Neurology Reviews

The quality and credibility of scientific publications have received increasing scrutiny. Findings from studies by Maria Ángeles Oviedo-García, PhD, from the Department of Business and Marketing at the University of Seville in Spain, highlight growing concerns about the integrity of published research. Insights from the journal Science and the US blog Retraction Watch reveal similar concerns regarding research integrity.

Artificial Intelligence (AI) Spurs Low-Quality Submissions

According to a report in Science, journals are inundated with low-quality contributions such as letters and comments generated by AI. Daniel Prevedello, MD, editor in chief of Neurosurgical Review, announced that the journal would temporarily stop accepting these submissions because of their poor quality.

Neurosurgical Review is not the only journal to experience low-quality submissions. In the journal Oral Oncology Reports (Elsevier), comments comprised 70% of the content, whereas in the International Journal of Surgery Open (Wolters Kluwer), they accounted for nearly half. In Neurosurgical Review, letters, comments, and editorials made up 58% of the total content from January to October 2024, compared with only 9% in the previous year.

This trend benefits authors by allowing them to inflate their publication lists with quickly produced contributions that bypass peer review. Publishers may also profit, as many charge fees to publish comments. Additionally, universities and research institutions find this type of content generation useful as more publications can enhance their reputation.

 

Concerns Over Peer Reviews

The troubling behavior described by Oviedo-García in the journal Scientometrics raises further doubts. An analysis of 263 peer reviews from 37 journals revealed that reviewers often used identical or very similar phrases in their evaluations, regardless of the content. In one case, the reviewer used the same wording in 52 reviews. This suggests that some reviewers read the studies that they are supposed to evaluate only superficially. Such practices can lead to valueless reviews and jeopardize the integrity of scientific literature. “Some other researchers will probably base their future research on these fake reports, which is frightening, especially when it comes to health and medicine,” Oviedo-García stated.

She suspects that the reviewers may have relied on templates to produce their reports quickly. This allowed them to list this work on their resumes for potential career advantages. Some reviewers have reportedly even “requested” the authors of the studies they reviewed to cite their own scientific work.

 

AI Complicates Peer Review

The process of research and publication has become increasingly challenging in recent years, and more standard and predatory journals allow anyone to publish their work for a fee. Roger W. Byard, MD, PhD, from the University of Adelaide in Australia, explained this trend in the journal Forensic Science, Medicine and Pathology. AI is increasingly being used to generate articles. At international conferences, experts have highlighted claims that AI can complete papers in just a few weeks and dissertations in less than a year. According to the authors of a letter in Critical Care, generative AI is infiltrating the peer review process.

Moreover, the peer review process can be bypassed by publishing research findings on online platforms (eg, preprint servers). Another issue is that some publications have hundreds of authors who can extend their publication list in this manner, even if their contribution to the publication is ambiguous or not substantial.

In a guest article for the Laborjournal, Ulrich Dirnagl, MD, PhD, from the Charité — Universitätsmedizin Berlin in Germany, emphasized that the scientific papers have become so complex that two or three experts often cannot thoroughly assess everything presented. The review process is time-consuming and can take several days for reviewers. Currently, very few people have time, especially because it is an unpaid and anonymous task. Dirnagl stated, “the self-correction of science no longer works as it claims.”

The old Russian saying ‘Dowjerjaj, no prowjerjaj: Trust, but verify’  remains a timeless recommendation that is likely to stay relevant for years to come.

This story was translated from Univadis Germany 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.

The quality and credibility of scientific publications have received increasing scrutiny. Findings from studies by Maria Ángeles Oviedo-García, PhD, from the Department of Business and Marketing at the University of Seville in Spain, highlight growing concerns about the integrity of published research. Insights from the journal Science and the US blog Retraction Watch reveal similar concerns regarding research integrity.

Artificial Intelligence (AI) Spurs Low-Quality Submissions

According to a report in Science, journals are inundated with low-quality contributions such as letters and comments generated by AI. Daniel Prevedello, MD, editor in chief of Neurosurgical Review, announced that the journal would temporarily stop accepting these submissions because of their poor quality.

Neurosurgical Review is not the only journal to experience low-quality submissions. In the journal Oral Oncology Reports (Elsevier), comments comprised 70% of the content, whereas in the International Journal of Surgery Open (Wolters Kluwer), they accounted for nearly half. In Neurosurgical Review, letters, comments, and editorials made up 58% of the total content from January to October 2024, compared with only 9% in the previous year.

This trend benefits authors by allowing them to inflate their publication lists with quickly produced contributions that bypass peer review. Publishers may also profit, as many charge fees to publish comments. Additionally, universities and research institutions find this type of content generation useful as more publications can enhance their reputation.

 

Concerns Over Peer Reviews

The troubling behavior described by Oviedo-García in the journal Scientometrics raises further doubts. An analysis of 263 peer reviews from 37 journals revealed that reviewers often used identical or very similar phrases in their evaluations, regardless of the content. In one case, the reviewer used the same wording in 52 reviews. This suggests that some reviewers read the studies that they are supposed to evaluate only superficially. Such practices can lead to valueless reviews and jeopardize the integrity of scientific literature. “Some other researchers will probably base their future research on these fake reports, which is frightening, especially when it comes to health and medicine,” Oviedo-García stated.

She suspects that the reviewers may have relied on templates to produce their reports quickly. This allowed them to list this work on their resumes for potential career advantages. Some reviewers have reportedly even “requested” the authors of the studies they reviewed to cite their own scientific work.

 

AI Complicates Peer Review

The process of research and publication has become increasingly challenging in recent years, and more standard and predatory journals allow anyone to publish their work for a fee. Roger W. Byard, MD, PhD, from the University of Adelaide in Australia, explained this trend in the journal Forensic Science, Medicine and Pathology. AI is increasingly being used to generate articles. At international conferences, experts have highlighted claims that AI can complete papers in just a few weeks and dissertations in less than a year. According to the authors of a letter in Critical Care, generative AI is infiltrating the peer review process.

Moreover, the peer review process can be bypassed by publishing research findings on online platforms (eg, preprint servers). Another issue is that some publications have hundreds of authors who can extend their publication list in this manner, even if their contribution to the publication is ambiguous or not substantial.

In a guest article for the Laborjournal, Ulrich Dirnagl, MD, PhD, from the Charité — Universitätsmedizin Berlin in Germany, emphasized that the scientific papers have become so complex that two or three experts often cannot thoroughly assess everything presented. The review process is time-consuming and can take several days for reviewers. Currently, very few people have time, especially because it is an unpaid and anonymous task. Dirnagl stated, “the self-correction of science no longer works as it claims.”

The old Russian saying ‘Dowjerjaj, no prowjerjaj: Trust, but verify’  remains a timeless recommendation that is likely to stay relevant for years to come.

This story was translated from Univadis Germany 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.

The quality and credibility of scientific publications have received increasing scrutiny. Findings from studies by Maria Ángeles Oviedo-García, PhD, from the Department of Business and Marketing at the University of Seville in Spain, highlight growing concerns about the integrity of published research. Insights from the journal Science and the US blog Retraction Watch reveal similar concerns regarding research integrity.

Artificial Intelligence (AI) Spurs Low-Quality Submissions

According to a report in Science, journals are inundated with low-quality contributions such as letters and comments generated by AI. Daniel Prevedello, MD, editor in chief of Neurosurgical Review, announced that the journal would temporarily stop accepting these submissions because of their poor quality.

Neurosurgical Review is not the only journal to experience low-quality submissions. In the journal Oral Oncology Reports (Elsevier), comments comprised 70% of the content, whereas in the International Journal of Surgery Open (Wolters Kluwer), they accounted for nearly half. In Neurosurgical Review, letters, comments, and editorials made up 58% of the total content from January to October 2024, compared with only 9% in the previous year.

This trend benefits authors by allowing them to inflate their publication lists with quickly produced contributions that bypass peer review. Publishers may also profit, as many charge fees to publish comments. Additionally, universities and research institutions find this type of content generation useful as more publications can enhance their reputation.

 

Concerns Over Peer Reviews

The troubling behavior described by Oviedo-García in the journal Scientometrics raises further doubts. An analysis of 263 peer reviews from 37 journals revealed that reviewers often used identical or very similar phrases in their evaluations, regardless of the content. In one case, the reviewer used the same wording in 52 reviews. This suggests that some reviewers read the studies that they are supposed to evaluate only superficially. Such practices can lead to valueless reviews and jeopardize the integrity of scientific literature. “Some other researchers will probably base their future research on these fake reports, which is frightening, especially when it comes to health and medicine,” Oviedo-García stated.

She suspects that the reviewers may have relied on templates to produce their reports quickly. This allowed them to list this work on their resumes for potential career advantages. Some reviewers have reportedly even “requested” the authors of the studies they reviewed to cite their own scientific work.

 

AI Complicates Peer Review

The process of research and publication has become increasingly challenging in recent years, and more standard and predatory journals allow anyone to publish their work for a fee. Roger W. Byard, MD, PhD, from the University of Adelaide in Australia, explained this trend in the journal Forensic Science, Medicine and Pathology. AI is increasingly being used to generate articles. At international conferences, experts have highlighted claims that AI can complete papers in just a few weeks and dissertations in less than a year. According to the authors of a letter in Critical Care, generative AI is infiltrating the peer review process.

Moreover, the peer review process can be bypassed by publishing research findings on online platforms (eg, preprint servers). Another issue is that some publications have hundreds of authors who can extend their publication list in this manner, even if their contribution to the publication is ambiguous or not substantial.

In a guest article for the Laborjournal, Ulrich Dirnagl, MD, PhD, from the Charité — Universitätsmedizin Berlin in Germany, emphasized that the scientific papers have become so complex that two or three experts often cannot thoroughly assess everything presented. The review process is time-consuming and can take several days for reviewers. Currently, very few people have time, especially because it is an unpaid and anonymous task. Dirnagl stated, “the self-correction of science no longer works as it claims.”

The old Russian saying ‘Dowjerjaj, no prowjerjaj: Trust, but verify’  remains a timeless recommendation that is likely to stay relevant for years to come.

This story was translated from Univadis Germany 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.

Tina is a lovely 67-year-old woman who was recently found to be an APOE gene carrier (a gene associated with increased risk of developing Alzheimer’s disease as well as an earlier age of disease onset), with diffused amyloid protein deposition her brain. 

Her neuropsychiatric testing was consistent with mild cognitive impairment. Although Tina is not a doctor herself, her entire family consists of doctors, and she came to me under their advisement to consider semaglutide (Ozempic) for early Alzheimer’s disease prevention. 

This would usually be simple, but in Tina’s case, there was a complicating factor: At 5’ and 90 pounds, she was already considerably underweight and was at risk of becoming severely undernourished. 

To understand the potential role for glucagon-like peptide-1 (GLP-1) receptor agonists such as Ozempic in prevention, a quick primer on Alzheimer’s Disease is necessary.

The exact cause of Alzheimer’s disease remains elusive, but it is probably due to a combination of factors, including:

• Buildup of abnormal amyloid and tau proteins around brain cells
• Brain shrinkage, with subsequent damage to blood vessels and mitochondria, and inflammation
• Genetic predisposition
• Lifestyle factors, including obesity, high blood pressure, high cholesterol, and diabetes.

GLP-1 receptor agonists can cross the blood-brain barrier and bind to GLP-1 receptors expressed by neurons. Once in the brain, they can reduce inflammation and improve functioning of the neurons. In early rodent trials, GLP-1 receptor agonists led to reduced amyloid and tau aggregation, downregulation of inflammation, and improved memory.

In 2021, multiple studies showed that liraglutide, an early GLP-1 receptor agonist, improved cognitive function and MRI volume in patients with Alzheimer’s disease. 

A study recently published in Alzheimer’s & Dementia analyzed data from 1 million people with type 2 diabetes and no prior Alzheimer’s disease diagnosis. The authors compared Alzheimer’s disease occurrence in patients taking various diabetes medications, including insulin, metformin, and GLP-1 receptor agonists. The study found that participants taking semaglutide had up to a 70% reduction in Alzheimer’s risk. The results were consistent across gender, age, and weight.

Given the reassuring safety profile of GLP-1 receptor agonists and lack of other effective treatment or prophylaxis for Alzheimer’s disease, I agreed to start her on dulaglutide (Trulicity). My rationale was twofold:

1. In studies, dulaglutide has the highest uptake in the brain tissue at 68%. By contrast, there is virtually zero uptake in brain tissue for semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound). Because this class of drugs exert their effects in the brain tissue, I wanted to give her a GLP-1 receptor agonist with a high percent uptake.

2. Trulicity has a minimal effect on weight loss compared with the newer-generation GLP-1 receptor agonists. Even so, I connected Tina to my dietitian to ensure that she would receive a high-protein, high-calorie diet.

Tina has now been taking Trulicity for 6 months. Although it is certainly too early to draw firm conclusions about the efficacy of her treatment, she is not experiencing any weight loss and is cognitively stable, according to her neurologist. 

The EVOKE and EVOKE+ phase 3 trials are currently underway to evaluate the efficacy of semaglutide to treat mild cognitive impairment and early Alzheimer’s in amyloid-positive patients. Results are expected in 2025, but in the meantime, I feel comforted knowing that Tina is receiving a potentially beneficial and definitively low-risk treatment. 

 

Dr Messer, Clinical Assistant Professor, Mount Sinai School of Medicine; Associate Professor, Hofstra School of Medicine, New York, NY, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Tina is a lovely 67-year-old woman who was recently found to be an APOE gene carrier (a gene associated with increased risk of developing Alzheimer’s disease as well as an earlier age of disease onset), with diffused amyloid protein deposition her brain. 

Her neuropsychiatric testing was consistent with mild cognitive impairment. Although Tina is not a doctor herself, her entire family consists of doctors, and she came to me under their advisement to consider semaglutide (Ozempic) for early Alzheimer’s disease prevention. 

This would usually be simple, but in Tina’s case, there was a complicating factor: At 5’ and 90 pounds, she was already considerably underweight and was at risk of becoming severely undernourished. 

To understand the potential role for glucagon-like peptide-1 (GLP-1) receptor agonists such as Ozempic in prevention, a quick primer on Alzheimer’s Disease is necessary.

The exact cause of Alzheimer’s disease remains elusive, but it is probably due to a combination of factors, including:

• Buildup of abnormal amyloid and tau proteins around brain cells
• Brain shrinkage, with subsequent damage to blood vessels and mitochondria, and inflammation
• Genetic predisposition
• Lifestyle factors, including obesity, high blood pressure, high cholesterol, and diabetes.

GLP-1 receptor agonists can cross the blood-brain barrier and bind to GLP-1 receptors expressed by neurons. Once in the brain, they can reduce inflammation and improve functioning of the neurons. In early rodent trials, GLP-1 receptor agonists led to reduced amyloid and tau aggregation, downregulation of inflammation, and improved memory.

In 2021, multiple studies showed that liraglutide, an early GLP-1 receptor agonist, improved cognitive function and MRI volume in patients with Alzheimer’s disease. 

A study recently published in Alzheimer’s & Dementia analyzed data from 1 million people with type 2 diabetes and no prior Alzheimer’s disease diagnosis. The authors compared Alzheimer’s disease occurrence in patients taking various diabetes medications, including insulin, metformin, and GLP-1 receptor agonists. The study found that participants taking semaglutide had up to a 70% reduction in Alzheimer’s risk. The results were consistent across gender, age, and weight.

Given the reassuring safety profile of GLP-1 receptor agonists and lack of other effective treatment or prophylaxis for Alzheimer’s disease, I agreed to start her on dulaglutide (Trulicity). My rationale was twofold:

1. In studies, dulaglutide has the highest uptake in the brain tissue at 68%. By contrast, there is virtually zero uptake in brain tissue for semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound). Because this class of drugs exert their effects in the brain tissue, I wanted to give her a GLP-1 receptor agonist with a high percent uptake.

2. Trulicity has a minimal effect on weight loss compared with the newer-generation GLP-1 receptor agonists. Even so, I connected Tina to my dietitian to ensure that she would receive a high-protein, high-calorie diet.

Tina has now been taking Trulicity for 6 months. Although it is certainly too early to draw firm conclusions about the efficacy of her treatment, she is not experiencing any weight loss and is cognitively stable, according to her neurologist. 

The EVOKE and EVOKE+ phase 3 trials are currently underway to evaluate the efficacy of semaglutide to treat mild cognitive impairment and early Alzheimer’s in amyloid-positive patients. Results are expected in 2025, but in the meantime, I feel comforted knowing that Tina is receiving a potentially beneficial and definitively low-risk treatment. 

 

Dr Messer, Clinical Assistant Professor, Mount Sinai School of Medicine; Associate Professor, Hofstra School of Medicine, New York, NY, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

Tina is a lovely 67-year-old woman who was recently found to be an APOE gene carrier (a gene associated with increased risk of developing Alzheimer’s disease as well as an earlier age of disease onset), with diffused amyloid protein deposition her brain. 

Her neuropsychiatric testing was consistent with mild cognitive impairment. Although Tina is not a doctor herself, her entire family consists of doctors, and she came to me under their advisement to consider semaglutide (Ozempic) for early Alzheimer’s disease prevention. 

This would usually be simple, but in Tina’s case, there was a complicating factor: At 5’ and 90 pounds, she was already considerably underweight and was at risk of becoming severely undernourished. 

To understand the potential role for glucagon-like peptide-1 (GLP-1) receptor agonists such as Ozempic in prevention, a quick primer on Alzheimer’s Disease is necessary.

The exact cause of Alzheimer’s disease remains elusive, but it is probably due to a combination of factors, including:

• Buildup of abnormal amyloid and tau proteins around brain cells
• Brain shrinkage, with subsequent damage to blood vessels and mitochondria, and inflammation
• Genetic predisposition
• Lifestyle factors, including obesity, high blood pressure, high cholesterol, and diabetes.

GLP-1 receptor agonists can cross the blood-brain barrier and bind to GLP-1 receptors expressed by neurons. Once in the brain, they can reduce inflammation and improve functioning of the neurons. In early rodent trials, GLP-1 receptor agonists led to reduced amyloid and tau aggregation, downregulation of inflammation, and improved memory.

In 2021, multiple studies showed that liraglutide, an early GLP-1 receptor agonist, improved cognitive function and MRI volume in patients with Alzheimer’s disease. 

A study recently published in Alzheimer’s & Dementia analyzed data from 1 million people with type 2 diabetes and no prior Alzheimer’s disease diagnosis. The authors compared Alzheimer’s disease occurrence in patients taking various diabetes medications, including insulin, metformin, and GLP-1 receptor agonists. The study found that participants taking semaglutide had up to a 70% reduction in Alzheimer’s risk. The results were consistent across gender, age, and weight.

Given the reassuring safety profile of GLP-1 receptor agonists and lack of other effective treatment or prophylaxis for Alzheimer’s disease, I agreed to start her on dulaglutide (Trulicity). My rationale was twofold:

1. In studies, dulaglutide has the highest uptake in the brain tissue at 68%. By contrast, there is virtually zero uptake in brain tissue for semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound). Because this class of drugs exert their effects in the brain tissue, I wanted to give her a GLP-1 receptor agonist with a high percent uptake.

2. Trulicity has a minimal effect on weight loss compared with the newer-generation GLP-1 receptor agonists. Even so, I connected Tina to my dietitian to ensure that she would receive a high-protein, high-calorie diet.

Tina has now been taking Trulicity for 6 months. Although it is certainly too early to draw firm conclusions about the efficacy of her treatment, she is not experiencing any weight loss and is cognitively stable, according to her neurologist. 

The EVOKE and EVOKE+ phase 3 trials are currently underway to evaluate the efficacy of semaglutide to treat mild cognitive impairment and early Alzheimer’s in amyloid-positive patients. Results are expected in 2025, but in the meantime, I feel comforted knowing that Tina is receiving a potentially beneficial and definitively low-risk treatment. 

 

Dr Messer, Clinical Assistant Professor, Mount Sinai School of Medicine; Associate Professor, Hofstra School of Medicine, New York, NY, has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

MRI-invisible prostate lesions. It sounds like the stuff of science fiction and fantasy, a creation from the minds of H.G. Wells, who wrote The Invisible Man, or J.K. Rowling, who authored the Harry Potter series.

But MRI-invisible prostate lesions are real. And what these lesions may, or may not, indicate is the subject of intense debate.

MRI plays an increasingly important role in detecting and diagnosing prostate cancer, staging prostate cancer as well as monitoring disease progression. However, on occasion, a puzzling phenomenon arises. Certain prostate lesions that appear when pathologists examine biopsied tissue samples under a microscope are not visible on MRI. The prostate tissue will, instead, appear normal to a radiologist’s eye.

Why are certain lesions invisible with MRI? And is it dangerous for patients if these lesions are not detected? 

Some experts believe these MRI-invisible lesions are nothing to worry about.

If the clinician can’t see the cancer on MRI, then it simply isn’t a threat, according to Mark Emberton, MD, a pioneer in prostate MRIs and director of interventional oncology at University College London, England.

Laurence Klotz, MD, of the University of Toronto, Ontario, Canada, agreed, noting that “invisible cancers are clinically insignificant and don’t require systematic biopsies.”

Emberton and Klotz compared MRI-invisible lesions to grade group 1 prostate cancer (Gleason score ≤ 6) — the least aggressive category that indicates the cancer that is not likely to spread or kill. For patients on active surveillance, those with MRI-invisible cancers do drastically better than those with visible cancers, Klotz explained.

But other experts in the field are skeptical that MRI-invisible lesions are truly innocuous.

Although statistically an MRI-visible prostate lesion indicates a more aggressive tumor, that is not always the case for every individual, said Brian Helfand, MD, PhD, chief of urology at NorthShore University Health System, Evanston, Illinois.

MRIs can lead to false negatives in about 10%-20% of patients who have clinically significant prostate cancer, though estimates vary.

In one analysis, 16% of men with no suspicious lesions on MRI had clinically significant prostate cancer identified after undergoing a systematic biopsy. Another analysis found that about 35% of MRI-invisible prostate cancers identified via biopsy were clinically significant.

Other studies, however, have indicated that negative MRI results accurately indicate patients at low risk of developing clinically significant cancers. A recent JAMA Oncology analysis, for instance, found that only seven of 233 men (3%) with negative MRI results at baseline who completed 3 years of monitoring were diagnosed with clinically significant prostate cancer.

When a patient has an MRI-invisible prostate tumor, there are a couple of reasons the MRI may not be picking it up, said urologic oncologist Alexander Putnam Cole, MD, assistant professor of surgery, Harvard Medical School, Boston, Massachusetts. “One is that the cancer is aggressive but just very small,” said Cole.

“Another possibility is that the cancer looks very similar to background prostate tissue, which is something that you might expect if you think about more of a low-grade cancer,” he explained.

The experience level of the radiologist interpreting the MRI can also play into the accuracy of the reading.

But Cole agreed that “in general, MRI visibility is associated with molecular and histologic features of progression and aggressiveness and non-visible cancers are less likely to have aggressive features.”

The genomic profiles of MRI-visible and -invisible cancers bear this out.

According to Todd Morgan, MD, chief of urologic oncology at Michigan Medicine, University of Michigan, Ann Arbor, the gene expression in visible disease tends to be linked to more aggressive prostate tumors whereas gene expression in invisible disease does not.

In one analysis, for instance, researchers found that four genes — PHYHD1, CENPF, ALDH2, and GDF15 — associated with worse progression-free survival and metastasis-free survival in prostate cancer also predicted MRI visibility.

“Genes that are associated with visibility are essentially the same genes that are associated with aggressive cancers,” Klotz said.

 

Next Steps After Negative MRI Result

What do MRI-invisible lesions mean for patient care? If, for instance, a patient has elevated PSA levels but a normal MRI, is a targeted or systematic biopsy warranted?

The overarching message, according to Klotz, is that “you don’t need to find them.” Klotz noted, however, that patients with a negative MRI result should still be followed with periodic repeat imaging.

Several trials support this approach of using MRI to decide who needs a biopsy and delaying a biopsy in men with normal MRIs.

The recent JAMA Oncology analysis found that, among men with negative MRI results, 86% avoided a biopsy over 3 years, with clinically significant prostate cancer detected in only 4% of men across the study period — four in the initial diagnostic phase and seven in the 3-year monitoring phase. However, during the initial diagnostic phase, more than half the men with positive MRI findings had clinically significant prostate cancer detected.

Another recent study found that patients with negative MRI results were much less likely to upgrade to higher Gleason scores over time. Among 522 patients who underwent a systematic and targeted biopsy within 18 months of their grade group 1 designation, 9.2% with negative MRI findings had tumors reclassified as grade group 2 or higher vs 27% with positive MRI findings, and 2.3% with negative MRI findings had tumors reclassified as grade group 3 or higher vs 7.8% with positive MRI findings.

These data suggest that men with grade group 1 cancer and negative MRI result “may be able to avoid confirmatory biopsies until a routine surveillance biopsy in 2-3 years,” according to study author Christian Pavlovich, MD, professor of urologic oncology at the Johns Hopkins University School of Medicine, Baltimore.

Cole used MRI findings to triage who gets a biopsy. When a biopsy is warranted, “I usually recommend adding in some systematic sampling of the other side to assess for nonvisible cancers,” he noted.

Sampling prostate tissue outside the target area “adds maybe 1-2 minutes to the procedure and doesn’t drastically increase the morbidity or risks,” Cole said. It also can help “confirm there is cancer in the MRI target and also confirm there is no cancer in the nonvisible areas.” 

According to Klotz, if imaging demonstrates progression, patients should receive a biopsy — in most cases, a targeted biopsy only. And, Klotz noted, skipping routine prostate biopsies in men with negative MRI results can save thousands of men from these procedures, which carry risks for infections and sepsis.

Looking beyond Gleason scores for risk prediction, MRI “visibility is a very powerful risk stratifier,” he said.

A version of this article appeared on Medscape.com.

MRI-invisible prostate lesions. It sounds like the stuff of science fiction and fantasy, a creation from the minds of H.G. Wells, who wrote The Invisible Man, or J.K. Rowling, who authored the Harry Potter series.

But MRI-invisible prostate lesions are real. And what these lesions may, or may not, indicate is the subject of intense debate.

MRI plays an increasingly important role in detecting and diagnosing prostate cancer, staging prostate cancer as well as monitoring disease progression. However, on occasion, a puzzling phenomenon arises. Certain prostate lesions that appear when pathologists examine biopsied tissue samples under a microscope are not visible on MRI. The prostate tissue will, instead, appear normal to a radiologist’s eye.

Why are certain lesions invisible with MRI? And is it dangerous for patients if these lesions are not detected? 

Some experts believe these MRI-invisible lesions are nothing to worry about.

If the clinician can’t see the cancer on MRI, then it simply isn’t a threat, according to Mark Emberton, MD, a pioneer in prostate MRIs and director of interventional oncology at University College London, England.

Laurence Klotz, MD, of the University of Toronto, Ontario, Canada, agreed, noting that “invisible cancers are clinically insignificant and don’t require systematic biopsies.”

Emberton and Klotz compared MRI-invisible lesions to grade group 1 prostate cancer (Gleason score ≤ 6) — the least aggressive category that indicates the cancer that is not likely to spread or kill. For patients on active surveillance, those with MRI-invisible cancers do drastically better than those with visible cancers, Klotz explained.

But other experts in the field are skeptical that MRI-invisible lesions are truly innocuous.

Although statistically an MRI-visible prostate lesion indicates a more aggressive tumor, that is not always the case for every individual, said Brian Helfand, MD, PhD, chief of urology at NorthShore University Health System, Evanston, Illinois.

MRIs can lead to false negatives in about 10%-20% of patients who have clinically significant prostate cancer, though estimates vary.

In one analysis, 16% of men with no suspicious lesions on MRI had clinically significant prostate cancer identified after undergoing a systematic biopsy. Another analysis found that about 35% of MRI-invisible prostate cancers identified via biopsy were clinically significant.

Other studies, however, have indicated that negative MRI results accurately indicate patients at low risk of developing clinically significant cancers. A recent JAMA Oncology analysis, for instance, found that only seven of 233 men (3%) with negative MRI results at baseline who completed 3 years of monitoring were diagnosed with clinically significant prostate cancer.

When a patient has an MRI-invisible prostate tumor, there are a couple of reasons the MRI may not be picking it up, said urologic oncologist Alexander Putnam Cole, MD, assistant professor of surgery, Harvard Medical School, Boston, Massachusetts. “One is that the cancer is aggressive but just very small,” said Cole.

“Another possibility is that the cancer looks very similar to background prostate tissue, which is something that you might expect if you think about more of a low-grade cancer,” he explained.

The experience level of the radiologist interpreting the MRI can also play into the accuracy of the reading.

But Cole agreed that “in general, MRI visibility is associated with molecular and histologic features of progression and aggressiveness and non-visible cancers are less likely to have aggressive features.”

The genomic profiles of MRI-visible and -invisible cancers bear this out.

According to Todd Morgan, MD, chief of urologic oncology at Michigan Medicine, University of Michigan, Ann Arbor, the gene expression in visible disease tends to be linked to more aggressive prostate tumors whereas gene expression in invisible disease does not.

In one analysis, for instance, researchers found that four genes — PHYHD1, CENPF, ALDH2, and GDF15 — associated with worse progression-free survival and metastasis-free survival in prostate cancer also predicted MRI visibility.

“Genes that are associated with visibility are essentially the same genes that are associated with aggressive cancers,” Klotz said.

 

Next Steps After Negative MRI Result

What do MRI-invisible lesions mean for patient care? If, for instance, a patient has elevated PSA levels but a normal MRI, is a targeted or systematic biopsy warranted?

The overarching message, according to Klotz, is that “you don’t need to find them.” Klotz noted, however, that patients with a negative MRI result should still be followed with periodic repeat imaging.

Several trials support this approach of using MRI to decide who needs a biopsy and delaying a biopsy in men with normal MRIs.

The recent JAMA Oncology analysis found that, among men with negative MRI results, 86% avoided a biopsy over 3 years, with clinically significant prostate cancer detected in only 4% of men across the study period — four in the initial diagnostic phase and seven in the 3-year monitoring phase. However, during the initial diagnostic phase, more than half the men with positive MRI findings had clinically significant prostate cancer detected.

Another recent study found that patients with negative MRI results were much less likely to upgrade to higher Gleason scores over time. Among 522 patients who underwent a systematic and targeted biopsy within 18 months of their grade group 1 designation, 9.2% with negative MRI findings had tumors reclassified as grade group 2 or higher vs 27% with positive MRI findings, and 2.3% with negative MRI findings had tumors reclassified as grade group 3 or higher vs 7.8% with positive MRI findings.

These data suggest that men with grade group 1 cancer and negative MRI result “may be able to avoid confirmatory biopsies until a routine surveillance biopsy in 2-3 years,” according to study author Christian Pavlovich, MD, professor of urologic oncology at the Johns Hopkins University School of Medicine, Baltimore.

Cole used MRI findings to triage who gets a biopsy. When a biopsy is warranted, “I usually recommend adding in some systematic sampling of the other side to assess for nonvisible cancers,” he noted.

Sampling prostate tissue outside the target area “adds maybe 1-2 minutes to the procedure and doesn’t drastically increase the morbidity or risks,” Cole said. It also can help “confirm there is cancer in the MRI target and also confirm there is no cancer in the nonvisible areas.” 

According to Klotz, if imaging demonstrates progression, patients should receive a biopsy — in most cases, a targeted biopsy only. And, Klotz noted, skipping routine prostate biopsies in men with negative MRI results can save thousands of men from these procedures, which carry risks for infections and sepsis.

Looking beyond Gleason scores for risk prediction, MRI “visibility is a very powerful risk stratifier,” he said.

A version of this article appeared on Medscape.com.

MRI-invisible prostate lesions. It sounds like the stuff of science fiction and fantasy, a creation from the minds of H.G. Wells, who wrote The Invisible Man, or J.K. Rowling, who authored the Harry Potter series.

But MRI-invisible prostate lesions are real. And what these lesions may, or may not, indicate is the subject of intense debate.

MRI plays an increasingly important role in detecting and diagnosing prostate cancer, staging prostate cancer as well as monitoring disease progression. However, on occasion, a puzzling phenomenon arises. Certain prostate lesions that appear when pathologists examine biopsied tissue samples under a microscope are not visible on MRI. The prostate tissue will, instead, appear normal to a radiologist’s eye.

Why are certain lesions invisible with MRI? And is it dangerous for patients if these lesions are not detected? 

Some experts believe these MRI-invisible lesions are nothing to worry about.

If the clinician can’t see the cancer on MRI, then it simply isn’t a threat, according to Mark Emberton, MD, a pioneer in prostate MRIs and director of interventional oncology at University College London, England.

Laurence Klotz, MD, of the University of Toronto, Ontario, Canada, agreed, noting that “invisible cancers are clinically insignificant and don’t require systematic biopsies.”

Emberton and Klotz compared MRI-invisible lesions to grade group 1 prostate cancer (Gleason score ≤ 6) — the least aggressive category that indicates the cancer that is not likely to spread or kill. For patients on active surveillance, those with MRI-invisible cancers do drastically better than those with visible cancers, Klotz explained.

But other experts in the field are skeptical that MRI-invisible lesions are truly innocuous.

Although statistically an MRI-visible prostate lesion indicates a more aggressive tumor, that is not always the case for every individual, said Brian Helfand, MD, PhD, chief of urology at NorthShore University Health System, Evanston, Illinois.

MRIs can lead to false negatives in about 10%-20% of patients who have clinically significant prostate cancer, though estimates vary.

In one analysis, 16% of men with no suspicious lesions on MRI had clinically significant prostate cancer identified after undergoing a systematic biopsy. Another analysis found that about 35% of MRI-invisible prostate cancers identified via biopsy were clinically significant.

Other studies, however, have indicated that negative MRI results accurately indicate patients at low risk of developing clinically significant cancers. A recent JAMA Oncology analysis, for instance, found that only seven of 233 men (3%) with negative MRI results at baseline who completed 3 years of monitoring were diagnosed with clinically significant prostate cancer.

When a patient has an MRI-invisible prostate tumor, there are a couple of reasons the MRI may not be picking it up, said urologic oncologist Alexander Putnam Cole, MD, assistant professor of surgery, Harvard Medical School, Boston, Massachusetts. “One is that the cancer is aggressive but just very small,” said Cole.

“Another possibility is that the cancer looks very similar to background prostate tissue, which is something that you might expect if you think about more of a low-grade cancer,” he explained.

The experience level of the radiologist interpreting the MRI can also play into the accuracy of the reading.

But Cole agreed that “in general, MRI visibility is associated with molecular and histologic features of progression and aggressiveness and non-visible cancers are less likely to have aggressive features.”

The genomic profiles of MRI-visible and -invisible cancers bear this out.

According to Todd Morgan, MD, chief of urologic oncology at Michigan Medicine, University of Michigan, Ann Arbor, the gene expression in visible disease tends to be linked to more aggressive prostate tumors whereas gene expression in invisible disease does not.

In one analysis, for instance, researchers found that four genes — PHYHD1, CENPF, ALDH2, and GDF15 — associated with worse progression-free survival and metastasis-free survival in prostate cancer also predicted MRI visibility.

“Genes that are associated with visibility are essentially the same genes that are associated with aggressive cancers,” Klotz said.

 

Next Steps After Negative MRI Result

What do MRI-invisible lesions mean for patient care? If, for instance, a patient has elevated PSA levels but a normal MRI, is a targeted or systematic biopsy warranted?

The overarching message, according to Klotz, is that “you don’t need to find them.” Klotz noted, however, that patients with a negative MRI result should still be followed with periodic repeat imaging.

Several trials support this approach of using MRI to decide who needs a biopsy and delaying a biopsy in men with normal MRIs.

The recent JAMA Oncology analysis found that, among men with negative MRI results, 86% avoided a biopsy over 3 years, with clinically significant prostate cancer detected in only 4% of men across the study period — four in the initial diagnostic phase and seven in the 3-year monitoring phase. However, during the initial diagnostic phase, more than half the men with positive MRI findings had clinically significant prostate cancer detected.

Another recent study found that patients with negative MRI results were much less likely to upgrade to higher Gleason scores over time. Among 522 patients who underwent a systematic and targeted biopsy within 18 months of their grade group 1 designation, 9.2% with negative MRI findings had tumors reclassified as grade group 2 or higher vs 27% with positive MRI findings, and 2.3% with negative MRI findings had tumors reclassified as grade group 3 or higher vs 7.8% with positive MRI findings.

These data suggest that men with grade group 1 cancer and negative MRI result “may be able to avoid confirmatory biopsies until a routine surveillance biopsy in 2-3 years,” according to study author Christian Pavlovich, MD, professor of urologic oncology at the Johns Hopkins University School of Medicine, Baltimore.

Cole used MRI findings to triage who gets a biopsy. When a biopsy is warranted, “I usually recommend adding in some systematic sampling of the other side to assess for nonvisible cancers,” he noted.

Sampling prostate tissue outside the target area “adds maybe 1-2 minutes to the procedure and doesn’t drastically increase the morbidity or risks,” Cole said. It also can help “confirm there is cancer in the MRI target and also confirm there is no cancer in the nonvisible areas.” 

According to Klotz, if imaging demonstrates progression, patients should receive a biopsy — in most cases, a targeted biopsy only. And, Klotz noted, skipping routine prostate biopsies in men with negative MRI results can save thousands of men from these procedures, which carry risks for infections and sepsis.

Looking beyond Gleason scores for risk prediction, MRI “visibility is a very powerful risk stratifier,” he said.

A version of this article appeared on Medscape.com.

Mild traumatic brain injury (TBI) may reactivate latent herpes simplex virus type 1 (HSV-1) in the brain and contribute to neurodegeneration and development of Alzheimer’s disease pathology, a new study suggested.

Using a three-dimensional (3D) human brain tissue model, researchers observed that quiescent HSV-1 can be reactivated by a mechanical jolt mimicking concussion, leading to signature markers of Alzheimer’s disease, including neuroinflammation and production of amyloid beta and phosphorylated tau (p-tau) and gliosis — a phenotype made worse by repeated head injury.

“This opens the question as to whether antiviral drugs or anti-inflammatory agents might be useful as early preventive treatments after head trauma to stop HSV-1 activation in its tracks and lower the risk of Alzheimer’s disease,” lead investigator Dana Cairns, PhD, with the Department of Biomedical Engineering at Tufts University, Medford, Massachusetts, said in a statement.

But outside experts urged caution in drawing any firm conclusions, pending further study.

The study was published online in the journal Science Signaling.

 

HSV-1: A Major Alzheimer’s Disease Risk Factor?

TBI is a major risk factor for Alzheimer’s disease and dementia, but the pathways in the brain leading from TBI to dementia are unknown.

HSV-1 is found in over 80% of people; varicella zoster virus (VZV) is found in about 95%. Both viruses are known to enter the brain and lay dormant in neurons and glial cells. Prior evidence indicates that HSV-1 in the brain of APOE-ε4 carriers confers a strong risk for Alzheimer’s disease.

A number of years ago, the team created a 3D model of human brain tissue to study the link between TBI, the viruses, and dementia. The model is 6 mm wide, shaped like a donut, and made of a spongy material of silk protein and collagen saturated with neural stem cells. The cells mature into neurons, communicate with each other, and form a network that mimics the brain environment.

In an earlier study using the model quiescently infected with HSV-1, Cairns and colleagues found that subsequent exposure to VZV created the inflammatory conditions that led to reactivation of HSV-1.

This led them to wonder what would happen if they subjected the brain tissue model to a physical disruption akin to a concussion. Would HSV-1 wake up and start the process of neurodegeneration?

To investigate, they examined the effects of one or more controlled blows to the 3D human brain tissue model in the absence or presence of quiescent HSV-1 infection.

After repeated, mild controlled blows, researchers found that the latently infected 3D brain tissue displayed reactivated HSV-1 and the production and accumulation of amyloid beta and p-tau — which promotes neurodegeneration. The blows also activated gliosis, which is associated with destructive neuroinflammation.

These effects are collectively associated with Alzheimer’s disease, dementia, and chronic traumatic encephalopathy, they pointed out, and were increased with additional injury but were absent in tissue not infected with HSV-1.

“These data suggest that HSV-1 in the brain is pivotal in increasing the risk of Alzheimer’s disease, as other recent studies using cerebral organoids have suggested,” the researchers wrote.

They propose that following brain injury, “whether by infection or mechanical damage, the resulting inflammation induces HSV-1 reactivation in the brain leading to the development of Alzheimer’s disease/dementia and that HSV-1 is a major cause of the disease, especially in APOE4 carriers.”

Future studies should investigate “possible ways of mitigating or stopping the damage caused by head injury, thereby reducing subsequent development of Alzheimer’s disease by implementing efforts to prevent the reactivation of virus in brain such as anti-inflammatory and/or antiviral treatment post-injury,” researchers suggested.

 

Outside Experts Weigh in

Several outside experts offered perspective on the study in a statement from the UK nonprofit Science Media Centre.

Tara Spires-Jones, PhD, president of the British Neuroscience Association and group leader at the UK Dementia Research Institute, London, England, said that, while the study is interesting, there are limitations.

“The increase in Alzheimer’s-like brain changes in these latent virus-containing cells subjected to injury does not resemble the pathology that is found in the brain of people with Alzheimer’s disease,” Spires-Jones noted.

“These experiments were also in cells grown in artificial conditions without important Alzheimer’s-related factors such as age and blood vessel changes. Finally, these experiments were repeated in a small number of experimental replicates (three times per experiment), so these results will need to be confirmed in more relevant biological systems with larger studies to be sure there is a biological link between latent herpes simplex virus type 1, brain injury, and Alzheimer’s pathology,” Spires-Jones cautioned.

Robert Howard, MD, MRCPsych, University College London (UCL) Division of Psychiatry, said the study suggests a possible mechanism for the association between HSV-1, brain injury, and Alzheimer’s disease.

“However, as so often in science, it is very important to bear in mind that association does not mean causation. Much more research will be needed before this can be seriously considered a plausible mechanism for the development of dementia,” Howard cautioned.

“Avoidance of brain injuries, such as those encountered in some contact sports, is already known to be an important way to prevent dementia, and I’m unconvinced that this reflects anything more complicated than mechanical damage causing death of brain cells,” he added.

Jennifer Pocock, PhD, with UCL Queen Square Institute of Neurology, noted the role of microglia, which are activated by mild and repetitive TBI, isn’t addressed in the study.

“This paper seems to suggest that only astrocytes contribute to the reported neuroinflammation in brain tissue. Also, the inclusion of APOE3/4 is not clearly defined. Because of this, the findings are likely to represent an over interpretation for the ‘real world’ as the inclusion of microglia may negate or accentuate them, depending on the severity of the TBI,” Pocock said.

The study was funded by the US Army Research Office and Department of Defense. The authors have declared no relevant conflicts of interest. Spires-Jones and Howard had no relevant disclosures related to this study. Pocock has received research funding from AstraZeneca and Daiichi Sankyo.

A version of this article appeared on Medscape.com.

Mild traumatic brain injury (TBI) may reactivate latent herpes simplex virus type 1 (HSV-1) in the brain and contribute to neurodegeneration and development of Alzheimer’s disease pathology, a new study suggested.

Using a three-dimensional (3D) human brain tissue model, researchers observed that quiescent HSV-1 can be reactivated by a mechanical jolt mimicking concussion, leading to signature markers of Alzheimer’s disease, including neuroinflammation and production of amyloid beta and phosphorylated tau (p-tau) and gliosis — a phenotype made worse by repeated head injury.

“This opens the question as to whether antiviral drugs or anti-inflammatory agents might be useful as early preventive treatments after head trauma to stop HSV-1 activation in its tracks and lower the risk of Alzheimer’s disease,” lead investigator Dana Cairns, PhD, with the Department of Biomedical Engineering at Tufts University, Medford, Massachusetts, said in a statement.

But outside experts urged caution in drawing any firm conclusions, pending further study.

The study was published online in the journal Science Signaling.

 

HSV-1: A Major Alzheimer’s Disease Risk Factor?

TBI is a major risk factor for Alzheimer’s disease and dementia, but the pathways in the brain leading from TBI to dementia are unknown.

HSV-1 is found in over 80% of people; varicella zoster virus (VZV) is found in about 95%. Both viruses are known to enter the brain and lay dormant in neurons and glial cells. Prior evidence indicates that HSV-1 in the brain of APOE-ε4 carriers confers a strong risk for Alzheimer’s disease.

A number of years ago, the team created a 3D model of human brain tissue to study the link between TBI, the viruses, and dementia. The model is 6 mm wide, shaped like a donut, and made of a spongy material of silk protein and collagen saturated with neural stem cells. The cells mature into neurons, communicate with each other, and form a network that mimics the brain environment.

In an earlier study using the model quiescently infected with HSV-1, Cairns and colleagues found that subsequent exposure to VZV created the inflammatory conditions that led to reactivation of HSV-1.

This led them to wonder what would happen if they subjected the brain tissue model to a physical disruption akin to a concussion. Would HSV-1 wake up and start the process of neurodegeneration?

To investigate, they examined the effects of one or more controlled blows to the 3D human brain tissue model in the absence or presence of quiescent HSV-1 infection.

After repeated, mild controlled blows, researchers found that the latently infected 3D brain tissue displayed reactivated HSV-1 and the production and accumulation of amyloid beta and p-tau — which promotes neurodegeneration. The blows also activated gliosis, which is associated with destructive neuroinflammation.

These effects are collectively associated with Alzheimer’s disease, dementia, and chronic traumatic encephalopathy, they pointed out, and were increased with additional injury but were absent in tissue not infected with HSV-1.

“These data suggest that HSV-1 in the brain is pivotal in increasing the risk of Alzheimer’s disease, as other recent studies using cerebral organoids have suggested,” the researchers wrote.

They propose that following brain injury, “whether by infection or mechanical damage, the resulting inflammation induces HSV-1 reactivation in the brain leading to the development of Alzheimer’s disease/dementia and that HSV-1 is a major cause of the disease, especially in APOE4 carriers.”

Future studies should investigate “possible ways of mitigating or stopping the damage caused by head injury, thereby reducing subsequent development of Alzheimer’s disease by implementing efforts to prevent the reactivation of virus in brain such as anti-inflammatory and/or antiviral treatment post-injury,” researchers suggested.

 

Outside Experts Weigh in

Several outside experts offered perspective on the study in a statement from the UK nonprofit Science Media Centre.

Tara Spires-Jones, PhD, president of the British Neuroscience Association and group leader at the UK Dementia Research Institute, London, England, said that, while the study is interesting, there are limitations.

“The increase in Alzheimer’s-like brain changes in these latent virus-containing cells subjected to injury does not resemble the pathology that is found in the brain of people with Alzheimer’s disease,” Spires-Jones noted.

“These experiments were also in cells grown in artificial conditions without important Alzheimer’s-related factors such as age and blood vessel changes. Finally, these experiments were repeated in a small number of experimental replicates (three times per experiment), so these results will need to be confirmed in more relevant biological systems with larger studies to be sure there is a biological link between latent herpes simplex virus type 1, brain injury, and Alzheimer’s pathology,” Spires-Jones cautioned.

Robert Howard, MD, MRCPsych, University College London (UCL) Division of Psychiatry, said the study suggests a possible mechanism for the association between HSV-1, brain injury, and Alzheimer’s disease.

“However, as so often in science, it is very important to bear in mind that association does not mean causation. Much more research will be needed before this can be seriously considered a plausible mechanism for the development of dementia,” Howard cautioned.

“Avoidance of brain injuries, such as those encountered in some contact sports, is already known to be an important way to prevent dementia, and I’m unconvinced that this reflects anything more complicated than mechanical damage causing death of brain cells,” he added.

Jennifer Pocock, PhD, with UCL Queen Square Institute of Neurology, noted the role of microglia, which are activated by mild and repetitive TBI, isn’t addressed in the study.

“This paper seems to suggest that only astrocytes contribute to the reported neuroinflammation in brain tissue. Also, the inclusion of APOE3/4 is not clearly defined. Because of this, the findings are likely to represent an over interpretation for the ‘real world’ as the inclusion of microglia may negate or accentuate them, depending on the severity of the TBI,” Pocock said.

The study was funded by the US Army Research Office and Department of Defense. The authors have declared no relevant conflicts of interest. Spires-Jones and Howard had no relevant disclosures related to this study. Pocock has received research funding from AstraZeneca and Daiichi Sankyo.

A version of this article appeared on Medscape.com.

Mild traumatic brain injury (TBI) may reactivate latent herpes simplex virus type 1 (HSV-1) in the brain and contribute to neurodegeneration and development of Alzheimer’s disease pathology, a new study suggested.

Using a three-dimensional (3D) human brain tissue model, researchers observed that quiescent HSV-1 can be reactivated by a mechanical jolt mimicking concussion, leading to signature markers of Alzheimer’s disease, including neuroinflammation and production of amyloid beta and phosphorylated tau (p-tau) and gliosis — a phenotype made worse by repeated head injury.

“This opens the question as to whether antiviral drugs or anti-inflammatory agents might be useful as early preventive treatments after head trauma to stop HSV-1 activation in its tracks and lower the risk of Alzheimer’s disease,” lead investigator Dana Cairns, PhD, with the Department of Biomedical Engineering at Tufts University, Medford, Massachusetts, said in a statement.

But outside experts urged caution in drawing any firm conclusions, pending further study.

The study was published online in the journal Science Signaling.

 

HSV-1: A Major Alzheimer’s Disease Risk Factor?

TBI is a major risk factor for Alzheimer’s disease and dementia, but the pathways in the brain leading from TBI to dementia are unknown.

HSV-1 is found in over 80% of people; varicella zoster virus (VZV) is found in about 95%. Both viruses are known to enter the brain and lay dormant in neurons and glial cells. Prior evidence indicates that HSV-1 in the brain of APOE-ε4 carriers confers a strong risk for Alzheimer’s disease.

A number of years ago, the team created a 3D model of human brain tissue to study the link between TBI, the viruses, and dementia. The model is 6 mm wide, shaped like a donut, and made of a spongy material of silk protein and collagen saturated with neural stem cells. The cells mature into neurons, communicate with each other, and form a network that mimics the brain environment.

In an earlier study using the model quiescently infected with HSV-1, Cairns and colleagues found that subsequent exposure to VZV created the inflammatory conditions that led to reactivation of HSV-1.

This led them to wonder what would happen if they subjected the brain tissue model to a physical disruption akin to a concussion. Would HSV-1 wake up and start the process of neurodegeneration?

To investigate, they examined the effects of one or more controlled blows to the 3D human brain tissue model in the absence or presence of quiescent HSV-1 infection.

After repeated, mild controlled blows, researchers found that the latently infected 3D brain tissue displayed reactivated HSV-1 and the production and accumulation of amyloid beta and p-tau — which promotes neurodegeneration. The blows also activated gliosis, which is associated with destructive neuroinflammation.

These effects are collectively associated with Alzheimer’s disease, dementia, and chronic traumatic encephalopathy, they pointed out, and were increased with additional injury but were absent in tissue not infected with HSV-1.

“These data suggest that HSV-1 in the brain is pivotal in increasing the risk of Alzheimer’s disease, as other recent studies using cerebral organoids have suggested,” the researchers wrote.

They propose that following brain injury, “whether by infection or mechanical damage, the resulting inflammation induces HSV-1 reactivation in the brain leading to the development of Alzheimer’s disease/dementia and that HSV-1 is a major cause of the disease, especially in APOE4 carriers.”

Future studies should investigate “possible ways of mitigating or stopping the damage caused by head injury, thereby reducing subsequent development of Alzheimer’s disease by implementing efforts to prevent the reactivation of virus in brain such as anti-inflammatory and/or antiviral treatment post-injury,” researchers suggested.

 

Outside Experts Weigh in

Several outside experts offered perspective on the study in a statement from the UK nonprofit Science Media Centre.

Tara Spires-Jones, PhD, president of the British Neuroscience Association and group leader at the UK Dementia Research Institute, London, England, said that, while the study is interesting, there are limitations.

“The increase in Alzheimer’s-like brain changes in these latent virus-containing cells subjected to injury does not resemble the pathology that is found in the brain of people with Alzheimer’s disease,” Spires-Jones noted.

“These experiments were also in cells grown in artificial conditions without important Alzheimer’s-related factors such as age and blood vessel changes. Finally, these experiments were repeated in a small number of experimental replicates (three times per experiment), so these results will need to be confirmed in more relevant biological systems with larger studies to be sure there is a biological link between latent herpes simplex virus type 1, brain injury, and Alzheimer’s pathology,” Spires-Jones cautioned.

Robert Howard, MD, MRCPsych, University College London (UCL) Division of Psychiatry, said the study suggests a possible mechanism for the association between HSV-1, brain injury, and Alzheimer’s disease.

“However, as so often in science, it is very important to bear in mind that association does not mean causation. Much more research will be needed before this can be seriously considered a plausible mechanism for the development of dementia,” Howard cautioned.

“Avoidance of brain injuries, such as those encountered in some contact sports, is already known to be an important way to prevent dementia, and I’m unconvinced that this reflects anything more complicated than mechanical damage causing death of brain cells,” he added.

Jennifer Pocock, PhD, with UCL Queen Square Institute of Neurology, noted the role of microglia, which are activated by mild and repetitive TBI, isn’t addressed in the study.

“This paper seems to suggest that only astrocytes contribute to the reported neuroinflammation in brain tissue. Also, the inclusion of APOE3/4 is not clearly defined. Because of this, the findings are likely to represent an over interpretation for the ‘real world’ as the inclusion of microglia may negate or accentuate them, depending on the severity of the TBI,” Pocock said.

The study was funded by the US Army Research Office and Department of Defense. The authors have declared no relevant conflicts of interest. Spires-Jones and Howard had no relevant disclosures related to this study. Pocock has received research funding from AstraZeneca and Daiichi Sankyo.

A version of this article appeared on Medscape.com.

Gestational hypertension, preeclampsia, or eclampsia is associated with a significantly higher risk for neurologic disorders such as migraine or epilepsy in the years following a first pregnancy, new research suggests.

The risk was highest in those with gestational eclampsia, who had a 70% increased chance of developing a neurologic disorder, including a fivefold increased risk for epilepsy, investigators found.

“When consulting women with new-onset neurological disorders, it’s important to inquire about their pregnancy history, as pregnancy complications such as gestational hypertension, preeclampsia, and eclampsia have been associated with an increased risk of neurological disorders later in life.” Therese Friis, MD, PhD student, Department of Women’s and Children’s Health, Uppsala University in Sweden, said in an interview.

The findings were published online in JAMA Neurology.

Most studies of maternal outcomes after gestational hypertension, preeclampsia, or eclampsia have focused on long-term risks for cardiovascular disease or neurologic complications such as stroke, dementia, and cognitive impairment. And many of these studies were relatively small and based on interviews or questionnaires.

“We wanted to investigate whether women with a hypertensive disorder of pregnancy also had a risk of other neurological complications, closer in time to the pregnancy,” said Friis.

The new study included 648,385 women (mean age, 28.5 years) whose first pregnancy occurred between 2005 and 2018. Of these, 94% had a normotensive pregnancy, 2% had gestational hypertension, 4% had preeclampsia without eclampsia, and 0.1% had eclampsia.

Gestational hypertension was defined as new-onset systolic blood pressure of ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg; preeclampsia was defined as gestational hypertension accompanied by proteinuria; and eclampsia was defined as tonic-clonic seizures without other etiology accompanied by preeclampsia.

Researchers used linked Swedish national registries that collect data on pregnancies, births, and infant and maternal characteristics. Among other things, they controlled for maternal age, early pregnancy body mass index, education level, and pregestational and gestational diabetes.

The primary outcome was a composite of five new-onset neurologic diagnoses: Migraine, headache, epilepsy, sleep disorder, and mental fatigue (neurasthenia), although one diagnosis was sufficient, from 42 days to 15 years after childbirth. Mean follow-up was 7.7 years.

 

Fivefold Epilepsy Risk

Compared with normotensive pregnancies, the risk for the primary outcome was 70% greater in those with eclampsia (adjusted hazard ratio [aHR], 1.70; 95% CI, 1.16-2.50), 27% higher for gestational hypertension (aHR, 1.27; 95% CI, 1.12-1.45), and 32% for preeclampsia (aHR, 1.32; 95% CI, 1.22-1.42).

Researchers also looked at the risk for individual neurologic disorders. There were too few neurasthenia events to generate meaningful results, so this diagnosis was omitted from the analysis.

Here, the study found women with eclampsia had five times the risk for epilepsy (aHR, 5.31; 95% CI, 2.85-9.89) compared with women with normotensive pregnancies.

The underlying mechanism for this association is unclear. However, said Friis, eclampsia and epilepsy share common pathways, such as neuroinflammation, and women with epilepsy before pregnancy run an increased risk for eclampsia.

“So common underlying pathways might increase the risk both for eclampsia in cases of a seizure disorder and a future seizure disorder after eclampsia,” she said.

In addition, preeclampsia and, in particular, eclampsia can cause irreversible subclinical cerebral infarcts found in areas of cerebral edema, she added. “These infarcts or scarring of brain tissue could potentially serve as foci for later epileptic activity.”

Researchers separated women with preeclampsia (with or without eclampsia) into those with preterm (less than 37 weeks; 21%) and term (79%) deliveries. As Friis explained, women with preterm preeclampsia have a higher risk for acute complications and long-term cardiovascular outcomes than those with term preeclampsia.

Compared with those with normotensive pregnancies, investigators found an increased risk for the composite neurologic outcome among women with preterm preeclampsia (aHR, 1.54; 95% CI, 1.34-1.79), but also for those with term preeclampsia (aHR, 1.27; 95% CI, 1.17-1.38).

 

Common Vascular Component

The study also showed gestational hypertension and preeclampsia were associated with a later diagnosis of migraine, suggesting a possible common underlying vascular component.

“The increased risk of migraine following preeclampsia could be linked to endothelial damage at the blood-brain barrier level and alterations in cerebral blood flow and arterial vasospasm found in eclampsia, but this is only speculation,” said Friis.

The analysis also found an association between preeclampsia and a later diagnosis of headache. But this result likely encompasses several headache diagnoses, including migraine, so “it’s challenging to draw conclusions about the underlying mechanisms,” Friis added.

The study didn’t consider diagnoses from primary healthcare, which resulted in relatively few outcomes. The authors explained they could only identify the most severe cases; for example, women referred to specialized care.

Another potential study limitation is that Swedish registers don’t include information on race or ethnicity. Evidence shows there are racial differences in the risk for cardiovascular outcomes after preeclampsia.

This area of research is important as most women will experience at least one pregnancy in their lifetime, and preeclampsia affects 3%-5% of pregnancies. Further research is needed to understand the underlying pathophysiological mechanisms and the long-term consequences of this disorder, said Friis.

She added she hopes more therapeutic options will be available in the future for neuroprotective treatment for women with gestational hypertensive disorders.

Asked to comment, Thomas Vidic, MD, clinical professor of neurology, Indiana University School of Medicine, South Bend, said in an interview that this is an important study that includes robust data.

In his opinion, the most significant study finding is the marked increase in epilepsy risk after gestational eclampsia.

“In women who have new-onset epilepsy of unknown cause, asking about having eclampsia or preeclampsia during pregnancy is definitely a worthwhile question,” he said.

Confirming an etiology paints “a better picture” for patients wondering why they’re experiencing seizures, he added.

As with any registry-based study, this one had some acknowledged limitations, “but at the same time, the authors were able to have such a large database that I think this study is very worthwhile,” said Vidic.

The study received support from the Swedish Research Council. Neither Friis nor Vidic had relevant conflicts of interest.

A version of this article appeared on Medscape.com.

Gestational hypertension, preeclampsia, or eclampsia is associated with a significantly higher risk for neurologic disorders such as migraine or epilepsy in the years following a first pregnancy, new research suggests.

The risk was highest in those with gestational eclampsia, who had a 70% increased chance of developing a neurologic disorder, including a fivefold increased risk for epilepsy, investigators found.

“When consulting women with new-onset neurological disorders, it’s important to inquire about their pregnancy history, as pregnancy complications such as gestational hypertension, preeclampsia, and eclampsia have been associated with an increased risk of neurological disorders later in life.” Therese Friis, MD, PhD student, Department of Women’s and Children’s Health, Uppsala University in Sweden, said in an interview.

The findings were published online in JAMA Neurology.

Most studies of maternal outcomes after gestational hypertension, preeclampsia, or eclampsia have focused on long-term risks for cardiovascular disease or neurologic complications such as stroke, dementia, and cognitive impairment. And many of these studies were relatively small and based on interviews or questionnaires.

“We wanted to investigate whether women with a hypertensive disorder of pregnancy also had a risk of other neurological complications, closer in time to the pregnancy,” said Friis.

The new study included 648,385 women (mean age, 28.5 years) whose first pregnancy occurred between 2005 and 2018. Of these, 94% had a normotensive pregnancy, 2% had gestational hypertension, 4% had preeclampsia without eclampsia, and 0.1% had eclampsia.

Gestational hypertension was defined as new-onset systolic blood pressure of ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg; preeclampsia was defined as gestational hypertension accompanied by proteinuria; and eclampsia was defined as tonic-clonic seizures without other etiology accompanied by preeclampsia.

Researchers used linked Swedish national registries that collect data on pregnancies, births, and infant and maternal characteristics. Among other things, they controlled for maternal age, early pregnancy body mass index, education level, and pregestational and gestational diabetes.

The primary outcome was a composite of five new-onset neurologic diagnoses: Migraine, headache, epilepsy, sleep disorder, and mental fatigue (neurasthenia), although one diagnosis was sufficient, from 42 days to 15 years after childbirth. Mean follow-up was 7.7 years.

 

Fivefold Epilepsy Risk

Compared with normotensive pregnancies, the risk for the primary outcome was 70% greater in those with eclampsia (adjusted hazard ratio [aHR], 1.70; 95% CI, 1.16-2.50), 27% higher for gestational hypertension (aHR, 1.27; 95% CI, 1.12-1.45), and 32% for preeclampsia (aHR, 1.32; 95% CI, 1.22-1.42).

Researchers also looked at the risk for individual neurologic disorders. There were too few neurasthenia events to generate meaningful results, so this diagnosis was omitted from the analysis.

Here, the study found women with eclampsia had five times the risk for epilepsy (aHR, 5.31; 95% CI, 2.85-9.89) compared with women with normotensive pregnancies.

The underlying mechanism for this association is unclear. However, said Friis, eclampsia and epilepsy share common pathways, such as neuroinflammation, and women with epilepsy before pregnancy run an increased risk for eclampsia.

“So common underlying pathways might increase the risk both for eclampsia in cases of a seizure disorder and a future seizure disorder after eclampsia,” she said.

In addition, preeclampsia and, in particular, eclampsia can cause irreversible subclinical cerebral infarcts found in areas of cerebral edema, she added. “These infarcts or scarring of brain tissue could potentially serve as foci for later epileptic activity.”

Researchers separated women with preeclampsia (with or without eclampsia) into those with preterm (less than 37 weeks; 21%) and term (79%) deliveries. As Friis explained, women with preterm preeclampsia have a higher risk for acute complications and long-term cardiovascular outcomes than those with term preeclampsia.

Compared with those with normotensive pregnancies, investigators found an increased risk for the composite neurologic outcome among women with preterm preeclampsia (aHR, 1.54; 95% CI, 1.34-1.79), but also for those with term preeclampsia (aHR, 1.27; 95% CI, 1.17-1.38).

 

Common Vascular Component

The study also showed gestational hypertension and preeclampsia were associated with a later diagnosis of migraine, suggesting a possible common underlying vascular component.

“The increased risk of migraine following preeclampsia could be linked to endothelial damage at the blood-brain barrier level and alterations in cerebral blood flow and arterial vasospasm found in eclampsia, but this is only speculation,” said Friis.

The analysis also found an association between preeclampsia and a later diagnosis of headache. But this result likely encompasses several headache diagnoses, including migraine, so “it’s challenging to draw conclusions about the underlying mechanisms,” Friis added.

The study didn’t consider diagnoses from primary healthcare, which resulted in relatively few outcomes. The authors explained they could only identify the most severe cases; for example, women referred to specialized care.

Another potential study limitation is that Swedish registers don’t include information on race or ethnicity. Evidence shows there are racial differences in the risk for cardiovascular outcomes after preeclampsia.

This area of research is important as most women will experience at least one pregnancy in their lifetime, and preeclampsia affects 3%-5% of pregnancies. Further research is needed to understand the underlying pathophysiological mechanisms and the long-term consequences of this disorder, said Friis.

She added she hopes more therapeutic options will be available in the future for neuroprotective treatment for women with gestational hypertensive disorders.

Asked to comment, Thomas Vidic, MD, clinical professor of neurology, Indiana University School of Medicine, South Bend, said in an interview that this is an important study that includes robust data.

In his opinion, the most significant study finding is the marked increase in epilepsy risk after gestational eclampsia.

“In women who have new-onset epilepsy of unknown cause, asking about having eclampsia or preeclampsia during pregnancy is definitely a worthwhile question,” he said.

Confirming an etiology paints “a better picture” for patients wondering why they’re experiencing seizures, he added.

As with any registry-based study, this one had some acknowledged limitations, “but at the same time, the authors were able to have such a large database that I think this study is very worthwhile,” said Vidic.

The study received support from the Swedish Research Council. Neither Friis nor Vidic had relevant conflicts of interest.

A version of this article appeared on Medscape.com.

Gestational hypertension, preeclampsia, or eclampsia is associated with a significantly higher risk for neurologic disorders such as migraine or epilepsy in the years following a first pregnancy, new research suggests.

The risk was highest in those with gestational eclampsia, who had a 70% increased chance of developing a neurologic disorder, including a fivefold increased risk for epilepsy, investigators found.

“When consulting women with new-onset neurological disorders, it’s important to inquire about their pregnancy history, as pregnancy complications such as gestational hypertension, preeclampsia, and eclampsia have been associated with an increased risk of neurological disorders later in life.” Therese Friis, MD, PhD student, Department of Women’s and Children’s Health, Uppsala University in Sweden, said in an interview.

The findings were published online in JAMA Neurology.

Most studies of maternal outcomes after gestational hypertension, preeclampsia, or eclampsia have focused on long-term risks for cardiovascular disease or neurologic complications such as stroke, dementia, and cognitive impairment. And many of these studies were relatively small and based on interviews or questionnaires.

“We wanted to investigate whether women with a hypertensive disorder of pregnancy also had a risk of other neurological complications, closer in time to the pregnancy,” said Friis.

The new study included 648,385 women (mean age, 28.5 years) whose first pregnancy occurred between 2005 and 2018. Of these, 94% had a normotensive pregnancy, 2% had gestational hypertension, 4% had preeclampsia without eclampsia, and 0.1% had eclampsia.

Gestational hypertension was defined as new-onset systolic blood pressure of ≥ 140 mm Hg and/or diastolic blood pressure ≥ 90 mm Hg; preeclampsia was defined as gestational hypertension accompanied by proteinuria; and eclampsia was defined as tonic-clonic seizures without other etiology accompanied by preeclampsia.

Researchers used linked Swedish national registries that collect data on pregnancies, births, and infant and maternal characteristics. Among other things, they controlled for maternal age, early pregnancy body mass index, education level, and pregestational and gestational diabetes.

The primary outcome was a composite of five new-onset neurologic diagnoses: Migraine, headache, epilepsy, sleep disorder, and mental fatigue (neurasthenia), although one diagnosis was sufficient, from 42 days to 15 years after childbirth. Mean follow-up was 7.7 years.

 

Fivefold Epilepsy Risk

Compared with normotensive pregnancies, the risk for the primary outcome was 70% greater in those with eclampsia (adjusted hazard ratio [aHR], 1.70; 95% CI, 1.16-2.50), 27% higher for gestational hypertension (aHR, 1.27; 95% CI, 1.12-1.45), and 32% for preeclampsia (aHR, 1.32; 95% CI, 1.22-1.42).

Researchers also looked at the risk for individual neurologic disorders. There were too few neurasthenia events to generate meaningful results, so this diagnosis was omitted from the analysis.

Here, the study found women with eclampsia had five times the risk for epilepsy (aHR, 5.31; 95% CI, 2.85-9.89) compared with women with normotensive pregnancies.

The underlying mechanism for this association is unclear. However, said Friis, eclampsia and epilepsy share common pathways, such as neuroinflammation, and women with epilepsy before pregnancy run an increased risk for eclampsia.

“So common underlying pathways might increase the risk both for eclampsia in cases of a seizure disorder and a future seizure disorder after eclampsia,” she said.

In addition, preeclampsia and, in particular, eclampsia can cause irreversible subclinical cerebral infarcts found in areas of cerebral edema, she added. “These infarcts or scarring of brain tissue could potentially serve as foci for later epileptic activity.”

Researchers separated women with preeclampsia (with or without eclampsia) into those with preterm (less than 37 weeks; 21%) and term (79%) deliveries. As Friis explained, women with preterm preeclampsia have a higher risk for acute complications and long-term cardiovascular outcomes than those with term preeclampsia.

Compared with those with normotensive pregnancies, investigators found an increased risk for the composite neurologic outcome among women with preterm preeclampsia (aHR, 1.54; 95% CI, 1.34-1.79), but also for those with term preeclampsia (aHR, 1.27; 95% CI, 1.17-1.38).

 

Common Vascular Component

The study also showed gestational hypertension and preeclampsia were associated with a later diagnosis of migraine, suggesting a possible common underlying vascular component.

“The increased risk of migraine following preeclampsia could be linked to endothelial damage at the blood-brain barrier level and alterations in cerebral blood flow and arterial vasospasm found in eclampsia, but this is only speculation,” said Friis.

The analysis also found an association between preeclampsia and a later diagnosis of headache. But this result likely encompasses several headache diagnoses, including migraine, so “it’s challenging to draw conclusions about the underlying mechanisms,” Friis added.

The study didn’t consider diagnoses from primary healthcare, which resulted in relatively few outcomes. The authors explained they could only identify the most severe cases; for example, women referred to specialized care.

Another potential study limitation is that Swedish registers don’t include information on race or ethnicity. Evidence shows there are racial differences in the risk for cardiovascular outcomes after preeclampsia.

This area of research is important as most women will experience at least one pregnancy in their lifetime, and preeclampsia affects 3%-5% of pregnancies. Further research is needed to understand the underlying pathophysiological mechanisms and the long-term consequences of this disorder, said Friis.

She added she hopes more therapeutic options will be available in the future for neuroprotective treatment for women with gestational hypertensive disorders.

Asked to comment, Thomas Vidic, MD, clinical professor of neurology, Indiana University School of Medicine, South Bend, said in an interview that this is an important study that includes robust data.

In his opinion, the most significant study finding is the marked increase in epilepsy risk after gestational eclampsia.

“In women who have new-onset epilepsy of unknown cause, asking about having eclampsia or preeclampsia during pregnancy is definitely a worthwhile question,” he said.

Confirming an etiology paints “a better picture” for patients wondering why they’re experiencing seizures, he added.

As with any registry-based study, this one had some acknowledged limitations, “but at the same time, the authors were able to have such a large database that I think this study is very worthwhile,” said Vidic.

The study received support from the Swedish Research Council. Neither Friis nor Vidic had relevant conflicts of interest.

A version of this article appeared on Medscape.com.

TOPLINE:

Donepezil was associated with improved verbal memory and enhanced recall and processing speed, compared with placebo, in patients with severe traumatic brain injury (TBI), with a favorable safety profile despite mild to moderate gastrointestinal side effects.

METHODOLOGY:

• A four-site, randomized, parallel-group, double-blind, placebo-controlled, 10-week clinical trial (MEMRI-TBI-D) was conducted between 2013 and 2019 to evaluate the efficacy of donepezil for verbal memory impairments following severe TBI.
• 75 adults (75% men; mean age, 37 years) with complicated mild, moderate, or severe nonpenetrating TBI at least 6 months prior to study participation were included and randomly assigned to receive donepezil (n = 37) or placebo (n = 38).
• Participants received 5 mg donepezil daily or matching placebo for 2 weeks, then donepezil at 10 mg daily or matching placebo for 8 weeks; treatment was discontinued at 10 weeks, with an additional 4-week observation period.
• Verbal memory was assessed using the Hopkins Verbal Learning Test–Revised (HVLT-R). The primary outcome measure was verbal learning, evaluated through the HVLT-R total recall (ie, Total Trials 1-3) score.

TAKEAWAY:

• Compared with placebo, donepezil was associated with significantly greater improvements in verbal learning in both modified intent-to-treat and per-protocol analyses (P = .034 and .036, respectively).
• Treatment-responder rates were significantly higher in the donepezil group than in the placebo group (42 vs 18%; P = .03), with donepezil responders showing significant improvements in delayed recall and processing speed.
• Although there were no serious adverse events in either group, treatment-emergent adverse events were significantly more common in the donepezil group vs placebo (46% vs 8%; P < .001). No serious adverse events occurred in either group.
• Diarrhea and nausea were significantly more common in the donepezil group than in the placebo group (Fisher’s exact test: diarrhea, P = .03; nausea, P = .01).

IN PRACTICE:

“This study demonstrates the efficacy of donepezil on severe, persistent verbal memory impairments after predominantly severe TBI, with significant benefit for a subset of persons with such injuries, as well as a relatively favorable safety and tolerability profile,” the investigators wrote.

SOURCE:

The study was led by David B. Arciniegas, MD, University of Colorado School of Medicine, Aurora. It was published online in The Journal of Neuropsychiatry and Clinical Neurosciences.

LIMITATIONS:

The study included a relatively small sample with predominantly severe TBI requiring hospitalization and inpatient rehabilitation. The sample characteristics limit the generalizability of the findings to persons with other severities of TBI, other types of memory impairments, or more complex neuropsychiatric presentations. The study population had an average of 14 years of education, making generalizability to individuals with lower education levels uncertain. Additionally, while measures of information processing speed and immediate auditory attention were included, specific measures of sustained or selective attention were not, making it difficult to rule out improvements in higher-level attention as potential contributors to the observed verbal memory performance improvements.

DISCLOSURES:

The study was funded by the National Institute on Disability, Independent Living, and Rehabilitation Research, with in-kind support from TIRR Memorial Hermann. Four authors disclosed various financial and professional affiliations, including advisory roles with pharmaceutical and diagnostic companies, support from institutional awards, and involvement in programs funded by external organizations. One author served as the editor of The Journal of Neuropsychiatry and Clinical Neurosciences, with an independent editor overseeing the review and publication process for this article.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Donepezil was associated with improved verbal memory and enhanced recall and processing speed, compared with placebo, in patients with severe traumatic brain injury (TBI), with a favorable safety profile despite mild to moderate gastrointestinal side effects.

METHODOLOGY:

• A four-site, randomized, parallel-group, double-blind, placebo-controlled, 10-week clinical trial (MEMRI-TBI-D) was conducted between 2013 and 2019 to evaluate the efficacy of donepezil for verbal memory impairments following severe TBI.
• 75 adults (75% men; mean age, 37 years) with complicated mild, moderate, or severe nonpenetrating TBI at least 6 months prior to study participation were included and randomly assigned to receive donepezil (n = 37) or placebo (n = 38).
• Participants received 5 mg donepezil daily or matching placebo for 2 weeks, then donepezil at 10 mg daily or matching placebo for 8 weeks; treatment was discontinued at 10 weeks, with an additional 4-week observation period.
• Verbal memory was assessed using the Hopkins Verbal Learning Test–Revised (HVLT-R). The primary outcome measure was verbal learning, evaluated through the HVLT-R total recall (ie, Total Trials 1-3) score.

TAKEAWAY:

• Compared with placebo, donepezil was associated with significantly greater improvements in verbal learning in both modified intent-to-treat and per-protocol analyses (P = .034 and .036, respectively).
• Treatment-responder rates were significantly higher in the donepezil group than in the placebo group (42 vs 18%; P = .03), with donepezil responders showing significant improvements in delayed recall and processing speed.
• Although there were no serious adverse events in either group, treatment-emergent adverse events were significantly more common in the donepezil group vs placebo (46% vs 8%; P < .001). No serious adverse events occurred in either group.
• Diarrhea and nausea were significantly more common in the donepezil group than in the placebo group (Fisher’s exact test: diarrhea, P = .03; nausea, P = .01).

IN PRACTICE:

“This study demonstrates the efficacy of donepezil on severe, persistent verbal memory impairments after predominantly severe TBI, with significant benefit for a subset of persons with such injuries, as well as a relatively favorable safety and tolerability profile,” the investigators wrote.

SOURCE:

The study was led by David B. Arciniegas, MD, University of Colorado School of Medicine, Aurora. It was published online in The Journal of Neuropsychiatry and Clinical Neurosciences.

LIMITATIONS:

The study included a relatively small sample with predominantly severe TBI requiring hospitalization and inpatient rehabilitation. The sample characteristics limit the generalizability of the findings to persons with other severities of TBI, other types of memory impairments, or more complex neuropsychiatric presentations. The study population had an average of 14 years of education, making generalizability to individuals with lower education levels uncertain. Additionally, while measures of information processing speed and immediate auditory attention were included, specific measures of sustained or selective attention were not, making it difficult to rule out improvements in higher-level attention as potential contributors to the observed verbal memory performance improvements.

DISCLOSURES:

The study was funded by the National Institute on Disability, Independent Living, and Rehabilitation Research, with in-kind support from TIRR Memorial Hermann. Four authors disclosed various financial and professional affiliations, including advisory roles with pharmaceutical and diagnostic companies, support from institutional awards, and involvement in programs funded by external organizations. One author served as the editor of The Journal of Neuropsychiatry and Clinical Neurosciences, with an independent editor overseeing the review and publication process for this article.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Donepezil was associated with improved verbal memory and enhanced recall and processing speed, compared with placebo, in patients with severe traumatic brain injury (TBI), with a favorable safety profile despite mild to moderate gastrointestinal side effects.

METHODOLOGY:

• A four-site, randomized, parallel-group, double-blind, placebo-controlled, 10-week clinical trial (MEMRI-TBI-D) was conducted between 2013 and 2019 to evaluate the efficacy of donepezil for verbal memory impairments following severe TBI.
• 75 adults (75% men; mean age, 37 years) with complicated mild, moderate, or severe nonpenetrating TBI at least 6 months prior to study participation were included and randomly assigned to receive donepezil (n = 37) or placebo (n = 38).
• Participants received 5 mg donepezil daily or matching placebo for 2 weeks, then donepezil at 10 mg daily or matching placebo for 8 weeks; treatment was discontinued at 10 weeks, with an additional 4-week observation period.
• Verbal memory was assessed using the Hopkins Verbal Learning Test–Revised (HVLT-R). The primary outcome measure was verbal learning, evaluated through the HVLT-R total recall (ie, Total Trials 1-3) score.

TAKEAWAY:

• Compared with placebo, donepezil was associated with significantly greater improvements in verbal learning in both modified intent-to-treat and per-protocol analyses (P = .034 and .036, respectively).
• Treatment-responder rates were significantly higher in the donepezil group than in the placebo group (42 vs 18%; P = .03), with donepezil responders showing significant improvements in delayed recall and processing speed.
• Although there were no serious adverse events in either group, treatment-emergent adverse events were significantly more common in the donepezil group vs placebo (46% vs 8%; P < .001). No serious adverse events occurred in either group.
• Diarrhea and nausea were significantly more common in the donepezil group than in the placebo group (Fisher’s exact test: diarrhea, P = .03; nausea, P = .01).

IN PRACTICE:

“This study demonstrates the efficacy of donepezil on severe, persistent verbal memory impairments after predominantly severe TBI, with significant benefit for a subset of persons with such injuries, as well as a relatively favorable safety and tolerability profile,” the investigators wrote.

SOURCE:

The study was led by David B. Arciniegas, MD, University of Colorado School of Medicine, Aurora. It was published online in The Journal of Neuropsychiatry and Clinical Neurosciences.

LIMITATIONS:

The study included a relatively small sample with predominantly severe TBI requiring hospitalization and inpatient rehabilitation. The sample characteristics limit the generalizability of the findings to persons with other severities of TBI, other types of memory impairments, or more complex neuropsychiatric presentations. The study population had an average of 14 years of education, making generalizability to individuals with lower education levels uncertain. Additionally, while measures of information processing speed and immediate auditory attention were included, specific measures of sustained or selective attention were not, making it difficult to rule out improvements in higher-level attention as potential contributors to the observed verbal memory performance improvements.

DISCLOSURES:

The study was funded by the National Institute on Disability, Independent Living, and Rehabilitation Research, with in-kind support from TIRR Memorial Hermann. Four authors disclosed various financial and professional affiliations, including advisory roles with pharmaceutical and diagnostic companies, support from institutional awards, and involvement in programs funded by external organizations. One author served as the editor of The Journal of Neuropsychiatry and Clinical Neurosciences, with an independent editor overseeing the review and publication process for this article.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

The newer biologics — interleukin (IL)–17, IL-12/23, and IL-23 inhibitors — demonstrate comparable cardiovascular safety profiles to tumor necrosis factor (TNF) inhibitors in biologic-naive patients with psoriasis or psoriatic arthritis (PsA).

METHODOLOGY:

• In a retrospective cohort study, researchers conducted an emulated target trial analysis using data of 32,098 biologic-naive patients with psoriasis or PsA who were treated with one of the newer biologics (infliximab, adalimumab, etanercept, certolizumab pegol, secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, and tildrakizumab) from the TriNetX Research Network between 2014 and 2022.
• Patients received TNF inhibitors (n = 20,314), IL-17 inhibitors (n = 5073), IL-12/23 inhibitors (n = 3573), or IL-23 inhibitors (n = 3138).
• A propensity-matched analysis compared each class of newer biologics with TNF inhibitors, adjusting for demographics, comorbidities, and medication use.
• The primary outcomes were major adverse cardiovascular events (MACE; myocardial infarction and stroke) or venous thromboembolic events (VTE).

TAKEAWAY:

• Compared with patients who received TNF inhibitors, the risk for MACE was not significantly different between patients who received IL-17 inhibitors (incidence rate ratio [IRR], 1.14; 95% CI, 0.86-1.52), IL-12/23 inhibitors (IRR, 1.24; 95% CI, 0.84-1.78), or IL-23 inhibitors (IRR, 0.93; 95% CI, 0.61-1.38)
• The VTE risk was also not significantly different between patients who received IL-17 inhibitors (IRR, 1.12; 95% CI, 0.63-2.08), IL-12/23 inhibitors (IRR, 1.51; 95% CI, 0.73-3.19), or IL-23 inhibitors (IRR, 1.42; 95% CI, 0.64-3.25) compared with those who received TNF inhibitors.
• Subgroup analyses for psoriasis or psoriatic arthritis alone confirmed consistent findings.
• Patients with preexisting hyperlipidemia and diabetes mellitus showed lower risks for MACE and VTE with newer biologics compared with TNF inhibitors. 

IN PRACTICE:

“No significant MACE and VTE risk differences were detected in patients with psoriasis or PsA between those receiving IL-17, IL-12/23, and IL-23 inhibitors and those with TNF inhibitors,” the authors concluded. These findings, they added “can be considered by physicians and patients when making treatment decisions” and also provide “evidence for future pharmacovigilance studies.”

SOURCE:

The study was led by Tai-Li Chen, MD, of the Department of Dermatology, Taipei Veterans General Hospital in Taipei, Taiwan. It was published online on December 27, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

Study limitations included potential residual confounding factors, lack of information on disease severity, and inclusion of predominantly White individuals.

DISCLOSURES:

The study received support from Taipei Veterans General Hospital and Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The newer biologics — interleukin (IL)–17, IL-12/23, and IL-23 inhibitors — demonstrate comparable cardiovascular safety profiles to tumor necrosis factor (TNF) inhibitors in biologic-naive patients with psoriasis or psoriatic arthritis (PsA).

METHODOLOGY:

• In a retrospective cohort study, researchers conducted an emulated target trial analysis using data of 32,098 biologic-naive patients with psoriasis or PsA who were treated with one of the newer biologics (infliximab, adalimumab, etanercept, certolizumab pegol, secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, and tildrakizumab) from the TriNetX Research Network between 2014 and 2022.
• Patients received TNF inhibitors (n = 20,314), IL-17 inhibitors (n = 5073), IL-12/23 inhibitors (n = 3573), or IL-23 inhibitors (n = 3138).
• A propensity-matched analysis compared each class of newer biologics with TNF inhibitors, adjusting for demographics, comorbidities, and medication use.
• The primary outcomes were major adverse cardiovascular events (MACE; myocardial infarction and stroke) or venous thromboembolic events (VTE).

TAKEAWAY:

• Compared with patients who received TNF inhibitors, the risk for MACE was not significantly different between patients who received IL-17 inhibitors (incidence rate ratio [IRR], 1.14; 95% CI, 0.86-1.52), IL-12/23 inhibitors (IRR, 1.24; 95% CI, 0.84-1.78), or IL-23 inhibitors (IRR, 0.93; 95% CI, 0.61-1.38)
• The VTE risk was also not significantly different between patients who received IL-17 inhibitors (IRR, 1.12; 95% CI, 0.63-2.08), IL-12/23 inhibitors (IRR, 1.51; 95% CI, 0.73-3.19), or IL-23 inhibitors (IRR, 1.42; 95% CI, 0.64-3.25) compared with those who received TNF inhibitors.
• Subgroup analyses for psoriasis or psoriatic arthritis alone confirmed consistent findings.
• Patients with preexisting hyperlipidemia and diabetes mellitus showed lower risks for MACE and VTE with newer biologics compared with TNF inhibitors. 

IN PRACTICE:

“No significant MACE and VTE risk differences were detected in patients with psoriasis or PsA between those receiving IL-17, IL-12/23, and IL-23 inhibitors and those with TNF inhibitors,” the authors concluded. These findings, they added “can be considered by physicians and patients when making treatment decisions” and also provide “evidence for future pharmacovigilance studies.”

SOURCE:

The study was led by Tai-Li Chen, MD, of the Department of Dermatology, Taipei Veterans General Hospital in Taipei, Taiwan. It was published online on December 27, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

Study limitations included potential residual confounding factors, lack of information on disease severity, and inclusion of predominantly White individuals.

DISCLOSURES:

The study received support from Taipei Veterans General Hospital and Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

The newer biologics — interleukin (IL)–17, IL-12/23, and IL-23 inhibitors — demonstrate comparable cardiovascular safety profiles to tumor necrosis factor (TNF) inhibitors in biologic-naive patients with psoriasis or psoriatic arthritis (PsA).

METHODOLOGY:

• In a retrospective cohort study, researchers conducted an emulated target trial analysis using data of 32,098 biologic-naive patients with psoriasis or PsA who were treated with one of the newer biologics (infliximab, adalimumab, etanercept, certolizumab pegol, secukinumab, ixekizumab, brodalumab, ustekinumab, risankizumab, guselkumab, and tildrakizumab) from the TriNetX Research Network between 2014 and 2022.
• Patients received TNF inhibitors (n = 20,314), IL-17 inhibitors (n = 5073), IL-12/23 inhibitors (n = 3573), or IL-23 inhibitors (n = 3138).
• A propensity-matched analysis compared each class of newer biologics with TNF inhibitors, adjusting for demographics, comorbidities, and medication use.
• The primary outcomes were major adverse cardiovascular events (MACE; myocardial infarction and stroke) or venous thromboembolic events (VTE).

TAKEAWAY:

• Compared with patients who received TNF inhibitors, the risk for MACE was not significantly different between patients who received IL-17 inhibitors (incidence rate ratio [IRR], 1.14; 95% CI, 0.86-1.52), IL-12/23 inhibitors (IRR, 1.24; 95% CI, 0.84-1.78), or IL-23 inhibitors (IRR, 0.93; 95% CI, 0.61-1.38)
• The VTE risk was also not significantly different between patients who received IL-17 inhibitors (IRR, 1.12; 95% CI, 0.63-2.08), IL-12/23 inhibitors (IRR, 1.51; 95% CI, 0.73-3.19), or IL-23 inhibitors (IRR, 1.42; 95% CI, 0.64-3.25) compared with those who received TNF inhibitors.
• Subgroup analyses for psoriasis or psoriatic arthritis alone confirmed consistent findings.
• Patients with preexisting hyperlipidemia and diabetes mellitus showed lower risks for MACE and VTE with newer biologics compared with TNF inhibitors. 

IN PRACTICE:

“No significant MACE and VTE risk differences were detected in patients with psoriasis or PsA between those receiving IL-17, IL-12/23, and IL-23 inhibitors and those with TNF inhibitors,” the authors concluded. These findings, they added “can be considered by physicians and patients when making treatment decisions” and also provide “evidence for future pharmacovigilance studies.”

SOURCE:

The study was led by Tai-Li Chen, MD, of the Department of Dermatology, Taipei Veterans General Hospital in Taipei, Taiwan. It was published online on December 27, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

Study limitations included potential residual confounding factors, lack of information on disease severity, and inclusion of predominantly White individuals.

DISCLOSURES:

The study received support from Taipei Veterans General Hospital and Ministry of Science and Technology, Taiwan. The authors reported no conflicts of interest.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

At the close of 2024, to an odd mix of disappointment and jubilation, Cassava Sciences announced that simufilam didn’t do anything for Alzheimer’s disease.

An Alzheimer’s drug trial failing is, unfortunately, nothing new. This one, however, had more baggage behind it than most.

Like all of these things, it was worth a try. It’s an interesting molecule with a reasonable mechanism of action.

 

But the trials have been raising questions for a few years, with allegations of misconduct against the drug’s co-discoverer Hoau-Yan Wang. He’s been indicted for defrauding the National Institutes of Health of $16 million in grants related to the drug. There have been concerns over doctored images and other not-so-minor issues in trying to move simufilam forward. Cassava itself agreed to pay the Securities and Exchange Commission $40 million in 2024 to settle charges about misleading investors.

Yet, like an innocent child with criminal parents, many of us hoped that the drug would work, regardless of the ethical shenanigans behind it. On the front lines we deal with a tragic disease that robs people of what makes them human and robs the families who have to live with it.

As the wheels started to come off the bus I told a friend, “it would be really sad if this drug is THE ONE and it never gets to finish trials because of everything else.”

Now we know it isn’t. Regardless of the controversy, the final data show that simufilam is just another placebo, joining the ranks of many others in the Alzheimer’s development graveyard.

Yes, there is a vague sense of jubilation behind it. I believe in fair play, and it’s good to know that those who misled investors and falsified data were wrong and will never have their day in the sun.

At the same time, however, I’m disappointed. I’m happy that the drug at least got a chance to prove itself, but when it’s all said and done, it doesn’t do anything.

I feel bad for the innocent people in the company, who had nothing to do with the scheming and were just hoping the drug would go somewhere. The majority, if not all, of them will likely lose their jobs. Like me, they have families, bills, and mortgages.

But I’m even more disappointed for the patients and families who only wanted an effective treatment for Alzheimer’s disease, and were hoping that, regardless of its dirty laundry, simufilam would work.

They’re the ones that I, and many other neurologists, have to face every day when they ask “is there anything new out?” and we sadly shake our heads.

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

At the close of 2024, to an odd mix of disappointment and jubilation, Cassava Sciences announced that simufilam didn’t do anything for Alzheimer’s disease.

An Alzheimer’s drug trial failing is, unfortunately, nothing new. This one, however, had more baggage behind it than most.

Like all of these things, it was worth a try. It’s an interesting molecule with a reasonable mechanism of action.

 

But the trials have been raising questions for a few years, with allegations of misconduct against the drug’s co-discoverer Hoau-Yan Wang. He’s been indicted for defrauding the National Institutes of Health of $16 million in grants related to the drug. There have been concerns over doctored images and other not-so-minor issues in trying to move simufilam forward. Cassava itself agreed to pay the Securities and Exchange Commission $40 million in 2024 to settle charges about misleading investors.

Yet, like an innocent child with criminal parents, many of us hoped that the drug would work, regardless of the ethical shenanigans behind it. On the front lines we deal with a tragic disease that robs people of what makes them human and robs the families who have to live with it.

As the wheels started to come off the bus I told a friend, “it would be really sad if this drug is THE ONE and it never gets to finish trials because of everything else.”

Now we know it isn’t. Regardless of the controversy, the final data show that simufilam is just another placebo, joining the ranks of many others in the Alzheimer’s development graveyard.

Yes, there is a vague sense of jubilation behind it. I believe in fair play, and it’s good to know that those who misled investors and falsified data were wrong and will never have their day in the sun.

At the same time, however, I’m disappointed. I’m happy that the drug at least got a chance to prove itself, but when it’s all said and done, it doesn’t do anything.

I feel bad for the innocent people in the company, who had nothing to do with the scheming and were just hoping the drug would go somewhere. The majority, if not all, of them will likely lose their jobs. Like me, they have families, bills, and mortgages.

But I’m even more disappointed for the patients and families who only wanted an effective treatment for Alzheimer’s disease, and were hoping that, regardless of its dirty laundry, simufilam would work.

They’re the ones that I, and many other neurologists, have to face every day when they ask “is there anything new out?” and we sadly shake our heads.

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

At the close of 2024, to an odd mix of disappointment and jubilation, Cassava Sciences announced that simufilam didn’t do anything for Alzheimer’s disease.

An Alzheimer’s drug trial failing is, unfortunately, nothing new. This one, however, had more baggage behind it than most.

Like all of these things, it was worth a try. It’s an interesting molecule with a reasonable mechanism of action.

 

But the trials have been raising questions for a few years, with allegations of misconduct against the drug’s co-discoverer Hoau-Yan Wang. He’s been indicted for defrauding the National Institutes of Health of $16 million in grants related to the drug. There have been concerns over doctored images and other not-so-minor issues in trying to move simufilam forward. Cassava itself agreed to pay the Securities and Exchange Commission $40 million in 2024 to settle charges about misleading investors.

Yet, like an innocent child with criminal parents, many of us hoped that the drug would work, regardless of the ethical shenanigans behind it. On the front lines we deal with a tragic disease that robs people of what makes them human and robs the families who have to live with it.

As the wheels started to come off the bus I told a friend, “it would be really sad if this drug is THE ONE and it never gets to finish trials because of everything else.”

Now we know it isn’t. Regardless of the controversy, the final data show that simufilam is just another placebo, joining the ranks of many others in the Alzheimer’s development graveyard.

Yes, there is a vague sense of jubilation behind it. I believe in fair play, and it’s good to know that those who misled investors and falsified data were wrong and will never have their day in the sun.

At the same time, however, I’m disappointed. I’m happy that the drug at least got a chance to prove itself, but when it’s all said and done, it doesn’t do anything.

I feel bad for the innocent people in the company, who had nothing to do with the scheming and were just hoping the drug would go somewhere. The majority, if not all, of them will likely lose their jobs. Like me, they have families, bills, and mortgages.

But I’m even more disappointed for the patients and families who only wanted an effective treatment for Alzheimer’s disease, and were hoping that, regardless of its dirty laundry, simufilam would work.

They’re the ones that I, and many other neurologists, have to face every day when they ask “is there anything new out?” and we sadly shake our heads.

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

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

A widely accepted assumption in the addiction field is that neuroanatomical changes observed in young people who use alcohol or other substances are largely the consequence of exposure to these substances.

But a new study suggests that neuroanatomical features in children, including greater whole brain and cortical volumes, are evident before exposure to any substances.

The investigators, led by Alex P. Miller, PhD, assistant professor, Department of Psychiatry, Indiana University, Indianapolis, noted that the findings add to a growing body of work that suggests individual brain structure, along with environmental exposure and genetic risk, may influence risk for substance use disorder. 

The findings were published online in JAMA Network Open.

 

Neuroanatomy a Predisposing Risk Factor?

Earlier research showed that substance use is associated with lower gray matter volume, thinner cortex, and less white matter integrity. While it has been widely thought that these changes were induced by the use of alcohol or illicit drugs, recent longitudinal and genetic studies suggest that the neuroanatomical changes may also be predisposing risk factors for substance use.

To better understand the issue, investigators analyzed data on 9804 children (mean baseline age, 9.9 years; 53% men; 76% White) at 22 US sites enrolled in the Adolescent Brain Cognitive Development (ABCD) Study that’s examining brain and behavioral development from middle childhood to young adulthood.

The researchers collected information on the use of alcohol, nicotine, cannabis, and other illicit substances from in-person interviews at baseline and years 1, 2, and 3, as well as interim phone interviews at 6, 18, and 30 months. MRI scans provided extensive brain structural data, including global and regional cortical volume, thickness, surface area, sulcal depth, and subcortical volume.

Of the total, 3460 participants (35%) initiated substance use before age 15, with 90% reporting alcohol use initiation. There was considerable overlap between initiation of alcohol, nicotine, and cannabis.

The researchers tested whether baseline neuroanatomical variability was associated with any substance use initiation before or up to 3 years following initial neuroimaging scans. Study covariates included baseline age, sex, pubertal status, familial relationship (eg, sibling or twin), and prenatal substance exposures. Researchers didn’t control for sociodemographic characteristics as these could influence associations.

 

Significant Brain Differences

Compared with no substance use initiation, any substance use initiation was associated with larger global neuroanatomical indices, including whole brain (beta = 0.05; P = 2.80 × 10^–8), total intracranial (beta = 0.04; P = 3.49 × 10⁻⁶), cortical (beta = 0.05; P = 4.31 × 10^–8), and subcortical volumes (beta = 0.05; P = 4.39 × 10^–8), as well as greater total cortical surface area (beta = 0.04; P = 6.05 × 10^–7).

The direction of associations between cortical thickness and substance use initiation was regionally specific; any substance use initiation was characterized by thinner cortex in all frontal regions (eg, rostral middle frontal gyrus, beta = −0.03; P = 6.99 × 10^–6), but thicker cortex in all other lobes. It was also associated with larger regional brain volumes, deeper regional sulci, and differences in regional cortical surface area.

The authors noted total cortical thickness peaks at age 1.7 years and steadily declines throughout life. By contrast, subcortical volumes peak at 14.4 years of age and generally remain stable before steep later life declines.

Secondary analyses compared initiation of the three most commonly used substances in early adolescence (alcohol, nicotine, and cannabis) with no substance use.

Findings for alcohol largely mirrored those for any substance use. However, the study uncovered additional significant associations, including greater left lateral occipital volume and bilateral para-hippocampal gyri cortical thickness and less bilateral superior frontal gyri cortical thickness.

Nicotine use was associated with lower right superior frontal gyrus volume and deeper left lateral orbitofrontal cortex sulci. And cannabis use was associated with thinner left precentral gyrus and lower right inferior parietal gyrus and right caudate volumes.

The authors noted results for nicotine and cannabis may not have had adequate statistical power, and small effects suggest these findings aren’t clinically informative for individuals. However, they wrote, “They do inform and challenge current theoretical models of addiction.”

 

Associations Precede Substance Use

A post hoc analysis further challenges current models of addiction. When researchers looked only at the 1203 youth who initiated substance use after the baseline neuroimaging session, they found most associations preceded substance use.

“That regional associations may precede substance use initiation, including less cortical thickness in the right rostral middle frontal gyrus, challenges predominant interpretations that these associations arise largely due to neurotoxic consequences of exposure and increases the plausibility that these features may, at least partially, reflect markers of predispositional risk,” wrote the authors.

A study limitation was that unmeasured confounders and undetected systemic differences in missing data may have influenced associations. Sociodemographic, environmental, and genetic variables that were not included as covariates are likely associated with both neuroanatomical variability and substance use initiation and may moderate associations between them, said the authors.

The ABCD Study provides “a robust and large database of longitudinal data” that goes beyond previous neuroimaging research “to understand the bidirectional relationship between brain structure and substance use,” Miller said in a press release.

“The hope is that these types of studies, in conjunction with other data on environmental exposures and genetic risk, could help change how we think about the development of substance use disorders and inform more accurate models of addiction moving forward,” Miller said.

 

Reevaluating Causal Assumptions

In an accompanying editorial, Felix Pichardo, MA, and Sylia Wilson, PhD, from the Institute of Child Development, University of Minnesota, Minneapolis, suggested that it may be time to “reevaluate the causal assumptions that underlie brain disease models of addiction” and the mechanisms by which it develops, persists, and becomes harmful.

Neurotoxic effects of substances are central to current brain disease models of addiction, wrote Pichardo and Wilson. “Substance exposure is thought to affect cortical and subcortical regions that support interrelated systems, resulting in desensitization of reward-related processing, increased stress that prompts cravings, negative emotions when cravings are unsated, and weakening of cognitive control abilities that leads to repeated returns to use.”

The editorial writers praised the ABCD Study for its large sample size for providing a level of precision, statistical accuracy, and ability to identify both larger and smaller effects, which are critical for addiction research.

Unlike most addiction research that relies on cross-sectional designs, the current study used longitudinal assessments, which is another of its strengths, they noted.

“Longitudinal study designs like in the ABCD Study are fundamental for establishing temporal ordering across constructs, which is important because establishing temporal precedence is a key step in determining causal links and underlying mechanisms.”

The inclusion of several genetically informative components, such as the family study design, nested twin subsamples, and DNA collection, “allows researchers to extend beyond temporal precedence toward increased causal inference and identification of mechanisms,” they added.

The study received support from the National Institutes of Health. The study authors and editorial writers had no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

A widely accepted assumption in the addiction field is that neuroanatomical changes observed in young people who use alcohol or other substances are largely the consequence of exposure to these substances.

But a new study suggests that neuroanatomical features in children, including greater whole brain and cortical volumes, are evident before exposure to any substances.

The investigators, led by Alex P. Miller, PhD, assistant professor, Department of Psychiatry, Indiana University, Indianapolis, noted that the findings add to a growing body of work that suggests individual brain structure, along with environmental exposure and genetic risk, may influence risk for substance use disorder. 

The findings were published online in JAMA Network Open.

 

Neuroanatomy a Predisposing Risk Factor?

Earlier research showed that substance use is associated with lower gray matter volume, thinner cortex, and less white matter integrity. While it has been widely thought that these changes were induced by the use of alcohol or illicit drugs, recent longitudinal and genetic studies suggest that the neuroanatomical changes may also be predisposing risk factors for substance use.

To better understand the issue, investigators analyzed data on 9804 children (mean baseline age, 9.9 years; 53% men; 76% White) at 22 US sites enrolled in the Adolescent Brain Cognitive Development (ABCD) Study that’s examining brain and behavioral development from middle childhood to young adulthood.

The researchers collected information on the use of alcohol, nicotine, cannabis, and other illicit substances from in-person interviews at baseline and years 1, 2, and 3, as well as interim phone interviews at 6, 18, and 30 months. MRI scans provided extensive brain structural data, including global and regional cortical volume, thickness, surface area, sulcal depth, and subcortical volume.

Of the total, 3460 participants (35%) initiated substance use before age 15, with 90% reporting alcohol use initiation. There was considerable overlap between initiation of alcohol, nicotine, and cannabis.

The researchers tested whether baseline neuroanatomical variability was associated with any substance use initiation before or up to 3 years following initial neuroimaging scans. Study covariates included baseline age, sex, pubertal status, familial relationship (eg, sibling or twin), and prenatal substance exposures. Researchers didn’t control for sociodemographic characteristics as these could influence associations.

 

Significant Brain Differences

Compared with no substance use initiation, any substance use initiation was associated with larger global neuroanatomical indices, including whole brain (beta = 0.05; P = 2.80 × 10^–8), total intracranial (beta = 0.04; P = 3.49 × 10⁻⁶), cortical (beta = 0.05; P = 4.31 × 10^–8), and subcortical volumes (beta = 0.05; P = 4.39 × 10^–8), as well as greater total cortical surface area (beta = 0.04; P = 6.05 × 10^–7).

The direction of associations between cortical thickness and substance use initiation was regionally specific; any substance use initiation was characterized by thinner cortex in all frontal regions (eg, rostral middle frontal gyrus, beta = −0.03; P = 6.99 × 10^–6), but thicker cortex in all other lobes. It was also associated with larger regional brain volumes, deeper regional sulci, and differences in regional cortical surface area.

The authors noted total cortical thickness peaks at age 1.7 years and steadily declines throughout life. By contrast, subcortical volumes peak at 14.4 years of age and generally remain stable before steep later life declines.

Secondary analyses compared initiation of the three most commonly used substances in early adolescence (alcohol, nicotine, and cannabis) with no substance use.

Findings for alcohol largely mirrored those for any substance use. However, the study uncovered additional significant associations, including greater left lateral occipital volume and bilateral para-hippocampal gyri cortical thickness and less bilateral superior frontal gyri cortical thickness.

Nicotine use was associated with lower right superior frontal gyrus volume and deeper left lateral orbitofrontal cortex sulci. And cannabis use was associated with thinner left precentral gyrus and lower right inferior parietal gyrus and right caudate volumes.

The authors noted results for nicotine and cannabis may not have had adequate statistical power, and small effects suggest these findings aren’t clinically informative for individuals. However, they wrote, “They do inform and challenge current theoretical models of addiction.”

 

Associations Precede Substance Use

A post hoc analysis further challenges current models of addiction. When researchers looked only at the 1203 youth who initiated substance use after the baseline neuroimaging session, they found most associations preceded substance use.

“That regional associations may precede substance use initiation, including less cortical thickness in the right rostral middle frontal gyrus, challenges predominant interpretations that these associations arise largely due to neurotoxic consequences of exposure and increases the plausibility that these features may, at least partially, reflect markers of predispositional risk,” wrote the authors.

A study limitation was that unmeasured confounders and undetected systemic differences in missing data may have influenced associations. Sociodemographic, environmental, and genetic variables that were not included as covariates are likely associated with both neuroanatomical variability and substance use initiation and may moderate associations between them, said the authors.

The ABCD Study provides “a robust and large database of longitudinal data” that goes beyond previous neuroimaging research “to understand the bidirectional relationship between brain structure and substance use,” Miller said in a press release.

“The hope is that these types of studies, in conjunction with other data on environmental exposures and genetic risk, could help change how we think about the development of substance use disorders and inform more accurate models of addiction moving forward,” Miller said.

 

Reevaluating Causal Assumptions

In an accompanying editorial, Felix Pichardo, MA, and Sylia Wilson, PhD, from the Institute of Child Development, University of Minnesota, Minneapolis, suggested that it may be time to “reevaluate the causal assumptions that underlie brain disease models of addiction” and the mechanisms by which it develops, persists, and becomes harmful.

Neurotoxic effects of substances are central to current brain disease models of addiction, wrote Pichardo and Wilson. “Substance exposure is thought to affect cortical and subcortical regions that support interrelated systems, resulting in desensitization of reward-related processing, increased stress that prompts cravings, negative emotions when cravings are unsated, and weakening of cognitive control abilities that leads to repeated returns to use.”

The editorial writers praised the ABCD Study for its large sample size for providing a level of precision, statistical accuracy, and ability to identify both larger and smaller effects, which are critical for addiction research.

Unlike most addiction research that relies on cross-sectional designs, the current study used longitudinal assessments, which is another of its strengths, they noted.

“Longitudinal study designs like in the ABCD Study are fundamental for establishing temporal ordering across constructs, which is important because establishing temporal precedence is a key step in determining causal links and underlying mechanisms.”

The inclusion of several genetically informative components, such as the family study design, nested twin subsamples, and DNA collection, “allows researchers to extend beyond temporal precedence toward increased causal inference and identification of mechanisms,” they added.

The study received support from the National Institutes of Health. The study authors and editorial writers had no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

A widely accepted assumption in the addiction field is that neuroanatomical changes observed in young people who use alcohol or other substances are largely the consequence of exposure to these substances.

But a new study suggests that neuroanatomical features in children, including greater whole brain and cortical volumes, are evident before exposure to any substances.

The investigators, led by Alex P. Miller, PhD, assistant professor, Department of Psychiatry, Indiana University, Indianapolis, noted that the findings add to a growing body of work that suggests individual brain structure, along with environmental exposure and genetic risk, may influence risk for substance use disorder. 

The findings were published online in JAMA Network Open.

 

Neuroanatomy a Predisposing Risk Factor?

Earlier research showed that substance use is associated with lower gray matter volume, thinner cortex, and less white matter integrity. While it has been widely thought that these changes were induced by the use of alcohol or illicit drugs, recent longitudinal and genetic studies suggest that the neuroanatomical changes may also be predisposing risk factors for substance use.

To better understand the issue, investigators analyzed data on 9804 children (mean baseline age, 9.9 years; 53% men; 76% White) at 22 US sites enrolled in the Adolescent Brain Cognitive Development (ABCD) Study that’s examining brain and behavioral development from middle childhood to young adulthood.

The researchers collected information on the use of alcohol, nicotine, cannabis, and other illicit substances from in-person interviews at baseline and years 1, 2, and 3, as well as interim phone interviews at 6, 18, and 30 months. MRI scans provided extensive brain structural data, including global and regional cortical volume, thickness, surface area, sulcal depth, and subcortical volume.

Of the total, 3460 participants (35%) initiated substance use before age 15, with 90% reporting alcohol use initiation. There was considerable overlap between initiation of alcohol, nicotine, and cannabis.

The researchers tested whether baseline neuroanatomical variability was associated with any substance use initiation before or up to 3 years following initial neuroimaging scans. Study covariates included baseline age, sex, pubertal status, familial relationship (eg, sibling or twin), and prenatal substance exposures. Researchers didn’t control for sociodemographic characteristics as these could influence associations.

 

Significant Brain Differences

Compared with no substance use initiation, any substance use initiation was associated with larger global neuroanatomical indices, including whole brain (beta = 0.05; P = 2.80 × 10^–8), total intracranial (beta = 0.04; P = 3.49 × 10⁻⁶), cortical (beta = 0.05; P = 4.31 × 10^–8), and subcortical volumes (beta = 0.05; P = 4.39 × 10^–8), as well as greater total cortical surface area (beta = 0.04; P = 6.05 × 10^–7).

The direction of associations between cortical thickness and substance use initiation was regionally specific; any substance use initiation was characterized by thinner cortex in all frontal regions (eg, rostral middle frontal gyrus, beta = −0.03; P = 6.99 × 10^–6), but thicker cortex in all other lobes. It was also associated with larger regional brain volumes, deeper regional sulci, and differences in regional cortical surface area.

The authors noted total cortical thickness peaks at age 1.7 years and steadily declines throughout life. By contrast, subcortical volumes peak at 14.4 years of age and generally remain stable before steep later life declines.

Secondary analyses compared initiation of the three most commonly used substances in early adolescence (alcohol, nicotine, and cannabis) with no substance use.

Findings for alcohol largely mirrored those for any substance use. However, the study uncovered additional significant associations, including greater left lateral occipital volume and bilateral para-hippocampal gyri cortical thickness and less bilateral superior frontal gyri cortical thickness.

Nicotine use was associated with lower right superior frontal gyrus volume and deeper left lateral orbitofrontal cortex sulci. And cannabis use was associated with thinner left precentral gyrus and lower right inferior parietal gyrus and right caudate volumes.

The authors noted results for nicotine and cannabis may not have had adequate statistical power, and small effects suggest these findings aren’t clinically informative for individuals. However, they wrote, “They do inform and challenge current theoretical models of addiction.”

 

Associations Precede Substance Use

A post hoc analysis further challenges current models of addiction. When researchers looked only at the 1203 youth who initiated substance use after the baseline neuroimaging session, they found most associations preceded substance use.

“That regional associations may precede substance use initiation, including less cortical thickness in the right rostral middle frontal gyrus, challenges predominant interpretations that these associations arise largely due to neurotoxic consequences of exposure and increases the plausibility that these features may, at least partially, reflect markers of predispositional risk,” wrote the authors.

A study limitation was that unmeasured confounders and undetected systemic differences in missing data may have influenced associations. Sociodemographic, environmental, and genetic variables that were not included as covariates are likely associated with both neuroanatomical variability and substance use initiation and may moderate associations between them, said the authors.

The ABCD Study provides “a robust and large database of longitudinal data” that goes beyond previous neuroimaging research “to understand the bidirectional relationship between brain structure and substance use,” Miller said in a press release.

“The hope is that these types of studies, in conjunction with other data on environmental exposures and genetic risk, could help change how we think about the development of substance use disorders and inform more accurate models of addiction moving forward,” Miller said.

 

Reevaluating Causal Assumptions

In an accompanying editorial, Felix Pichardo, MA, and Sylia Wilson, PhD, from the Institute of Child Development, University of Minnesota, Minneapolis, suggested that it may be time to “reevaluate the causal assumptions that underlie brain disease models of addiction” and the mechanisms by which it develops, persists, and becomes harmful.

Neurotoxic effects of substances are central to current brain disease models of addiction, wrote Pichardo and Wilson. “Substance exposure is thought to affect cortical and subcortical regions that support interrelated systems, resulting in desensitization of reward-related processing, increased stress that prompts cravings, negative emotions when cravings are unsated, and weakening of cognitive control abilities that leads to repeated returns to use.”

The editorial writers praised the ABCD Study for its large sample size for providing a level of precision, statistical accuracy, and ability to identify both larger and smaller effects, which are critical for addiction research.

Unlike most addiction research that relies on cross-sectional designs, the current study used longitudinal assessments, which is another of its strengths, they noted.

“Longitudinal study designs like in the ABCD Study are fundamental for establishing temporal ordering across constructs, which is important because establishing temporal precedence is a key step in determining causal links and underlying mechanisms.”

The inclusion of several genetically informative components, such as the family study design, nested twin subsamples, and DNA collection, “allows researchers to extend beyond temporal precedence toward increased causal inference and identification of mechanisms,” they added.

The study received support from the National Institutes of Health. The study authors and editorial writers had no relevant conflicts of interest.

A version of this article appeared on Medscape.com.