Will Pass

The Fibrosis-4 (FIB-4) index shows high discordance with liver stiffness measurement (LSM) via transient elastography, suggesting that many patients are misclassified, 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.

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“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.

The Fibrosis-4 (FIB-4) index shows high discordance with liver stiffness measurement (LSM) via transient elastography, suggesting that many patients are misclassified, 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.

swesabobogathobegeuecucheticrithucrufromocaphemaluclemulawromilokuswagucinobegitorilaspouaposididefrolowraprobeseswewrigivepr

“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.

The Fibrosis-4 (FIB-4) index shows high discordance with liver stiffness measurement (LSM) via transient elastography, suggesting that many patients are misclassified, 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.

swesabobogathobegeuecucheticrithucrufromocaphemaluclemulawromilokuswagucinobegitorilaspouaposididefrolowraprobeseswewrigivepr

“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.

Autonomous artificial intelligence (AI) can achieve similar accuracy to AI-assisted humans (AI-H) in the optical diagnosis of diminutive 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.

Autonomous artificial intelligence (AI) can achieve similar accuracy to AI-assisted humans (AI-H) in the optical diagnosis of diminutive 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.

Autonomous artificial intelligence (AI) can achieve similar accuracy to AI-assisted humans (AI-H) in the optical diagnosis of diminutive 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.

Colitis-induced small intestinal hypomotility is closely linked to the loss of enteroendocrine cells (EECs) in mice, revealing a potential therapeutic strategy for patients with inflammatory bowel disease (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.

Colitis-induced small intestinal hypomotility is closely linked to the loss of enteroendocrine cells (EECs) in mice, revealing a potential therapeutic strategy for patients with inflammatory bowel disease (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.

Colitis-induced small intestinal hypomotility is closely linked to the loss of enteroendocrine cells (EECs) in mice, revealing a potential therapeutic strategy for patients with inflammatory bowel disease (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.

Irisin levels in cerebrospinal fluid (CSF) are significantly lower among patients with Alzheimer’s disease, and levels positively correlate with amyloid beta 1-42 (Abeta42), increasing support for this emerging Alzheimer’s disease biomarker, according to investigators.

Irisin, a hormone released by muscles during physical exercise, also negatively correlated with Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) in female patients, pointing to a sex-specific disease phenomenon, reported by co-lead authors Manuela Dicarlo, PhD, and Patrizia Pignataro, MSc, of the University of Bari “A. Moro,” Bari, Italy, and colleagues.

Regular physical exercise can slow cognitive decline in individuals at risk for or with Alzheimer’s disease, and irisin appears to play a key role in this process, the investigators wrote in Annals of Neurology. Previous studies have shown that increased irisin levels in the brain are associated with improved cognitive function and reduced amyloid beta levels, suggesting the hormone’s potential as a biomarker and therapeutic target for Alzheimer’s disease.

“Based on the protective effect of irisin in Alzheimer’s disease shown in animal and cell models, the goal of the present study was to investigate the levels of irisin in the biological fluids of a large cohort of patients biologically characterized according to the amyloid/tau/neurodegeneration (ATN) scheme of the National Institute on Aging–Alzheimer’s Association (NIA-AA),” Dr. Dicarlo and colleagues wrote. “We aimed to understand whether there may be variations of irisin levels across the disease stages, identified through the ATN system.”
 

Lower Levels of Irisin Seen in Patients With Alzheimer’s Disease

The study included 82 patients with Alzheimer’s disease, 44 individuals with mild cognitive impairment (MCI), and 20 with subjective memory complaints (SMC). Participants underwent comprehensive assessments, including neurological and neuropsychological exams, nutritional evaluations, MRI scans, and routine lab tests. Cognitive impairment severity was measured using the CDR-SOB and other metrics.

Blood and CSF samples were collected from all patients, the latter via lumbar puncture. These samples were analyzed for irisin levels and known Alzheimer’s disease biomarkers, including Abeta42, total tau (t-tau), and hyperphosphorylated tau (p-tau).

Mean CSF irisin levels were significantly lower among patients with Alzheimer’s disease than those with SMC (0.80 vs 1.23 pg/mL; P < .0001), and among those with MCI vs SMC (0.95 vs 1.23 pg/mL; P = .046). Among patients with Alzheimer’s disease, irisin levels were significantly lower among women than men (0.70 vs 0.96 pg/mL; P = .031).

Further analyses revealed positive correlations between CSF irisin level and Abeta42 in both males (r = 0.262; P < 005) and females (r = 0.379; P < .001). Conversely, in female patients, a significant negative correlation was found between CSF irisin level and CDR-SOB score (r = −0.234; P < .05).

Although a negative trend was observed between CSF irisin and total tau (t-tau) in the overall patient population (r = −0.144; P = 0.082), and more notably in female patients (r = −0.189; P = 0.084), these results were not statistically significant.

Plasma irisin levels were not significantly correlated with any of the other biomarkers.
 

Clinical Implications

This study “verifies that irisin levels do have a relationship to the Alzheimer’s disease process,” said Dylan Wint, MD, director of Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas.

In a written comment, Dr. Wint speculated that measuring irisin levels could theoretically help individualize physical exercise routines designed to combat cognitive decline.

“For example, maybe someone who is exercising but has a low irisin level would need to change the type of exercise they’re doing in order to optimally protect their brain health,” he said. “Or maybe they won’t get the same benefits for brain health as someone whose irisin shoots up every time they walk a flight of stairs.”

dowukidronesifrawrebrisevushuvaricofrishouejufrucraslibrispoclaweprivawadidespoduswupiwofrephibrocuwuthovatrukoshobavaphastedoslethudrivitriphatropapukiuidrebiprudiwaphiwawrekocledrudofrophidruphawrocrebrelutiwicliswocevastifrugo

It’s “near-impossible to tell,” however, if irisin will be employed in clinical trials or real-world practice, he added.

“I don’t see this being a highly useful serum biomarker for Alzheimer’s disease itself because other serum biomarkers are so far ahead and have more face validity,” Dr. Wint said.

The route of collection could also cause challenges.

“In the United States, CSF-based biomarkers can be a difficult sell, especially for serial testing,” Dr. Wint said. “But we have usable serum biomarkers for Alzheimer’s disease only because we have had CSF biomarkers against which to evaluate them. They may develop a way to evaluate this in the serum.”

Dr. Dicarlo and colleagues suggested that more work is needed to determine the ultimate value of irisin measurement.“The true ability of irisin to represent a biomarker of disease progression and severity remains to be further investigated,” they concluded. “However, our findings might offer interesting perspectives toward the potential role of irisin in the modulation of AD pathology and can guide the exploration of medication targeting the irisin system.”

The study was supported by Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione, CIREMIC, the University of Bari, and Next Generation EU. The investigators and Dr. Wint disclosed no conflicts of interest.

Irisin levels in cerebrospinal fluid (CSF) are significantly lower among patients with Alzheimer’s disease, and levels positively correlate with amyloid beta 1-42 (Abeta42), increasing support for this emerging Alzheimer’s disease biomarker, according to investigators.

Irisin, a hormone released by muscles during physical exercise, also negatively correlated with Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) in female patients, pointing to a sex-specific disease phenomenon, reported by co-lead authors Manuela Dicarlo, PhD, and Patrizia Pignataro, MSc, of the University of Bari “A. Moro,” Bari, Italy, and colleagues.

Regular physical exercise can slow cognitive decline in individuals at risk for or with Alzheimer’s disease, and irisin appears to play a key role in this process, the investigators wrote in Annals of Neurology. Previous studies have shown that increased irisin levels in the brain are associated with improved cognitive function and reduced amyloid beta levels, suggesting the hormone’s potential as a biomarker and therapeutic target for Alzheimer’s disease.

“Based on the protective effect of irisin in Alzheimer’s disease shown in animal and cell models, the goal of the present study was to investigate the levels of irisin in the biological fluids of a large cohort of patients biologically characterized according to the amyloid/tau/neurodegeneration (ATN) scheme of the National Institute on Aging–Alzheimer’s Association (NIA-AA),” Dr. Dicarlo and colleagues wrote. “We aimed to understand whether there may be variations of irisin levels across the disease stages, identified through the ATN system.”
 

Lower Levels of Irisin Seen in Patients With Alzheimer’s Disease

The study included 82 patients with Alzheimer’s disease, 44 individuals with mild cognitive impairment (MCI), and 20 with subjective memory complaints (SMC). Participants underwent comprehensive assessments, including neurological and neuropsychological exams, nutritional evaluations, MRI scans, and routine lab tests. Cognitive impairment severity was measured using the CDR-SOB and other metrics.

Blood and CSF samples were collected from all patients, the latter via lumbar puncture. These samples were analyzed for irisin levels and known Alzheimer’s disease biomarkers, including Abeta42, total tau (t-tau), and hyperphosphorylated tau (p-tau).

Mean CSF irisin levels were significantly lower among patients with Alzheimer’s disease than those with SMC (0.80 vs 1.23 pg/mL; P < .0001), and among those with MCI vs SMC (0.95 vs 1.23 pg/mL; P = .046). Among patients with Alzheimer’s disease, irisin levels were significantly lower among women than men (0.70 vs 0.96 pg/mL; P = .031).

Further analyses revealed positive correlations between CSF irisin level and Abeta42 in both males (r = 0.262; P < 005) and females (r = 0.379; P < .001). Conversely, in female patients, a significant negative correlation was found between CSF irisin level and CDR-SOB score (r = −0.234; P < .05).

Although a negative trend was observed between CSF irisin and total tau (t-tau) in the overall patient population (r = −0.144; P = 0.082), and more notably in female patients (r = −0.189; P = 0.084), these results were not statistically significant.

Plasma irisin levels were not significantly correlated with any of the other biomarkers.
 

Clinical Implications

This study “verifies that irisin levels do have a relationship to the Alzheimer’s disease process,” said Dylan Wint, MD, director of Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas.

In a written comment, Dr. Wint speculated that measuring irisin levels could theoretically help individualize physical exercise routines designed to combat cognitive decline.

“For example, maybe someone who is exercising but has a low irisin level would need to change the type of exercise they’re doing in order to optimally protect their brain health,” he said. “Or maybe they won’t get the same benefits for brain health as someone whose irisin shoots up every time they walk a flight of stairs.”

dowukidronesifrawrebrisevushuvaricofrishouejufrucraslibrispoclaweprivawadidespoduswupiwofrephibrocuwuthovatrukoshobavaphastedoslethudrivitriphatropapukiuidrebiprudiwaphiwawrekocledrudofrophidruphawrocrebrelutiwicliswocevastifrugo

It’s “near-impossible to tell,” however, if irisin will be employed in clinical trials or real-world practice, he added.

“I don’t see this being a highly useful serum biomarker for Alzheimer’s disease itself because other serum biomarkers are so far ahead and have more face validity,” Dr. Wint said.

The route of collection could also cause challenges.

“In the United States, CSF-based biomarkers can be a difficult sell, especially for serial testing,” Dr. Wint said. “But we have usable serum biomarkers for Alzheimer’s disease only because we have had CSF biomarkers against which to evaluate them. They may develop a way to evaluate this in the serum.”

Dr. Dicarlo and colleagues suggested that more work is needed to determine the ultimate value of irisin measurement.“The true ability of irisin to represent a biomarker of disease progression and severity remains to be further investigated,” they concluded. “However, our findings might offer interesting perspectives toward the potential role of irisin in the modulation of AD pathology and can guide the exploration of medication targeting the irisin system.”

The study was supported by Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione, CIREMIC, the University of Bari, and Next Generation EU. The investigators and Dr. Wint disclosed no conflicts of interest.

Irisin levels in cerebrospinal fluid (CSF) are significantly lower among patients with Alzheimer’s disease, and levels positively correlate with amyloid beta 1-42 (Abeta42), increasing support for this emerging Alzheimer’s disease biomarker, according to investigators.

Irisin, a hormone released by muscles during physical exercise, also negatively correlated with Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) in female patients, pointing to a sex-specific disease phenomenon, reported by co-lead authors Manuela Dicarlo, PhD, and Patrizia Pignataro, MSc, of the University of Bari “A. Moro,” Bari, Italy, and colleagues.

Regular physical exercise can slow cognitive decline in individuals at risk for or with Alzheimer’s disease, and irisin appears to play a key role in this process, the investigators wrote in Annals of Neurology. Previous studies have shown that increased irisin levels in the brain are associated with improved cognitive function and reduced amyloid beta levels, suggesting the hormone’s potential as a biomarker and therapeutic target for Alzheimer’s disease.

“Based on the protective effect of irisin in Alzheimer’s disease shown in animal and cell models, the goal of the present study was to investigate the levels of irisin in the biological fluids of a large cohort of patients biologically characterized according to the amyloid/tau/neurodegeneration (ATN) scheme of the National Institute on Aging–Alzheimer’s Association (NIA-AA),” Dr. Dicarlo and colleagues wrote. “We aimed to understand whether there may be variations of irisin levels across the disease stages, identified through the ATN system.”
 

Lower Levels of Irisin Seen in Patients With Alzheimer’s Disease

The study included 82 patients with Alzheimer’s disease, 44 individuals with mild cognitive impairment (MCI), and 20 with subjective memory complaints (SMC). Participants underwent comprehensive assessments, including neurological and neuropsychological exams, nutritional evaluations, MRI scans, and routine lab tests. Cognitive impairment severity was measured using the CDR-SOB and other metrics.

Blood and CSF samples were collected from all patients, the latter via lumbar puncture. These samples were analyzed for irisin levels and known Alzheimer’s disease biomarkers, including Abeta42, total tau (t-tau), and hyperphosphorylated tau (p-tau).

Mean CSF irisin levels were significantly lower among patients with Alzheimer’s disease than those with SMC (0.80 vs 1.23 pg/mL; P < .0001), and among those with MCI vs SMC (0.95 vs 1.23 pg/mL; P = .046). Among patients with Alzheimer’s disease, irisin levels were significantly lower among women than men (0.70 vs 0.96 pg/mL; P = .031).

Further analyses revealed positive correlations between CSF irisin level and Abeta42 in both males (r = 0.262; P < 005) and females (r = 0.379; P < .001). Conversely, in female patients, a significant negative correlation was found between CSF irisin level and CDR-SOB score (r = −0.234; P < .05).

Although a negative trend was observed between CSF irisin and total tau (t-tau) in the overall patient population (r = −0.144; P = 0.082), and more notably in female patients (r = −0.189; P = 0.084), these results were not statistically significant.

Plasma irisin levels were not significantly correlated with any of the other biomarkers.
 

Clinical Implications

This study “verifies that irisin levels do have a relationship to the Alzheimer’s disease process,” said Dylan Wint, MD, director of Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas.

In a written comment, Dr. Wint speculated that measuring irisin levels could theoretically help individualize physical exercise routines designed to combat cognitive decline.

“For example, maybe someone who is exercising but has a low irisin level would need to change the type of exercise they’re doing in order to optimally protect their brain health,” he said. “Or maybe they won’t get the same benefits for brain health as someone whose irisin shoots up every time they walk a flight of stairs.”

dowukidronesifrawrebrisevushuvaricofrishouejufrucraslibrispoclaweprivawadidespoduswupiwofrephibrocuwuthovatrukoshobavaphastedoslethudrivitriphatropapukiuidrebiprudiwaphiwawrekocledrudofrophidruphawrocrebrelutiwicliswocevastifrugo

It’s “near-impossible to tell,” however, if irisin will be employed in clinical trials or real-world practice, he added.

“I don’t see this being a highly useful serum biomarker for Alzheimer’s disease itself because other serum biomarkers are so far ahead and have more face validity,” Dr. Wint said.

The route of collection could also cause challenges.

“In the United States, CSF-based biomarkers can be a difficult sell, especially for serial testing,” Dr. Wint said. “But we have usable serum biomarkers for Alzheimer’s disease only because we have had CSF biomarkers against which to evaluate them. They may develop a way to evaluate this in the serum.”

Dr. Dicarlo and colleagues suggested that more work is needed to determine the ultimate value of irisin measurement.“The true ability of irisin to represent a biomarker of disease progression and severity remains to be further investigated,” they concluded. “However, our findings might offer interesting perspectives toward the potential role of irisin in the modulation of AD pathology and can guide the exploration of medication targeting the irisin system.”

The study was supported by Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione, CIREMIC, the University of Bari, and Next Generation EU. The investigators and Dr. Wint disclosed no conflicts of interest.

A new clinical practice guideline by the American Society for Radiation Oncology (ASTRO) steers use of external beam radiation therapy (EBRT) for the palliation of symptomatic bone metastases, including recommendations concerning pain management and quality of life.

The guideline was needed to update previous recommendations and incorporate new high-quality evidence for the management of symptomatic bone metastases, Sara Alcorn, MD, PhD, of the University of Minnesota, Minneapolis, and colleagues wrote in Practical Radiation Oncology.

The focus was on the efficacy of EBRT in reducing pain, improving skeletal function, and enhancing quality of life, they wrote in the clinical practice guideline.

In developing their recommendations, the ASTRO task force reviewed evidence from 53 randomized controlled trials (RCTs) and 31 nonrandomized studies, and considered clinical experience.
 

Indications for Palliative Radiation

EBRT is strongly recommended for reducing pain from osseous metastasis and improving ambulatory status, sphincter function, and reducing pain in patients with spinal metastases causing compression of the spinal cord or cauda equina.

For patients with symptomatic bone metastases and an anticipated life expectancy of at least 4 weeks, EBRT is conditionally recommended to improve quality of life.

Implementation of other Treatments Alongside Palliative Radiation

Instead of RT alone, surgery with postoperative RT is conditionally recommended for patients with compression of the spinal cord or cauda equina.

Postoperative RT is strongly recommended for patients who have undergone surgery for non-spine bone metastases or spine metastases without involving spinal cord or cauda equina compression.

For patients with spinal bone metastases compressing the spinal cord or cauda equina, combining RT with dexamethasone is strongly recommended over RT alone.

Techniques, Dose-Fractionation, and Dose-Constraints for Initial Palliative Radiation

For patients with symptomatic bone metastases undergoing conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 3000 cGy in 10 fractions.

For patients with spinal bone metastases causing compression of the spinal cord or cauda equina who are not candidates for initial surgical decompression and are treated with conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 1600 cGy in 2 fractions, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions.

When selecting dose-fractionation, consider patient and disease factors such as prognosis and radiosensitivity, the authors wrote.

Highly conformal planning and delivery techniques, such as intensity-modulated radiation therapy, are conditionally recommended for patients with spinal bone metastases compressing the spinal cord or cauda equina who are receiving dose-escalated palliative RT.

The strongly recommended stereotactic body radiotherapy (SBRT) doses for patients with symptomatic bone metastases are 1200 to 1600 cGy in 1 fraction for non-spine metastases and 2400 cGy in 2 fractions for spine metastases. Other established SBRT dose and fractionation regimens with similar biologically effective doses may be considered based on patient tumor characteristics, normal tissue factors, and physician experience.

For patients with symptomatic bone metastases who have an ECOG PS of 0-2, are not undergoing surgical intervention, and have no neurological symptoms, SBRT is conditionally recommended over conventional palliative RT. Other factors to consider include life expectancy, tumor radiosensitivity, and metastatic disease burden, the guideline says.
 

Techniques, Dose-Fractionation, and Dose-Constraints for Palliative Reirradiation

For patients with spinal bone metastases requiring reirradiation to the same site, the strongly recommended conventional palliative RT regimens are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 2000 cGy in 8 fractions. When determining the RT dose-fractionation, consider the prior RT dose, time interval, and total spinal cord tolerance, the guideline says.

Treatment with SBRT is conditionally recommended for patients with spinal bone metastases needing reirradiation at the same site. When determining if SBRT is appropriate, consider patient factors such as urgency of treatment, prognosis, and radio-resistance. In addition, consider the prior RT dose, time interval, and total spinal cord tolerance when determining the RT dose-fractionation, the authors say.

The strongly recommended options for patients with symptomatic non-spine bone metastases needing reirradiation at the same site are single-fraction RT (800 cGy in 1 fraction) or multifraction conventional palliative RT (2000 cGy in 5 fractions or 2400 cGy in 6 fractions).
 

Impact of Techniques and Dose-fractionation on Quality of Life and Toxicity

For patients with bone metastases undergoing palliative radiation, it is strongly recommended to use a shared decision-making approach to determine the dose, fractionation, and supportive measures to optimize quality of life.

“Based on published data, the ASTRO task force’s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases,” the guideline panelists said.

Limitations

While the guideline provides comprehensive recommendations, the panelists underscored the importance of individualized treatment approaches. Future research is needed to address gaps in evidence, particularly regarding advanced RT techniques and reirradiation strategies.

Guideline development was funded by ASTRO, with the systematic evidence review funded by the Patient-Centered Outcomes Research Institute. The panelists disclosed relationships with AstraZeneca, Elekta, Teladoc, and others.

A new clinical practice guideline by the American Society for Radiation Oncology (ASTRO) steers use of external beam radiation therapy (EBRT) for the palliation of symptomatic bone metastases, including recommendations concerning pain management and quality of life.

The guideline was needed to update previous recommendations and incorporate new high-quality evidence for the management of symptomatic bone metastases, Sara Alcorn, MD, PhD, of the University of Minnesota, Minneapolis, and colleagues wrote in Practical Radiation Oncology.

The focus was on the efficacy of EBRT in reducing pain, improving skeletal function, and enhancing quality of life, they wrote in the clinical practice guideline.

In developing their recommendations, the ASTRO task force reviewed evidence from 53 randomized controlled trials (RCTs) and 31 nonrandomized studies, and considered clinical experience.
 

Indications for Palliative Radiation

EBRT is strongly recommended for reducing pain from osseous metastasis and improving ambulatory status, sphincter function, and reducing pain in patients with spinal metastases causing compression of the spinal cord or cauda equina.

For patients with symptomatic bone metastases and an anticipated life expectancy of at least 4 weeks, EBRT is conditionally recommended to improve quality of life.

Implementation of other Treatments Alongside Palliative Radiation

Instead of RT alone, surgery with postoperative RT is conditionally recommended for patients with compression of the spinal cord or cauda equina.

Postoperative RT is strongly recommended for patients who have undergone surgery for non-spine bone metastases or spine metastases without involving spinal cord or cauda equina compression.

For patients with spinal bone metastases compressing the spinal cord or cauda equina, combining RT with dexamethasone is strongly recommended over RT alone.

Techniques, Dose-Fractionation, and Dose-Constraints for Initial Palliative Radiation

For patients with symptomatic bone metastases undergoing conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 3000 cGy in 10 fractions.

For patients with spinal bone metastases causing compression of the spinal cord or cauda equina who are not candidates for initial surgical decompression and are treated with conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 1600 cGy in 2 fractions, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions.

When selecting dose-fractionation, consider patient and disease factors such as prognosis and radiosensitivity, the authors wrote.

Highly conformal planning and delivery techniques, such as intensity-modulated radiation therapy, are conditionally recommended for patients with spinal bone metastases compressing the spinal cord or cauda equina who are receiving dose-escalated palliative RT.

The strongly recommended stereotactic body radiotherapy (SBRT) doses for patients with symptomatic bone metastases are 1200 to 1600 cGy in 1 fraction for non-spine metastases and 2400 cGy in 2 fractions for spine metastases. Other established SBRT dose and fractionation regimens with similar biologically effective doses may be considered based on patient tumor characteristics, normal tissue factors, and physician experience.

For patients with symptomatic bone metastases who have an ECOG PS of 0-2, are not undergoing surgical intervention, and have no neurological symptoms, SBRT is conditionally recommended over conventional palliative RT. Other factors to consider include life expectancy, tumor radiosensitivity, and metastatic disease burden, the guideline says.
 

Techniques, Dose-Fractionation, and Dose-Constraints for Palliative Reirradiation

For patients with spinal bone metastases requiring reirradiation to the same site, the strongly recommended conventional palliative RT regimens are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 2000 cGy in 8 fractions. When determining the RT dose-fractionation, consider the prior RT dose, time interval, and total spinal cord tolerance, the guideline says.

Treatment with SBRT is conditionally recommended for patients with spinal bone metastases needing reirradiation at the same site. When determining if SBRT is appropriate, consider patient factors such as urgency of treatment, prognosis, and radio-resistance. In addition, consider the prior RT dose, time interval, and total spinal cord tolerance when determining the RT dose-fractionation, the authors say.

The strongly recommended options for patients with symptomatic non-spine bone metastases needing reirradiation at the same site are single-fraction RT (800 cGy in 1 fraction) or multifraction conventional palliative RT (2000 cGy in 5 fractions or 2400 cGy in 6 fractions).
 

Impact of Techniques and Dose-fractionation on Quality of Life and Toxicity

For patients with bone metastases undergoing palliative radiation, it is strongly recommended to use a shared decision-making approach to determine the dose, fractionation, and supportive measures to optimize quality of life.

“Based on published data, the ASTRO task force’s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases,” the guideline panelists said.

Limitations

While the guideline provides comprehensive recommendations, the panelists underscored the importance of individualized treatment approaches. Future research is needed to address gaps in evidence, particularly regarding advanced RT techniques and reirradiation strategies.

Guideline development was funded by ASTRO, with the systematic evidence review funded by the Patient-Centered Outcomes Research Institute. The panelists disclosed relationships with AstraZeneca, Elekta, Teladoc, and others.

A new clinical practice guideline by the American Society for Radiation Oncology (ASTRO) steers use of external beam radiation therapy (EBRT) for the palliation of symptomatic bone metastases, including recommendations concerning pain management and quality of life.

The guideline was needed to update previous recommendations and incorporate new high-quality evidence for the management of symptomatic bone metastases, Sara Alcorn, MD, PhD, of the University of Minnesota, Minneapolis, and colleagues wrote in Practical Radiation Oncology.

The focus was on the efficacy of EBRT in reducing pain, improving skeletal function, and enhancing quality of life, they wrote in the clinical practice guideline.

In developing their recommendations, the ASTRO task force reviewed evidence from 53 randomized controlled trials (RCTs) and 31 nonrandomized studies, and considered clinical experience.
 

Indications for Palliative Radiation

EBRT is strongly recommended for reducing pain from osseous metastasis and improving ambulatory status, sphincter function, and reducing pain in patients with spinal metastases causing compression of the spinal cord or cauda equina.

For patients with symptomatic bone metastases and an anticipated life expectancy of at least 4 weeks, EBRT is conditionally recommended to improve quality of life.

Implementation of other Treatments Alongside Palliative Radiation

Instead of RT alone, surgery with postoperative RT is conditionally recommended for patients with compression of the spinal cord or cauda equina.

Postoperative RT is strongly recommended for patients who have undergone surgery for non-spine bone metastases or spine metastases without involving spinal cord or cauda equina compression.

For patients with spinal bone metastases compressing the spinal cord or cauda equina, combining RT with dexamethasone is strongly recommended over RT alone.

Techniques, Dose-Fractionation, and Dose-Constraints for Initial Palliative Radiation

For patients with symptomatic bone metastases undergoing conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 3000 cGy in 10 fractions.

For patients with spinal bone metastases causing compression of the spinal cord or cauda equina who are not candidates for initial surgical decompression and are treated with conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 1600 cGy in 2 fractions, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions.

When selecting dose-fractionation, consider patient and disease factors such as prognosis and radiosensitivity, the authors wrote.

Highly conformal planning and delivery techniques, such as intensity-modulated radiation therapy, are conditionally recommended for patients with spinal bone metastases compressing the spinal cord or cauda equina who are receiving dose-escalated palliative RT.

The strongly recommended stereotactic body radiotherapy (SBRT) doses for patients with symptomatic bone metastases are 1200 to 1600 cGy in 1 fraction for non-spine metastases and 2400 cGy in 2 fractions for spine metastases. Other established SBRT dose and fractionation regimens with similar biologically effective doses may be considered based on patient tumor characteristics, normal tissue factors, and physician experience.

For patients with symptomatic bone metastases who have an ECOG PS of 0-2, are not undergoing surgical intervention, and have no neurological symptoms, SBRT is conditionally recommended over conventional palliative RT. Other factors to consider include life expectancy, tumor radiosensitivity, and metastatic disease burden, the guideline says.
 

Techniques, Dose-Fractionation, and Dose-Constraints for Palliative Reirradiation

For patients with spinal bone metastases requiring reirradiation to the same site, the strongly recommended conventional palliative RT regimens are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 2000 cGy in 8 fractions. When determining the RT dose-fractionation, consider the prior RT dose, time interval, and total spinal cord tolerance, the guideline says.

Treatment with SBRT is conditionally recommended for patients with spinal bone metastases needing reirradiation at the same site. When determining if SBRT is appropriate, consider patient factors such as urgency of treatment, prognosis, and radio-resistance. In addition, consider the prior RT dose, time interval, and total spinal cord tolerance when determining the RT dose-fractionation, the authors say.

The strongly recommended options for patients with symptomatic non-spine bone metastases needing reirradiation at the same site are single-fraction RT (800 cGy in 1 fraction) or multifraction conventional palliative RT (2000 cGy in 5 fractions or 2400 cGy in 6 fractions).
 

Impact of Techniques and Dose-fractionation on Quality of Life and Toxicity

For patients with bone metastases undergoing palliative radiation, it is strongly recommended to use a shared decision-making approach to determine the dose, fractionation, and supportive measures to optimize quality of life.

“Based on published data, the ASTRO task force’s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases,” the guideline panelists said.

Limitations

While the guideline provides comprehensive recommendations, the panelists underscored the importance of individualized treatment approaches. Future research is needed to address gaps in evidence, particularly regarding advanced RT techniques and reirradiation strategies.

Guideline development was funded by ASTRO, with the systematic evidence review funded by the Patient-Centered Outcomes Research Institute. The panelists disclosed relationships with AstraZeneca, Elekta, Teladoc, and others.

TOPLINE:

A rapid recommendation update from the American Society of Clinical Oncology (ASCO) offers guidance on use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, abemaciclib and ribociclib, for the adjuvant treatment of stage II and III breast cancer.

METHODOLOGY:

• The guideline update was needed to incorporate new high-quality evidence for the adjuvant use of CDK4/6 inhibitors in early breast cancer.
• The ASCO guideline expert panel reviewed evidence from phase 3 trials, including the monarchE and NATALEE studies, focusing on the efficacy of abemaciclib and ribociclib in improving invasive disease-free survival (IDFS) and distant disease-free survival (DDFS).

TAKEAWAY:

• Abemaciclib for 2 years plus endocrine therapy (ET) for at least 5 years is recommended for patients with resected, hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, including those with at least four positive axillary lymph nodes (ALNs) or one to three positive ALNs plus additional high-risk features.
• Ribociclib (400 mg once daily, 3 weeks on, 1 week off) for 3 years plus ET is recommended for patients with stage II or III breast cancer who have a high risk of recurrence, based on the NATALEE trial.
• For patients meeting both monarchE and NATALEE criteria, abemaciclib is preferred due to longer follow-up, a deepening benefit over time, and FDA approval in the adjuvant setting.
• Ribociclib is recommended for patients who cannot tolerate abemaciclib due to contraindications such as high-grade diarrhea.
• Benefits, risks, costs, and individual patient preferences should be considered when deciding on adjuvant CDK4/6 inhibitor therapy.

IN PRACTICE:

This rapid recommendation update addresses the adjuvant use of CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer.

SOURCE:

The clinical practice guideline update, led by Rachel A. Freedman, from Dana-Farber Cancer Institute, Boston, was published in the Journal of Clinical Oncology.

LIMITATIONS:

The guideline panelists noted that the clinical benefits of adjuvant CDK4/6 inhibitor therapy may not extend to all patients eligible for the trials, particularly those at lower risk. There are insufficient data to specify which subgroups of patients may not warrant therapy, emphasizing the need for individualized treatment decisions. More data are needed to provide long-term efficacy data and more detailed guidance on which specific patient populations will benefit most from adjuvant CDK4/6 inhibitor therapy.

DISCLOSURES:

Guideline development was funded by the American Society of Clinical Oncology (ASCO). The panelists disclosed relationships with Firefly Health, Eisai, Novartis, and others.

TOPLINE:

A rapid recommendation update from the American Society of Clinical Oncology (ASCO) offers guidance on use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, abemaciclib and ribociclib, for the adjuvant treatment of stage II and III breast cancer.

METHODOLOGY:

• The guideline update was needed to incorporate new high-quality evidence for the adjuvant use of CDK4/6 inhibitors in early breast cancer.
• The ASCO guideline expert panel reviewed evidence from phase 3 trials, including the monarchE and NATALEE studies, focusing on the efficacy of abemaciclib and ribociclib in improving invasive disease-free survival (IDFS) and distant disease-free survival (DDFS).

TAKEAWAY:

• Abemaciclib for 2 years plus endocrine therapy (ET) for at least 5 years is recommended for patients with resected, hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, including those with at least four positive axillary lymph nodes (ALNs) or one to three positive ALNs plus additional high-risk features.
• Ribociclib (400 mg once daily, 3 weeks on, 1 week off) for 3 years plus ET is recommended for patients with stage II or III breast cancer who have a high risk of recurrence, based on the NATALEE trial.
• For patients meeting both monarchE and NATALEE criteria, abemaciclib is preferred due to longer follow-up, a deepening benefit over time, and FDA approval in the adjuvant setting.
• Ribociclib is recommended for patients who cannot tolerate abemaciclib due to contraindications such as high-grade diarrhea.
• Benefits, risks, costs, and individual patient preferences should be considered when deciding on adjuvant CDK4/6 inhibitor therapy.

IN PRACTICE:

This rapid recommendation update addresses the adjuvant use of CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer.

SOURCE:

The clinical practice guideline update, led by Rachel A. Freedman, from Dana-Farber Cancer Institute, Boston, was published in the Journal of Clinical Oncology.

LIMITATIONS:

The guideline panelists noted that the clinical benefits of adjuvant CDK4/6 inhibitor therapy may not extend to all patients eligible for the trials, particularly those at lower risk. There are insufficient data to specify which subgroups of patients may not warrant therapy, emphasizing the need for individualized treatment decisions. More data are needed to provide long-term efficacy data and more detailed guidance on which specific patient populations will benefit most from adjuvant CDK4/6 inhibitor therapy.

DISCLOSURES:

Guideline development was funded by the American Society of Clinical Oncology (ASCO). The panelists disclosed relationships with Firefly Health, Eisai, Novartis, and others.

TOPLINE:

A rapid recommendation update from the American Society of Clinical Oncology (ASCO) offers guidance on use of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, abemaciclib and ribociclib, for the adjuvant treatment of stage II and III breast cancer.

METHODOLOGY:

• The guideline update was needed to incorporate new high-quality evidence for the adjuvant use of CDK4/6 inhibitors in early breast cancer.
• The ASCO guideline expert panel reviewed evidence from phase 3 trials, including the monarchE and NATALEE studies, focusing on the efficacy of abemaciclib and ribociclib in improving invasive disease-free survival (IDFS) and distant disease-free survival (DDFS).

TAKEAWAY:

• Abemaciclib for 2 years plus endocrine therapy (ET) for at least 5 years is recommended for patients with resected, hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, including those with at least four positive axillary lymph nodes (ALNs) or one to three positive ALNs plus additional high-risk features.
• Ribociclib (400 mg once daily, 3 weeks on, 1 week off) for 3 years plus ET is recommended for patients with stage II or III breast cancer who have a high risk of recurrence, based on the NATALEE trial.
• For patients meeting both monarchE and NATALEE criteria, abemaciclib is preferred due to longer follow-up, a deepening benefit over time, and FDA approval in the adjuvant setting.
• Ribociclib is recommended for patients who cannot tolerate abemaciclib due to contraindications such as high-grade diarrhea.
• Benefits, risks, costs, and individual patient preferences should be considered when deciding on adjuvant CDK4/6 inhibitor therapy.

IN PRACTICE:

This rapid recommendation update addresses the adjuvant use of CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer.

SOURCE:

The clinical practice guideline update, led by Rachel A. Freedman, from Dana-Farber Cancer Institute, Boston, was published in the Journal of Clinical Oncology.

LIMITATIONS:

The guideline panelists noted that the clinical benefits of adjuvant CDK4/6 inhibitor therapy may not extend to all patients eligible for the trials, particularly those at lower risk. There are insufficient data to specify which subgroups of patients may not warrant therapy, emphasizing the need for individualized treatment decisions. More data are needed to provide long-term efficacy data and more detailed guidance on which specific patient populations will benefit most from adjuvant CDK4/6 inhibitor therapy.

DISCLOSURES:

Guideline development was funded by the American Society of Clinical Oncology (ASCO). The panelists disclosed relationships with Firefly Health, Eisai, Novartis, and others.

Adjuvant therapy with aspirin offers no protection against recurrence or survival benefit in patients with high-risk nonmetastatic breast cancer, the results of a new phase 3 randomized controlled trial suggest.

These data are more robust than the efficacy signals from previous studies, meaning healthcare providers should not recommend aspirin as adjuvant therapy for breast cancer, reported lead author Wendy Y. Chen, MD, of Dana Farber Cancer Institute, Boston, and colleagues.

What Data Support Aspirin for Treating Breast Cancer?

“Multiple observational studies have reported a decreased risk of death among survivors of breast cancer who were regular aspirin users,” the investigators wrote in JAMA. “Even more compelling were data from randomized trials of aspirin for cardiovascular disease.”

This possible benefit was reported with mechanistic support, as aspirin’s anti-inflammatory and anti-platelet properties could theoretically control tumor growth, they added. Furthermore, aspirin impacts several cancer pathways currently targeted by agents approved by the US Food and Drug Administration (FDA).

Chen_Wendy_BOSTON_web.jpg

What Were The Key Findings From The A011502 Trial?

The A011502 trial enrolled 3,020 patients aged 18-70 years with ERBB2-negative breast cancer who had received standard therapy via routine clinical care. Eligibility required that chemotherapy and local therapy were complete, but ongoing endocrine therapy was allowed.

Participants were randomized in a 1:1 ratio to receive aspirin 300 mg per day or matching placebo for 5 years. The primary outcome was invasive disease-free survival, and the key secondary outcome was overall survival.

After a median follow-up of almost 3 years, at the first interim analysis, the study was suspended early due to statistical futility. By that timepoint, 253 invasive disease-free survival events occurred, of which 141 occurred in the aspirin group, compared with 112 in the placebo group, providing a hazard ratio of 1.27 (95% CI, 0.99-1.63) that was not statistically significant  (P = .06). No statistically significant difference in overall survival was observed (hazard ratio, 1.19; 95% CI, 0.82-1.72). Safety profiles were similar across groups.

How Will This Study Change Practice?

In an accompanying editorial, Jeanne S. Mandelblatt, MD, of Georgetown Lombardi Institute for Cancer and Aging Research, Washington, and colleagues, praised the trial for its comprehensive approach, but they predicted that the negative result could spell friction for health care providers.

“[C]linicians may find it challenging to communicate with their patients about the negative result in the Alliance trial, because prior lay press articles, observational studies, and meta-analyses of cardiovascular trials suggested that aspirin may decrease breast cancer recurrence,” they wrote.

Mandelblatt_Jeanne_DC_web.jpg

How Might the Findings From the A011502 Trial Impact Future Research?

Finally, and “most critically,” the editorialists raised concerns about health equity, noting the limited diversity in trial participants and the potential exclusion of subgroups that might benefit from aspirin use, particularly those more likely to experience accelerated biological aging and disparities in cancer risk and outcomes due to systemic racism or adverse social determinants of health.

They concluded by emphasizing the need to consider the intersectionality of aging, cancer, and disparities in designing future trials to advance health equity.

This study was funded by the Department of Defense Breast Cancer Research Program and the National Cancer Institute of the National Institutes of Health. The research was also supported in part by Bayer, which provided the study drug. The investigators disclosed relationships with Novartis, Seagen, Orum Clinical, and others. The editorialists disclosed relationships with Cantex Pharmaceuticals, and Pfizer.

Adjuvant therapy with aspirin offers no protection against recurrence or survival benefit in patients with high-risk nonmetastatic breast cancer, the results of a new phase 3 randomized controlled trial suggest.

These data are more robust than the efficacy signals from previous studies, meaning healthcare providers should not recommend aspirin as adjuvant therapy for breast cancer, reported lead author Wendy Y. Chen, MD, of Dana Farber Cancer Institute, Boston, and colleagues.

What Data Support Aspirin for Treating Breast Cancer?

“Multiple observational studies have reported a decreased risk of death among survivors of breast cancer who were regular aspirin users,” the investigators wrote in JAMA. “Even more compelling were data from randomized trials of aspirin for cardiovascular disease.”

This possible benefit was reported with mechanistic support, as aspirin’s anti-inflammatory and anti-platelet properties could theoretically control tumor growth, they added. Furthermore, aspirin impacts several cancer pathways currently targeted by agents approved by the US Food and Drug Administration (FDA).

Chen_Wendy_BOSTON_web.jpg

What Were The Key Findings From The A011502 Trial?

The A011502 trial enrolled 3,020 patients aged 18-70 years with ERBB2-negative breast cancer who had received standard therapy via routine clinical care. Eligibility required that chemotherapy and local therapy were complete, but ongoing endocrine therapy was allowed.

Participants were randomized in a 1:1 ratio to receive aspirin 300 mg per day or matching placebo for 5 years. The primary outcome was invasive disease-free survival, and the key secondary outcome was overall survival.

After a median follow-up of almost 3 years, at the first interim analysis, the study was suspended early due to statistical futility. By that timepoint, 253 invasive disease-free survival events occurred, of which 141 occurred in the aspirin group, compared with 112 in the placebo group, providing a hazard ratio of 1.27 (95% CI, 0.99-1.63) that was not statistically significant  (P = .06). No statistically significant difference in overall survival was observed (hazard ratio, 1.19; 95% CI, 0.82-1.72). Safety profiles were similar across groups.

How Will This Study Change Practice?

In an accompanying editorial, Jeanne S. Mandelblatt, MD, of Georgetown Lombardi Institute for Cancer and Aging Research, Washington, and colleagues, praised the trial for its comprehensive approach, but they predicted that the negative result could spell friction for health care providers.

“[C]linicians may find it challenging to communicate with their patients about the negative result in the Alliance trial, because prior lay press articles, observational studies, and meta-analyses of cardiovascular trials suggested that aspirin may decrease breast cancer recurrence,” they wrote.

Mandelblatt_Jeanne_DC_web.jpg

How Might the Findings From the A011502 Trial Impact Future Research?

Finally, and “most critically,” the editorialists raised concerns about health equity, noting the limited diversity in trial participants and the potential exclusion of subgroups that might benefit from aspirin use, particularly those more likely to experience accelerated biological aging and disparities in cancer risk and outcomes due to systemic racism or adverse social determinants of health.

They concluded by emphasizing the need to consider the intersectionality of aging, cancer, and disparities in designing future trials to advance health equity.

This study was funded by the Department of Defense Breast Cancer Research Program and the National Cancer Institute of the National Institutes of Health. The research was also supported in part by Bayer, which provided the study drug. The investigators disclosed relationships with Novartis, Seagen, Orum Clinical, and others. The editorialists disclosed relationships with Cantex Pharmaceuticals, and Pfizer.

Adjuvant therapy with aspirin offers no protection against recurrence or survival benefit in patients with high-risk nonmetastatic breast cancer, the results of a new phase 3 randomized controlled trial suggest.

These data are more robust than the efficacy signals from previous studies, meaning healthcare providers should not recommend aspirin as adjuvant therapy for breast cancer, reported lead author Wendy Y. Chen, MD, of Dana Farber Cancer Institute, Boston, and colleagues.

What Data Support Aspirin for Treating Breast Cancer?

“Multiple observational studies have reported a decreased risk of death among survivors of breast cancer who were regular aspirin users,” the investigators wrote in JAMA. “Even more compelling were data from randomized trials of aspirin for cardiovascular disease.”

This possible benefit was reported with mechanistic support, as aspirin’s anti-inflammatory and anti-platelet properties could theoretically control tumor growth, they added. Furthermore, aspirin impacts several cancer pathways currently targeted by agents approved by the US Food and Drug Administration (FDA).

Chen_Wendy_BOSTON_web.jpg

What Were The Key Findings From The A011502 Trial?

The A011502 trial enrolled 3,020 patients aged 18-70 years with ERBB2-negative breast cancer who had received standard therapy via routine clinical care. Eligibility required that chemotherapy and local therapy were complete, but ongoing endocrine therapy was allowed.

Participants were randomized in a 1:1 ratio to receive aspirin 300 mg per day or matching placebo for 5 years. The primary outcome was invasive disease-free survival, and the key secondary outcome was overall survival.

After a median follow-up of almost 3 years, at the first interim analysis, the study was suspended early due to statistical futility. By that timepoint, 253 invasive disease-free survival events occurred, of which 141 occurred in the aspirin group, compared with 112 in the placebo group, providing a hazard ratio of 1.27 (95% CI, 0.99-1.63) that was not statistically significant  (P = .06). No statistically significant difference in overall survival was observed (hazard ratio, 1.19; 95% CI, 0.82-1.72). Safety profiles were similar across groups.

How Will This Study Change Practice?

In an accompanying editorial, Jeanne S. Mandelblatt, MD, of Georgetown Lombardi Institute for Cancer and Aging Research, Washington, and colleagues, praised the trial for its comprehensive approach, but they predicted that the negative result could spell friction for health care providers.

“[C]linicians may find it challenging to communicate with their patients about the negative result in the Alliance trial, because prior lay press articles, observational studies, and meta-analyses of cardiovascular trials suggested that aspirin may decrease breast cancer recurrence,” they wrote.

Mandelblatt_Jeanne_DC_web.jpg

How Might the Findings From the A011502 Trial Impact Future Research?

Finally, and “most critically,” the editorialists raised concerns about health equity, noting the limited diversity in trial participants and the potential exclusion of subgroups that might benefit from aspirin use, particularly those more likely to experience accelerated biological aging and disparities in cancer risk and outcomes due to systemic racism or adverse social determinants of health.

They concluded by emphasizing the need to consider the intersectionality of aging, cancer, and disparities in designing future trials to advance health equity.

This study was funded by the Department of Defense Breast Cancer Research Program and the National Cancer Institute of the National Institutes of Health. The research was also supported in part by Bayer, which provided the study drug. The investigators disclosed relationships with Novartis, Seagen, Orum Clinical, and others. The editorialists disclosed relationships with Cantex Pharmaceuticals, and Pfizer.

A new American Gastroenterological Association (AGA) clinical practice update shines a light on cannabinoid hyperemesis syndrome (CHS).

CHS, which is triggered by chronic cannabis usage and manifests with GI and autonomic symptoms, is on the rise in the United States, yet underdiagnosis remains a challenge and clinical data are scarce, reported lead update panelist Alberto Rubio Tapia, MD, of Cleveland Clinic, Cleveland, Ohio, and colleagues.

RubioTapia_Alberto_OH_web.jpg

“Although cannabis use has been reported for many decades, some of its unique adverse effects of nausea, vomiting, and abdominal pain, termed CHS, were noted relatively recently,” the panelists wrote in Gastroenterology. “The objective of this article was to help practitioners define the appropriate approach to the diagnosis and management of CHS.”

According to the update, the typical CHS patient is male with a years-long history of daily or near-daily cannabis use. Paradoxically, while cannabis use drives this condition, some patients with CHS report that cannabis use relieves their symptoms.The update describes CHS as a subtype of cyclical vomiting syndrome (CVS), and offers diagnostic criteria for CHS, reproduced below verbatim:

• Clinical features: stereotypical episodic vomiting resembling CVS in terms of onset, with frequency 3 or more times annually;
• Cannabis use patterns: duration of cannabis use more than 1 year before symptom onset; frequency more than 4 times per week, on average;
• Cannabis cessation: resolution of symptoms after a period of abstinence from cannabis use for at least 6 months, or at least equal to the total duration of 3 typical vomiting cycles in that patient.

As CHS is a subtype of CVS, the update also provides an outline and management guide for this broader condition, which is characterized by four phases: inter-episodic, prodromal, emetic, and recovery.

During the inter-episodic phase, patients will have minimal or no symptoms, although almost one third will describe dyspepsia or nausea. Prophylactic medications in this period include tricyclics, mitochondrial supplements like CoQ10 and vitamin B12, NK1 antagonists, and anticonvulsants.

The prodromal phase is characterized by abdominal pain and nausea with a duration of 30-90 minutes. During this time patients may have autonomic symptoms like sweating and feeling hot or cold. Psychological symptoms may include feelings of panic and being “out of control.” Abortive medications are appropriate during this period, according to the update, like triptans and antiemetics.

Next comes the emetic phase, in which patients exhibit “relentless vomiting,” retching, abdominal pain, neurological symptoms and extreme thirst. Because an empty stomach may provide relief, inducing emesis may be considered, along with rest in a quiet dark room and supportive care.

Finally, the vomiting subsides during the recovery phase, when it is possible to restart oral intake and resume normal activities.

While this framework may be useful when managing patients with CHS, intervention should be centered around cannabis cessation, according to the update.

“For long-term management, counseling to achieve marijuana cessation and tricyclic antidepressants, such as amitriptyline, are the mainstay of therapy,” Dr. Rubio Tapia and colleagues wrote.

Advising patients to stop cannabis “cold turkey” is not recommended, they added, as this may bring on withdrawal symptoms, and it tends to be ineffective in this population, which has a high recidivism rate.

“Co-management with a psychologist or psychiatrist may be helpful for patients who have a lack of response to standard therapies or extensive psychiatric comorbidity,” the panelists wrote. “Anxiety and depression are very common associated conditions.”

Dr. Rubio Tapia and colleagues concluded with a call for more research.

“Further understanding of CHS pathophysiology and evidence-based therapies are urgently needed,” they wrote.

This update was commissioned and approved by the AGA. The update panelists disclosed relationships with Evoke Pharma, RedHill Biopharma, Takeda, and others.

A new American Gastroenterological Association (AGA) clinical practice update shines a light on cannabinoid hyperemesis syndrome (CHS).

CHS, which is triggered by chronic cannabis usage and manifests with GI and autonomic symptoms, is on the rise in the United States, yet underdiagnosis remains a challenge and clinical data are scarce, reported lead update panelist Alberto Rubio Tapia, MD, of Cleveland Clinic, Cleveland, Ohio, and colleagues.

RubioTapia_Alberto_OH_web.jpg

“Although cannabis use has been reported for many decades, some of its unique adverse effects of nausea, vomiting, and abdominal pain, termed CHS, were noted relatively recently,” the panelists wrote in Gastroenterology. “The objective of this article was to help practitioners define the appropriate approach to the diagnosis and management of CHS.”

According to the update, the typical CHS patient is male with a years-long history of daily or near-daily cannabis use. Paradoxically, while cannabis use drives this condition, some patients with CHS report that cannabis use relieves their symptoms.The update describes CHS as a subtype of cyclical vomiting syndrome (CVS), and offers diagnostic criteria for CHS, reproduced below verbatim:

• Clinical features: stereotypical episodic vomiting resembling CVS in terms of onset, with frequency 3 or more times annually;
• Cannabis use patterns: duration of cannabis use more than 1 year before symptom onset; frequency more than 4 times per week, on average;
• Cannabis cessation: resolution of symptoms after a period of abstinence from cannabis use for at least 6 months, or at least equal to the total duration of 3 typical vomiting cycles in that patient.

As CHS is a subtype of CVS, the update also provides an outline and management guide for this broader condition, which is characterized by four phases: inter-episodic, prodromal, emetic, and recovery.

During the inter-episodic phase, patients will have minimal or no symptoms, although almost one third will describe dyspepsia or nausea. Prophylactic medications in this period include tricyclics, mitochondrial supplements like CoQ10 and vitamin B12, NK1 antagonists, and anticonvulsants.

The prodromal phase is characterized by abdominal pain and nausea with a duration of 30-90 minutes. During this time patients may have autonomic symptoms like sweating and feeling hot or cold. Psychological symptoms may include feelings of panic and being “out of control.” Abortive medications are appropriate during this period, according to the update, like triptans and antiemetics.

Next comes the emetic phase, in which patients exhibit “relentless vomiting,” retching, abdominal pain, neurological symptoms and extreme thirst. Because an empty stomach may provide relief, inducing emesis may be considered, along with rest in a quiet dark room and supportive care.

Finally, the vomiting subsides during the recovery phase, when it is possible to restart oral intake and resume normal activities.

While this framework may be useful when managing patients with CHS, intervention should be centered around cannabis cessation, according to the update.

“For long-term management, counseling to achieve marijuana cessation and tricyclic antidepressants, such as amitriptyline, are the mainstay of therapy,” Dr. Rubio Tapia and colleagues wrote.

Advising patients to stop cannabis “cold turkey” is not recommended, they added, as this may bring on withdrawal symptoms, and it tends to be ineffective in this population, which has a high recidivism rate.

“Co-management with a psychologist or psychiatrist may be helpful for patients who have a lack of response to standard therapies or extensive psychiatric comorbidity,” the panelists wrote. “Anxiety and depression are very common associated conditions.”

Dr. Rubio Tapia and colleagues concluded with a call for more research.

“Further understanding of CHS pathophysiology and evidence-based therapies are urgently needed,” they wrote.

This update was commissioned and approved by the AGA. The update panelists disclosed relationships with Evoke Pharma, RedHill Biopharma, Takeda, and others.

A new American Gastroenterological Association (AGA) clinical practice update shines a light on cannabinoid hyperemesis syndrome (CHS).

CHS, which is triggered by chronic cannabis usage and manifests with GI and autonomic symptoms, is on the rise in the United States, yet underdiagnosis remains a challenge and clinical data are scarce, reported lead update panelist Alberto Rubio Tapia, MD, of Cleveland Clinic, Cleveland, Ohio, and colleagues.

RubioTapia_Alberto_OH_web.jpg

“Although cannabis use has been reported for many decades, some of its unique adverse effects of nausea, vomiting, and abdominal pain, termed CHS, were noted relatively recently,” the panelists wrote in Gastroenterology. “The objective of this article was to help practitioners define the appropriate approach to the diagnosis and management of CHS.”

According to the update, the typical CHS patient is male with a years-long history of daily or near-daily cannabis use. Paradoxically, while cannabis use drives this condition, some patients with CHS report that cannabis use relieves their symptoms.The update describes CHS as a subtype of cyclical vomiting syndrome (CVS), and offers diagnostic criteria for CHS, reproduced below verbatim:

• Clinical features: stereotypical episodic vomiting resembling CVS in terms of onset, with frequency 3 or more times annually;
• Cannabis use patterns: duration of cannabis use more than 1 year before symptom onset; frequency more than 4 times per week, on average;
• Cannabis cessation: resolution of symptoms after a period of abstinence from cannabis use for at least 6 months, or at least equal to the total duration of 3 typical vomiting cycles in that patient.

As CHS is a subtype of CVS, the update also provides an outline and management guide for this broader condition, which is characterized by four phases: inter-episodic, prodromal, emetic, and recovery.

During the inter-episodic phase, patients will have minimal or no symptoms, although almost one third will describe dyspepsia or nausea. Prophylactic medications in this period include tricyclics, mitochondrial supplements like CoQ10 and vitamin B12, NK1 antagonists, and anticonvulsants.

The prodromal phase is characterized by abdominal pain and nausea with a duration of 30-90 minutes. During this time patients may have autonomic symptoms like sweating and feeling hot or cold. Psychological symptoms may include feelings of panic and being “out of control.” Abortive medications are appropriate during this period, according to the update, like triptans and antiemetics.

Next comes the emetic phase, in which patients exhibit “relentless vomiting,” retching, abdominal pain, neurological symptoms and extreme thirst. Because an empty stomach may provide relief, inducing emesis may be considered, along with rest in a quiet dark room and supportive care.

Finally, the vomiting subsides during the recovery phase, when it is possible to restart oral intake and resume normal activities.

While this framework may be useful when managing patients with CHS, intervention should be centered around cannabis cessation, according to the update.

“For long-term management, counseling to achieve marijuana cessation and tricyclic antidepressants, such as amitriptyline, are the mainstay of therapy,” Dr. Rubio Tapia and colleagues wrote.

Advising patients to stop cannabis “cold turkey” is not recommended, they added, as this may bring on withdrawal symptoms, and it tends to be ineffective in this population, which has a high recidivism rate.

“Co-management with a psychologist or psychiatrist may be helpful for patients who have a lack of response to standard therapies or extensive psychiatric comorbidity,” the panelists wrote. “Anxiety and depression are very common associated conditions.”

Dr. Rubio Tapia and colleagues concluded with a call for more research.

“Further understanding of CHS pathophysiology and evidence-based therapies are urgently needed,” they wrote.

This update was commissioned and approved by the AGA. The update panelists disclosed relationships with Evoke Pharma, RedHill Biopharma, Takeda, and others.

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–targeting therapies still hold promise for treating cholangiocarcinoma (CCA) despite disappointing results in previous preclinical research, primarily due to the adaptive resistance and unexpected immune modulation, according to investigators.

Those prior studies evaluated a combination of immunotherapy and TRAIL agonism, but selective TRAIL antagonism shows greater potential via dual ligand/receptor (TRAIL/TRAIL-R) targeting to block immunosuppression, reported lead author Emilien J. Loeuillard, PhD, of Mayo Clinic, Rochester, Minnesota, and colleagues.

Loeuillard_Emilien_MN_web.jpg

“The TRAIL/TRAIL-R system has garnered considerable interest in cancer biology, especially as a potential anticancer therapy,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “However, TRAIL-R agonists have had very limited anticancer activity in human beings, challenging this concept of TRAIL as an anticancer agent.”

This may be because they were working in the wrong direction, Dr. Loeuillard and colleagues suggested, citing recent work linking TRAIL with tumor proliferation and invasion, possibly via modification of the tumor immune microenvironment.

Exact mechanisms of modification, however, remain unclear. While TRAIL has been associated with tumor-promoting effects like induction of a promyeloid secretome in adenocarcinoma, it has also been linked with anticancer effects like activation of natural killer cells and cytotoxic T lymphocytes.

“Thus, the potency and hierarchy of TRAIL anticancer vs procancer processes in cancer biology has yet to be defined,” the investigators wrote.

While TRAIL ligation of cognate receptors has been previously investigated and shown to trigger proapoptotic signaling pathways, noncanonical TRAIL-mediated signaling remains largely unexplored, particularly in CCA.

The present study evaluated TRAIL biology in CCA using immunocompetent mouse models.

These experiments showed that noncanonical TRAIL signaling immunosuppresses the tumor microenvironment by increasing quantity and activity of myeloid-derived suppressor cells (MDSCs). Blocking noncanonical TRAIL signaling by selective deletion of TRAIL-R in immune cells had significantly reduced tumor volumes alongside fewer MDSCs, driven by FLICE inhibitory protein (cFLIP)-dependent nuclear factor kappa-B activation (NF-kappa-B) in MDSCs, which has antiapoptotic activity. While MDSCs present one possible target in this chain of immunosuppression, “therapeutic strategies for targeting MDSCs are limited,” the investigators wrote, noting that available myeloid modulators have fallen short in clinical trials.

Instead, cFLIP may be a convincing option, they suggested, as targeting cFLIP can sensitize cancer cells to proapoptotic TRAIL signaling. What’s more, cFLIP appears to protect MDSCs from TRAIL-mediated apoptosis, so taking out this barrier could render MDSCs susceptible to therapy.

“Our studies suggest that switching prosurvival/proliferation TRAIL signaling to canonical proapoptotic TRAIL signaling will promote MDSC apoptosis, which in turn has therapeutic implications for CCA suppression,” the investigators wrote.

Hope therefore remains for targeting TRAIL in patients with CCA, but with selective antagonism instead of agonism, as previously attempted.

“In summary, our findings support the role of selective therapeutic targeting of TRAIL-positive cancer cells in an effort to block TRAIL/TRAIL-R–mediated tumor immunosuppression,” Dr. Loeuillard and colleagues concluded.

This study was funded by the Cholangiocarcinoma Foundation and the Mayo Clinic Eagles 5th District Cancer Telethon Funds for Research Fellowship Program, the CTSA/National Center for Advancing Translational Science, the National Institutes of Health/National Cancer Institute, and others. The investigators disclosed no conflicts of interest.

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–targeting therapies still hold promise for treating cholangiocarcinoma (CCA) despite disappointing results in previous preclinical research, primarily due to the adaptive resistance and unexpected immune modulation, according to investigators.

Those prior studies evaluated a combination of immunotherapy and TRAIL agonism, but selective TRAIL antagonism shows greater potential via dual ligand/receptor (TRAIL/TRAIL-R) targeting to block immunosuppression, reported lead author Emilien J. Loeuillard, PhD, of Mayo Clinic, Rochester, Minnesota, and colleagues.

Loeuillard_Emilien_MN_web.jpg

“The TRAIL/TRAIL-R system has garnered considerable interest in cancer biology, especially as a potential anticancer therapy,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “However, TRAIL-R agonists have had very limited anticancer activity in human beings, challenging this concept of TRAIL as an anticancer agent.”

This may be because they were working in the wrong direction, Dr. Loeuillard and colleagues suggested, citing recent work linking TRAIL with tumor proliferation and invasion, possibly via modification of the tumor immune microenvironment.

Exact mechanisms of modification, however, remain unclear. While TRAIL has been associated with tumor-promoting effects like induction of a promyeloid secretome in adenocarcinoma, it has also been linked with anticancer effects like activation of natural killer cells and cytotoxic T lymphocytes.

“Thus, the potency and hierarchy of TRAIL anticancer vs procancer processes in cancer biology has yet to be defined,” the investigators wrote.

While TRAIL ligation of cognate receptors has been previously investigated and shown to trigger proapoptotic signaling pathways, noncanonical TRAIL-mediated signaling remains largely unexplored, particularly in CCA.

The present study evaluated TRAIL biology in CCA using immunocompetent mouse models.

These experiments showed that noncanonical TRAIL signaling immunosuppresses the tumor microenvironment by increasing quantity and activity of myeloid-derived suppressor cells (MDSCs). Blocking noncanonical TRAIL signaling by selective deletion of TRAIL-R in immune cells had significantly reduced tumor volumes alongside fewer MDSCs, driven by FLICE inhibitory protein (cFLIP)-dependent nuclear factor kappa-B activation (NF-kappa-B) in MDSCs, which has antiapoptotic activity. While MDSCs present one possible target in this chain of immunosuppression, “therapeutic strategies for targeting MDSCs are limited,” the investigators wrote, noting that available myeloid modulators have fallen short in clinical trials.

Instead, cFLIP may be a convincing option, they suggested, as targeting cFLIP can sensitize cancer cells to proapoptotic TRAIL signaling. What’s more, cFLIP appears to protect MDSCs from TRAIL-mediated apoptosis, so taking out this barrier could render MDSCs susceptible to therapy.

“Our studies suggest that switching prosurvival/proliferation TRAIL signaling to canonical proapoptotic TRAIL signaling will promote MDSC apoptosis, which in turn has therapeutic implications for CCA suppression,” the investigators wrote.

Hope therefore remains for targeting TRAIL in patients with CCA, but with selective antagonism instead of agonism, as previously attempted.

“In summary, our findings support the role of selective therapeutic targeting of TRAIL-positive cancer cells in an effort to block TRAIL/TRAIL-R–mediated tumor immunosuppression,” Dr. Loeuillard and colleagues concluded.

This study was funded by the Cholangiocarcinoma Foundation and the Mayo Clinic Eagles 5th District Cancer Telethon Funds for Research Fellowship Program, the CTSA/National Center for Advancing Translational Science, the National Institutes of Health/National Cancer Institute, and others. The investigators disclosed no conflicts of interest.

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL)–targeting therapies still hold promise for treating cholangiocarcinoma (CCA) despite disappointing results in previous preclinical research, primarily due to the adaptive resistance and unexpected immune modulation, according to investigators.

Those prior studies evaluated a combination of immunotherapy and TRAIL agonism, but selective TRAIL antagonism shows greater potential via dual ligand/receptor (TRAIL/TRAIL-R) targeting to block immunosuppression, reported lead author Emilien J. Loeuillard, PhD, of Mayo Clinic, Rochester, Minnesota, and colleagues.

Loeuillard_Emilien_MN_web.jpg

“The TRAIL/TRAIL-R system has garnered considerable interest in cancer biology, especially as a potential anticancer therapy,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “However, TRAIL-R agonists have had very limited anticancer activity in human beings, challenging this concept of TRAIL as an anticancer agent.”

This may be because they were working in the wrong direction, Dr. Loeuillard and colleagues suggested, citing recent work linking TRAIL with tumor proliferation and invasion, possibly via modification of the tumor immune microenvironment.

Exact mechanisms of modification, however, remain unclear. While TRAIL has been associated with tumor-promoting effects like induction of a promyeloid secretome in adenocarcinoma, it has also been linked with anticancer effects like activation of natural killer cells and cytotoxic T lymphocytes.

“Thus, the potency and hierarchy of TRAIL anticancer vs procancer processes in cancer biology has yet to be defined,” the investigators wrote.

While TRAIL ligation of cognate receptors has been previously investigated and shown to trigger proapoptotic signaling pathways, noncanonical TRAIL-mediated signaling remains largely unexplored, particularly in CCA.

The present study evaluated TRAIL biology in CCA using immunocompetent mouse models.

These experiments showed that noncanonical TRAIL signaling immunosuppresses the tumor microenvironment by increasing quantity and activity of myeloid-derived suppressor cells (MDSCs). Blocking noncanonical TRAIL signaling by selective deletion of TRAIL-R in immune cells had significantly reduced tumor volumes alongside fewer MDSCs, driven by FLICE inhibitory protein (cFLIP)-dependent nuclear factor kappa-B activation (NF-kappa-B) in MDSCs, which has antiapoptotic activity. While MDSCs present one possible target in this chain of immunosuppression, “therapeutic strategies for targeting MDSCs are limited,” the investigators wrote, noting that available myeloid modulators have fallen short in clinical trials.

Instead, cFLIP may be a convincing option, they suggested, as targeting cFLIP can sensitize cancer cells to proapoptotic TRAIL signaling. What’s more, cFLIP appears to protect MDSCs from TRAIL-mediated apoptosis, so taking out this barrier could render MDSCs susceptible to therapy.

“Our studies suggest that switching prosurvival/proliferation TRAIL signaling to canonical proapoptotic TRAIL signaling will promote MDSC apoptosis, which in turn has therapeutic implications for CCA suppression,” the investigators wrote.

Hope therefore remains for targeting TRAIL in patients with CCA, but with selective antagonism instead of agonism, as previously attempted.

“In summary, our findings support the role of selective therapeutic targeting of TRAIL-positive cancer cells in an effort to block TRAIL/TRAIL-R–mediated tumor immunosuppression,” Dr. Loeuillard and colleagues concluded.

This study was funded by the Cholangiocarcinoma Foundation and the Mayo Clinic Eagles 5th District Cancer Telethon Funds for Research Fellowship Program, the CTSA/National Center for Advancing Translational Science, the National Institutes of Health/National Cancer Institute, and others. The investigators disclosed no conflicts of interest.

Histologic inflammation in women with inflammatory bowel disease (IBD) may lead to reduced fertility, according to a Swedish nationwide cohort study.

Reduced fertility was linked with histologic inflammation even in the absence of clinical disease activity, highlighting the importance of achieving deep remission in women planning pregnancy, reported lead author Karl Mårild, MD, PhD, of Sahlgrenska Academy, Gothenburg, Sweden, and colleagues.

“Reduced female fertility (ie, number of live births) is believed to be primarily confined to women with clinically active IBD, especially in Crohn’s disease (CD), where symptoms may inhibit sexual activity, and inflammation may affect the fallopian tubes and ovaries,” the investigators wrote in Gastroenterology. “Despite the increasing appreciation of histologic activity in IBD, its association with female fertility has not been clarified, including whether histologic activity in the absence of clinical disease activity impairs fertility.”

Marild_Karl_SWE_2_web.jpg

Dr. Mårild and colleagues aimed to address this knowledge gap by analyzing fertility rates and histologic inflammation or IBD activity in two cohorts of women with IBD aged 15-44 years. The first group included approximately 21,000 women with and without histologic inflammation from 1990 to 2016. The second group included approximately 25,000 women with or without IBD clinical activity from 2006 to 2020. In each group, the relationship between fertility and IBD was compared with fertility in matched general population comparator individuals.

This approach showed that clinical IBD activity was associated with an adjusted fertility rate ratio (aFRR) of 0.76 (95% CI, 0.72-0.79), which equates to one fewer child per six women with 10 years of clinical activity. Impacts on fertility were similar for UC (aFRR, 0.75) and CD (aFRR, 0.76).

“Fertility rates were notably reduced during periods of clinical IBD activity and, contrary to a generally accepted belief, equally reduced in clinically active UC and CD,” the investigators wrote. “Besides inflammation, clinically active IBD may reduce fertility through psychological mechanisms (eg, depression), dyspareunia (especially in perianal CD), bowel pain, urgency, and other symptoms that hinder sexual activity.”

Compared with histologic remission, histologic inflammation was also associated with reduced fertility (aFRR, 0.90). This means that in periods of histologic inflammation, 6.35 live births occurred per 100 person-years of follow-up, compared with 7.09 lives births for periods of histologic remission. This amounts to one fewer child per 14 women with 10 years of histologic inflammation.

Finally, the study revealed that, in women with clinically quiescent IBD, those with histologic inflammation had significantly reduced fertility, compared with those in histologic remission (aFRR, 0.85). This association persisted after controlling for contraceptive use.

“Even if histologic inflammation was associated with an overall modest fertility reduction … its impact on the individual might be substantial, with potential ramifications beyond reproductive health, given that reduced female fertility is linked to poor quality of life and mental health,” Dr. Mårild and colleagues wrote. “At a societal level, involuntary childlessness causes high and increasing costs, highlighting the need to focus on preventable causes of reduced fertility.”

The investigators suggested that inflammation may be driving infertility by reducing ovulation and fertilization, or by reducing endometrial receptivity, which increases risk of pregnancy loss.

“This is the first study, to our knowledge, to show reduced fertility during histologic inflammation in IBD compared to histologic remission,” the investigators wrote. “Our findings suggest that achieving histologic remission may improve the fertility of women with IBD, even in the absence of clinically defined disease activity.”

The investigators disclosed relationships with AbbVie, Pfizer, Janssen, and others.

Histologic inflammation in women with inflammatory bowel disease (IBD) may lead to reduced fertility, according to a Swedish nationwide cohort study.

Reduced fertility was linked with histologic inflammation even in the absence of clinical disease activity, highlighting the importance of achieving deep remission in women planning pregnancy, reported lead author Karl Mårild, MD, PhD, of Sahlgrenska Academy, Gothenburg, Sweden, and colleagues.

“Reduced female fertility (ie, number of live births) is believed to be primarily confined to women with clinically active IBD, especially in Crohn’s disease (CD), where symptoms may inhibit sexual activity, and inflammation may affect the fallopian tubes and ovaries,” the investigators wrote in Gastroenterology. “Despite the increasing appreciation of histologic activity in IBD, its association with female fertility has not been clarified, including whether histologic activity in the absence of clinical disease activity impairs fertility.”

Marild_Karl_SWE_2_web.jpg

Dr. Mårild and colleagues aimed to address this knowledge gap by analyzing fertility rates and histologic inflammation or IBD activity in two cohorts of women with IBD aged 15-44 years. The first group included approximately 21,000 women with and without histologic inflammation from 1990 to 2016. The second group included approximately 25,000 women with or without IBD clinical activity from 2006 to 2020. In each group, the relationship between fertility and IBD was compared with fertility in matched general population comparator individuals.

This approach showed that clinical IBD activity was associated with an adjusted fertility rate ratio (aFRR) of 0.76 (95% CI, 0.72-0.79), which equates to one fewer child per six women with 10 years of clinical activity. Impacts on fertility were similar for UC (aFRR, 0.75) and CD (aFRR, 0.76).

“Fertility rates were notably reduced during periods of clinical IBD activity and, contrary to a generally accepted belief, equally reduced in clinically active UC and CD,” the investigators wrote. “Besides inflammation, clinically active IBD may reduce fertility through psychological mechanisms (eg, depression), dyspareunia (especially in perianal CD), bowel pain, urgency, and other symptoms that hinder sexual activity.”

Compared with histologic remission, histologic inflammation was also associated with reduced fertility (aFRR, 0.90). This means that in periods of histologic inflammation, 6.35 live births occurred per 100 person-years of follow-up, compared with 7.09 lives births for periods of histologic remission. This amounts to one fewer child per 14 women with 10 years of histologic inflammation.

Finally, the study revealed that, in women with clinically quiescent IBD, those with histologic inflammation had significantly reduced fertility, compared with those in histologic remission (aFRR, 0.85). This association persisted after controlling for contraceptive use.

“Even if histologic inflammation was associated with an overall modest fertility reduction … its impact on the individual might be substantial, with potential ramifications beyond reproductive health, given that reduced female fertility is linked to poor quality of life and mental health,” Dr. Mårild and colleagues wrote. “At a societal level, involuntary childlessness causes high and increasing costs, highlighting the need to focus on preventable causes of reduced fertility.”

The investigators suggested that inflammation may be driving infertility by reducing ovulation and fertilization, or by reducing endometrial receptivity, which increases risk of pregnancy loss.

“This is the first study, to our knowledge, to show reduced fertility during histologic inflammation in IBD compared to histologic remission,” the investigators wrote. “Our findings suggest that achieving histologic remission may improve the fertility of women with IBD, even in the absence of clinically defined disease activity.”

The investigators disclosed relationships with AbbVie, Pfizer, Janssen, and others.

Histologic inflammation in women with inflammatory bowel disease (IBD) may lead to reduced fertility, according to a Swedish nationwide cohort study.

Reduced fertility was linked with histologic inflammation even in the absence of clinical disease activity, highlighting the importance of achieving deep remission in women planning pregnancy, reported lead author Karl Mårild, MD, PhD, of Sahlgrenska Academy, Gothenburg, Sweden, and colleagues.

“Reduced female fertility (ie, number of live births) is believed to be primarily confined to women with clinically active IBD, especially in Crohn’s disease (CD), where symptoms may inhibit sexual activity, and inflammation may affect the fallopian tubes and ovaries,” the investigators wrote in Gastroenterology. “Despite the increasing appreciation of histologic activity in IBD, its association with female fertility has not been clarified, including whether histologic activity in the absence of clinical disease activity impairs fertility.”

Marild_Karl_SWE_2_web.jpg

Dr. Mårild and colleagues aimed to address this knowledge gap by analyzing fertility rates and histologic inflammation or IBD activity in two cohorts of women with IBD aged 15-44 years. The first group included approximately 21,000 women with and without histologic inflammation from 1990 to 2016. The second group included approximately 25,000 women with or without IBD clinical activity from 2006 to 2020. In each group, the relationship between fertility and IBD was compared with fertility in matched general population comparator individuals.

This approach showed that clinical IBD activity was associated with an adjusted fertility rate ratio (aFRR) of 0.76 (95% CI, 0.72-0.79), which equates to one fewer child per six women with 10 years of clinical activity. Impacts on fertility were similar for UC (aFRR, 0.75) and CD (aFRR, 0.76).

“Fertility rates were notably reduced during periods of clinical IBD activity and, contrary to a generally accepted belief, equally reduced in clinically active UC and CD,” the investigators wrote. “Besides inflammation, clinically active IBD may reduce fertility through psychological mechanisms (eg, depression), dyspareunia (especially in perianal CD), bowel pain, urgency, and other symptoms that hinder sexual activity.”

Compared with histologic remission, histologic inflammation was also associated with reduced fertility (aFRR, 0.90). This means that in periods of histologic inflammation, 6.35 live births occurred per 100 person-years of follow-up, compared with 7.09 lives births for periods of histologic remission. This amounts to one fewer child per 14 women with 10 years of histologic inflammation.

Finally, the study revealed that, in women with clinically quiescent IBD, those with histologic inflammation had significantly reduced fertility, compared with those in histologic remission (aFRR, 0.85). This association persisted after controlling for contraceptive use.

“Even if histologic inflammation was associated with an overall modest fertility reduction … its impact on the individual might be substantial, with potential ramifications beyond reproductive health, given that reduced female fertility is linked to poor quality of life and mental health,” Dr. Mårild and colleagues wrote. “At a societal level, involuntary childlessness causes high and increasing costs, highlighting the need to focus on preventable causes of reduced fertility.”

The investigators suggested that inflammation may be driving infertility by reducing ovulation and fertilization, or by reducing endometrial receptivity, which increases risk of pregnancy loss.

“This is the first study, to our knowledge, to show reduced fertility during histologic inflammation in IBD compared to histologic remission,” the investigators wrote. “Our findings suggest that achieving histologic remission may improve the fertility of women with IBD, even in the absence of clinically defined disease activity.”

The investigators disclosed relationships with AbbVie, Pfizer, Janssen, and others.