.

But the UK Biobank study was confined to a UK population, Dr. Desai noted in an interview, and the data were less detailed than those in the present investigation.

“In terms of risk, the part that was lacking in previous studies was a comprehensive assessment of risk factors that increase risk for all these cancers,” Dr. Desai said. “For example, for breast cancer, we had very detailed data on [participants’] Gail risk score, which is known to impact breast cancer risk. We also had mammogram data and colonoscopy data.”

In an accompanying editorial, Koichi Takahashi, MD, PhD , and Nehali Shah, BS, of The University of Texas MD Anderson Cancer Center, Houston, Texas, pointed out the same UK Biobank findings, then noted that CHIP has also been linked with worse overall survival in unselected cancer patients. Still, they wrote, “the impact of CH on cancer risk and mortality remains controversial due to conflicting data and context‐dependent effects,” necessitating studies like this one by Dr. Desai and colleagues.
 

How Was the Relationship Between CHIP, MCA, and Solid Tumor Risk Assessed?

To explore possible associations between CHIP, mCA, and solid tumors, the investigators analyzed whole genome sequencing data from 10,866 women in the WHI, a multi-study program that began in 1992 and involved 161,808 women in both observational and clinical trial cohorts.

In 2002, the first big data release from the WHI suggested that hormone replacement therapy (HRT) increased breast cancer risk, leading to widespread reduction in HRT use.

More recent reports continue to shape our understanding of these risks, suggesting differences across cancer types. For breast cancer, the WHI data suggested that HRT-associated risk was largely driven by formulations involving progesterone and estrogen, whereas estrogen-only formulations, now more common, are generally considered to present an acceptable risk profile for suitable patients.

The new study accounted for this potential HRT-associated risk, including by adjusting for patients who received HRT, type of HRT received, and duration of HRT received. According to Desai, this approach is commonly used when analyzing data from the WHI, nullifying concerns about the potentially deleterious effects of the hormones used in the study.

“Our question was not ‘does HRT cause cancer?’ ” Dr. Desai said in an interview. “But HRT can be linked to breast cancer risk and has a potential to be a confounder, and hence the above methodology.

“So I can say that the confounding/effect modification that HRT would have contributed to in the relationship between exposure (CH and mCA) and outcome (cancer) is well adjusted for as described above. This is standard in WHI analyses,” she continued.

“Every Women’s Health Initiative analysis that comes out — not just for our study — uses a standard method ... where you account for hormonal therapy,” Dr. Desai added, again noting that many other potential risk factors were considered, enabling a “detailed, robust” analysis.

Dr. Takahashi and Ms. Shah agreed. “A notable strength of this study is its adjustment for many confounding factors,” they wrote. “The cohort’s well‐annotated data on other known cancer risk factors allowed for a robust assessment of CH’s independent risk.”
 

How Do Findings Compare With Those of the UK Biobank Study?

CHIP was associated with a 30% increased risk for breast cancer (hazard ratio [HR], 1.30; 95% CI, 1.03-1.64; P = .02), strengthening the borderline association reported by the UK Biobank study.

In contrast with the UK Biobank study, CHIP was not associated with lung cancer risk, although this may have been caused by fewer cases of lung cancer and a lack of male patients, Dr. Desai suggested.

“The discrepancy between the studies lies in the risk of lung cancer, although the point estimate in the current study suggested a positive association,” wrote Dr. Takahashi and Ms. Shah.

As in the UK Biobank study, CHIP was not associated with increased risk of developing colorectal cancer.

Mortality analysis, however, which was not conducted in the UK Biobank study, offered a new insight: Patients with existing colorectal cancer and CHIP had a significantly higher mortality risk than those without CHIP. Before stage adjustment, risk for mortality among those with colorectal cancer and CHIP was fourfold higher than those without CHIP (HR, 3.99; 95% CI, 2.41-6.62; P < .001). After stage adjustment, CHIP was still associated with a twofold higher mortality risk (HR, 2.50; 95% CI, 1.32-4.72; P = .004).

The investigators’ first mCA analyses, which employed a cell fraction cutoff greater than 3%, were unfruitful. But raising the cell fraction threshold to 5% in an exploratory analysis showed that autosomal mCA was associated with a 39% increased risk for breast cancer (HR, 1.39; 95% CI, 1.06-1.83; P = .01). No such associations were found between mCA and colorectal or lung cancer, regardless of cell fraction threshold.

The original 3% cell fraction threshold was selected on the basis of previous studies reporting a link between mCA and hematologic malignancies at this cutoff, Dr. Desai said.

She and her colleagues said a higher 5% cutoff might be needed, as they suspected that the link between mCA and solid tumors may not be causal, requiring a higher mutation rate.
 

Why Do Results Differ Between These Types of Studies?

Dr. Takahashi and Ms. Shah suggested that one possible limitation of the new study, and an obstacle to comparing results with the UK Biobank study and others like it, goes beyond population heterogeneity; incongruent findings could also be explained by differences in whole genome sequencing (WGS) technique.

“Although WGS allows sensitive detection of mCA through broad genomic coverage, it is less effective at detecting CHIP with low variant allele frequency (VAF) due to its relatively shallow depth (30x),” they wrote. “Consequently, the prevalence of mCA (18.8%) was much higher than that of CHIP (8.3%) in this cohort, contrasting with other studies using deeper sequencing.” As a result, the present study may have underestimated CHIP prevalence because of shallow sequencing depth.

“This inconsistency is a common challenge in CH population studies due to the lack of standardized methodologies and the frequent reliance on preexisting data not originally intended for CH detection,” Dr. Takahashi and Ms. Shah said.

Even so, despite the “heavily context-dependent” nature of these reported risks, the body of evidence to date now offers a convincing biological rationale linking CH with cancer development and outcomes, they added.
 

How Do the CHIP- and mCA-associated Risks Differ Between Solid Tumors and Blood Cancers?

“[These solid tumor risks are] not causal in the way CHIP mutations are causal for blood cancers,” Dr. Desai said. “Here we are talking about solid tumor risk, and it’s kind of scattered. It’s not just breast cancer ... there’s also increased colon cancer mortality. So I feel these mutations are doing something different ... they are sort of an added factor.”

Specific mechanisms remain unclear, Dr. Desai said, although she speculated about possible impacts on the inflammatory state or alterations to the tumor microenvironment.

“These are blood cells, right?” Dr. Desai asked. “They’re everywhere, and they’re changing something inherently in these tumors.”
 

Future research and therapeutic development

Siddhartha Jaiswal, MD, PhD, assistant professor in the Department of Pathology at Stanford University in California, whose lab focuses on clonal hematopoiesis, said the causality question is central to future research.

“The key question is, are these mutations acting because they alter the function of blood cells in some way to promote cancer risk, or is it reflective of some sort of shared etiology that’s not causal?” Dr. Jaiswal said in an interview.

Available data support both possibilities.

On one side, “reasonable evidence” supports the noncausal view, Dr. Jaiswal noted, because telomere length is one of the most common genetic risk factors for clonal hematopoiesis and also for solid tumors, suggesting a shared genetic factor. On the other hand, CHIP and mCA could be directly protumorigenic via conferred disturbances of immune cell function.

When asked if both causal and noncausal factors could be at play, Dr. Jaiswal said, “yeah, absolutely.”

The presence of a causal association could be promising from a therapeutic standpoint.

“If it turns out that this association is driven by a direct causal effect of the mutations, perhaps related to immune cell function or dysfunction, then targeting that dysfunction could be a therapeutic path to improve outcomes in people, and there’s a lot of interest in this,” Dr. Jaiswal said. He went on to explain how a trial exploring this approach via interleukin-8 inhibition in lung cancer fell short.

Yet earlier intervention may still hold promise, according to experts.

“[This study] provokes the hypothesis that CH‐targeted interventions could potentially reduce cancer risk in the future,” Dr. Takahashi and Ms. Shah said in their editorial.

The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The investigators disclosed relationships with Eli Lilly, AbbVie, Celgene, and others. Dr. Jaiswal reported stock equity in a company that has an interest in clonal hematopoiesis.

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

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are associated with an increased risk for breast cancer, and CHIP is associated with increased mortality in patients with colon cancer, according to the authors of new research.

These findings, drawn from almost 11,000 patients in the Women’s Health Initiative (WHI) study, add further evidence that CHIP and mCA drive solid tumor risk, alongside known associations with hematologic malignancies, reported lead author Pinkal Desai, MD, associate professor of medicine and clinical director of molecular aging at Englander Institute for Precision Medicine, Weill Cornell Medical College, New York City, and colleagues.
 

How This Study Differs From Others of Breast Cancer Risk Factors

“The independent effect of CHIP and mCA on risk and mortality from solid tumors has not been elucidated due to lack of detailed data on mortality outcomes and risk factors,” the investigators wrote in Cancer, although some previous studies have suggested a link.

In particular, the investigators highlighted a 2022 UK Biobank study, which reported an association between CHIP and lung cancer and a borderline association with breast cancer that did not quite reach statistical significance.

But the UK Biobank study was confined to a UK population, Dr. Desai noted in an interview, and the data were less detailed than those in the present investigation.

“In terms of risk, the part that was lacking in previous studies was a comprehensive assessment of risk factors that increase risk for all these cancers,” Dr. Desai said. “For example, for breast cancer, we had very detailed data on [participants’] Gail risk score, which is known to impact breast cancer risk. We also had mammogram data and colonoscopy data.”

In an accompanying editorial, Koichi Takahashi, MD, PhD , and Nehali Shah, BS, of The University of Texas MD Anderson Cancer Center, Houston, Texas, pointed out the same UK Biobank findings, then noted that CHIP has also been linked with worse overall survival in unselected cancer patients. Still, they wrote, “the impact of CH on cancer risk and mortality remains controversial due to conflicting data and context‐dependent effects,” necessitating studies like this one by Dr. Desai and colleagues.
 

How Was the Relationship Between CHIP, MCA, and Solid Tumor Risk Assessed?

To explore possible associations between CHIP, mCA, and solid tumors, the investigators analyzed whole genome sequencing data from 10,866 women in the WHI, a multi-study program that began in 1992 and involved 161,808 women in both observational and clinical trial cohorts.

In 2002, the first big data release from the WHI suggested that hormone replacement therapy (HRT) increased breast cancer risk, leading to widespread reduction in HRT use.

More recent reports continue to shape our understanding of these risks, suggesting differences across cancer types. For breast cancer, the WHI data suggested that HRT-associated risk was largely driven by formulations involving progesterone and estrogen, whereas estrogen-only formulations, now more common, are generally considered to present an acceptable risk profile for suitable patients.

The new study accounted for this potential HRT-associated risk, including by adjusting for patients who received HRT, type of HRT received, and duration of HRT received. According to Desai, this approach is commonly used when analyzing data from the WHI, nullifying concerns about the potentially deleterious effects of the hormones used in the study.

“Our question was not ‘does HRT cause cancer?’ ” Dr. Desai said in an interview. “But HRT can be linked to breast cancer risk and has a potential to be a confounder, and hence the above methodology.

“So I can say that the confounding/effect modification that HRT would have contributed to in the relationship between exposure (CH and mCA) and outcome (cancer) is well adjusted for as described above. This is standard in WHI analyses,” she continued.

“Every Women’s Health Initiative analysis that comes out — not just for our study — uses a standard method ... where you account for hormonal therapy,” Dr. Desai added, again noting that many other potential risk factors were considered, enabling a “detailed, robust” analysis.

Dr. Takahashi and Ms. Shah agreed. “A notable strength of this study is its adjustment for many confounding factors,” they wrote. “The cohort’s well‐annotated data on other known cancer risk factors allowed for a robust assessment of CH’s independent risk.”
 

How Do Findings Compare With Those of the UK Biobank Study?

CHIP was associated with a 30% increased risk for breast cancer (hazard ratio [HR], 1.30; 95% CI, 1.03-1.64; P = .02), strengthening the borderline association reported by the UK Biobank study.

In contrast with the UK Biobank study, CHIP was not associated with lung cancer risk, although this may have been caused by fewer cases of lung cancer and a lack of male patients, Dr. Desai suggested.

“The discrepancy between the studies lies in the risk of lung cancer, although the point estimate in the current study suggested a positive association,” wrote Dr. Takahashi and Ms. Shah.

As in the UK Biobank study, CHIP was not associated with increased risk of developing colorectal cancer.

Mortality analysis, however, which was not conducted in the UK Biobank study, offered a new insight: Patients with existing colorectal cancer and CHIP had a significantly higher mortality risk than those without CHIP. Before stage adjustment, risk for mortality among those with colorectal cancer and CHIP was fourfold higher than those without CHIP (HR, 3.99; 95% CI, 2.41-6.62; P < .001). After stage adjustment, CHIP was still associated with a twofold higher mortality risk (HR, 2.50; 95% CI, 1.32-4.72; P = .004).

The investigators’ first mCA analyses, which employed a cell fraction cutoff greater than 3%, were unfruitful. But raising the cell fraction threshold to 5% in an exploratory analysis showed that autosomal mCA was associated with a 39% increased risk for breast cancer (HR, 1.39; 95% CI, 1.06-1.83; P = .01). No such associations were found between mCA and colorectal or lung cancer, regardless of cell fraction threshold.

The original 3% cell fraction threshold was selected on the basis of previous studies reporting a link between mCA and hematologic malignancies at this cutoff, Dr. Desai said.

She and her colleagues said a higher 5% cutoff might be needed, as they suspected that the link between mCA and solid tumors may not be causal, requiring a higher mutation rate.
 

Why Do Results Differ Between These Types of Studies?

Dr. Takahashi and Ms. Shah suggested that one possible limitation of the new study, and an obstacle to comparing results with the UK Biobank study and others like it, goes beyond population heterogeneity; incongruent findings could also be explained by differences in whole genome sequencing (WGS) technique.

“Although WGS allows sensitive detection of mCA through broad genomic coverage, it is less effective at detecting CHIP with low variant allele frequency (VAF) due to its relatively shallow depth (30x),” they wrote. “Consequently, the prevalence of mCA (18.8%) was much higher than that of CHIP (8.3%) in this cohort, contrasting with other studies using deeper sequencing.” As a result, the present study may have underestimated CHIP prevalence because of shallow sequencing depth.

“This inconsistency is a common challenge in CH population studies due to the lack of standardized methodologies and the frequent reliance on preexisting data not originally intended for CH detection,” Dr. Takahashi and Ms. Shah said.

Even so, despite the “heavily context-dependent” nature of these reported risks, the body of evidence to date now offers a convincing biological rationale linking CH with cancer development and outcomes, they added.
 

How Do the CHIP- and mCA-associated Risks Differ Between Solid Tumors and Blood Cancers?

“[These solid tumor risks are] not causal in the way CHIP mutations are causal for blood cancers,” Dr. Desai said. “Here we are talking about solid tumor risk, and it’s kind of scattered. It’s not just breast cancer ... there’s also increased colon cancer mortality. So I feel these mutations are doing something different ... they are sort of an added factor.”

Specific mechanisms remain unclear, Dr. Desai said, although she speculated about possible impacts on the inflammatory state or alterations to the tumor microenvironment.

“These are blood cells, right?” Dr. Desai asked. “They’re everywhere, and they’re changing something inherently in these tumors.”
 

Future research and therapeutic development

Siddhartha Jaiswal, MD, PhD, assistant professor in the Department of Pathology at Stanford University in California, whose lab focuses on clonal hematopoiesis, said the causality question is central to future research.

“The key question is, are these mutations acting because they alter the function of blood cells in some way to promote cancer risk, or is it reflective of some sort of shared etiology that’s not causal?” Dr. Jaiswal said in an interview.

Available data support both possibilities.

On one side, “reasonable evidence” supports the noncausal view, Dr. Jaiswal noted, because telomere length is one of the most common genetic risk factors for clonal hematopoiesis and also for solid tumors, suggesting a shared genetic factor. On the other hand, CHIP and mCA could be directly protumorigenic via conferred disturbances of immune cell function.

When asked if both causal and noncausal factors could be at play, Dr. Jaiswal said, “yeah, absolutely.”

The presence of a causal association could be promising from a therapeutic standpoint.

“If it turns out that this association is driven by a direct causal effect of the mutations, perhaps related to immune cell function or dysfunction, then targeting that dysfunction could be a therapeutic path to improve outcomes in people, and there’s a lot of interest in this,” Dr. Jaiswal said. He went on to explain how a trial exploring this approach via interleukin-8 inhibition in lung cancer fell short.

Yet earlier intervention may still hold promise, according to experts.

“[This study] provokes the hypothesis that CH‐targeted interventions could potentially reduce cancer risk in the future,” Dr. Takahashi and Ms. Shah said in their editorial.

The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The investigators disclosed relationships with Eli Lilly, AbbVie, Celgene, and others. Dr. Jaiswal reported stock equity in a company that has an interest in clonal hematopoiesis.

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

Clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) are associated with an increased risk for breast cancer, and CHIP is associated with increased mortality in patients with colon cancer, according to the authors of new research.

These findings, drawn from almost 11,000 patients in the Women’s Health Initiative (WHI) study, add further evidence that CHIP and mCA drive solid tumor risk, alongside known associations with hematologic malignancies, reported lead author Pinkal Desai, MD, associate professor of medicine and clinical director of molecular aging at Englander Institute for Precision Medicine, Weill Cornell Medical College, New York City, and colleagues.
 

How This Study Differs From Others of Breast Cancer Risk Factors

“The independent effect of CHIP and mCA on risk and mortality from solid tumors has not been elucidated due to lack of detailed data on mortality outcomes and risk factors,” the investigators wrote in Cancer, although some previous studies have suggested a link.

In particular, the investigators highlighted a 2022 UK Biobank study, which reported an association between CHIP and lung cancer and a borderline association with breast cancer that did not quite reach statistical significance.

But the UK Biobank study was confined to a UK population, Dr. Desai noted in an interview, and the data were less detailed than those in the present investigation.

“In terms of risk, the part that was lacking in previous studies was a comprehensive assessment of risk factors that increase risk for all these cancers,” Dr. Desai said. “For example, for breast cancer, we had very detailed data on [participants’] Gail risk score, which is known to impact breast cancer risk. We also had mammogram data and colonoscopy data.”

In an accompanying editorial, Koichi Takahashi, MD, PhD , and Nehali Shah, BS, of The University of Texas MD Anderson Cancer Center, Houston, Texas, pointed out the same UK Biobank findings, then noted that CHIP has also been linked with worse overall survival in unselected cancer patients. Still, they wrote, “the impact of CH on cancer risk and mortality remains controversial due to conflicting data and context‐dependent effects,” necessitating studies like this one by Dr. Desai and colleagues.
 

How Was the Relationship Between CHIP, MCA, and Solid Tumor Risk Assessed?

To explore possible associations between CHIP, mCA, and solid tumors, the investigators analyzed whole genome sequencing data from 10,866 women in the WHI, a multi-study program that began in 1992 and involved 161,808 women in both observational and clinical trial cohorts.

In 2002, the first big data release from the WHI suggested that hormone replacement therapy (HRT) increased breast cancer risk, leading to widespread reduction in HRT use.

More recent reports continue to shape our understanding of these risks, suggesting differences across cancer types. For breast cancer, the WHI data suggested that HRT-associated risk was largely driven by formulations involving progesterone and estrogen, whereas estrogen-only formulations, now more common, are generally considered to present an acceptable risk profile for suitable patients.

The new study accounted for this potential HRT-associated risk, including by adjusting for patients who received HRT, type of HRT received, and duration of HRT received. According to Desai, this approach is commonly used when analyzing data from the WHI, nullifying concerns about the potentially deleterious effects of the hormones used in the study.

“Our question was not ‘does HRT cause cancer?’ ” Dr. Desai said in an interview. “But HRT can be linked to breast cancer risk and has a potential to be a confounder, and hence the above methodology.

“So I can say that the confounding/effect modification that HRT would have contributed to in the relationship between exposure (CH and mCA) and outcome (cancer) is well adjusted for as described above. This is standard in WHI analyses,” she continued.

“Every Women’s Health Initiative analysis that comes out — not just for our study — uses a standard method ... where you account for hormonal therapy,” Dr. Desai added, again noting that many other potential risk factors were considered, enabling a “detailed, robust” analysis.

Dr. Takahashi and Ms. Shah agreed. “A notable strength of this study is its adjustment for many confounding factors,” they wrote. “The cohort’s well‐annotated data on other known cancer risk factors allowed for a robust assessment of CH’s independent risk.”
 

How Do Findings Compare With Those of the UK Biobank Study?

CHIP was associated with a 30% increased risk for breast cancer (hazard ratio [HR], 1.30; 95% CI, 1.03-1.64; P = .02), strengthening the borderline association reported by the UK Biobank study.

In contrast with the UK Biobank study, CHIP was not associated with lung cancer risk, although this may have been caused by fewer cases of lung cancer and a lack of male patients, Dr. Desai suggested.

“The discrepancy between the studies lies in the risk of lung cancer, although the point estimate in the current study suggested a positive association,” wrote Dr. Takahashi and Ms. Shah.

As in the UK Biobank study, CHIP was not associated with increased risk of developing colorectal cancer.

Mortality analysis, however, which was not conducted in the UK Biobank study, offered a new insight: Patients with existing colorectal cancer and CHIP had a significantly higher mortality risk than those without CHIP. Before stage adjustment, risk for mortality among those with colorectal cancer and CHIP was fourfold higher than those without CHIP (HR, 3.99; 95% CI, 2.41-6.62; P < .001). After stage adjustment, CHIP was still associated with a twofold higher mortality risk (HR, 2.50; 95% CI, 1.32-4.72; P = .004).

The investigators’ first mCA analyses, which employed a cell fraction cutoff greater than 3%, were unfruitful. But raising the cell fraction threshold to 5% in an exploratory analysis showed that autosomal mCA was associated with a 39% increased risk for breast cancer (HR, 1.39; 95% CI, 1.06-1.83; P = .01). No such associations were found between mCA and colorectal or lung cancer, regardless of cell fraction threshold.

The original 3% cell fraction threshold was selected on the basis of previous studies reporting a link between mCA and hematologic malignancies at this cutoff, Dr. Desai said.

She and her colleagues said a higher 5% cutoff might be needed, as they suspected that the link between mCA and solid tumors may not be causal, requiring a higher mutation rate.
 

Why Do Results Differ Between These Types of Studies?

Dr. Takahashi and Ms. Shah suggested that one possible limitation of the new study, and an obstacle to comparing results with the UK Biobank study and others like it, goes beyond population heterogeneity; incongruent findings could also be explained by differences in whole genome sequencing (WGS) technique.

“Although WGS allows sensitive detection of mCA through broad genomic coverage, it is less effective at detecting CHIP with low variant allele frequency (VAF) due to its relatively shallow depth (30x),” they wrote. “Consequently, the prevalence of mCA (18.8%) was much higher than that of CHIP (8.3%) in this cohort, contrasting with other studies using deeper sequencing.” As a result, the present study may have underestimated CHIP prevalence because of shallow sequencing depth.

“This inconsistency is a common challenge in CH population studies due to the lack of standardized methodologies and the frequent reliance on preexisting data not originally intended for CH detection,” Dr. Takahashi and Ms. Shah said.

Even so, despite the “heavily context-dependent” nature of these reported risks, the body of evidence to date now offers a convincing biological rationale linking CH with cancer development and outcomes, they added.
 

How Do the CHIP- and mCA-associated Risks Differ Between Solid Tumors and Blood Cancers?

“[These solid tumor risks are] not causal in the way CHIP mutations are causal for blood cancers,” Dr. Desai said. “Here we are talking about solid tumor risk, and it’s kind of scattered. It’s not just breast cancer ... there’s also increased colon cancer mortality. So I feel these mutations are doing something different ... they are sort of an added factor.”

Specific mechanisms remain unclear, Dr. Desai said, although she speculated about possible impacts on the inflammatory state or alterations to the tumor microenvironment.

“These are blood cells, right?” Dr. Desai asked. “They’re everywhere, and they’re changing something inherently in these tumors.”
 

Future research and therapeutic development

Siddhartha Jaiswal, MD, PhD, assistant professor in the Department of Pathology at Stanford University in California, whose lab focuses on clonal hematopoiesis, said the causality question is central to future research.

“The key question is, are these mutations acting because they alter the function of blood cells in some way to promote cancer risk, or is it reflective of some sort of shared etiology that’s not causal?” Dr. Jaiswal said in an interview.

Available data support both possibilities.

On one side, “reasonable evidence” supports the noncausal view, Dr. Jaiswal noted, because telomere length is one of the most common genetic risk factors for clonal hematopoiesis and also for solid tumors, suggesting a shared genetic factor. On the other hand, CHIP and mCA could be directly protumorigenic via conferred disturbances of immune cell function.

When asked if both causal and noncausal factors could be at play, Dr. Jaiswal said, “yeah, absolutely.”

The presence of a causal association could be promising from a therapeutic standpoint.

“If it turns out that this association is driven by a direct causal effect of the mutations, perhaps related to immune cell function or dysfunction, then targeting that dysfunction could be a therapeutic path to improve outcomes in people, and there’s a lot of interest in this,” Dr. Jaiswal said. He went on to explain how a trial exploring this approach via interleukin-8 inhibition in lung cancer fell short.

Yet earlier intervention may still hold promise, according to experts.

“[This study] provokes the hypothesis that CH‐targeted interventions could potentially reduce cancer risk in the future,” Dr. Takahashi and Ms. Shah said in their editorial.

The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the Department of Health & Human Services. The investigators disclosed relationships with Eli Lilly, AbbVie, Celgene, and others. Dr. Jaiswal reported stock equity in a company that has an interest in clonal hematopoiesis.

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