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Stool-Based Methylation Test May Improve CRC Screening
based on a prospective, real-world study.
These findings suggest that the mSDC2 assay could improve the efficacy and resource utilization of existing screening programs, reported co–lead authors Shengbing Zhao, MD and Zixuan He, MD, of Naval Medical University, Shanghai, China, and colleagues.
“Conventional risk-stratification strategies, such as fecal immunochemical test (FIT) and life risk factors, are still criticized for being inferior at identifying early-stage CRC and ACN, and their real-world performance is probably further weakened by the low annual participation rate and compliance of subsequent colonoscopy,” the investigators wrote in Gastroenterology. Recent case studies have reported “high diagnostic performance” using stool-based testing for mSDC2, which is “the most accurate single-targeted gene” for colorectal neoplasia, according to the investigators; however, real-world outcomes have yet to be demonstrated, prompting the present study. The prospective, multicenter, community-based trial compared the diagnostic performance of the mSDC2 test against FIT and Asia-Pacific Colorectal Screening (APCS) scores.
The primary outcome was detection of ACN. Secondary outcomes included detection of CRC, early-stage CRC, ACN, colorectal neoplasia (CN), and clinically relevant serrated polyp (CRSP). Screening strategies were also compared in terms of cost-effectiveness and impact on colonoscopy workload.The final dataset included 10,360 participants aged 45-75 years who underwent screening between 2020 and 2022.
After determining APCS scores, stool samples were analyzed for mSDC2 and FIT markers. Based on risk stratification results, participants were invited to undergo colonoscopy. A total of 3,381 participants completed colonoscopy, with 1914 from the increased-risk population and 1467 from the average-risk population. Participants who tested positive for mSDC2 had significantly higher detection rates for all measured outcomes than those who tested negative (all, P < .05). For example, the detection rate for ACN was 26.6% in mSDC2-positive participants, compared with 9.3% in mSDC2-negative participants, with a relative risk of 2.87 (95% CI, 2.39-3.44). For CRC, the detection rate was 4.2% in mSDC2-positive participants vs 0.1% in mSDC2-negative participants, yielding a relative risk of 29.73 (95% CI, 10.29-85.91). Performance held steady across subgroups.The mSDC2 test demonstrated cost-effectiveness by significantly reducing the number of colonoscopies needed to detect one case of ACN or CRC. Specifically, the number of colonoscopies needed to screen for ACN and CRC was reduced by 56.2% and 81.5%, respectively. Parallel combinations of mSDC2 with APCS or FIT enhanced both diagnostic performance and cost-effectiveness.
“This study further illustrates that the mSDC2 test consistently improves predictive abilities for CN, CRSP, ACN, and CRC, which is not influenced by subgroups of lesion location or risk factors, even under the risk stratification by FIT or APCS,” the investigators wrote. “The excellent diagnostic ability of mSDC2 in premalignant lesions, early-stage CRC, and early-onset CRC indicates a promising value in early detection and prevention of CRC ... the mSDC2 test or a parallel combination of multiple screening methods might be promising to improve real-world CRC screening performance and reduce colonoscopy workload in community practice.”The study was supported by the National Key Research and Development Program of China, Deep Blue Project of Naval Medical University, the Creative Biosciences, and others. The investigators reported no conflicts of interest.
based on a prospective, real-world study.
These findings suggest that the mSDC2 assay could improve the efficacy and resource utilization of existing screening programs, reported co–lead authors Shengbing Zhao, MD and Zixuan He, MD, of Naval Medical University, Shanghai, China, and colleagues.
“Conventional risk-stratification strategies, such as fecal immunochemical test (FIT) and life risk factors, are still criticized for being inferior at identifying early-stage CRC and ACN, and their real-world performance is probably further weakened by the low annual participation rate and compliance of subsequent colonoscopy,” the investigators wrote in Gastroenterology. Recent case studies have reported “high diagnostic performance” using stool-based testing for mSDC2, which is “the most accurate single-targeted gene” for colorectal neoplasia, according to the investigators; however, real-world outcomes have yet to be demonstrated, prompting the present study. The prospective, multicenter, community-based trial compared the diagnostic performance of the mSDC2 test against FIT and Asia-Pacific Colorectal Screening (APCS) scores.
The primary outcome was detection of ACN. Secondary outcomes included detection of CRC, early-stage CRC, ACN, colorectal neoplasia (CN), and clinically relevant serrated polyp (CRSP). Screening strategies were also compared in terms of cost-effectiveness and impact on colonoscopy workload.The final dataset included 10,360 participants aged 45-75 years who underwent screening between 2020 and 2022.
After determining APCS scores, stool samples were analyzed for mSDC2 and FIT markers. Based on risk stratification results, participants were invited to undergo colonoscopy. A total of 3,381 participants completed colonoscopy, with 1914 from the increased-risk population and 1467 from the average-risk population. Participants who tested positive for mSDC2 had significantly higher detection rates for all measured outcomes than those who tested negative (all, P < .05). For example, the detection rate for ACN was 26.6% in mSDC2-positive participants, compared with 9.3% in mSDC2-negative participants, with a relative risk of 2.87 (95% CI, 2.39-3.44). For CRC, the detection rate was 4.2% in mSDC2-positive participants vs 0.1% in mSDC2-negative participants, yielding a relative risk of 29.73 (95% CI, 10.29-85.91). Performance held steady across subgroups.The mSDC2 test demonstrated cost-effectiveness by significantly reducing the number of colonoscopies needed to detect one case of ACN or CRC. Specifically, the number of colonoscopies needed to screen for ACN and CRC was reduced by 56.2% and 81.5%, respectively. Parallel combinations of mSDC2 with APCS or FIT enhanced both diagnostic performance and cost-effectiveness.
“This study further illustrates that the mSDC2 test consistently improves predictive abilities for CN, CRSP, ACN, and CRC, which is not influenced by subgroups of lesion location or risk factors, even under the risk stratification by FIT or APCS,” the investigators wrote. “The excellent diagnostic ability of mSDC2 in premalignant lesions, early-stage CRC, and early-onset CRC indicates a promising value in early detection and prevention of CRC ... the mSDC2 test or a parallel combination of multiple screening methods might be promising to improve real-world CRC screening performance and reduce colonoscopy workload in community practice.”The study was supported by the National Key Research and Development Program of China, Deep Blue Project of Naval Medical University, the Creative Biosciences, and others. The investigators reported no conflicts of interest.
based on a prospective, real-world study.
These findings suggest that the mSDC2 assay could improve the efficacy and resource utilization of existing screening programs, reported co–lead authors Shengbing Zhao, MD and Zixuan He, MD, of Naval Medical University, Shanghai, China, and colleagues.
“Conventional risk-stratification strategies, such as fecal immunochemical test (FIT) and life risk factors, are still criticized for being inferior at identifying early-stage CRC and ACN, and their real-world performance is probably further weakened by the low annual participation rate and compliance of subsequent colonoscopy,” the investigators wrote in Gastroenterology. Recent case studies have reported “high diagnostic performance” using stool-based testing for mSDC2, which is “the most accurate single-targeted gene” for colorectal neoplasia, according to the investigators; however, real-world outcomes have yet to be demonstrated, prompting the present study. The prospective, multicenter, community-based trial compared the diagnostic performance of the mSDC2 test against FIT and Asia-Pacific Colorectal Screening (APCS) scores.
The primary outcome was detection of ACN. Secondary outcomes included detection of CRC, early-stage CRC, ACN, colorectal neoplasia (CN), and clinically relevant serrated polyp (CRSP). Screening strategies were also compared in terms of cost-effectiveness and impact on colonoscopy workload.The final dataset included 10,360 participants aged 45-75 years who underwent screening between 2020 and 2022.
After determining APCS scores, stool samples were analyzed for mSDC2 and FIT markers. Based on risk stratification results, participants were invited to undergo colonoscopy. A total of 3,381 participants completed colonoscopy, with 1914 from the increased-risk population and 1467 from the average-risk population. Participants who tested positive for mSDC2 had significantly higher detection rates for all measured outcomes than those who tested negative (all, P < .05). For example, the detection rate for ACN was 26.6% in mSDC2-positive participants, compared with 9.3% in mSDC2-negative participants, with a relative risk of 2.87 (95% CI, 2.39-3.44). For CRC, the detection rate was 4.2% in mSDC2-positive participants vs 0.1% in mSDC2-negative participants, yielding a relative risk of 29.73 (95% CI, 10.29-85.91). Performance held steady across subgroups.The mSDC2 test demonstrated cost-effectiveness by significantly reducing the number of colonoscopies needed to detect one case of ACN or CRC. Specifically, the number of colonoscopies needed to screen for ACN and CRC was reduced by 56.2% and 81.5%, respectively. Parallel combinations of mSDC2 with APCS or FIT enhanced both diagnostic performance and cost-effectiveness.
“This study further illustrates that the mSDC2 test consistently improves predictive abilities for CN, CRSP, ACN, and CRC, which is not influenced by subgroups of lesion location or risk factors, even under the risk stratification by FIT or APCS,” the investigators wrote. “The excellent diagnostic ability of mSDC2 in premalignant lesions, early-stage CRC, and early-onset CRC indicates a promising value in early detection and prevention of CRC ... the mSDC2 test or a parallel combination of multiple screening methods might be promising to improve real-world CRC screening performance and reduce colonoscopy workload in community practice.”The study was supported by the National Key Research and Development Program of China, Deep Blue Project of Naval Medical University, the Creative Biosciences, and others. The investigators reported no conflicts of interest.
FROM GASTROENTEROLOGY
AHS White Paper Guides Treatment of Posttraumatic Headache in Youth
The guidance document, the first of its kind, covers risk factors for prolonged recovery, along with pharmacologic and nonpharmacologic management strategies, and supports an emphasis on multidisciplinary care, lead author Carlyn Patterson Gentile, MD, PhD, attending physician in the Division of Neurology at Children’s Hospital of Philadelphia in Pennsylvania, and colleagues reported.
“There are no guidelines to inform the management of posttraumatic headache in youth, but multiple studies have been conducted over the past 2 decades,” the authors wrote in Headache. “This white paper aims to provide a thorough review of the current literature, identify gaps in knowledge, and provide a road map for [posttraumatic headache] management in youth based on available evidence and expert opinion.”
Clarity for an Underrecognized Issue
According to Russell Lonser, MD, professor and chair of neurological surgery at Ohio State University, Columbus, the white paper is important because it offers concrete guidance for health care providers who may be less familiar with posttraumatic headache in youth.
“It brings together all of the previous literature ... in a very well-written way,” Dr. Lonser said in an interview. “More than anything, it could reassure [providers] that they shouldn’t be hunting down potentially magical cures, and reassure them in symptomatic management.”
Meeryo C. Choe, MD, associate clinical professor of pediatric neurology at UCLA Health in Calabasas, California, said the paper also helps shine a light on what may be a more common condition than the public suspects.
“While the media focuses on the effects of concussion in professional sports athletes, the biggest population of athletes is in our youth population,” Dr. Choe said in a written comment. “Almost 25 million children participate in sports throughout the country, and yet we lack guidelines on how to treat posttraumatic headache which can often develop into persistent postconcussive symptoms.”
This white paper, she noted, builds on Dr. Gentile’s 2021 systematic review, introduces new management recommendations, and aligns with the latest consensus statement from the Concussion in Sport Group.
Risk Factors
The white paper first emphasizes the importance of early identification of youth at high risk for prolonged recovery from posttraumatic headache. Risk factors include female sex, adolescent age, a high number of acute symptoms following the initial injury, and social determinants of health.
“I agree that it is important to identify these patients early to improve the recovery trajectory,” Dr. Choe said.
Identifying these individuals quickly allows for timely intervention with both pharmacologic and nonpharmacologic therapies, Dr. Gentile and colleagues noted, potentially mitigating persistent symptoms. Clinicians are encouraged to perform thorough initial assessments to identify these risk factors and initiate early, personalized management plans.
Initial Management of Acute Posttraumatic Headache
For the initial management of acute posttraumatic headache, the white paper recommends a scheduled dosing regimen of simple analgesics. Ibuprofen at a dosage of 10 mg/kg every 6-8 hours (up to a maximum of 600 mg per dose) combined with acetaminophen has shown the best evidence for efficacy. Provided the patient is clinically stable, this regimen should be initiated within 48 hours of the injury and maintained with scheduled dosing for 3-10 days.
If effective, these medications can subsequently be used on an as-needed basis. Careful usage of analgesics is crucial, the white paper cautions, as overadministration can lead to medication-overuse headaches, complicating the recovery process.
Secondary Treatment Options
In cases where first-line oral medications are ineffective, the AHS white paper outlines several secondary treatment options. These include acute intravenous therapies such as ketorolac, dopamine receptor antagonists, and intravenous fluids. Nerve blocks and oral corticosteroid bridges may also be considered.
The white paper stresses the importance of individualized treatment plans that consider the specific needs and responses of each patient, noting that the evidence supporting these approaches is primarily derived from retrospective studies and case reports.
“Patient preferences should be factored in,” said Sean Rose, MD, pediatric neurologist and codirector of the Complex Concussion Clinic at Nationwide Children’s Hospital, Columbus, Ohio.
Supplements and Preventive Measures
For adolescents and young adults at high risk of prolonged posttraumatic headache, the white paper suggests the use of riboflavin and magnesium supplements. Small randomized clinical trials suggest that these supplements may aid in speeding recovery when administered for 1-2 weeks within 48 hours of injury.
If significant headache persists after 2 weeks, a regimen of riboflavin 400 mg daily and magnesium 400-500 mg nightly can be trialed for 6-8 weeks, in line with recommendations for migraine prevention. Additionally, melatonin at a dose of 3-5 mg nightly for an 8-week course may be considered for patients experiencing comorbid sleep disturbances.
Targeted Preventative Therapy
The white paper emphasizes the importance of targeting preventative therapy to the primary headache phenotype.
For instance, patients presenting with a migraine phenotype, or those with a personal or family history of migraines, may be most likely to respond to medications proven effective in migraine prevention, such as amitriptyline, topiramate, and propranolol.
“Most research evidence [for treating posttraumatic headache in youth] is still based on the treatment of migraine,” Dr. Rose pointed out in a written comment.
Dr. Gentile and colleagues recommend initiating preventive therapies 4-6 weeks post injury if headaches are not improving, occur more than 1-2 days per week, or significantly impact daily functioning.
Specialist Referrals and Physical Activity
Referral to a headache specialist is advised for patients who do not respond to first-line acute and preventive therapies. Specialists can offer advanced diagnostic and therapeutic options, the authors noted, ensuring a comprehensive approach to managing posttraumatic headache.
The white paper also recommends noncontact, sub–symptom threshold aerobic physical activity and activities of daily living after an initial 24-48 hour period of symptom-limited cognitive and physical rest. Engaging in these activities may promote faster recovery and help patients gradually return to their normal routines.
“This has been a shift in the concussion treatment approach over the last decade, and is one of the most important interventions we can recommend as physicians,” Dr. Choe noted. “This is where pediatricians and emergency department physicians seeing children acutely can really make a difference in the recovery trajectory for a child after a concussion. ‘Cocoon therapy’ has been proven not only to not work, but be detrimental to recovery.”
Nonpharmacologic Interventions
Based on clinical assessment, nonpharmacologic interventions may also be considered, according to the white paper. These interventions include cervico-vestibular therapy, which addresses neck and balance issues, and cognitive-behavioral therapy, which helps manage the psychological aspects of chronic headache. Dr. Gentile and colleagues highlighted the potential benefits of a collaborative care model that incorporates these nonpharmacologic interventions alongside pharmacologic treatments, providing a holistic approach to posttraumatic headache management.
“Persisting headaches after concussion are often driven by multiple factors,” Dr. Rose said. “Multidisciplinary concussion clinics can offer multiple treatment approaches such as behavioral, physical therapy, exercise, and medication options.”
Unmet Needs
The white paper concludes by calling for high-quality prospective cohort studies and placebo-controlled, randomized, controlled trials to further advance the understanding and treatment of posttraumatic headache in children.
Dr. Lonser, Dr. Choe, and Dr. Rose all agreed.
“More focused treatment trials are needed to gauge efficacy in children with headache after concussion,” Dr. Rose said.
Specifically, Dr. Gentile and colleagues underscored the need to standardize data collection via common elements, which could improve the ability to compare results across studies and develop more effective treatments. In addition, research into the underlying pathophysiology of posttraumatic headache is crucial for identifying new therapeutic targets and clinical and biological markers that can personalize patient care.
They also stressed the importance of exploring the impact of health disparities and social determinants on posttraumatic headache outcomes, aiming to develop interventions that are equitable and accessible to all patient populations.The white paper was approved by the AHS, and supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke K23 NS124986. The authors disclosed relationships with Eli Lilly, Pfizer, Amgen, and others. The interviewees disclosed no conflicts of interest.
The guidance document, the first of its kind, covers risk factors for prolonged recovery, along with pharmacologic and nonpharmacologic management strategies, and supports an emphasis on multidisciplinary care, lead author Carlyn Patterson Gentile, MD, PhD, attending physician in the Division of Neurology at Children’s Hospital of Philadelphia in Pennsylvania, and colleagues reported.
“There are no guidelines to inform the management of posttraumatic headache in youth, but multiple studies have been conducted over the past 2 decades,” the authors wrote in Headache. “This white paper aims to provide a thorough review of the current literature, identify gaps in knowledge, and provide a road map for [posttraumatic headache] management in youth based on available evidence and expert opinion.”
Clarity for an Underrecognized Issue
According to Russell Lonser, MD, professor and chair of neurological surgery at Ohio State University, Columbus, the white paper is important because it offers concrete guidance for health care providers who may be less familiar with posttraumatic headache in youth.
“It brings together all of the previous literature ... in a very well-written way,” Dr. Lonser said in an interview. “More than anything, it could reassure [providers] that they shouldn’t be hunting down potentially magical cures, and reassure them in symptomatic management.”
Meeryo C. Choe, MD, associate clinical professor of pediatric neurology at UCLA Health in Calabasas, California, said the paper also helps shine a light on what may be a more common condition than the public suspects.
“While the media focuses on the effects of concussion in professional sports athletes, the biggest population of athletes is in our youth population,” Dr. Choe said in a written comment. “Almost 25 million children participate in sports throughout the country, and yet we lack guidelines on how to treat posttraumatic headache which can often develop into persistent postconcussive symptoms.”
This white paper, she noted, builds on Dr. Gentile’s 2021 systematic review, introduces new management recommendations, and aligns with the latest consensus statement from the Concussion in Sport Group.
Risk Factors
The white paper first emphasizes the importance of early identification of youth at high risk for prolonged recovery from posttraumatic headache. Risk factors include female sex, adolescent age, a high number of acute symptoms following the initial injury, and social determinants of health.
“I agree that it is important to identify these patients early to improve the recovery trajectory,” Dr. Choe said.
Identifying these individuals quickly allows for timely intervention with both pharmacologic and nonpharmacologic therapies, Dr. Gentile and colleagues noted, potentially mitigating persistent symptoms. Clinicians are encouraged to perform thorough initial assessments to identify these risk factors and initiate early, personalized management plans.
Initial Management of Acute Posttraumatic Headache
For the initial management of acute posttraumatic headache, the white paper recommends a scheduled dosing regimen of simple analgesics. Ibuprofen at a dosage of 10 mg/kg every 6-8 hours (up to a maximum of 600 mg per dose) combined with acetaminophen has shown the best evidence for efficacy. Provided the patient is clinically stable, this regimen should be initiated within 48 hours of the injury and maintained with scheduled dosing for 3-10 days.
If effective, these medications can subsequently be used on an as-needed basis. Careful usage of analgesics is crucial, the white paper cautions, as overadministration can lead to medication-overuse headaches, complicating the recovery process.
Secondary Treatment Options
In cases where first-line oral medications are ineffective, the AHS white paper outlines several secondary treatment options. These include acute intravenous therapies such as ketorolac, dopamine receptor antagonists, and intravenous fluids. Nerve blocks and oral corticosteroid bridges may also be considered.
The white paper stresses the importance of individualized treatment plans that consider the specific needs and responses of each patient, noting that the evidence supporting these approaches is primarily derived from retrospective studies and case reports.
“Patient preferences should be factored in,” said Sean Rose, MD, pediatric neurologist and codirector of the Complex Concussion Clinic at Nationwide Children’s Hospital, Columbus, Ohio.
Supplements and Preventive Measures
For adolescents and young adults at high risk of prolonged posttraumatic headache, the white paper suggests the use of riboflavin and magnesium supplements. Small randomized clinical trials suggest that these supplements may aid in speeding recovery when administered for 1-2 weeks within 48 hours of injury.
If significant headache persists after 2 weeks, a regimen of riboflavin 400 mg daily and magnesium 400-500 mg nightly can be trialed for 6-8 weeks, in line with recommendations for migraine prevention. Additionally, melatonin at a dose of 3-5 mg nightly for an 8-week course may be considered for patients experiencing comorbid sleep disturbances.
Targeted Preventative Therapy
The white paper emphasizes the importance of targeting preventative therapy to the primary headache phenotype.
For instance, patients presenting with a migraine phenotype, or those with a personal or family history of migraines, may be most likely to respond to medications proven effective in migraine prevention, such as amitriptyline, topiramate, and propranolol.
“Most research evidence [for treating posttraumatic headache in youth] is still based on the treatment of migraine,” Dr. Rose pointed out in a written comment.
Dr. Gentile and colleagues recommend initiating preventive therapies 4-6 weeks post injury if headaches are not improving, occur more than 1-2 days per week, or significantly impact daily functioning.
Specialist Referrals and Physical Activity
Referral to a headache specialist is advised for patients who do not respond to first-line acute and preventive therapies. Specialists can offer advanced diagnostic and therapeutic options, the authors noted, ensuring a comprehensive approach to managing posttraumatic headache.
The white paper also recommends noncontact, sub–symptom threshold aerobic physical activity and activities of daily living after an initial 24-48 hour period of symptom-limited cognitive and physical rest. Engaging in these activities may promote faster recovery and help patients gradually return to their normal routines.
“This has been a shift in the concussion treatment approach over the last decade, and is one of the most important interventions we can recommend as physicians,” Dr. Choe noted. “This is where pediatricians and emergency department physicians seeing children acutely can really make a difference in the recovery trajectory for a child after a concussion. ‘Cocoon therapy’ has been proven not only to not work, but be detrimental to recovery.”
Nonpharmacologic Interventions
Based on clinical assessment, nonpharmacologic interventions may also be considered, according to the white paper. These interventions include cervico-vestibular therapy, which addresses neck and balance issues, and cognitive-behavioral therapy, which helps manage the psychological aspects of chronic headache. Dr. Gentile and colleagues highlighted the potential benefits of a collaborative care model that incorporates these nonpharmacologic interventions alongside pharmacologic treatments, providing a holistic approach to posttraumatic headache management.
“Persisting headaches after concussion are often driven by multiple factors,” Dr. Rose said. “Multidisciplinary concussion clinics can offer multiple treatment approaches such as behavioral, physical therapy, exercise, and medication options.”
Unmet Needs
The white paper concludes by calling for high-quality prospective cohort studies and placebo-controlled, randomized, controlled trials to further advance the understanding and treatment of posttraumatic headache in children.
Dr. Lonser, Dr. Choe, and Dr. Rose all agreed.
“More focused treatment trials are needed to gauge efficacy in children with headache after concussion,” Dr. Rose said.
Specifically, Dr. Gentile and colleagues underscored the need to standardize data collection via common elements, which could improve the ability to compare results across studies and develop more effective treatments. In addition, research into the underlying pathophysiology of posttraumatic headache is crucial for identifying new therapeutic targets and clinical and biological markers that can personalize patient care.
They also stressed the importance of exploring the impact of health disparities and social determinants on posttraumatic headache outcomes, aiming to develop interventions that are equitable and accessible to all patient populations.The white paper was approved by the AHS, and supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke K23 NS124986. The authors disclosed relationships with Eli Lilly, Pfizer, Amgen, and others. The interviewees disclosed no conflicts of interest.
The guidance document, the first of its kind, covers risk factors for prolonged recovery, along with pharmacologic and nonpharmacologic management strategies, and supports an emphasis on multidisciplinary care, lead author Carlyn Patterson Gentile, MD, PhD, attending physician in the Division of Neurology at Children’s Hospital of Philadelphia in Pennsylvania, and colleagues reported.
“There are no guidelines to inform the management of posttraumatic headache in youth, but multiple studies have been conducted over the past 2 decades,” the authors wrote in Headache. “This white paper aims to provide a thorough review of the current literature, identify gaps in knowledge, and provide a road map for [posttraumatic headache] management in youth based on available evidence and expert opinion.”
Clarity for an Underrecognized Issue
According to Russell Lonser, MD, professor and chair of neurological surgery at Ohio State University, Columbus, the white paper is important because it offers concrete guidance for health care providers who may be less familiar with posttraumatic headache in youth.
“It brings together all of the previous literature ... in a very well-written way,” Dr. Lonser said in an interview. “More than anything, it could reassure [providers] that they shouldn’t be hunting down potentially magical cures, and reassure them in symptomatic management.”
Meeryo C. Choe, MD, associate clinical professor of pediatric neurology at UCLA Health in Calabasas, California, said the paper also helps shine a light on what may be a more common condition than the public suspects.
“While the media focuses on the effects of concussion in professional sports athletes, the biggest population of athletes is in our youth population,” Dr. Choe said in a written comment. “Almost 25 million children participate in sports throughout the country, and yet we lack guidelines on how to treat posttraumatic headache which can often develop into persistent postconcussive symptoms.”
This white paper, she noted, builds on Dr. Gentile’s 2021 systematic review, introduces new management recommendations, and aligns with the latest consensus statement from the Concussion in Sport Group.
Risk Factors
The white paper first emphasizes the importance of early identification of youth at high risk for prolonged recovery from posttraumatic headache. Risk factors include female sex, adolescent age, a high number of acute symptoms following the initial injury, and social determinants of health.
“I agree that it is important to identify these patients early to improve the recovery trajectory,” Dr. Choe said.
Identifying these individuals quickly allows for timely intervention with both pharmacologic and nonpharmacologic therapies, Dr. Gentile and colleagues noted, potentially mitigating persistent symptoms. Clinicians are encouraged to perform thorough initial assessments to identify these risk factors and initiate early, personalized management plans.
Initial Management of Acute Posttraumatic Headache
For the initial management of acute posttraumatic headache, the white paper recommends a scheduled dosing regimen of simple analgesics. Ibuprofen at a dosage of 10 mg/kg every 6-8 hours (up to a maximum of 600 mg per dose) combined with acetaminophen has shown the best evidence for efficacy. Provided the patient is clinically stable, this regimen should be initiated within 48 hours of the injury and maintained with scheduled dosing for 3-10 days.
If effective, these medications can subsequently be used on an as-needed basis. Careful usage of analgesics is crucial, the white paper cautions, as overadministration can lead to medication-overuse headaches, complicating the recovery process.
Secondary Treatment Options
In cases where first-line oral medications are ineffective, the AHS white paper outlines several secondary treatment options. These include acute intravenous therapies such as ketorolac, dopamine receptor antagonists, and intravenous fluids. Nerve blocks and oral corticosteroid bridges may also be considered.
The white paper stresses the importance of individualized treatment plans that consider the specific needs and responses of each patient, noting that the evidence supporting these approaches is primarily derived from retrospective studies and case reports.
“Patient preferences should be factored in,” said Sean Rose, MD, pediatric neurologist and codirector of the Complex Concussion Clinic at Nationwide Children’s Hospital, Columbus, Ohio.
Supplements and Preventive Measures
For adolescents and young adults at high risk of prolonged posttraumatic headache, the white paper suggests the use of riboflavin and magnesium supplements. Small randomized clinical trials suggest that these supplements may aid in speeding recovery when administered for 1-2 weeks within 48 hours of injury.
If significant headache persists after 2 weeks, a regimen of riboflavin 400 mg daily and magnesium 400-500 mg nightly can be trialed for 6-8 weeks, in line with recommendations for migraine prevention. Additionally, melatonin at a dose of 3-5 mg nightly for an 8-week course may be considered for patients experiencing comorbid sleep disturbances.
Targeted Preventative Therapy
The white paper emphasizes the importance of targeting preventative therapy to the primary headache phenotype.
For instance, patients presenting with a migraine phenotype, or those with a personal or family history of migraines, may be most likely to respond to medications proven effective in migraine prevention, such as amitriptyline, topiramate, and propranolol.
“Most research evidence [for treating posttraumatic headache in youth] is still based on the treatment of migraine,” Dr. Rose pointed out in a written comment.
Dr. Gentile and colleagues recommend initiating preventive therapies 4-6 weeks post injury if headaches are not improving, occur more than 1-2 days per week, or significantly impact daily functioning.
Specialist Referrals and Physical Activity
Referral to a headache specialist is advised for patients who do not respond to first-line acute and preventive therapies. Specialists can offer advanced diagnostic and therapeutic options, the authors noted, ensuring a comprehensive approach to managing posttraumatic headache.
The white paper also recommends noncontact, sub–symptom threshold aerobic physical activity and activities of daily living after an initial 24-48 hour period of symptom-limited cognitive and physical rest. Engaging in these activities may promote faster recovery and help patients gradually return to their normal routines.
“This has been a shift in the concussion treatment approach over the last decade, and is one of the most important interventions we can recommend as physicians,” Dr. Choe noted. “This is where pediatricians and emergency department physicians seeing children acutely can really make a difference in the recovery trajectory for a child after a concussion. ‘Cocoon therapy’ has been proven not only to not work, but be detrimental to recovery.”
Nonpharmacologic Interventions
Based on clinical assessment, nonpharmacologic interventions may also be considered, according to the white paper. These interventions include cervico-vestibular therapy, which addresses neck and balance issues, and cognitive-behavioral therapy, which helps manage the psychological aspects of chronic headache. Dr. Gentile and colleagues highlighted the potential benefits of a collaborative care model that incorporates these nonpharmacologic interventions alongside pharmacologic treatments, providing a holistic approach to posttraumatic headache management.
“Persisting headaches after concussion are often driven by multiple factors,” Dr. Rose said. “Multidisciplinary concussion clinics can offer multiple treatment approaches such as behavioral, physical therapy, exercise, and medication options.”
Unmet Needs
The white paper concludes by calling for high-quality prospective cohort studies and placebo-controlled, randomized, controlled trials to further advance the understanding and treatment of posttraumatic headache in children.
Dr. Lonser, Dr. Choe, and Dr. Rose all agreed.
“More focused treatment trials are needed to gauge efficacy in children with headache after concussion,” Dr. Rose said.
Specifically, Dr. Gentile and colleagues underscored the need to standardize data collection via common elements, which could improve the ability to compare results across studies and develop more effective treatments. In addition, research into the underlying pathophysiology of posttraumatic headache is crucial for identifying new therapeutic targets and clinical and biological markers that can personalize patient care.
They also stressed the importance of exploring the impact of health disparities and social determinants on posttraumatic headache outcomes, aiming to develop interventions that are equitable and accessible to all patient populations.The white paper was approved by the AHS, and supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke K23 NS124986. The authors disclosed relationships with Eli Lilly, Pfizer, Amgen, and others. The interviewees disclosed no conflicts of interest.
FROM HEADACHE
Late ERCP After Cholecystectomy Linked with Worse Outcomes
, according to investigators.
These findings suggest a need for more careful patient selection with ERCP, and greater reliance upon noninvasive imaging prior to considering the procedure, reported lead author Nikhil R. Thiruvengadam, MD, of Loma Linda University Health, Loma Linda, California, and colleagues.
“It is assumed that cholecystectomy is a definitive procedure for symptomatic gallstone disease in patients without concomitant choledocholithiasis,” the investigators wrote in Clinical Gastroenterology and Hepatology. “This is because the development of primary choledocholithiasis is rare. Despite this, many patients have persistent or new gastrointestinal symptoms post cholecystectomy.”
Symptoms such as a dilated bile duct or abnormal liver function tests may suggest choledocholithiasis or sphincter of Oddi disorders (SOD), they noted, but recent data supporting ERCP for SOD show no significant benefit for patients with normal-sized ducts.
“Guidelines advocate for confirming the presence of choledocholithiasis using magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS) given the substantial risks associated with ERCP,” Dr. Thiruvengadam and colleagues wrote.
Real-world implementation of this and associated strategies, however, remain unclear, prompting the present study.
The dataset, drawn from the Optum Clinformatics Data Mart, included 583,712 adults who had undergone cholecystectomy from 2004 to 2019, focusing on 4274 individuals who had their first ERCP more than one year post surgery. The investigators assessed the incidence, characteristics, and outcomes of these late ERCP procedures, exploring their association with patient comorbidities and the use of biliary imaging techniques such as MRCP and EUS.
From 2004 to 2021, use of noninvasive biliary imaging approximately doubled from 35.9% to 65.5% (P < .001). Yet incidence of first-time ERCP more than 1 year after cholecystectomy increased much more — by eightfold — from 0.5 to 4.2 per 1000 person-years (P < .001). Less than half (44%) of these late ERCP procedures involved gallstone removal.
Patients undergoing late ERCP were more likely to have higher baseline comorbidities, including disorders of gut-brain interaction (DGBI) and metabolic dysfunction-associated steatotic liver disease. They were also more likely to be taking an antispasmodic, anxiolytic, or chronic opioid medication.
“Late ERCP is more common and associated with worse outcomes, presumably because of higher baseline comorbidities that overlap with DGBI and mimickers of choledocholithiasis,” the investigators noted. “These highly symptomatic individuals are more likely to undergo noninvasive biliary imaging, which seems to be prompting more late ERCP.”
In turn, late ERCP is incurring more adverse events, including post-ERCP pancreatitis (7.1%), hospitalization (13.1%), and new chronic opioid use (9.7%).
“Given the known risks of ERCP, especially in this context, there remains a need to be more restrictive with offering ERCP in this setting,” Dr. Thiruvengadam and colleagues concluded. “ERCP should be used sparingly for patients who do not have confirmed choledocholithiasis until future studies ... can define which patients with a remote history of cholecystectomy respond to ERCP interventions.”
The investigators disclosed relationships with Olympus, Medtronic, ACI, and others.
, according to investigators.
These findings suggest a need for more careful patient selection with ERCP, and greater reliance upon noninvasive imaging prior to considering the procedure, reported lead author Nikhil R. Thiruvengadam, MD, of Loma Linda University Health, Loma Linda, California, and colleagues.
“It is assumed that cholecystectomy is a definitive procedure for symptomatic gallstone disease in patients without concomitant choledocholithiasis,” the investigators wrote in Clinical Gastroenterology and Hepatology. “This is because the development of primary choledocholithiasis is rare. Despite this, many patients have persistent or new gastrointestinal symptoms post cholecystectomy.”
Symptoms such as a dilated bile duct or abnormal liver function tests may suggest choledocholithiasis or sphincter of Oddi disorders (SOD), they noted, but recent data supporting ERCP for SOD show no significant benefit for patients with normal-sized ducts.
“Guidelines advocate for confirming the presence of choledocholithiasis using magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS) given the substantial risks associated with ERCP,” Dr. Thiruvengadam and colleagues wrote.
Real-world implementation of this and associated strategies, however, remain unclear, prompting the present study.
The dataset, drawn from the Optum Clinformatics Data Mart, included 583,712 adults who had undergone cholecystectomy from 2004 to 2019, focusing on 4274 individuals who had their first ERCP more than one year post surgery. The investigators assessed the incidence, characteristics, and outcomes of these late ERCP procedures, exploring their association with patient comorbidities and the use of biliary imaging techniques such as MRCP and EUS.
From 2004 to 2021, use of noninvasive biliary imaging approximately doubled from 35.9% to 65.5% (P < .001). Yet incidence of first-time ERCP more than 1 year after cholecystectomy increased much more — by eightfold — from 0.5 to 4.2 per 1000 person-years (P < .001). Less than half (44%) of these late ERCP procedures involved gallstone removal.
Patients undergoing late ERCP were more likely to have higher baseline comorbidities, including disorders of gut-brain interaction (DGBI) and metabolic dysfunction-associated steatotic liver disease. They were also more likely to be taking an antispasmodic, anxiolytic, or chronic opioid medication.
“Late ERCP is more common and associated with worse outcomes, presumably because of higher baseline comorbidities that overlap with DGBI and mimickers of choledocholithiasis,” the investigators noted. “These highly symptomatic individuals are more likely to undergo noninvasive biliary imaging, which seems to be prompting more late ERCP.”
In turn, late ERCP is incurring more adverse events, including post-ERCP pancreatitis (7.1%), hospitalization (13.1%), and new chronic opioid use (9.7%).
“Given the known risks of ERCP, especially in this context, there remains a need to be more restrictive with offering ERCP in this setting,” Dr. Thiruvengadam and colleagues concluded. “ERCP should be used sparingly for patients who do not have confirmed choledocholithiasis until future studies ... can define which patients with a remote history of cholecystectomy respond to ERCP interventions.”
The investigators disclosed relationships with Olympus, Medtronic, ACI, and others.
, according to investigators.
These findings suggest a need for more careful patient selection with ERCP, and greater reliance upon noninvasive imaging prior to considering the procedure, reported lead author Nikhil R. Thiruvengadam, MD, of Loma Linda University Health, Loma Linda, California, and colleagues.
“It is assumed that cholecystectomy is a definitive procedure for symptomatic gallstone disease in patients without concomitant choledocholithiasis,” the investigators wrote in Clinical Gastroenterology and Hepatology. “This is because the development of primary choledocholithiasis is rare. Despite this, many patients have persistent or new gastrointestinal symptoms post cholecystectomy.”
Symptoms such as a dilated bile duct or abnormal liver function tests may suggest choledocholithiasis or sphincter of Oddi disorders (SOD), they noted, but recent data supporting ERCP for SOD show no significant benefit for patients with normal-sized ducts.
“Guidelines advocate for confirming the presence of choledocholithiasis using magnetic resonance cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS) given the substantial risks associated with ERCP,” Dr. Thiruvengadam and colleagues wrote.
Real-world implementation of this and associated strategies, however, remain unclear, prompting the present study.
The dataset, drawn from the Optum Clinformatics Data Mart, included 583,712 adults who had undergone cholecystectomy from 2004 to 2019, focusing on 4274 individuals who had their first ERCP more than one year post surgery. The investigators assessed the incidence, characteristics, and outcomes of these late ERCP procedures, exploring their association with patient comorbidities and the use of biliary imaging techniques such as MRCP and EUS.
From 2004 to 2021, use of noninvasive biliary imaging approximately doubled from 35.9% to 65.5% (P < .001). Yet incidence of first-time ERCP more than 1 year after cholecystectomy increased much more — by eightfold — from 0.5 to 4.2 per 1000 person-years (P < .001). Less than half (44%) of these late ERCP procedures involved gallstone removal.
Patients undergoing late ERCP were more likely to have higher baseline comorbidities, including disorders of gut-brain interaction (DGBI) and metabolic dysfunction-associated steatotic liver disease. They were also more likely to be taking an antispasmodic, anxiolytic, or chronic opioid medication.
“Late ERCP is more common and associated with worse outcomes, presumably because of higher baseline comorbidities that overlap with DGBI and mimickers of choledocholithiasis,” the investigators noted. “These highly symptomatic individuals are more likely to undergo noninvasive biliary imaging, which seems to be prompting more late ERCP.”
In turn, late ERCP is incurring more adverse events, including post-ERCP pancreatitis (7.1%), hospitalization (13.1%), and new chronic opioid use (9.7%).
“Given the known risks of ERCP, especially in this context, there remains a need to be more restrictive with offering ERCP in this setting,” Dr. Thiruvengadam and colleagues concluded. “ERCP should be used sparingly for patients who do not have confirmed choledocholithiasis until future studies ... can define which patients with a remote history of cholecystectomy respond to ERCP interventions.”
The investigators disclosed relationships with Olympus, Medtronic, ACI, and others.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Could total mesometrial resection become a new standard treatment for cervical cancer?
These findings suggest that TMMR may be considered a primary treatment option for both early-stage and locally advanced cervical cancer confined to the Müllerian compartment, reported lead author Henrik Falconer, MD, PhD, of Karolinska Institutet, Stockholm, Sweden, and colleagues.
What is the rationale behind TMMR?
“Current international guidelines [for cervical cancer] are primarily based on retrospective case series and a small number of outdated randomized controlled trials,” the investigators wrote in EClinicalMedicine, part of The Lancet publication platform. “The stage-dependent treatment recommendations, with surgery advised for early-stage and radiation therapy for locally advanced disease, may be considered too simplistic, suggesting that early stages of cervical cancer cannot be controlled with surgical resection alone or that locally advanced cervical cancer is inoperable.”
This mindset, they noted, overlooks the complexities of cancer spread. In contrast, TMMR and similar surgical approaches based on the cancer field model are mapped along routes of locoregional dissemination, leading to “excellent local control” in more than 600 cases at the University Hospital of Leipzig, Leipzig, Germany.
To date, however, TMMR’s adoption has been limited, and it has not been compared directly with current guideline treatments, prompting the present study.
What methods were used to compare TMMR with standard treatment?
The study compared TMMR plus therapeutic lymph node dissection (tLND) without adjuvant radiation versus standard treatment (ST) for early-stage (FIGO 2009 IB1, IIA1) and locally advanced (FIGO 2009 IB2, IIA2, IIB) cervical cancer. Standard treatment for patients with early-stage disease involved radical hysterectomy and pelvic lymphadenectomy, with adjuvant chemoradiation dependent upon final pathology. Those with locally advanced disease received definitive chemoradiation.
Data for the standard treatment group were drawn from population-based registries in Sweden, while those for the TMMR group came from the Leipzig Mesometrial Resection Study Database. The final dataset included 1,007 women treated between 2011 and 2020, with 733 undergoing standard treatment and 274 receiving TMMR.
Outcomes included RFS and OS, adjusted for clinical and tumor-related variables.
How did TMMR compare with standard treatment?
TMMR was associated with superior oncologic outcomes compared with standard treatment for early-stage cervical cancer.
Specifically, 5-year RFS was 91.2% for TMMR versus 81.8% for standard therapy (P = .002). In the adjusted analysis, TMMR was associated with a significantly lower hazard of recurrence (hazard ratio [HR], 0.39; 95% CI, 0.22–0.69) and death (HR, 0.42; 95% CI, 0.21-0.86). Also favoring TMMR, absolute difference in the risk of recurrence at 5 years was 9.4% (95% CI 3.2–15.7). In addition, 5-year OS was better in the TMMR group, at 93.3%, compared with 90.3% for standard treatment (P = .034).
Among patients with locally advanced disease, no significant differences in RFS or OS were observed.
Are these data strong enough to make TMMR the new standard treatment?
Dr. Falconer and colleagues concluded that TMMR with tLND “may replace the standard treatment approach in early-stage cervical cancer and furthermore be evaluated as an option in locally advanced cervical cancer confined to the Müllerian compartment.”
While the investigators anticipated demands for randomized controlled trials, they questioned the value of such studies, suggesting that any control arm would be “based on inconsistent or flawed concepts.”
Susan C. Modesitt, MD, director of the gynecologic oncology division of Winship Cancer Institute of Emory University, Atlanta, offered a different perspective.
“They do show encouraging data in the early stage,” Dr. Modesitt said in an interview, “but I would still want to see a randomized controlled trial, because we’ve been burned before.”
She cited the LACC trial, which dispelled strong convictions about the alleged superiority of minimally invasive radical hysterectomy.
“We thought minimally invasive was so good, and we should be doing that to everybody, but we did a trial, and we found worse outcomes,” Dr. Modesitt said. “More of those early-stage women died.”
Dr. Modesitt also pointed out the lack of safety data in the present publication.
“TMMR is a bigger procedure, so I would expect more complications,” she said, noting that rates of urinary injury, nerve injury, and readmission need to be considered alongside efficacy outcomes.
How does TMMR fit into the current treatment landscape for cervical cancer?
“This is a very niche surgery that most places don’t do,” Dr. Modesitt said.
She pointed out that “multiple variations” on the standard radical hysterectomy have been proposed in the past, such as the laterally extended endopelvic resection.
“[TMMR] is not a new concept,” she said. “It’s just a question of how radical it is.”
Instead of developing new types of radical surgery, she said, the trend in the United States is toward de-escalation of surgical treatments altogether, with greater reliance upon medical options, such as immunotherapy.
“[This study] is thought provoking, and I applaud them for doing it,” Dr. Modesitt said. “But I’m not going to go out and do that on my next patient.”
This study was supported by grants from Centre for Clinical Research Sörmland (Sweden) and Region Stockholm (Sweden). Dr. Falconer is a board member of Surgical Science.
These findings suggest that TMMR may be considered a primary treatment option for both early-stage and locally advanced cervical cancer confined to the Müllerian compartment, reported lead author Henrik Falconer, MD, PhD, of Karolinska Institutet, Stockholm, Sweden, and colleagues.
What is the rationale behind TMMR?
“Current international guidelines [for cervical cancer] are primarily based on retrospective case series and a small number of outdated randomized controlled trials,” the investigators wrote in EClinicalMedicine, part of The Lancet publication platform. “The stage-dependent treatment recommendations, with surgery advised for early-stage and radiation therapy for locally advanced disease, may be considered too simplistic, suggesting that early stages of cervical cancer cannot be controlled with surgical resection alone or that locally advanced cervical cancer is inoperable.”
This mindset, they noted, overlooks the complexities of cancer spread. In contrast, TMMR and similar surgical approaches based on the cancer field model are mapped along routes of locoregional dissemination, leading to “excellent local control” in more than 600 cases at the University Hospital of Leipzig, Leipzig, Germany.
To date, however, TMMR’s adoption has been limited, and it has not been compared directly with current guideline treatments, prompting the present study.
What methods were used to compare TMMR with standard treatment?
The study compared TMMR plus therapeutic lymph node dissection (tLND) without adjuvant radiation versus standard treatment (ST) for early-stage (FIGO 2009 IB1, IIA1) and locally advanced (FIGO 2009 IB2, IIA2, IIB) cervical cancer. Standard treatment for patients with early-stage disease involved radical hysterectomy and pelvic lymphadenectomy, with adjuvant chemoradiation dependent upon final pathology. Those with locally advanced disease received definitive chemoradiation.
Data for the standard treatment group were drawn from population-based registries in Sweden, while those for the TMMR group came from the Leipzig Mesometrial Resection Study Database. The final dataset included 1,007 women treated between 2011 and 2020, with 733 undergoing standard treatment and 274 receiving TMMR.
Outcomes included RFS and OS, adjusted for clinical and tumor-related variables.
How did TMMR compare with standard treatment?
TMMR was associated with superior oncologic outcomes compared with standard treatment for early-stage cervical cancer.
Specifically, 5-year RFS was 91.2% for TMMR versus 81.8% for standard therapy (P = .002). In the adjusted analysis, TMMR was associated with a significantly lower hazard of recurrence (hazard ratio [HR], 0.39; 95% CI, 0.22–0.69) and death (HR, 0.42; 95% CI, 0.21-0.86). Also favoring TMMR, absolute difference in the risk of recurrence at 5 years was 9.4% (95% CI 3.2–15.7). In addition, 5-year OS was better in the TMMR group, at 93.3%, compared with 90.3% for standard treatment (P = .034).
Among patients with locally advanced disease, no significant differences in RFS or OS were observed.
Are these data strong enough to make TMMR the new standard treatment?
Dr. Falconer and colleagues concluded that TMMR with tLND “may replace the standard treatment approach in early-stage cervical cancer and furthermore be evaluated as an option in locally advanced cervical cancer confined to the Müllerian compartment.”
While the investigators anticipated demands for randomized controlled trials, they questioned the value of such studies, suggesting that any control arm would be “based on inconsistent or flawed concepts.”
Susan C. Modesitt, MD, director of the gynecologic oncology division of Winship Cancer Institute of Emory University, Atlanta, offered a different perspective.
“They do show encouraging data in the early stage,” Dr. Modesitt said in an interview, “but I would still want to see a randomized controlled trial, because we’ve been burned before.”
She cited the LACC trial, which dispelled strong convictions about the alleged superiority of minimally invasive radical hysterectomy.
“We thought minimally invasive was so good, and we should be doing that to everybody, but we did a trial, and we found worse outcomes,” Dr. Modesitt said. “More of those early-stage women died.”
Dr. Modesitt also pointed out the lack of safety data in the present publication.
“TMMR is a bigger procedure, so I would expect more complications,” she said, noting that rates of urinary injury, nerve injury, and readmission need to be considered alongside efficacy outcomes.
How does TMMR fit into the current treatment landscape for cervical cancer?
“This is a very niche surgery that most places don’t do,” Dr. Modesitt said.
She pointed out that “multiple variations” on the standard radical hysterectomy have been proposed in the past, such as the laterally extended endopelvic resection.
“[TMMR] is not a new concept,” she said. “It’s just a question of how radical it is.”
Instead of developing new types of radical surgery, she said, the trend in the United States is toward de-escalation of surgical treatments altogether, with greater reliance upon medical options, such as immunotherapy.
“[This study] is thought provoking, and I applaud them for doing it,” Dr. Modesitt said. “But I’m not going to go out and do that on my next patient.”
This study was supported by grants from Centre for Clinical Research Sörmland (Sweden) and Region Stockholm (Sweden). Dr. Falconer is a board member of Surgical Science.
These findings suggest that TMMR may be considered a primary treatment option for both early-stage and locally advanced cervical cancer confined to the Müllerian compartment, reported lead author Henrik Falconer, MD, PhD, of Karolinska Institutet, Stockholm, Sweden, and colleagues.
What is the rationale behind TMMR?
“Current international guidelines [for cervical cancer] are primarily based on retrospective case series and a small number of outdated randomized controlled trials,” the investigators wrote in EClinicalMedicine, part of The Lancet publication platform. “The stage-dependent treatment recommendations, with surgery advised for early-stage and radiation therapy for locally advanced disease, may be considered too simplistic, suggesting that early stages of cervical cancer cannot be controlled with surgical resection alone or that locally advanced cervical cancer is inoperable.”
This mindset, they noted, overlooks the complexities of cancer spread. In contrast, TMMR and similar surgical approaches based on the cancer field model are mapped along routes of locoregional dissemination, leading to “excellent local control” in more than 600 cases at the University Hospital of Leipzig, Leipzig, Germany.
To date, however, TMMR’s adoption has been limited, and it has not been compared directly with current guideline treatments, prompting the present study.
What methods were used to compare TMMR with standard treatment?
The study compared TMMR plus therapeutic lymph node dissection (tLND) without adjuvant radiation versus standard treatment (ST) for early-stage (FIGO 2009 IB1, IIA1) and locally advanced (FIGO 2009 IB2, IIA2, IIB) cervical cancer. Standard treatment for patients with early-stage disease involved radical hysterectomy and pelvic lymphadenectomy, with adjuvant chemoradiation dependent upon final pathology. Those with locally advanced disease received definitive chemoradiation.
Data for the standard treatment group were drawn from population-based registries in Sweden, while those for the TMMR group came from the Leipzig Mesometrial Resection Study Database. The final dataset included 1,007 women treated between 2011 and 2020, with 733 undergoing standard treatment and 274 receiving TMMR.
Outcomes included RFS and OS, adjusted for clinical and tumor-related variables.
How did TMMR compare with standard treatment?
TMMR was associated with superior oncologic outcomes compared with standard treatment for early-stage cervical cancer.
Specifically, 5-year RFS was 91.2% for TMMR versus 81.8% for standard therapy (P = .002). In the adjusted analysis, TMMR was associated with a significantly lower hazard of recurrence (hazard ratio [HR], 0.39; 95% CI, 0.22–0.69) and death (HR, 0.42; 95% CI, 0.21-0.86). Also favoring TMMR, absolute difference in the risk of recurrence at 5 years was 9.4% (95% CI 3.2–15.7). In addition, 5-year OS was better in the TMMR group, at 93.3%, compared with 90.3% for standard treatment (P = .034).
Among patients with locally advanced disease, no significant differences in RFS or OS were observed.
Are these data strong enough to make TMMR the new standard treatment?
Dr. Falconer and colleagues concluded that TMMR with tLND “may replace the standard treatment approach in early-stage cervical cancer and furthermore be evaluated as an option in locally advanced cervical cancer confined to the Müllerian compartment.”
While the investigators anticipated demands for randomized controlled trials, they questioned the value of such studies, suggesting that any control arm would be “based on inconsistent or flawed concepts.”
Susan C. Modesitt, MD, director of the gynecologic oncology division of Winship Cancer Institute of Emory University, Atlanta, offered a different perspective.
“They do show encouraging data in the early stage,” Dr. Modesitt said in an interview, “but I would still want to see a randomized controlled trial, because we’ve been burned before.”
She cited the LACC trial, which dispelled strong convictions about the alleged superiority of minimally invasive radical hysterectomy.
“We thought minimally invasive was so good, and we should be doing that to everybody, but we did a trial, and we found worse outcomes,” Dr. Modesitt said. “More of those early-stage women died.”
Dr. Modesitt also pointed out the lack of safety data in the present publication.
“TMMR is a bigger procedure, so I would expect more complications,” she said, noting that rates of urinary injury, nerve injury, and readmission need to be considered alongside efficacy outcomes.
How does TMMR fit into the current treatment landscape for cervical cancer?
“This is a very niche surgery that most places don’t do,” Dr. Modesitt said.
She pointed out that “multiple variations” on the standard radical hysterectomy have been proposed in the past, such as the laterally extended endopelvic resection.
“[TMMR] is not a new concept,” she said. “It’s just a question of how radical it is.”
Instead of developing new types of radical surgery, she said, the trend in the United States is toward de-escalation of surgical treatments altogether, with greater reliance upon medical options, such as immunotherapy.
“[This study] is thought provoking, and I applaud them for doing it,” Dr. Modesitt said. “But I’m not going to go out and do that on my next patient.”
This study was supported by grants from Centre for Clinical Research Sörmland (Sweden) and Region Stockholm (Sweden). Dr. Falconer is a board member of Surgical Science.
FROM THE LANCET
Could an EHR Nudge Reduce Unnecessary Biopsies?
Participating surgeons noted that the reminder system added minimal friction to their workflow, as it did not require additional clicks or actions on the day of the patient visit, reported lead author Neil Carleton, PhD, of UPMC Hillman Cancer Center, Pittsburgh, and colleagues in JAMA Surgery (JAMA Surg. 2024 Jul 17. doi: 10.1001/jamasurg.2024.2407).
This effort to reduce the rate of SLNB stems from the Choosing Wisely campaign, which recommends against axillary staging in women 70 years and older with early-stage, clinically node-negative (cN0), hormone receptor–positive (HR+) breast cancer, the investigators said.
“These recommendations were developed because axillary staging did not impact survival, and rates of SLN positivity were low because of the tumor’s biological phenotype,” they wrote. “Even in older patients with tumors that exhibit concerning clinicopathologic features, limited nodal involvement does not often alter receipt of chemotherapy independently from genomic testing. Despite these recommendations, most women still receive axillary surgery.”
How Did the Nudge System Aim to Reduce the Rate of SLNB?
The nudge intervention involved adding a new column to the Epic schedule view, which flagged eligible patients during their first outpatient surgical consultation. The flag appeared as a caution sign or red clipboard icon. When surgeons hovered over the icon, a text box appeared, reminding them to consider omitting SLNB after a detailed review of core biopsy pathology and ultrasonographic imaging.
The intervention was evaluated at eight outpatient clinics within an integrated healthcare system that included seven breast surgical oncologists.
The study began with a 12-month preintervention period to serve as a control, during which time SLNB rate was determined via 194 patients in the target demographic. SLNB rate was again collected during the 12-month intervention period, which involved 193 patients meeting enrollment criteria. Between these periods, the investigators conducted a brief session lasting less than 30 minutes to introduce the surgeons to the rationale and design of the nudge column.
How Effective Was the Nudge System?
The intervention reduced the SLNB rate from 46.9% to 23.8%, representing a 49.3% decrease in use of SLNB. Efficacy was further supported by a significant reduction in SLNB according to an interrupted time series model (adjusted odds ratio, 0.26; 95% confidence interval, 0.07 to 0.90; P = .03). Extended follow-up showed that this effect was durable beyond the intervention period, with a 6-month mean reduction in SLNB of 15.6%.
Omission of SLNB led to higher rates of pathological node positivity during the intervention period (15.2% vs 8.8%), with all positive cases staged as pN1. Adjuvant therapy recommendations were similar between groups and driven by genomic testing, not nodal status. The intervention period also saw a decrease in referrals for lymphedema evaluation (3.6% vs. 6.2%).
How Might the Nudge System Be Implemented in Other Practices?
Although the SLNB nudge system was effective in the present study, likelihood of uptake among practices could vary widely, according to Anne M. Wallace, MD, professor of clinical surgery at UC San Diego Health and director of the Moores Comprehensive Breast Health Program.
On a fundamental level, not all centers use Epic software, which could present issues with compatibility, Dr. Wallace said in an interview. More importantly, she added, many institutions already have EHR-based alerts and reminders in place, so it is not always feasible to add a new nudge for every possible clinical scenario.
“Already there are so many little icons that we have to go through now when we close a note,” she said. “That’s why electronic medical records are becoming one of the leading stressors in medicine.”
This presents a more complex challenge, Dr. Wallace said, particularly as potentially practice-changing data are becoming available, and physicians may not have time to learn about them and integrate them into routine practice. She suggested that the present system may be most appropriate for oncologists in solo practice, or in small group practices where it is more challenging to have routine conversations about changing standards of care.
What Are the Risks of Using the Nudge System?
One of those conversations may surround the validity of the recommendation implemented in the present study.
Although the Society of Surgical Oncology recommends against SLNB in the described demographic, other experts, including Dr. Wallace, take a more nuanced view of the decision.
She noted that some patients with a chronological age of 70 may have a lower biological age, casting doubt on the legitimacy of the age threshold, and those near the threshold may wish to make the decision about staging for themselves.
Beyond these concerns, Dr. Wallace described two potential risks involved in forgoing SLNB.
First, there’s the potential for underestimating the tumor’s severity, she said, as this could mean a trip back to the operating room. A tumor initially thought to be low-grade might later be found to be high-grade, necessitating further surgery. Some patients might refuse additional surgery, leaving the more aggressive tumor untreated.
Second, the nudge system could complicate radiation treatment decisions, Dr. Wallace said. Without full nodal status, some radiation oncologists might push for additional radiation therapy, which incurs a greater treatment burden than SNLB.
What Are Some Alternatives to the Nudge System?
After discussing the strengths and weaknesses of the present EHR-based nudge system, and others like it, Dr. Wallace returned to the importance of ongoing communication among colleagues managing complex cases.
At UC San Diego Health, where oncologists meet weekly for a 2-hour breast cancer conference, “we nudge each other,” she said.
This study was supported by the Shear Family Foundation, UPMC eRecord Ambulatory Decision Support and Analytics, UPMC Hillman Cancer Center Biostatistics Facility, and National Institutes of Health. The investigators disclosed relationships with Pfizer, Amgen, the Lewin Group, and Milestone Pennsylvania, and others.
Participating surgeons noted that the reminder system added minimal friction to their workflow, as it did not require additional clicks or actions on the day of the patient visit, reported lead author Neil Carleton, PhD, of UPMC Hillman Cancer Center, Pittsburgh, and colleagues in JAMA Surgery (JAMA Surg. 2024 Jul 17. doi: 10.1001/jamasurg.2024.2407).
This effort to reduce the rate of SLNB stems from the Choosing Wisely campaign, which recommends against axillary staging in women 70 years and older with early-stage, clinically node-negative (cN0), hormone receptor–positive (HR+) breast cancer, the investigators said.
“These recommendations were developed because axillary staging did not impact survival, and rates of SLN positivity were low because of the tumor’s biological phenotype,” they wrote. “Even in older patients with tumors that exhibit concerning clinicopathologic features, limited nodal involvement does not often alter receipt of chemotherapy independently from genomic testing. Despite these recommendations, most women still receive axillary surgery.”
How Did the Nudge System Aim to Reduce the Rate of SLNB?
The nudge intervention involved adding a new column to the Epic schedule view, which flagged eligible patients during their first outpatient surgical consultation. The flag appeared as a caution sign or red clipboard icon. When surgeons hovered over the icon, a text box appeared, reminding them to consider omitting SLNB after a detailed review of core biopsy pathology and ultrasonographic imaging.
The intervention was evaluated at eight outpatient clinics within an integrated healthcare system that included seven breast surgical oncologists.
The study began with a 12-month preintervention period to serve as a control, during which time SLNB rate was determined via 194 patients in the target demographic. SLNB rate was again collected during the 12-month intervention period, which involved 193 patients meeting enrollment criteria. Between these periods, the investigators conducted a brief session lasting less than 30 minutes to introduce the surgeons to the rationale and design of the nudge column.
How Effective Was the Nudge System?
The intervention reduced the SLNB rate from 46.9% to 23.8%, representing a 49.3% decrease in use of SLNB. Efficacy was further supported by a significant reduction in SLNB according to an interrupted time series model (adjusted odds ratio, 0.26; 95% confidence interval, 0.07 to 0.90; P = .03). Extended follow-up showed that this effect was durable beyond the intervention period, with a 6-month mean reduction in SLNB of 15.6%.
Omission of SLNB led to higher rates of pathological node positivity during the intervention period (15.2% vs 8.8%), with all positive cases staged as pN1. Adjuvant therapy recommendations were similar between groups and driven by genomic testing, not nodal status. The intervention period also saw a decrease in referrals for lymphedema evaluation (3.6% vs. 6.2%).
How Might the Nudge System Be Implemented in Other Practices?
Although the SLNB nudge system was effective in the present study, likelihood of uptake among practices could vary widely, according to Anne M. Wallace, MD, professor of clinical surgery at UC San Diego Health and director of the Moores Comprehensive Breast Health Program.
On a fundamental level, not all centers use Epic software, which could present issues with compatibility, Dr. Wallace said in an interview. More importantly, she added, many institutions already have EHR-based alerts and reminders in place, so it is not always feasible to add a new nudge for every possible clinical scenario.
“Already there are so many little icons that we have to go through now when we close a note,” she said. “That’s why electronic medical records are becoming one of the leading stressors in medicine.”
This presents a more complex challenge, Dr. Wallace said, particularly as potentially practice-changing data are becoming available, and physicians may not have time to learn about them and integrate them into routine practice. She suggested that the present system may be most appropriate for oncologists in solo practice, or in small group practices where it is more challenging to have routine conversations about changing standards of care.
What Are the Risks of Using the Nudge System?
One of those conversations may surround the validity of the recommendation implemented in the present study.
Although the Society of Surgical Oncology recommends against SLNB in the described demographic, other experts, including Dr. Wallace, take a more nuanced view of the decision.
She noted that some patients with a chronological age of 70 may have a lower biological age, casting doubt on the legitimacy of the age threshold, and those near the threshold may wish to make the decision about staging for themselves.
Beyond these concerns, Dr. Wallace described two potential risks involved in forgoing SLNB.
First, there’s the potential for underestimating the tumor’s severity, she said, as this could mean a trip back to the operating room. A tumor initially thought to be low-grade might later be found to be high-grade, necessitating further surgery. Some patients might refuse additional surgery, leaving the more aggressive tumor untreated.
Second, the nudge system could complicate radiation treatment decisions, Dr. Wallace said. Without full nodal status, some radiation oncologists might push for additional radiation therapy, which incurs a greater treatment burden than SNLB.
What Are Some Alternatives to the Nudge System?
After discussing the strengths and weaknesses of the present EHR-based nudge system, and others like it, Dr. Wallace returned to the importance of ongoing communication among colleagues managing complex cases.
At UC San Diego Health, where oncologists meet weekly for a 2-hour breast cancer conference, “we nudge each other,” she said.
This study was supported by the Shear Family Foundation, UPMC eRecord Ambulatory Decision Support and Analytics, UPMC Hillman Cancer Center Biostatistics Facility, and National Institutes of Health. The investigators disclosed relationships with Pfizer, Amgen, the Lewin Group, and Milestone Pennsylvania, and others.
Participating surgeons noted that the reminder system added minimal friction to their workflow, as it did not require additional clicks or actions on the day of the patient visit, reported lead author Neil Carleton, PhD, of UPMC Hillman Cancer Center, Pittsburgh, and colleagues in JAMA Surgery (JAMA Surg. 2024 Jul 17. doi: 10.1001/jamasurg.2024.2407).
This effort to reduce the rate of SLNB stems from the Choosing Wisely campaign, which recommends against axillary staging in women 70 years and older with early-stage, clinically node-negative (cN0), hormone receptor–positive (HR+) breast cancer, the investigators said.
“These recommendations were developed because axillary staging did not impact survival, and rates of SLN positivity were low because of the tumor’s biological phenotype,” they wrote. “Even in older patients with tumors that exhibit concerning clinicopathologic features, limited nodal involvement does not often alter receipt of chemotherapy independently from genomic testing. Despite these recommendations, most women still receive axillary surgery.”
How Did the Nudge System Aim to Reduce the Rate of SLNB?
The nudge intervention involved adding a new column to the Epic schedule view, which flagged eligible patients during their first outpatient surgical consultation. The flag appeared as a caution sign or red clipboard icon. When surgeons hovered over the icon, a text box appeared, reminding them to consider omitting SLNB after a detailed review of core biopsy pathology and ultrasonographic imaging.
The intervention was evaluated at eight outpatient clinics within an integrated healthcare system that included seven breast surgical oncologists.
The study began with a 12-month preintervention period to serve as a control, during which time SLNB rate was determined via 194 patients in the target demographic. SLNB rate was again collected during the 12-month intervention period, which involved 193 patients meeting enrollment criteria. Between these periods, the investigators conducted a brief session lasting less than 30 minutes to introduce the surgeons to the rationale and design of the nudge column.
How Effective Was the Nudge System?
The intervention reduced the SLNB rate from 46.9% to 23.8%, representing a 49.3% decrease in use of SLNB. Efficacy was further supported by a significant reduction in SLNB according to an interrupted time series model (adjusted odds ratio, 0.26; 95% confidence interval, 0.07 to 0.90; P = .03). Extended follow-up showed that this effect was durable beyond the intervention period, with a 6-month mean reduction in SLNB of 15.6%.
Omission of SLNB led to higher rates of pathological node positivity during the intervention period (15.2% vs 8.8%), with all positive cases staged as pN1. Adjuvant therapy recommendations were similar between groups and driven by genomic testing, not nodal status. The intervention period also saw a decrease in referrals for lymphedema evaluation (3.6% vs. 6.2%).
How Might the Nudge System Be Implemented in Other Practices?
Although the SLNB nudge system was effective in the present study, likelihood of uptake among practices could vary widely, according to Anne M. Wallace, MD, professor of clinical surgery at UC San Diego Health and director of the Moores Comprehensive Breast Health Program.
On a fundamental level, not all centers use Epic software, which could present issues with compatibility, Dr. Wallace said in an interview. More importantly, she added, many institutions already have EHR-based alerts and reminders in place, so it is not always feasible to add a new nudge for every possible clinical scenario.
“Already there are so many little icons that we have to go through now when we close a note,” she said. “That’s why electronic medical records are becoming one of the leading stressors in medicine.”
This presents a more complex challenge, Dr. Wallace said, particularly as potentially practice-changing data are becoming available, and physicians may not have time to learn about them and integrate them into routine practice. She suggested that the present system may be most appropriate for oncologists in solo practice, or in small group practices where it is more challenging to have routine conversations about changing standards of care.
What Are the Risks of Using the Nudge System?
One of those conversations may surround the validity of the recommendation implemented in the present study.
Although the Society of Surgical Oncology recommends against SLNB in the described demographic, other experts, including Dr. Wallace, take a more nuanced view of the decision.
She noted that some patients with a chronological age of 70 may have a lower biological age, casting doubt on the legitimacy of the age threshold, and those near the threshold may wish to make the decision about staging for themselves.
Beyond these concerns, Dr. Wallace described two potential risks involved in forgoing SLNB.
First, there’s the potential for underestimating the tumor’s severity, she said, as this could mean a trip back to the operating room. A tumor initially thought to be low-grade might later be found to be high-grade, necessitating further surgery. Some patients might refuse additional surgery, leaving the more aggressive tumor untreated.
Second, the nudge system could complicate radiation treatment decisions, Dr. Wallace said. Without full nodal status, some radiation oncologists might push for additional radiation therapy, which incurs a greater treatment burden than SNLB.
What Are Some Alternatives to the Nudge System?
After discussing the strengths and weaknesses of the present EHR-based nudge system, and others like it, Dr. Wallace returned to the importance of ongoing communication among colleagues managing complex cases.
At UC San Diego Health, where oncologists meet weekly for a 2-hour breast cancer conference, “we nudge each other,” she said.
This study was supported by the Shear Family Foundation, UPMC eRecord Ambulatory Decision Support and Analytics, UPMC Hillman Cancer Center Biostatistics Facility, and National Institutes of Health. The investigators disclosed relationships with Pfizer, Amgen, the Lewin Group, and Milestone Pennsylvania, and others.
FROM JAMA SURGERY
Esophageal Cancer Risk Unchanged After Helicobacter Eradication
This finding suggests that eradication of H pylori is safe with regard to esophageal cancer risk, and eradication campaigns are not contributing to the rising incidence of esophageal adenocarcinoma (EAC) over the past four decades, reported lead author Anna-Klara Wiklund, MD, of Karolinska Institutet, Stockholm, Sweden, and colleagues.“The decreased risk of esophageal adenocarcinoma seen in individuals with H pylori infection is probably explained by the H pylori–induced gastric atrophy, which reduces gastric acid production and thus acidic gastroesophageal reflux, the main risk factor for this tumor,” the investigators wrote in Gastroenterology. “It seems plausible that eradication of H pylori would increase the risk of EAC, although the answer to this question is unknown with the only study on the topic (from our group) having too few cases and too short follow-up.”
That study involved only 11 cases of EAC.
For the present study, Dr. Wiklund and colleagues aggregated data from all individuals who had undergone H pylori eradication in Finland, Denmark, Iceland, Norway, and Sweden from 1995 to 2019. The dataset comprised 661,987 such individuals with more than 5 million person-years after eradication therapy, including 550 cases of EAC. Median follow-up time was approximately 8 years, ranging from 1 to 24 years.
Analyzing these data revealed that standardized incidence ratio (SIR) of EAC was not increased after eradication therapy (0.89; 95% CI, 0.82-0.97). In fact, SIR decreased over time after eradication, reaching as low as 0.73 (95% CI, 0.61-0.86) during the follow-up period of 11-24 years. These findings were maintained regardless of age or sex, and within country-by-country analyses.
SIR for esophageal squamous cell carcinoma, which was calculated for comparison, showed no association with eradication therapy (0.99; 95% CI, 0.89-1.11).
“This study found no evidence supporting the hypothesis of a gradually increasing risk of esophageal adenocarcinoma over time after H pylori eradication treatment,” the investigators wrote.
Other risks were detected, including an overall increased SIR of EAC observed among participants with gastroesophageal reflux disease (GERD) and those using long-term proton pump inhibitors (PPIs). These were expected, however, “considering the strong and well-established association with EAC.”
Dr. Wiklund and colleagues suggested that more studies are needed to confirm their findings, although the present data provide confidence that H pylori eradication does not raise risk of EAC.
“This is valuable knowledge when considering eradication treatment for individual patients and eradication programs in high-risk populations of gastric cancer,” they wrote. “The results should be generalizable to other high-income countries with low prevalence of H pylori and high incidence of EAC, but studies from other regions with different patterns of these conditions are warranted.”
They also called for more basic research to understand why eradicating H pylori does not lead to an increased risk of EAC.The study was supported by Sjoberg Foundation, Nordic Cancer Union, Stockholm County Council, Stockholm Cancer Society. Investigators disclosed no conflicts of interest.
Understanding the demographic and biomarker risk predictors of esophageal cancer continues to be a research priority. Many esophageal cancer patients fall outside of current screening guidelines. Updated recommendations have suggested including high risk-women, driven by higher quality datasets, emerging biomarkers, and cost effective non-endoscopic screening devices.
In this article, Wiklund et al. challenge another dogma that Helicobacter pylori infection offers protection against esophageal cancer. More specifically that overtreatment of H pylori is associated with increased incidence of esophageal adenocarcinoma. Their Nordic data set identified 550 cases of esophageal cancer in the 661,987 patients treated for H pylori from 1995–2018 who were followed >5 million person-years. Interestingly, standardized incidence ratio of esophageal adenocarcinoma decreased over time.
This large dataset continues to encourage us to treat H pylori in patients at risk of progressing to gastric cancer. This parallels a growing fund of literature encouraging us to move away from the linear pathophysiologic logic that eliminating H pylori-induced gastric atrophy provokes gastroesophageal reflux disease and esophageal cancer. Instead we should factor in other parameters, including the complex interaction between the esophageal microbiome and gastric H pylori. Some postulated mechanisms include an extension of the gastric inflammatory milieu into the esophagus, and potential crosstalk with the esophageal microbiome.
Such studies underscore the need to personalize both foregut cancer screening criteria and treatment of inflammatory conditions at a patient and population level, so that we can make meaningful impacts in disease prevalence and cancer survival.
Fouad Otaki, MD, is associate professor in the Division of Gastroenterology & Hepatology at Oregon Health & Science University, Portland.
Understanding the demographic and biomarker risk predictors of esophageal cancer continues to be a research priority. Many esophageal cancer patients fall outside of current screening guidelines. Updated recommendations have suggested including high risk-women, driven by higher quality datasets, emerging biomarkers, and cost effective non-endoscopic screening devices.
In this article, Wiklund et al. challenge another dogma that Helicobacter pylori infection offers protection against esophageal cancer. More specifically that overtreatment of H pylori is associated with increased incidence of esophageal adenocarcinoma. Their Nordic data set identified 550 cases of esophageal cancer in the 661,987 patients treated for H pylori from 1995–2018 who were followed >5 million person-years. Interestingly, standardized incidence ratio of esophageal adenocarcinoma decreased over time.
This large dataset continues to encourage us to treat H pylori in patients at risk of progressing to gastric cancer. This parallels a growing fund of literature encouraging us to move away from the linear pathophysiologic logic that eliminating H pylori-induced gastric atrophy provokes gastroesophageal reflux disease and esophageal cancer. Instead we should factor in other parameters, including the complex interaction between the esophageal microbiome and gastric H pylori. Some postulated mechanisms include an extension of the gastric inflammatory milieu into the esophagus, and potential crosstalk with the esophageal microbiome.
Such studies underscore the need to personalize both foregut cancer screening criteria and treatment of inflammatory conditions at a patient and population level, so that we can make meaningful impacts in disease prevalence and cancer survival.
Fouad Otaki, MD, is associate professor in the Division of Gastroenterology & Hepatology at Oregon Health & Science University, Portland.
Understanding the demographic and biomarker risk predictors of esophageal cancer continues to be a research priority. Many esophageal cancer patients fall outside of current screening guidelines. Updated recommendations have suggested including high risk-women, driven by higher quality datasets, emerging biomarkers, and cost effective non-endoscopic screening devices.
In this article, Wiklund et al. challenge another dogma that Helicobacter pylori infection offers protection against esophageal cancer. More specifically that overtreatment of H pylori is associated with increased incidence of esophageal adenocarcinoma. Their Nordic data set identified 550 cases of esophageal cancer in the 661,987 patients treated for H pylori from 1995–2018 who were followed >5 million person-years. Interestingly, standardized incidence ratio of esophageal adenocarcinoma decreased over time.
This large dataset continues to encourage us to treat H pylori in patients at risk of progressing to gastric cancer. This parallels a growing fund of literature encouraging us to move away from the linear pathophysiologic logic that eliminating H pylori-induced gastric atrophy provokes gastroesophageal reflux disease and esophageal cancer. Instead we should factor in other parameters, including the complex interaction between the esophageal microbiome and gastric H pylori. Some postulated mechanisms include an extension of the gastric inflammatory milieu into the esophagus, and potential crosstalk with the esophageal microbiome.
Such studies underscore the need to personalize both foregut cancer screening criteria and treatment of inflammatory conditions at a patient and population level, so that we can make meaningful impacts in disease prevalence and cancer survival.
Fouad Otaki, MD, is associate professor in the Division of Gastroenterology & Hepatology at Oregon Health & Science University, Portland.
This finding suggests that eradication of H pylori is safe with regard to esophageal cancer risk, and eradication campaigns are not contributing to the rising incidence of esophageal adenocarcinoma (EAC) over the past four decades, reported lead author Anna-Klara Wiklund, MD, of Karolinska Institutet, Stockholm, Sweden, and colleagues.“The decreased risk of esophageal adenocarcinoma seen in individuals with H pylori infection is probably explained by the H pylori–induced gastric atrophy, which reduces gastric acid production and thus acidic gastroesophageal reflux, the main risk factor for this tumor,” the investigators wrote in Gastroenterology. “It seems plausible that eradication of H pylori would increase the risk of EAC, although the answer to this question is unknown with the only study on the topic (from our group) having too few cases and too short follow-up.”
That study involved only 11 cases of EAC.
For the present study, Dr. Wiklund and colleagues aggregated data from all individuals who had undergone H pylori eradication in Finland, Denmark, Iceland, Norway, and Sweden from 1995 to 2019. The dataset comprised 661,987 such individuals with more than 5 million person-years after eradication therapy, including 550 cases of EAC. Median follow-up time was approximately 8 years, ranging from 1 to 24 years.
Analyzing these data revealed that standardized incidence ratio (SIR) of EAC was not increased after eradication therapy (0.89; 95% CI, 0.82-0.97). In fact, SIR decreased over time after eradication, reaching as low as 0.73 (95% CI, 0.61-0.86) during the follow-up period of 11-24 years. These findings were maintained regardless of age or sex, and within country-by-country analyses.
SIR for esophageal squamous cell carcinoma, which was calculated for comparison, showed no association with eradication therapy (0.99; 95% CI, 0.89-1.11).
“This study found no evidence supporting the hypothesis of a gradually increasing risk of esophageal adenocarcinoma over time after H pylori eradication treatment,” the investigators wrote.
Other risks were detected, including an overall increased SIR of EAC observed among participants with gastroesophageal reflux disease (GERD) and those using long-term proton pump inhibitors (PPIs). These were expected, however, “considering the strong and well-established association with EAC.”
Dr. Wiklund and colleagues suggested that more studies are needed to confirm their findings, although the present data provide confidence that H pylori eradication does not raise risk of EAC.
“This is valuable knowledge when considering eradication treatment for individual patients and eradication programs in high-risk populations of gastric cancer,” they wrote. “The results should be generalizable to other high-income countries with low prevalence of H pylori and high incidence of EAC, but studies from other regions with different patterns of these conditions are warranted.”
They also called for more basic research to understand why eradicating H pylori does not lead to an increased risk of EAC.The study was supported by Sjoberg Foundation, Nordic Cancer Union, Stockholm County Council, Stockholm Cancer Society. Investigators disclosed no conflicts of interest.
This finding suggests that eradication of H pylori is safe with regard to esophageal cancer risk, and eradication campaigns are not contributing to the rising incidence of esophageal adenocarcinoma (EAC) over the past four decades, reported lead author Anna-Klara Wiklund, MD, of Karolinska Institutet, Stockholm, Sweden, and colleagues.“The decreased risk of esophageal adenocarcinoma seen in individuals with H pylori infection is probably explained by the H pylori–induced gastric atrophy, which reduces gastric acid production and thus acidic gastroesophageal reflux, the main risk factor for this tumor,” the investigators wrote in Gastroenterology. “It seems plausible that eradication of H pylori would increase the risk of EAC, although the answer to this question is unknown with the only study on the topic (from our group) having too few cases and too short follow-up.”
That study involved only 11 cases of EAC.
For the present study, Dr. Wiklund and colleagues aggregated data from all individuals who had undergone H pylori eradication in Finland, Denmark, Iceland, Norway, and Sweden from 1995 to 2019. The dataset comprised 661,987 such individuals with more than 5 million person-years after eradication therapy, including 550 cases of EAC. Median follow-up time was approximately 8 years, ranging from 1 to 24 years.
Analyzing these data revealed that standardized incidence ratio (SIR) of EAC was not increased after eradication therapy (0.89; 95% CI, 0.82-0.97). In fact, SIR decreased over time after eradication, reaching as low as 0.73 (95% CI, 0.61-0.86) during the follow-up period of 11-24 years. These findings were maintained regardless of age or sex, and within country-by-country analyses.
SIR for esophageal squamous cell carcinoma, which was calculated for comparison, showed no association with eradication therapy (0.99; 95% CI, 0.89-1.11).
“This study found no evidence supporting the hypothesis of a gradually increasing risk of esophageal adenocarcinoma over time after H pylori eradication treatment,” the investigators wrote.
Other risks were detected, including an overall increased SIR of EAC observed among participants with gastroesophageal reflux disease (GERD) and those using long-term proton pump inhibitors (PPIs). These were expected, however, “considering the strong and well-established association with EAC.”
Dr. Wiklund and colleagues suggested that more studies are needed to confirm their findings, although the present data provide confidence that H pylori eradication does not raise risk of EAC.
“This is valuable knowledge when considering eradication treatment for individual patients and eradication programs in high-risk populations of gastric cancer,” they wrote. “The results should be generalizable to other high-income countries with low prevalence of H pylori and high incidence of EAC, but studies from other regions with different patterns of these conditions are warranted.”
They also called for more basic research to understand why eradicating H pylori does not lead to an increased risk of EAC.The study was supported by Sjoberg Foundation, Nordic Cancer Union, Stockholm County Council, Stockholm Cancer Society. Investigators disclosed no conflicts of interest.
FROM GASTROENTEROLOGY
Eosinophilic Esophagitis Often Persists Despite Treatment
based on a recent retrospective study.
Challenging patient journeys were common across age groups, with a range of ongoing symptoms and histological abnormalities supporting high unmet need among patients with EoE, lead author Olulade Ayodele, MBBS, MPH, of Takeda Development Center Americas and colleagues reported.
“Recent studies have found that patients with EoE experience a complicated journey to diagnosis and a substantial disease burden, which requires significant healthcare resource utilization,” the investigators wrote in Gastro Hep Advances . “Reasons for this may include delays in diagnosis owing to nonspecific symptoms, adaptive behaviors, progression of silent disease, lack of adequate follow-up or referral, or suboptimal treatment after diagnosis.”Two medications are currently Food and Drug administration approved for EoE: dupilumab, a biologic for patients aged 1 year and older, and budesonide oral suspension, a topical corticosteroid for patients aged 11 years and older.
The investigators noted that “biologic therapies may not always be selected as first-line treatment, and are often associated with high costs”; however, the effects of real-world treatment decisions like these are poorly documented, prompting the present study.
The final dataset comprised 613 patients with newly diagnosed EoE treated in a rural integrated healthcare system, all of whom had at least 12 months of data before and after a predetermined index date. Individuals were stratified by age, including 182 children, 146 adolescents, 244 adults, and 41 older adults.
Signs and symptoms of EoE frequently worsened after the index date, including dysphagia (34.6% before, 49.9% after), abdominal pain (33.0% before, 48.1% after), and nausea/vomiting (20.1% before, 31.5% after).
At baseline, 80.5% of endoscopies were abnormal and 87.9% of patients had more than 15 eosinophils/high-power field. These parameters improved post index; however, 3 years later, 62.3% of patients still had abnormal endoscopic appearance and 51.2% had abnormal histologic activity.
Before and after index, the most prescribed treatments were corticosteroids (47.3% before, 87.9% after) and proton pump inhibitors (51.1% before, 96.1% after).
After index, 44.0% of patients discontinued their first-line treatment, and 13.9% experienced disease progression.
“We found that a substantial portion of patients with EoE received variable medical treatments, and did not report undergoing follow-up care, consulting with specialists, or routinely undergoing endoscopy with biopsy after diagnosis; the reasons for this are unknown, but experiences do not appear to be consistent with current guideline recommendations,” Dr. Ayodele and colleagues wrote.
They also noted substantial healthcare resource utilization; more than half of the patients visited emergency departments, and nearly one in five were admitted as inpatients.
“Our findings outline the persistent disease activity and difficult therapeutic journeys faced by patients with EoE irrespective of their age, as well as the substantial disease burden,” the investigators concluded. “These data highlight the potential unmet medical need of patients with EoE in the United States.”The study was funded by Shire Human Genetic Therapies, a member of the Takeda group of companies. The investigators disclosed additional relationships with RTI Health Solutions and Receptos/Celgene.
In a large, retrospective, real-world cohort study, investigators examined the patient journey in 613 child, adolescent, and adult patients with eosinophilic esophagitis (EoE) via healthcare claims database and electronic medical record data. As we enter into an exciting era in novel biologic therapies in EoE, the article provides comprehensive and reliable information in several critical and actionable areas with respect to EoE diagnosis and management.
The study highlights the heterogeneity of the patient experience in EoE and suggests that improvements in the reliability and precision of EoE care models will impact healthcare utilization. In particular, the findings support the need for structured and systematic mechanisms for appropriate follow-up after the index diagnosis and increased use and continued development of novel therapies.
Anand Jain, MD, is assistant professor in the Division of Digestive Diseases at Emory University School of Medicine, Atlanta, Georgia. Ravinder Mittal, MD, AGAF, is professor in the Division of Gastroenterology at the University of California, San Diego, and staff physician at the San Diego VA Hospital. They report no conflicts of interest.
In a large, retrospective, real-world cohort study, investigators examined the patient journey in 613 child, adolescent, and adult patients with eosinophilic esophagitis (EoE) via healthcare claims database and electronic medical record data. As we enter into an exciting era in novel biologic therapies in EoE, the article provides comprehensive and reliable information in several critical and actionable areas with respect to EoE diagnosis and management.
The study highlights the heterogeneity of the patient experience in EoE and suggests that improvements in the reliability and precision of EoE care models will impact healthcare utilization. In particular, the findings support the need for structured and systematic mechanisms for appropriate follow-up after the index diagnosis and increased use and continued development of novel therapies.
Anand Jain, MD, is assistant professor in the Division of Digestive Diseases at Emory University School of Medicine, Atlanta, Georgia. Ravinder Mittal, MD, AGAF, is professor in the Division of Gastroenterology at the University of California, San Diego, and staff physician at the San Diego VA Hospital. They report no conflicts of interest.
In a large, retrospective, real-world cohort study, investigators examined the patient journey in 613 child, adolescent, and adult patients with eosinophilic esophagitis (EoE) via healthcare claims database and electronic medical record data. As we enter into an exciting era in novel biologic therapies in EoE, the article provides comprehensive and reliable information in several critical and actionable areas with respect to EoE diagnosis and management.
The study highlights the heterogeneity of the patient experience in EoE and suggests that improvements in the reliability and precision of EoE care models will impact healthcare utilization. In particular, the findings support the need for structured and systematic mechanisms for appropriate follow-up after the index diagnosis and increased use and continued development of novel therapies.
Anand Jain, MD, is assistant professor in the Division of Digestive Diseases at Emory University School of Medicine, Atlanta, Georgia. Ravinder Mittal, MD, AGAF, is professor in the Division of Gastroenterology at the University of California, San Diego, and staff physician at the San Diego VA Hospital. They report no conflicts of interest.
based on a recent retrospective study.
Challenging patient journeys were common across age groups, with a range of ongoing symptoms and histological abnormalities supporting high unmet need among patients with EoE, lead author Olulade Ayodele, MBBS, MPH, of Takeda Development Center Americas and colleagues reported.
“Recent studies have found that patients with EoE experience a complicated journey to diagnosis and a substantial disease burden, which requires significant healthcare resource utilization,” the investigators wrote in Gastro Hep Advances . “Reasons for this may include delays in diagnosis owing to nonspecific symptoms, adaptive behaviors, progression of silent disease, lack of adequate follow-up or referral, or suboptimal treatment after diagnosis.”Two medications are currently Food and Drug administration approved for EoE: dupilumab, a biologic for patients aged 1 year and older, and budesonide oral suspension, a topical corticosteroid for patients aged 11 years and older.
The investigators noted that “biologic therapies may not always be selected as first-line treatment, and are often associated with high costs”; however, the effects of real-world treatment decisions like these are poorly documented, prompting the present study.
The final dataset comprised 613 patients with newly diagnosed EoE treated in a rural integrated healthcare system, all of whom had at least 12 months of data before and after a predetermined index date. Individuals were stratified by age, including 182 children, 146 adolescents, 244 adults, and 41 older adults.
Signs and symptoms of EoE frequently worsened after the index date, including dysphagia (34.6% before, 49.9% after), abdominal pain (33.0% before, 48.1% after), and nausea/vomiting (20.1% before, 31.5% after).
At baseline, 80.5% of endoscopies were abnormal and 87.9% of patients had more than 15 eosinophils/high-power field. These parameters improved post index; however, 3 years later, 62.3% of patients still had abnormal endoscopic appearance and 51.2% had abnormal histologic activity.
Before and after index, the most prescribed treatments were corticosteroids (47.3% before, 87.9% after) and proton pump inhibitors (51.1% before, 96.1% after).
After index, 44.0% of patients discontinued their first-line treatment, and 13.9% experienced disease progression.
“We found that a substantial portion of patients with EoE received variable medical treatments, and did not report undergoing follow-up care, consulting with specialists, or routinely undergoing endoscopy with biopsy after diagnosis; the reasons for this are unknown, but experiences do not appear to be consistent with current guideline recommendations,” Dr. Ayodele and colleagues wrote.
They also noted substantial healthcare resource utilization; more than half of the patients visited emergency departments, and nearly one in five were admitted as inpatients.
“Our findings outline the persistent disease activity and difficult therapeutic journeys faced by patients with EoE irrespective of their age, as well as the substantial disease burden,” the investigators concluded. “These data highlight the potential unmet medical need of patients with EoE in the United States.”The study was funded by Shire Human Genetic Therapies, a member of the Takeda group of companies. The investigators disclosed additional relationships with RTI Health Solutions and Receptos/Celgene.
based on a recent retrospective study.
Challenging patient journeys were common across age groups, with a range of ongoing symptoms and histological abnormalities supporting high unmet need among patients with EoE, lead author Olulade Ayodele, MBBS, MPH, of Takeda Development Center Americas and colleagues reported.
“Recent studies have found that patients with EoE experience a complicated journey to diagnosis and a substantial disease burden, which requires significant healthcare resource utilization,” the investigators wrote in Gastro Hep Advances . “Reasons for this may include delays in diagnosis owing to nonspecific symptoms, adaptive behaviors, progression of silent disease, lack of adequate follow-up or referral, or suboptimal treatment after diagnosis.”Two medications are currently Food and Drug administration approved for EoE: dupilumab, a biologic for patients aged 1 year and older, and budesonide oral suspension, a topical corticosteroid for patients aged 11 years and older.
The investigators noted that “biologic therapies may not always be selected as first-line treatment, and are often associated with high costs”; however, the effects of real-world treatment decisions like these are poorly documented, prompting the present study.
The final dataset comprised 613 patients with newly diagnosed EoE treated in a rural integrated healthcare system, all of whom had at least 12 months of data before and after a predetermined index date. Individuals were stratified by age, including 182 children, 146 adolescents, 244 adults, and 41 older adults.
Signs and symptoms of EoE frequently worsened after the index date, including dysphagia (34.6% before, 49.9% after), abdominal pain (33.0% before, 48.1% after), and nausea/vomiting (20.1% before, 31.5% after).
At baseline, 80.5% of endoscopies were abnormal and 87.9% of patients had more than 15 eosinophils/high-power field. These parameters improved post index; however, 3 years later, 62.3% of patients still had abnormal endoscopic appearance and 51.2% had abnormal histologic activity.
Before and after index, the most prescribed treatments were corticosteroids (47.3% before, 87.9% after) and proton pump inhibitors (51.1% before, 96.1% after).
After index, 44.0% of patients discontinued their first-line treatment, and 13.9% experienced disease progression.
“We found that a substantial portion of patients with EoE received variable medical treatments, and did not report undergoing follow-up care, consulting with specialists, or routinely undergoing endoscopy with biopsy after diagnosis; the reasons for this are unknown, but experiences do not appear to be consistent with current guideline recommendations,” Dr. Ayodele and colleagues wrote.
They also noted substantial healthcare resource utilization; more than half of the patients visited emergency departments, and nearly one in five were admitted as inpatients.
“Our findings outline the persistent disease activity and difficult therapeutic journeys faced by patients with EoE irrespective of their age, as well as the substantial disease burden,” the investigators concluded. “These data highlight the potential unmet medical need of patients with EoE in the United States.”The study was funded by Shire Human Genetic Therapies, a member of the Takeda group of companies. The investigators disclosed additional relationships with RTI Health Solutions and Receptos/Celgene.
FROM GASTRO HEP ADVANCES
FIB-4 Index Misclassifies Many Patients
, potentially impacting clinical decisions, according to investigators.
These findings call for a cautious interpretation of low-risk FIB-4 results among patients at greatest risk of misclassification, and/or use of alternative assessment strategies, reported Mazen Noureddin, MD, MHSc, of Houston Methodist Hospital, and coauthors.
“Currently, the AGA/AASLD Pathways recommends identifying patients at risk for metabolic dysfunction-associated steatotic liver disease (MASLD), then using sequential testing with FIB-4 followed by FibroScan to risk-stratify patients,” the investigators wrote in Clinical Gastroenterology and Hepatology.
Yet the performance of the FIB-4 index in this context remains unclear.
“Previous studies have shown FIB-4 to have low accuracy for screening liver fibrosis, especially among obese and diabetic patients,” the investigators wrote. “Thus, there is a concern that classifying patients with FIB-4 can lead to misclassification and missed diagnosis.”
To explore this concern, Dr. Noureddin and colleagues turned to data from the 2017-2020 National Health and Nutrition Examination Surveys, including 5285 subjects at risk for MASLD. Exclusions were made for those with excessive alcohol intake or other liver diseases, resulting in a final cohort of 3741 individuals.
All subjects were classified as low-, indeterminate-, or high-risk for advanced liver fibrosis based on FIB-4 scores. These scores were then compared with liver stiffness measurements (LSM) obtained through transient elastography (FibroScan).
Out of 2776 subjects classified as low-risk by FIB-4, 277 (10%) were reclassified as higher risk by LSM, including 75 (2.7%) who were found to be at high risk. Out of 879 subjects with indeterminate FIB-4 scores, 37 (4.2%) were at high risk according to LSM. Finally, among the 86 subjects classified as high risk by FIB-4, 68 (79.1%) were reclassified as lower risk by LSM, including 54 (62.8%) who were deemed low risk.
Subjects misclassified as low risk by FIB-4 were typically older and had higher waist circumferences, body mass indices, glycohemoglobin A1c levels, fasting glucose levels, liver enzyme levels, diastolic blood pressures, controlled attenuation parameter scores, white blood cell counts, and alkaline phosphatase levels, but lower high-density lipoprotein and albumin levels (all P less than .05). They were also more likely to have prediabetes or diabetes.
“[I]t is important to acknowledge that 10% of the subjects were misclassified as low risk by FIB-4,” Dr. Noureddin and colleagues wrote, including 2.7% of patients who were actually high risk. “This misclassification of high-risk patients can lead to missed diagnoses, delaying crucial medical treatments or lifestyle interventions.”
They therefore suggested cautious interpretation of low-risk FIB-4 results among patients with factors predicting misclassification, or even use of alternative diagnostic strategies.
“Some possible alternatives to FIB-4 include new serum tests such NIS-2+, MASEF, SAFE score, and machine learning methods,” Dr. Noureddin and colleagues wrote. “However, additional confirmatory and cost-effective studies are required to validate the effectiveness of these tests, including studies conducted on the general population.”
The investigators disclosed relationships with AbbVie, Corcept, Galectin, and others.
, potentially impacting clinical decisions, according to investigators.
These findings call for a cautious interpretation of low-risk FIB-4 results among patients at greatest risk of misclassification, and/or use of alternative assessment strategies, reported Mazen Noureddin, MD, MHSc, of Houston Methodist Hospital, and coauthors.
“Currently, the AGA/AASLD Pathways recommends identifying patients at risk for metabolic dysfunction-associated steatotic liver disease (MASLD), then using sequential testing with FIB-4 followed by FibroScan to risk-stratify patients,” the investigators wrote in Clinical Gastroenterology and Hepatology.
Yet the performance of the FIB-4 index in this context remains unclear.
“Previous studies have shown FIB-4 to have low accuracy for screening liver fibrosis, especially among obese and diabetic patients,” the investigators wrote. “Thus, there is a concern that classifying patients with FIB-4 can lead to misclassification and missed diagnosis.”
To explore this concern, Dr. Noureddin and colleagues turned to data from the 2017-2020 National Health and Nutrition Examination Surveys, including 5285 subjects at risk for MASLD. Exclusions were made for those with excessive alcohol intake or other liver diseases, resulting in a final cohort of 3741 individuals.
All subjects were classified as low-, indeterminate-, or high-risk for advanced liver fibrosis based on FIB-4 scores. These scores were then compared with liver stiffness measurements (LSM) obtained through transient elastography (FibroScan).
Out of 2776 subjects classified as low-risk by FIB-4, 277 (10%) were reclassified as higher risk by LSM, including 75 (2.7%) who were found to be at high risk. Out of 879 subjects with indeterminate FIB-4 scores, 37 (4.2%) were at high risk according to LSM. Finally, among the 86 subjects classified as high risk by FIB-4, 68 (79.1%) were reclassified as lower risk by LSM, including 54 (62.8%) who were deemed low risk.
Subjects misclassified as low risk by FIB-4 were typically older and had higher waist circumferences, body mass indices, glycohemoglobin A1c levels, fasting glucose levels, liver enzyme levels, diastolic blood pressures, controlled attenuation parameter scores, white blood cell counts, and alkaline phosphatase levels, but lower high-density lipoprotein and albumin levels (all P less than .05). They were also more likely to have prediabetes or diabetes.
“[I]t is important to acknowledge that 10% of the subjects were misclassified as low risk by FIB-4,” Dr. Noureddin and colleagues wrote, including 2.7% of patients who were actually high risk. “This misclassification of high-risk patients can lead to missed diagnoses, delaying crucial medical treatments or lifestyle interventions.”
They therefore suggested cautious interpretation of low-risk FIB-4 results among patients with factors predicting misclassification, or even use of alternative diagnostic strategies.
“Some possible alternatives to FIB-4 include new serum tests such NIS-2+, MASEF, SAFE score, and machine learning methods,” Dr. Noureddin and colleagues wrote. “However, additional confirmatory and cost-effective studies are required to validate the effectiveness of these tests, including studies conducted on the general population.”
The investigators disclosed relationships with AbbVie, Corcept, Galectin, and others.
, potentially impacting clinical decisions, according to investigators.
These findings call for a cautious interpretation of low-risk FIB-4 results among patients at greatest risk of misclassification, and/or use of alternative assessment strategies, reported Mazen Noureddin, MD, MHSc, of Houston Methodist Hospital, and coauthors.
“Currently, the AGA/AASLD Pathways recommends identifying patients at risk for metabolic dysfunction-associated steatotic liver disease (MASLD), then using sequential testing with FIB-4 followed by FibroScan to risk-stratify patients,” the investigators wrote in Clinical Gastroenterology and Hepatology.
Yet the performance of the FIB-4 index in this context remains unclear.
“Previous studies have shown FIB-4 to have low accuracy for screening liver fibrosis, especially among obese and diabetic patients,” the investigators wrote. “Thus, there is a concern that classifying patients with FIB-4 can lead to misclassification and missed diagnosis.”
To explore this concern, Dr. Noureddin and colleagues turned to data from the 2017-2020 National Health and Nutrition Examination Surveys, including 5285 subjects at risk for MASLD. Exclusions were made for those with excessive alcohol intake or other liver diseases, resulting in a final cohort of 3741 individuals.
All subjects were classified as low-, indeterminate-, or high-risk for advanced liver fibrosis based on FIB-4 scores. These scores were then compared with liver stiffness measurements (LSM) obtained through transient elastography (FibroScan).
Out of 2776 subjects classified as low-risk by FIB-4, 277 (10%) were reclassified as higher risk by LSM, including 75 (2.7%) who were found to be at high risk. Out of 879 subjects with indeterminate FIB-4 scores, 37 (4.2%) were at high risk according to LSM. Finally, among the 86 subjects classified as high risk by FIB-4, 68 (79.1%) were reclassified as lower risk by LSM, including 54 (62.8%) who were deemed low risk.
Subjects misclassified as low risk by FIB-4 were typically older and had higher waist circumferences, body mass indices, glycohemoglobin A1c levels, fasting glucose levels, liver enzyme levels, diastolic blood pressures, controlled attenuation parameter scores, white blood cell counts, and alkaline phosphatase levels, but lower high-density lipoprotein and albumin levels (all P less than .05). They were also more likely to have prediabetes or diabetes.
“[I]t is important to acknowledge that 10% of the subjects were misclassified as low risk by FIB-4,” Dr. Noureddin and colleagues wrote, including 2.7% of patients who were actually high risk. “This misclassification of high-risk patients can lead to missed diagnoses, delaying crucial medical treatments or lifestyle interventions.”
They therefore suggested cautious interpretation of low-risk FIB-4 results among patients with factors predicting misclassification, or even use of alternative diagnostic strategies.
“Some possible alternatives to FIB-4 include new serum tests such NIS-2+, MASEF, SAFE score, and machine learning methods,” Dr. Noureddin and colleagues wrote. “However, additional confirmatory and cost-effective studies are required to validate the effectiveness of these tests, including studies conducted on the general population.”
The investigators disclosed relationships with AbbVie, Corcept, Galectin, and others.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Autonomous AI Outperforms Humans in Optical Diagnosis of Colorectal Polyps
, while providing greater alignment with pathology-based surveillance intervals, based on a randomized controlled trial.
These findings suggest that autonomous AI may one day replace histologic assessment of diminutive polyps, reported lead author Roupen Djinbachian, MD, of the Montreal University Hospital Research Center, Montreal, Quebec, Canada, and colleagues.Optical diagnosis of diminutive colorectal polyps has been proposed as a cost-effective alternative to histologic diagnosis, but its implementation in general clinical practice has been hindered by endoscopists’ concerns about incorrect diagnoses, the investigators wrote in Gastroenterology.“AI-based systems (CADx) have been proposed as a solution to these barriers to implementation, with studies showing high adherence to Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) thresholds when using AI-H,” they wrote. “However, the efficacy and safety of autonomous AI-based diagnostic platforms have not yet been evaluated.”
To address this knowledge gap, Dr. Djinbachian and colleagues conducted a randomized controlled noninferiority trial involving 467 patients, all of whom underwent elective colonoscopies at a single academic institution.
Participants were randomly assigned to one of two groups. The first group received an optical diagnosis of diminutive (1-5 mm) colorectal polyps using an autonomous AI-based CADx system without any human input. The second group had diagnoses performed by endoscopists who used AI-H to make their optical diagnoses.
The primary outcome was the accuracy of optical diagnosis compared with the gold standard of histologic evaluation. Secondarily, the investigators explored associations between pathology-based surveillance intervals and various measures of accuracy, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).
The results showed that the accuracy of optical diagnosis for diminutive polyps was similar between the two groups, supporting noninferiority. Autonomous AI achieved an accuracy rate of 77.2%, while the AI-H group had an accuracy of 72.1%, which was not statistically significant (P = .86).
But when it came to pathology-based surveillance intervals, autonomous AI showed a clear advantage; the autonomous AI system achieved a 91.5% agreement rate, compared with 82.1% for the AI-H group (P = .016).
“These findings indicate that autonomous AI not only matches but also surpasses AI-H in accuracy for determining surveillance intervals,” the investigators wrote, noting that this finding highlights the “complexities of human interaction with AI modules where human intervention could lead to worse outcomes.”
Further analysis revealed that the sensitivity of autonomous AI for identifying adenomas was 84.8%, slightly higher than the 83.6% sensitivity of the AI-H group. Specificity was 64.4% for autonomous AI vs 63.8% for AI-H. While PPV was higher in the autonomous AI group (85.6%), compared with the AI-H group (78.6%), NPV was lower for autonomous AI than AI-H (63.0% vs 71.0%).
Dr. Djinbachian and colleagues suggested that future research should focus on larger, multicenter trials to validate these findings and further explore the integration of autonomous AI systems in clinical practice. They also noted that improving AI algorithms to accurately diagnose sessile serrated lesions could enhance the overall effectiveness of AI-based optical diagnosis.
“The performance of autonomous AI in accurately diagnosing diminutive polyps and determining appropriate surveillance intervals suggests that it could play a crucial role in streamlining colorectal cancer screening processes, reducing the burden on pathologists, and potentially lowering healthcare costs,” the investigators concluded.The study was supported by Fujifilm, which had no role in the study design or data analysis. Dr. von Renteln reported additional research funding from Vantage and Fujifilm.
In the era of computer vision for endoscopy and colonoscopy, current paradigms rely on AI as a co-pilot or second observer, with the physician serving as the final arbiter in procedure-related decision-making. This study by Djinbachian and Haumesser et al brings up the interesting wrinkle of autonomous AI as a potentially superior (or noninferior) option in narrow, task-specific use cases.
In this study, human input from the endoscopist after CADx diagnosis led to lower agreement between the AI-predicted diagnosis and corresponding surveillance intervals; human oversight more often incorrectly changed the resultant diagnosis and led to shorter than recommended surveillance intervals.
This study offers a small but very important update to the growing body of literature on CADx in colonoscopy. So far, prospective validation of CADx compared with the human eye for in-situ diagnosis of polyps has provided mixed results. This study is one of the first to examine the potential role of “automatic” CADx without additional human input and sheds light on the importance of the AI-human hybrid in medical care. How do the ways in which humans interact with the user interface and output of AI lead to changes in outcome? How can we optimize the AI-human interaction in order to provide optimal results?
Jeremy R. Glissen Brown is an assistant professor in the Department of Internal Medicine and Division of Gastroenterology at Duke University Medical Center, Durham, North Carolina. He has served as a consultant for Medtronic and Olympus, and on the advisory board for Odin Vision.
In the era of computer vision for endoscopy and colonoscopy, current paradigms rely on AI as a co-pilot or second observer, with the physician serving as the final arbiter in procedure-related decision-making. This study by Djinbachian and Haumesser et al brings up the interesting wrinkle of autonomous AI as a potentially superior (or noninferior) option in narrow, task-specific use cases.
In this study, human input from the endoscopist after CADx diagnosis led to lower agreement between the AI-predicted diagnosis and corresponding surveillance intervals; human oversight more often incorrectly changed the resultant diagnosis and led to shorter than recommended surveillance intervals.
This study offers a small but very important update to the growing body of literature on CADx in colonoscopy. So far, prospective validation of CADx compared with the human eye for in-situ diagnosis of polyps has provided mixed results. This study is one of the first to examine the potential role of “automatic” CADx without additional human input and sheds light on the importance of the AI-human hybrid in medical care. How do the ways in which humans interact with the user interface and output of AI lead to changes in outcome? How can we optimize the AI-human interaction in order to provide optimal results?
Jeremy R. Glissen Brown is an assistant professor in the Department of Internal Medicine and Division of Gastroenterology at Duke University Medical Center, Durham, North Carolina. He has served as a consultant for Medtronic and Olympus, and on the advisory board for Odin Vision.
In the era of computer vision for endoscopy and colonoscopy, current paradigms rely on AI as a co-pilot or second observer, with the physician serving as the final arbiter in procedure-related decision-making. This study by Djinbachian and Haumesser et al brings up the interesting wrinkle of autonomous AI as a potentially superior (or noninferior) option in narrow, task-specific use cases.
In this study, human input from the endoscopist after CADx diagnosis led to lower agreement between the AI-predicted diagnosis and corresponding surveillance intervals; human oversight more often incorrectly changed the resultant diagnosis and led to shorter than recommended surveillance intervals.
This study offers a small but very important update to the growing body of literature on CADx in colonoscopy. So far, prospective validation of CADx compared with the human eye for in-situ diagnosis of polyps has provided mixed results. This study is one of the first to examine the potential role of “automatic” CADx without additional human input and sheds light on the importance of the AI-human hybrid in medical care. How do the ways in which humans interact with the user interface and output of AI lead to changes in outcome? How can we optimize the AI-human interaction in order to provide optimal results?
Jeremy R. Glissen Brown is an assistant professor in the Department of Internal Medicine and Division of Gastroenterology at Duke University Medical Center, Durham, North Carolina. He has served as a consultant for Medtronic and Olympus, and on the advisory board for Odin Vision.
, while providing greater alignment with pathology-based surveillance intervals, based on a randomized controlled trial.
These findings suggest that autonomous AI may one day replace histologic assessment of diminutive polyps, reported lead author Roupen Djinbachian, MD, of the Montreal University Hospital Research Center, Montreal, Quebec, Canada, and colleagues.Optical diagnosis of diminutive colorectal polyps has been proposed as a cost-effective alternative to histologic diagnosis, but its implementation in general clinical practice has been hindered by endoscopists’ concerns about incorrect diagnoses, the investigators wrote in Gastroenterology.“AI-based systems (CADx) have been proposed as a solution to these barriers to implementation, with studies showing high adherence to Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) thresholds when using AI-H,” they wrote. “However, the efficacy and safety of autonomous AI-based diagnostic platforms have not yet been evaluated.”
To address this knowledge gap, Dr. Djinbachian and colleagues conducted a randomized controlled noninferiority trial involving 467 patients, all of whom underwent elective colonoscopies at a single academic institution.
Participants were randomly assigned to one of two groups. The first group received an optical diagnosis of diminutive (1-5 mm) colorectal polyps using an autonomous AI-based CADx system without any human input. The second group had diagnoses performed by endoscopists who used AI-H to make their optical diagnoses.
The primary outcome was the accuracy of optical diagnosis compared with the gold standard of histologic evaluation. Secondarily, the investigators explored associations between pathology-based surveillance intervals and various measures of accuracy, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).
The results showed that the accuracy of optical diagnosis for diminutive polyps was similar between the two groups, supporting noninferiority. Autonomous AI achieved an accuracy rate of 77.2%, while the AI-H group had an accuracy of 72.1%, which was not statistically significant (P = .86).
But when it came to pathology-based surveillance intervals, autonomous AI showed a clear advantage; the autonomous AI system achieved a 91.5% agreement rate, compared with 82.1% for the AI-H group (P = .016).
“These findings indicate that autonomous AI not only matches but also surpasses AI-H in accuracy for determining surveillance intervals,” the investigators wrote, noting that this finding highlights the “complexities of human interaction with AI modules where human intervention could lead to worse outcomes.”
Further analysis revealed that the sensitivity of autonomous AI for identifying adenomas was 84.8%, slightly higher than the 83.6% sensitivity of the AI-H group. Specificity was 64.4% for autonomous AI vs 63.8% for AI-H. While PPV was higher in the autonomous AI group (85.6%), compared with the AI-H group (78.6%), NPV was lower for autonomous AI than AI-H (63.0% vs 71.0%).
Dr. Djinbachian and colleagues suggested that future research should focus on larger, multicenter trials to validate these findings and further explore the integration of autonomous AI systems in clinical practice. They also noted that improving AI algorithms to accurately diagnose sessile serrated lesions could enhance the overall effectiveness of AI-based optical diagnosis.
“The performance of autonomous AI in accurately diagnosing diminutive polyps and determining appropriate surveillance intervals suggests that it could play a crucial role in streamlining colorectal cancer screening processes, reducing the burden on pathologists, and potentially lowering healthcare costs,” the investigators concluded.The study was supported by Fujifilm, which had no role in the study design or data analysis. Dr. von Renteln reported additional research funding from Vantage and Fujifilm.
, while providing greater alignment with pathology-based surveillance intervals, based on a randomized controlled trial.
These findings suggest that autonomous AI may one day replace histologic assessment of diminutive polyps, reported lead author Roupen Djinbachian, MD, of the Montreal University Hospital Research Center, Montreal, Quebec, Canada, and colleagues.Optical diagnosis of diminutive colorectal polyps has been proposed as a cost-effective alternative to histologic diagnosis, but its implementation in general clinical practice has been hindered by endoscopists’ concerns about incorrect diagnoses, the investigators wrote in Gastroenterology.“AI-based systems (CADx) have been proposed as a solution to these barriers to implementation, with studies showing high adherence to Preservation and Incorporation of Valuable Endoscopic Innovations (PIVI) thresholds when using AI-H,” they wrote. “However, the efficacy and safety of autonomous AI-based diagnostic platforms have not yet been evaluated.”
To address this knowledge gap, Dr. Djinbachian and colleagues conducted a randomized controlled noninferiority trial involving 467 patients, all of whom underwent elective colonoscopies at a single academic institution.
Participants were randomly assigned to one of two groups. The first group received an optical diagnosis of diminutive (1-5 mm) colorectal polyps using an autonomous AI-based CADx system without any human input. The second group had diagnoses performed by endoscopists who used AI-H to make their optical diagnoses.
The primary outcome was the accuracy of optical diagnosis compared with the gold standard of histologic evaluation. Secondarily, the investigators explored associations between pathology-based surveillance intervals and various measures of accuracy, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).
The results showed that the accuracy of optical diagnosis for diminutive polyps was similar between the two groups, supporting noninferiority. Autonomous AI achieved an accuracy rate of 77.2%, while the AI-H group had an accuracy of 72.1%, which was not statistically significant (P = .86).
But when it came to pathology-based surveillance intervals, autonomous AI showed a clear advantage; the autonomous AI system achieved a 91.5% agreement rate, compared with 82.1% for the AI-H group (P = .016).
“These findings indicate that autonomous AI not only matches but also surpasses AI-H in accuracy for determining surveillance intervals,” the investigators wrote, noting that this finding highlights the “complexities of human interaction with AI modules where human intervention could lead to worse outcomes.”
Further analysis revealed that the sensitivity of autonomous AI for identifying adenomas was 84.8%, slightly higher than the 83.6% sensitivity of the AI-H group. Specificity was 64.4% for autonomous AI vs 63.8% for AI-H. While PPV was higher in the autonomous AI group (85.6%), compared with the AI-H group (78.6%), NPV was lower for autonomous AI than AI-H (63.0% vs 71.0%).
Dr. Djinbachian and colleagues suggested that future research should focus on larger, multicenter trials to validate these findings and further explore the integration of autonomous AI systems in clinical practice. They also noted that improving AI algorithms to accurately diagnose sessile serrated lesions could enhance the overall effectiveness of AI-based optical diagnosis.
“The performance of autonomous AI in accurately diagnosing diminutive polyps and determining appropriate surveillance intervals suggests that it could play a crucial role in streamlining colorectal cancer screening processes, reducing the burden on pathologists, and potentially lowering healthcare costs,” the investigators concluded.The study was supported by Fujifilm, which had no role in the study design or data analysis. Dr. von Renteln reported additional research funding from Vantage and Fujifilm.
FROM GASTROENTEROLOGY
Targeting Enteroendocrine Cells Could Hold Promise for IBD
, according to investigators.
These findings suggest that restoring EEC function could alleviate some of the more general abdominal symptoms associated with IBD, reported lead author Zachariah Raouf, MD, of Johns Hopkins University School of Medicine, Baltimore, and colleagues.
“The symptoms experienced by patients with IBD, especially ulcerative colitis, may include those that are colonic in nature, such as bloody stools, abdominal pain, and weight loss, as well as those that are more general in nature, such as severe nausea and abdominal bloating,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology . “Although the first set of symptoms may be attributable to the effects of colonic inflammation itself, those that are more vague seem to overlap with the symptoms that patients with small intestinal dysmotility experience, such as occur in response to medications, or diabetes.”
Supporting this notion, several previous studies have reported the onset of intestinal dysmotility in experimental models of colitis, which is believed to be caused by impaired enteric nervous system function. But the precise mechanisms behind the impaired intestinal motility observed in colitis patients remain unclear.
To learn more, Dr. Raouf and colleagues conducted experiments involving three groups of mice: wild-type mice, mice genetically engineered to overexpress EECs, and mice lacking EECs.
To induce colitis, the mice were administered dextran sulfate sodium (DSS) in drinking water at concentrations of 2.5% or 5% for 7 days. Small intestinal motility was evaluated by measuring the transit of fluorescein isothiocyanate (FITC)-dextran. Immunohistochemical analyses were conducted to assess EEC number and differentiation, while quantitative reverse-transcriptase polymerase chain reaction was used to examine the expression of genes related to serotonin synthesis and transport.
The researchers examined colon length and signs of colonic inflammation, monitored weight loss, and measured the expression of proinflammatory cytokines. Histological analyses of colon and small intestine tissues were performed to further understand the effects of colitis. The presence and number of EEC cells was evaluated using chromogranin A (ChgA) staining, while apoptosis in EECs was measured via TUNEL staining. The expression of serotonin-related genes was also assessed.
These experiments revealed that DSS-induced colitis led to significant small-bowel hypomotility and a reduction in EEC density. Of note, genetic overexpression of EECs or treatment with prucalopride, a 5-hydroxytryptamine receptor 4 agonist, improved small intestinal motility.
“It is noteworthy that there were no significant changes in the density of other intestinal epithelial cells, or in other cell types that are linked to motility, such as enteric glia and neurons, suggesting the specificity of the effect,” the investigators wrote. “Importantly, treatment with a serotonin agonist ameliorated the colitis-induced, small-bowel hypomotility and attenuated the severity of colitis, providing potential clinical relevance of the current findings. Taken together, these results identify mechanisms to explain the intestinal hypomotility observed in the setting of colitis.”Dr. Raouf and colleagues called for human clinical trials to their findings. Specifically, they suggested exploring therapies targeting enteroendocrine cells or serotonin pathways and examining the role of different EEC types in gut motility during inflammation. The study was supported by the National Institutes of Health. The investigators disclosed no conflicts of interest.
Inflammatory bowel disease (IBD) typically manifests with colonic symptoms but is also associated with intestinal inflammation and dysmotility of the small intestine. Clinical research debates whether IBD causes small intestine hypermotility or hypomotility, but these motility dysfunctions are often attributed to alterations of the gut’s intrinsic nervous system.
Dr. Raouf and colleagues focus on the role of enteroendocrine cells, an epithelial cell subtype with neuron-like features that secrete serotonin, one of the most important regulators of intestinal motility. Their population is reduced in colitis, and the subsequent alteration of serotonin signaling induces small intestine dysmotility. The observed loss of enteroendocrine cells in the small bowel may result from low-grade local inflammation increasing enteroendocrine cell apoptosis, or impaired gene expression in their differentiation pathways. However, more research is required to elucidate the underlying mechanisms of this loss.
This study enhances our understanding of the small intestine dysfunction associated with colitis and raises the exciting possibility of enteroendocrine cell-based therapeutic approaches in IBD.
Jacques A. Gonzales, PhD, is a postdoctoral fellow in the Gulbransen laboratory at Michigan State University, East Lansing. He has no conflicts of interest.
Inflammatory bowel disease (IBD) typically manifests with colonic symptoms but is also associated with intestinal inflammation and dysmotility of the small intestine. Clinical research debates whether IBD causes small intestine hypermotility or hypomotility, but these motility dysfunctions are often attributed to alterations of the gut’s intrinsic nervous system.
Dr. Raouf and colleagues focus on the role of enteroendocrine cells, an epithelial cell subtype with neuron-like features that secrete serotonin, one of the most important regulators of intestinal motility. Their population is reduced in colitis, and the subsequent alteration of serotonin signaling induces small intestine dysmotility. The observed loss of enteroendocrine cells in the small bowel may result from low-grade local inflammation increasing enteroendocrine cell apoptosis, or impaired gene expression in their differentiation pathways. However, more research is required to elucidate the underlying mechanisms of this loss.
This study enhances our understanding of the small intestine dysfunction associated with colitis and raises the exciting possibility of enteroendocrine cell-based therapeutic approaches in IBD.
Jacques A. Gonzales, PhD, is a postdoctoral fellow in the Gulbransen laboratory at Michigan State University, East Lansing. He has no conflicts of interest.
Inflammatory bowel disease (IBD) typically manifests with colonic symptoms but is also associated with intestinal inflammation and dysmotility of the small intestine. Clinical research debates whether IBD causes small intestine hypermotility or hypomotility, but these motility dysfunctions are often attributed to alterations of the gut’s intrinsic nervous system.
Dr. Raouf and colleagues focus on the role of enteroendocrine cells, an epithelial cell subtype with neuron-like features that secrete serotonin, one of the most important regulators of intestinal motility. Their population is reduced in colitis, and the subsequent alteration of serotonin signaling induces small intestine dysmotility. The observed loss of enteroendocrine cells in the small bowel may result from low-grade local inflammation increasing enteroendocrine cell apoptosis, or impaired gene expression in their differentiation pathways. However, more research is required to elucidate the underlying mechanisms of this loss.
This study enhances our understanding of the small intestine dysfunction associated with colitis and raises the exciting possibility of enteroendocrine cell-based therapeutic approaches in IBD.
Jacques A. Gonzales, PhD, is a postdoctoral fellow in the Gulbransen laboratory at Michigan State University, East Lansing. He has no conflicts of interest.
, according to investigators.
These findings suggest that restoring EEC function could alleviate some of the more general abdominal symptoms associated with IBD, reported lead author Zachariah Raouf, MD, of Johns Hopkins University School of Medicine, Baltimore, and colleagues.
“The symptoms experienced by patients with IBD, especially ulcerative colitis, may include those that are colonic in nature, such as bloody stools, abdominal pain, and weight loss, as well as those that are more general in nature, such as severe nausea and abdominal bloating,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology . “Although the first set of symptoms may be attributable to the effects of colonic inflammation itself, those that are more vague seem to overlap with the symptoms that patients with small intestinal dysmotility experience, such as occur in response to medications, or diabetes.”
Supporting this notion, several previous studies have reported the onset of intestinal dysmotility in experimental models of colitis, which is believed to be caused by impaired enteric nervous system function. But the precise mechanisms behind the impaired intestinal motility observed in colitis patients remain unclear.
To learn more, Dr. Raouf and colleagues conducted experiments involving three groups of mice: wild-type mice, mice genetically engineered to overexpress EECs, and mice lacking EECs.
To induce colitis, the mice were administered dextran sulfate sodium (DSS) in drinking water at concentrations of 2.5% or 5% for 7 days. Small intestinal motility was evaluated by measuring the transit of fluorescein isothiocyanate (FITC)-dextran. Immunohistochemical analyses were conducted to assess EEC number and differentiation, while quantitative reverse-transcriptase polymerase chain reaction was used to examine the expression of genes related to serotonin synthesis and transport.
The researchers examined colon length and signs of colonic inflammation, monitored weight loss, and measured the expression of proinflammatory cytokines. Histological analyses of colon and small intestine tissues were performed to further understand the effects of colitis. The presence and number of EEC cells was evaluated using chromogranin A (ChgA) staining, while apoptosis in EECs was measured via TUNEL staining. The expression of serotonin-related genes was also assessed.
These experiments revealed that DSS-induced colitis led to significant small-bowel hypomotility and a reduction in EEC density. Of note, genetic overexpression of EECs or treatment with prucalopride, a 5-hydroxytryptamine receptor 4 agonist, improved small intestinal motility.
“It is noteworthy that there were no significant changes in the density of other intestinal epithelial cells, or in other cell types that are linked to motility, such as enteric glia and neurons, suggesting the specificity of the effect,” the investigators wrote. “Importantly, treatment with a serotonin agonist ameliorated the colitis-induced, small-bowel hypomotility and attenuated the severity of colitis, providing potential clinical relevance of the current findings. Taken together, these results identify mechanisms to explain the intestinal hypomotility observed in the setting of colitis.”Dr. Raouf and colleagues called for human clinical trials to their findings. Specifically, they suggested exploring therapies targeting enteroendocrine cells or serotonin pathways and examining the role of different EEC types in gut motility during inflammation. The study was supported by the National Institutes of Health. The investigators disclosed no conflicts of interest.
, according to investigators.
These findings suggest that restoring EEC function could alleviate some of the more general abdominal symptoms associated with IBD, reported lead author Zachariah Raouf, MD, of Johns Hopkins University School of Medicine, Baltimore, and colleagues.
“The symptoms experienced by patients with IBD, especially ulcerative colitis, may include those that are colonic in nature, such as bloody stools, abdominal pain, and weight loss, as well as those that are more general in nature, such as severe nausea and abdominal bloating,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology . “Although the first set of symptoms may be attributable to the effects of colonic inflammation itself, those that are more vague seem to overlap with the symptoms that patients with small intestinal dysmotility experience, such as occur in response to medications, or diabetes.”
Supporting this notion, several previous studies have reported the onset of intestinal dysmotility in experimental models of colitis, which is believed to be caused by impaired enteric nervous system function. But the precise mechanisms behind the impaired intestinal motility observed in colitis patients remain unclear.
To learn more, Dr. Raouf and colleagues conducted experiments involving three groups of mice: wild-type mice, mice genetically engineered to overexpress EECs, and mice lacking EECs.
To induce colitis, the mice were administered dextran sulfate sodium (DSS) in drinking water at concentrations of 2.5% or 5% for 7 days. Small intestinal motility was evaluated by measuring the transit of fluorescein isothiocyanate (FITC)-dextran. Immunohistochemical analyses were conducted to assess EEC number and differentiation, while quantitative reverse-transcriptase polymerase chain reaction was used to examine the expression of genes related to serotonin synthesis and transport.
The researchers examined colon length and signs of colonic inflammation, monitored weight loss, and measured the expression of proinflammatory cytokines. Histological analyses of colon and small intestine tissues were performed to further understand the effects of colitis. The presence and number of EEC cells was evaluated using chromogranin A (ChgA) staining, while apoptosis in EECs was measured via TUNEL staining. The expression of serotonin-related genes was also assessed.
These experiments revealed that DSS-induced colitis led to significant small-bowel hypomotility and a reduction in EEC density. Of note, genetic overexpression of EECs or treatment with prucalopride, a 5-hydroxytryptamine receptor 4 agonist, improved small intestinal motility.
“It is noteworthy that there were no significant changes in the density of other intestinal epithelial cells, or in other cell types that are linked to motility, such as enteric glia and neurons, suggesting the specificity of the effect,” the investigators wrote. “Importantly, treatment with a serotonin agonist ameliorated the colitis-induced, small-bowel hypomotility and attenuated the severity of colitis, providing potential clinical relevance of the current findings. Taken together, these results identify mechanisms to explain the intestinal hypomotility observed in the setting of colitis.”Dr. Raouf and colleagues called for human clinical trials to their findings. Specifically, they suggested exploring therapies targeting enteroendocrine cells or serotonin pathways and examining the role of different EEC types in gut motility during inflammation. The study was supported by the National Institutes of Health. The investigators disclosed no conflicts of interest.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY