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AGA publishes CPU for AI in colon polyp diagnosis and management
The American Gastroenterological Association has published a Clinical Practice Update (CPU) on artificial intelligence (AI) for diagnosing and managing colorectal polyps.
The CPU, authored by Jason Samarasena, MD, of UCI Health, Orange, Calif., and colleagues, draws on recent studies and clinical experience to discuss ways that AI is already reshaping colonoscopy, and what opportunities may lie ahead.
“As with any emerging technology, there are important questions and challenges that need to be addressed to ensure that AI tools are introduced safely and effectively into clinical endoscopic practice, ”they wrote in Gastroenterology.
With advances in processing speed and deep-learning technology, AI “computer vision” can now analyze live video of a colonoscopy in progress, enabling computer-aided detection (CADe) and computer-aided diagnosis (CADx), which the panelists described as the two most important developments in the area.
CADe
“In the last several years, numerous prospective, multicenter studies have found that real-time use of AI CADe tools during colonoscopy leads to improvements in adenoma detection and other related performance metrics,” Dr. Samarasena and colleagues wrote.
CADe has yielded mixed success in real-world practice, however, with some studies reporting worse detection metrics after implementing the new technology. Dr. Samarasena and colleagues offered a variety of possible explanations for these findings, including a “ceiling effect” among highly adept endoscopists, reduced operator vigilance caused by false confidence in the technology, and potential confounding inherent to unblinded trials.
CADe may also increase health care costs and burden, they suggested, as the technology tends to catch small benign polyps, prompting unnecessary resections and shortened colonoscopy surveillance intervals.
CADx
The above, unintended consequences of CADe may be counteracted by CADx, which uses computer vision to predict which lesions have benign histology, enabling “resect-and discard” or “diagnose-and-leave” strategies.
Such approaches could significantly reduce rates of polypectomy and/or histopathology, saving an estimated $33 million–150 million per year, according to the update.
Results of real-time CADx clinical trials have been “encouraging,” Dr. Samarasena and colleagues wrote, noting that emerging technology–compatible white-light endoscopy can achieve a negative predictive value of almost 98% for lesions less than 5 mm in diameter, potentially reducing polypectomy rate by almost half.
“Increasing endoscopist confidence in optical diagnosis may be an important step toward broader implementation of leave in situ and resect-and-discard strategies, but successful implementation will also require CADx tools that seamlessly integrate the endoscopic work flow, without the need for image enhancement or magnification,” the panelists wrote.
Reimbursement models may also need to be reworked, they suggested, as many GI practices depend on a steady stream of revenue from pathology services.
Computer-aided quality assessment systems
Beyond optical detection and diagnosis, AI tools are also being developed to improve colonoscopy technique.
Investigators are studying quality assessment systems that use AI offer feedback on a range of endoscopist skills, including colonic-fold evaluation, level of mucosal exposure, and withdrawal time, the latter of which is visualized by a “speedometer” that “paints” the mucosa with “a graphical representation of the colon.”
“In the future, these types of AI-based systems may support trainees and lower-performing endoscopists to reduce exposure errors and, more broadly, may empower physician practices and hospital systems with more nuanced and actionable data on an array of factors that contribute to colonoscopy quality,” the panelists wrote.
Looking ahead
Dr. Samarasena and colleagues concluded by suggesting that the AI tools in usage and development are just the beginning of a wave of technology that will revolutionize how colonoscopies are performed.
“Eventually, we predict an AI suite of tools for colonoscopy will seem indispensable, as a powerful adjunct to support safe and efficient clinical practice,” they wrote. “As technological innovation progresses, we can expect that the future for AI in endoscopy will be a hybrid model, where the unique capabilities of physicians and our AI tools will be seamlessly intertwined to optimize patient care.”
This CPU was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board. The investigators disclosed relationships with Olympus, Neptune Medical, Conmed, and others.
The American Gastroenterological Association has published a Clinical Practice Update (CPU) on artificial intelligence (AI) for diagnosing and managing colorectal polyps.
The CPU, authored by Jason Samarasena, MD, of UCI Health, Orange, Calif., and colleagues, draws on recent studies and clinical experience to discuss ways that AI is already reshaping colonoscopy, and what opportunities may lie ahead.
“As with any emerging technology, there are important questions and challenges that need to be addressed to ensure that AI tools are introduced safely and effectively into clinical endoscopic practice, ”they wrote in Gastroenterology.
With advances in processing speed and deep-learning technology, AI “computer vision” can now analyze live video of a colonoscopy in progress, enabling computer-aided detection (CADe) and computer-aided diagnosis (CADx), which the panelists described as the two most important developments in the area.
CADe
“In the last several years, numerous prospective, multicenter studies have found that real-time use of AI CADe tools during colonoscopy leads to improvements in adenoma detection and other related performance metrics,” Dr. Samarasena and colleagues wrote.
CADe has yielded mixed success in real-world practice, however, with some studies reporting worse detection metrics after implementing the new technology. Dr. Samarasena and colleagues offered a variety of possible explanations for these findings, including a “ceiling effect” among highly adept endoscopists, reduced operator vigilance caused by false confidence in the technology, and potential confounding inherent to unblinded trials.
CADe may also increase health care costs and burden, they suggested, as the technology tends to catch small benign polyps, prompting unnecessary resections and shortened colonoscopy surveillance intervals.
CADx
The above, unintended consequences of CADe may be counteracted by CADx, which uses computer vision to predict which lesions have benign histology, enabling “resect-and discard” or “diagnose-and-leave” strategies.
Such approaches could significantly reduce rates of polypectomy and/or histopathology, saving an estimated $33 million–150 million per year, according to the update.
Results of real-time CADx clinical trials have been “encouraging,” Dr. Samarasena and colleagues wrote, noting that emerging technology–compatible white-light endoscopy can achieve a negative predictive value of almost 98% for lesions less than 5 mm in diameter, potentially reducing polypectomy rate by almost half.
“Increasing endoscopist confidence in optical diagnosis may be an important step toward broader implementation of leave in situ and resect-and-discard strategies, but successful implementation will also require CADx tools that seamlessly integrate the endoscopic work flow, without the need for image enhancement or magnification,” the panelists wrote.
Reimbursement models may also need to be reworked, they suggested, as many GI practices depend on a steady stream of revenue from pathology services.
Computer-aided quality assessment systems
Beyond optical detection and diagnosis, AI tools are also being developed to improve colonoscopy technique.
Investigators are studying quality assessment systems that use AI offer feedback on a range of endoscopist skills, including colonic-fold evaluation, level of mucosal exposure, and withdrawal time, the latter of which is visualized by a “speedometer” that “paints” the mucosa with “a graphical representation of the colon.”
“In the future, these types of AI-based systems may support trainees and lower-performing endoscopists to reduce exposure errors and, more broadly, may empower physician practices and hospital systems with more nuanced and actionable data on an array of factors that contribute to colonoscopy quality,” the panelists wrote.
Looking ahead
Dr. Samarasena and colleagues concluded by suggesting that the AI tools in usage and development are just the beginning of a wave of technology that will revolutionize how colonoscopies are performed.
“Eventually, we predict an AI suite of tools for colonoscopy will seem indispensable, as a powerful adjunct to support safe and efficient clinical practice,” they wrote. “As technological innovation progresses, we can expect that the future for AI in endoscopy will be a hybrid model, where the unique capabilities of physicians and our AI tools will be seamlessly intertwined to optimize patient care.”
This CPU was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board. The investigators disclosed relationships with Olympus, Neptune Medical, Conmed, and others.
The American Gastroenterological Association has published a Clinical Practice Update (CPU) on artificial intelligence (AI) for diagnosing and managing colorectal polyps.
The CPU, authored by Jason Samarasena, MD, of UCI Health, Orange, Calif., and colleagues, draws on recent studies and clinical experience to discuss ways that AI is already reshaping colonoscopy, and what opportunities may lie ahead.
“As with any emerging technology, there are important questions and challenges that need to be addressed to ensure that AI tools are introduced safely and effectively into clinical endoscopic practice, ”they wrote in Gastroenterology.
With advances in processing speed and deep-learning technology, AI “computer vision” can now analyze live video of a colonoscopy in progress, enabling computer-aided detection (CADe) and computer-aided diagnosis (CADx), which the panelists described as the two most important developments in the area.
CADe
“In the last several years, numerous prospective, multicenter studies have found that real-time use of AI CADe tools during colonoscopy leads to improvements in adenoma detection and other related performance metrics,” Dr. Samarasena and colleagues wrote.
CADe has yielded mixed success in real-world practice, however, with some studies reporting worse detection metrics after implementing the new technology. Dr. Samarasena and colleagues offered a variety of possible explanations for these findings, including a “ceiling effect” among highly adept endoscopists, reduced operator vigilance caused by false confidence in the technology, and potential confounding inherent to unblinded trials.
CADe may also increase health care costs and burden, they suggested, as the technology tends to catch small benign polyps, prompting unnecessary resections and shortened colonoscopy surveillance intervals.
CADx
The above, unintended consequences of CADe may be counteracted by CADx, which uses computer vision to predict which lesions have benign histology, enabling “resect-and discard” or “diagnose-and-leave” strategies.
Such approaches could significantly reduce rates of polypectomy and/or histopathology, saving an estimated $33 million–150 million per year, according to the update.
Results of real-time CADx clinical trials have been “encouraging,” Dr. Samarasena and colleagues wrote, noting that emerging technology–compatible white-light endoscopy can achieve a negative predictive value of almost 98% for lesions less than 5 mm in diameter, potentially reducing polypectomy rate by almost half.
“Increasing endoscopist confidence in optical diagnosis may be an important step toward broader implementation of leave in situ and resect-and-discard strategies, but successful implementation will also require CADx tools that seamlessly integrate the endoscopic work flow, without the need for image enhancement or magnification,” the panelists wrote.
Reimbursement models may also need to be reworked, they suggested, as many GI practices depend on a steady stream of revenue from pathology services.
Computer-aided quality assessment systems
Beyond optical detection and diagnosis, AI tools are also being developed to improve colonoscopy technique.
Investigators are studying quality assessment systems that use AI offer feedback on a range of endoscopist skills, including colonic-fold evaluation, level of mucosal exposure, and withdrawal time, the latter of which is visualized by a “speedometer” that “paints” the mucosa with “a graphical representation of the colon.”
“In the future, these types of AI-based systems may support trainees and lower-performing endoscopists to reduce exposure errors and, more broadly, may empower physician practices and hospital systems with more nuanced and actionable data on an array of factors that contribute to colonoscopy quality,” the panelists wrote.
Looking ahead
Dr. Samarasena and colleagues concluded by suggesting that the AI tools in usage and development are just the beginning of a wave of technology that will revolutionize how colonoscopies are performed.
“Eventually, we predict an AI suite of tools for colonoscopy will seem indispensable, as a powerful adjunct to support safe and efficient clinical practice,” they wrote. “As technological innovation progresses, we can expect that the future for AI in endoscopy will be a hybrid model, where the unique capabilities of physicians and our AI tools will be seamlessly intertwined to optimize patient care.”
This CPU was commissioned and approved by the AGA Institute Clinical Practice Updates Committee and the AGA Governing Board. The investigators disclosed relationships with Olympus, Neptune Medical, Conmed, and others.
FROM GASTROENTEROLOGY
Even a short course of opioids could jeopardize IBD patient health
These findings amplify the safety signal from previous inpatient studies by showing that even a short course of opioids in an outpatient setting may increase risks of corticosteroid use and emergency department utilization, prompting caution among prescribers, reported Laura Telfer, MS, of Penn State College of Medicine, Hershey, Pa., and colleagues.
“Opioids are frequently prescribed to treat pain associated with IBD,” the investigators wrote in Gastro Hep Advances. “Unfortunately, they are associated with many problems in IBD, including increased risk of emergency room visits, hospitalization, surgery, and mortality. Chronic opioid use may also exacerbate symptoms and induce IBD flares, prompting discontinuation, thus increasing the risk of opioid withdrawal syndrome. Ironically, there is no published evidence that opioids even help to improve abdominal pain in IBD, particularly in the long term. Notably, most studies investigating opioid use in IBD have been limited to hospitalized patients, and few have directly evaluated the impact of opioid prescription length.”
To address this knowledge gap, Ms. Telfer and colleagues conducted a retrospective, population-based cohort study involving patients with IBD who were classified as either long-term opioid users, short-term opioid users, or nonusers. Drawing data from more than 80,000 patients in the TriNetX Diamond Network, the investigators evaluated relative, intergroup risks for corticosteroid use, emergency department utilization, mortality, and IBD-related surgery.
Comparing short-term opioid users and nonusers revealed that short-term use more than doubled the risk of corticosteroid prescription (relative risk [RR], 2.517; P less than .001), and increased the risk of an emergency department visit by approximately 32% (RR, 1.315; P less than .001). Long-term use was associated with a similar doubling in risk of corticosteroid prescription (RR, 2.383; P less than .001), and an even greater risk of emergency department utilization (RR, 2.083; P less than .001). Risks of death or IBD-related surgery did not differ for either of these comparisons.
Next, the investigators compared long-term opioid use versus short-term opioid use. This suggested a duration-related effect, as long-term users were 57% more likely than were short-term users to utilize emergency department services (RR, 1.572; P less than .001). No significant differences for the other outcomes were detected in this comparison.
“Unlike previous studies, we did not find an association between opioid use and IBD-related surgery or death,” the investigators wrote. “Notably, these [previously reported] associations utilized opioid dosage (e.g., morphine equivalent or number of prescriptions), rather than length of opioid prescription (as we did). We also focused on IBD outpatients, while prior studies evaluated (in part or completely) inpatient populations, who typically present with more severe illness.”
Still, they added, the present findings should serve as a warning to prescribers considering even a short course of opioids for patients with IBD.
“This study demonstrates that prescribing opioids to IBD outpatients carries significant, specific risks, regardless of prescription length,” Ms. Telfer and colleagues wrote. “Healthcare professionals should exercise caution before prescribing these agents.”
The study was supported by the Peter and Marshia Carlino Early Career Professorship in Inflammatory Bowel Disease, the Margot E. Walrath Career Development Professorship in Gastroenterology, and the National Institutes of Health. The investigators disclosed no conflicts of interest.
Given that objective control of inflammation does not always correlate with improvement in abdominal pain scores, the use of opioids in patients with inflammatory bowel diseases (IBD) remains a difficult area of clinical practice and research. In this study, Telfer and colleagues performed a retrospective analysis using the TriNetX Diamond Network to assess the impact of opioid use on health-associated outcomes and evaluate for a differential impact on outcomes depending on the length of opioid prescription. When compared to non–opioid users, both short- and long-term opioid users were more likely to utilize corticosteroids and emergency department services. However, in contrast to prior studies, there was no increased risk for mortality demonstrated among those patients with short- or long-term opioid use.
Edward L. Barnes, MD, MPH, is assistant professor of medicine at the University of North Carolina at Chapel Hill. He disclosed having served as a consultant for Target RWE (not relevant to this commentary).
Given that objective control of inflammation does not always correlate with improvement in abdominal pain scores, the use of opioids in patients with inflammatory bowel diseases (IBD) remains a difficult area of clinical practice and research. In this study, Telfer and colleagues performed a retrospective analysis using the TriNetX Diamond Network to assess the impact of opioid use on health-associated outcomes and evaluate for a differential impact on outcomes depending on the length of opioid prescription. When compared to non–opioid users, both short- and long-term opioid users were more likely to utilize corticosteroids and emergency department services. However, in contrast to prior studies, there was no increased risk for mortality demonstrated among those patients with short- or long-term opioid use.
Edward L. Barnes, MD, MPH, is assistant professor of medicine at the University of North Carolina at Chapel Hill. He disclosed having served as a consultant for Target RWE (not relevant to this commentary).
Given that objective control of inflammation does not always correlate with improvement in abdominal pain scores, the use of opioids in patients with inflammatory bowel diseases (IBD) remains a difficult area of clinical practice and research. In this study, Telfer and colleagues performed a retrospective analysis using the TriNetX Diamond Network to assess the impact of opioid use on health-associated outcomes and evaluate for a differential impact on outcomes depending on the length of opioid prescription. When compared to non–opioid users, both short- and long-term opioid users were more likely to utilize corticosteroids and emergency department services. However, in contrast to prior studies, there was no increased risk for mortality demonstrated among those patients with short- or long-term opioid use.
Edward L. Barnes, MD, MPH, is assistant professor of medicine at the University of North Carolina at Chapel Hill. He disclosed having served as a consultant for Target RWE (not relevant to this commentary).
These findings amplify the safety signal from previous inpatient studies by showing that even a short course of opioids in an outpatient setting may increase risks of corticosteroid use and emergency department utilization, prompting caution among prescribers, reported Laura Telfer, MS, of Penn State College of Medicine, Hershey, Pa., and colleagues.
“Opioids are frequently prescribed to treat pain associated with IBD,” the investigators wrote in Gastro Hep Advances. “Unfortunately, they are associated with many problems in IBD, including increased risk of emergency room visits, hospitalization, surgery, and mortality. Chronic opioid use may also exacerbate symptoms and induce IBD flares, prompting discontinuation, thus increasing the risk of opioid withdrawal syndrome. Ironically, there is no published evidence that opioids even help to improve abdominal pain in IBD, particularly in the long term. Notably, most studies investigating opioid use in IBD have been limited to hospitalized patients, and few have directly evaluated the impact of opioid prescription length.”
To address this knowledge gap, Ms. Telfer and colleagues conducted a retrospective, population-based cohort study involving patients with IBD who were classified as either long-term opioid users, short-term opioid users, or nonusers. Drawing data from more than 80,000 patients in the TriNetX Diamond Network, the investigators evaluated relative, intergroup risks for corticosteroid use, emergency department utilization, mortality, and IBD-related surgery.
Comparing short-term opioid users and nonusers revealed that short-term use more than doubled the risk of corticosteroid prescription (relative risk [RR], 2.517; P less than .001), and increased the risk of an emergency department visit by approximately 32% (RR, 1.315; P less than .001). Long-term use was associated with a similar doubling in risk of corticosteroid prescription (RR, 2.383; P less than .001), and an even greater risk of emergency department utilization (RR, 2.083; P less than .001). Risks of death or IBD-related surgery did not differ for either of these comparisons.
Next, the investigators compared long-term opioid use versus short-term opioid use. This suggested a duration-related effect, as long-term users were 57% more likely than were short-term users to utilize emergency department services (RR, 1.572; P less than .001). No significant differences for the other outcomes were detected in this comparison.
“Unlike previous studies, we did not find an association between opioid use and IBD-related surgery or death,” the investigators wrote. “Notably, these [previously reported] associations utilized opioid dosage (e.g., morphine equivalent or number of prescriptions), rather than length of opioid prescription (as we did). We also focused on IBD outpatients, while prior studies evaluated (in part or completely) inpatient populations, who typically present with more severe illness.”
Still, they added, the present findings should serve as a warning to prescribers considering even a short course of opioids for patients with IBD.
“This study demonstrates that prescribing opioids to IBD outpatients carries significant, specific risks, regardless of prescription length,” Ms. Telfer and colleagues wrote. “Healthcare professionals should exercise caution before prescribing these agents.”
The study was supported by the Peter and Marshia Carlino Early Career Professorship in Inflammatory Bowel Disease, the Margot E. Walrath Career Development Professorship in Gastroenterology, and the National Institutes of Health. The investigators disclosed no conflicts of interest.
These findings amplify the safety signal from previous inpatient studies by showing that even a short course of opioids in an outpatient setting may increase risks of corticosteroid use and emergency department utilization, prompting caution among prescribers, reported Laura Telfer, MS, of Penn State College of Medicine, Hershey, Pa., and colleagues.
“Opioids are frequently prescribed to treat pain associated with IBD,” the investigators wrote in Gastro Hep Advances. “Unfortunately, they are associated with many problems in IBD, including increased risk of emergency room visits, hospitalization, surgery, and mortality. Chronic opioid use may also exacerbate symptoms and induce IBD flares, prompting discontinuation, thus increasing the risk of opioid withdrawal syndrome. Ironically, there is no published evidence that opioids even help to improve abdominal pain in IBD, particularly in the long term. Notably, most studies investigating opioid use in IBD have been limited to hospitalized patients, and few have directly evaluated the impact of opioid prescription length.”
To address this knowledge gap, Ms. Telfer and colleagues conducted a retrospective, population-based cohort study involving patients with IBD who were classified as either long-term opioid users, short-term opioid users, or nonusers. Drawing data from more than 80,000 patients in the TriNetX Diamond Network, the investigators evaluated relative, intergroup risks for corticosteroid use, emergency department utilization, mortality, and IBD-related surgery.
Comparing short-term opioid users and nonusers revealed that short-term use more than doubled the risk of corticosteroid prescription (relative risk [RR], 2.517; P less than .001), and increased the risk of an emergency department visit by approximately 32% (RR, 1.315; P less than .001). Long-term use was associated with a similar doubling in risk of corticosteroid prescription (RR, 2.383; P less than .001), and an even greater risk of emergency department utilization (RR, 2.083; P less than .001). Risks of death or IBD-related surgery did not differ for either of these comparisons.
Next, the investigators compared long-term opioid use versus short-term opioid use. This suggested a duration-related effect, as long-term users were 57% more likely than were short-term users to utilize emergency department services (RR, 1.572; P less than .001). No significant differences for the other outcomes were detected in this comparison.
“Unlike previous studies, we did not find an association between opioid use and IBD-related surgery or death,” the investigators wrote. “Notably, these [previously reported] associations utilized opioid dosage (e.g., morphine equivalent or number of prescriptions), rather than length of opioid prescription (as we did). We also focused on IBD outpatients, while prior studies evaluated (in part or completely) inpatient populations, who typically present with more severe illness.”
Still, they added, the present findings should serve as a warning to prescribers considering even a short course of opioids for patients with IBD.
“This study demonstrates that prescribing opioids to IBD outpatients carries significant, specific risks, regardless of prescription length,” Ms. Telfer and colleagues wrote. “Healthcare professionals should exercise caution before prescribing these agents.”
The study was supported by the Peter and Marshia Carlino Early Career Professorship in Inflammatory Bowel Disease, the Margot E. Walrath Career Development Professorship in Gastroenterology, and the National Institutes of Health. The investigators disclosed no conflicts of interest.
FROM GASTRO HEP ADVANCES
Microsimulation model identifies 4-year window for pancreatic cancer screening
, based on a microsimulation model.
To seize this opportunity, however, a greater understanding of natural disease course is needed, along with more sensitive screening tools, reported Brechtje D. M. Koopmann, MD, of Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues.
Previous studies have suggested that the window of opportunity for pancreatic cancer screening may span decades, with estimates ranging from 12 to 50 years, the investigators wrote. Their report was published in Gastroenterology.
“Unfortunately, the poor results of pancreatic cancer screening do not align with this assumption, leaving unanswered whether this large window of opportunity truly exists,” they noted. “Microsimulation modeling, combined with available, if limited data, can provide new information on the natural disease course.”
For the present study, the investigators used the Microsimulation Screening Analysis (MISCAN) model, which has guided development of screening programs around the world for cervical, breast, and colorectal cancer. The model incorporates natural disease course, screening, and demographic data, then uses observable inputs such as precursor lesion prevalence and cancer incidence to estimate unobservable outcomes like stage durations and precursor lesion onset.
Dr. Koopmann and colleagues programmed this model with Dutch pancreatic cancer incidence data and findings from Japanese autopsy cases without pancreatic cancer.
First, the model offered insights into precursor lesion prevalence.
The estimated prevalence of any cystic lesion in the pancreas was 6.1% for individuals 50 years of age and 29.6% for those 80 years of age. Solid precursor lesions (PanINs) were estimated to be mainly multifocal (three or more lesions) in individuals older than 80 years. By this age, almost 12% had at least two PanINs. For those lesions that eventually became cancerous, the mean time since cyst onset was estimated to be 8.8 years, and mean time since PanIN onset was 9.0 years.
However, less than 10% of cystic and PanIN lesions progress to become cancers. PanIN lesions are not visible on imaging, and therefore current screening focuses on finding cystic precursor lesions, although these represent only about 10% of pancreatic cancers.
“Given the low pancreatic cancer progression risk of cysts, evaluation of the efficiency of current surveillance guidelines is necessary,” the investigators noted.
Screening should instead focus on identifying high-grade dysplastic lesions, they suggested. While these lesions may have a very low estimated prevalence, at just 0.3% among individuals 90 years of age, they present the greatest risk of pancreatic cancer.
For precursor cysts exhibiting HGD that progressed to pancreatic cancer, the mean interval between dysplasia and cancer was just 4 years. Among 13.7% of individuals, the interval was less than 1 year, suggesting an even shorter window of opportunity for screening.
Beyond this brief timeframe, low test sensitivity explains why screening efforts to date have fallen short, the investigators wrote.
Better tests are “urgently needed,” they added, while acknowledging the challenges inherent to this endeavor. Previous research has shown that precursor lesions in the pancreas are often less than 5 mm in diameter, making them extremely challenging to detect. An effective tool would need to identify solid precursor lesions (PanINs), and also need to simultaneously determine grade of dysplasia.
“Biomarkers could be the future in this matter,” the investigators suggested.
Dr. Koopmann and colleagues concluded by noting that more research is needed to characterize the pathophysiology of pancreatic cancer. On their part, “the current model will be validated, adjusted, and improved whenever new data from autopsy or prospective surveillance studies become available.”
The study was funded in part by Maag Lever Darm Stichting. The investigators disclosed no conflicts of interest.
We continue to search for a way to effectively screen for and prevent pancreatic cancer. Most pancreatic cancers come from pancreatic intraepithelial neoplasms (PanINs), which are essentially invisible on imaging. Pancreatic cysts are relatively common, and only a small number will progress to cancer. Screening via MRI or EUS can look for high-risk features of visible cysts or find early-stage cancers, but whom to screen, how often, and what to do with the results remains unclear. Many of the steps from development of the initial cyst or PanIN to the transformation to cancer cannot be observed, and as such this is a perfect application for disease modeling that allows us to fill in the gaps of what can be observed and estimate what we cannot see. 
Mary Linton B. Peters, MD, MS, is a medical oncologist specializing in hepatic and pancreatobiliary cancers at Beth Israel Deaconess Medical Center, Boston, an assistant professor at Harvard Medical School, and a senior scientist at the Institute for Technology Assessment of Massachusetts General Hospital. She reports unrelated institutional research funding from NuCana and Helsinn.
We continue to search for a way to effectively screen for and prevent pancreatic cancer. Most pancreatic cancers come from pancreatic intraepithelial neoplasms (PanINs), which are essentially invisible on imaging. Pancreatic cysts are relatively common, and only a small number will progress to cancer. Screening via MRI or EUS can look for high-risk features of visible cysts or find early-stage cancers, but whom to screen, how often, and what to do with the results remains unclear. Many of the steps from development of the initial cyst or PanIN to the transformation to cancer cannot be observed, and as such this is a perfect application for disease modeling that allows us to fill in the gaps of what can be observed and estimate what we cannot see.
Mary Linton B. Peters, MD, MS, is a medical oncologist specializing in hepatic and pancreatobiliary cancers at Beth Israel Deaconess Medical Center, Boston, an assistant professor at Harvard Medical School, and a senior scientist at the Institute for Technology Assessment of Massachusetts General Hospital. She reports unrelated institutional research funding from NuCana and Helsinn.
We continue to search for a way to effectively screen for and prevent pancreatic cancer. Most pancreatic cancers come from pancreatic intraepithelial neoplasms (PanINs), which are essentially invisible on imaging. Pancreatic cysts are relatively common, and only a small number will progress to cancer. Screening via MRI or EUS can look for high-risk features of visible cysts or find early-stage cancers, but whom to screen, how often, and what to do with the results remains unclear. Many of the steps from development of the initial cyst or PanIN to the transformation to cancer cannot be observed, and as such this is a perfect application for disease modeling that allows us to fill in the gaps of what can be observed and estimate what we cannot see.
Mary Linton B. Peters, MD, MS, is a medical oncologist specializing in hepatic and pancreatobiliary cancers at Beth Israel Deaconess Medical Center, Boston, an assistant professor at Harvard Medical School, and a senior scientist at the Institute for Technology Assessment of Massachusetts General Hospital. She reports unrelated institutional research funding from NuCana and Helsinn.
, based on a microsimulation model.
To seize this opportunity, however, a greater understanding of natural disease course is needed, along with more sensitive screening tools, reported Brechtje D. M. Koopmann, MD, of Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues.
Previous studies have suggested that the window of opportunity for pancreatic cancer screening may span decades, with estimates ranging from 12 to 50 years, the investigators wrote. Their report was published in Gastroenterology.
“Unfortunately, the poor results of pancreatic cancer screening do not align with this assumption, leaving unanswered whether this large window of opportunity truly exists,” they noted. “Microsimulation modeling, combined with available, if limited data, can provide new information on the natural disease course.”
For the present study, the investigators used the Microsimulation Screening Analysis (MISCAN) model, which has guided development of screening programs around the world for cervical, breast, and colorectal cancer. The model incorporates natural disease course, screening, and demographic data, then uses observable inputs such as precursor lesion prevalence and cancer incidence to estimate unobservable outcomes like stage durations and precursor lesion onset.
Dr. Koopmann and colleagues programmed this model with Dutch pancreatic cancer incidence data and findings from Japanese autopsy cases without pancreatic cancer.
First, the model offered insights into precursor lesion prevalence.
The estimated prevalence of any cystic lesion in the pancreas was 6.1% for individuals 50 years of age and 29.6% for those 80 years of age. Solid precursor lesions (PanINs) were estimated to be mainly multifocal (three or more lesions) in individuals older than 80 years. By this age, almost 12% had at least two PanINs. For those lesions that eventually became cancerous, the mean time since cyst onset was estimated to be 8.8 years, and mean time since PanIN onset was 9.0 years.
However, less than 10% of cystic and PanIN lesions progress to become cancers. PanIN lesions are not visible on imaging, and therefore current screening focuses on finding cystic precursor lesions, although these represent only about 10% of pancreatic cancers.
“Given the low pancreatic cancer progression risk of cysts, evaluation of the efficiency of current surveillance guidelines is necessary,” the investigators noted.
Screening should instead focus on identifying high-grade dysplastic lesions, they suggested. While these lesions may have a very low estimated prevalence, at just 0.3% among individuals 90 years of age, they present the greatest risk of pancreatic cancer.
For precursor cysts exhibiting HGD that progressed to pancreatic cancer, the mean interval between dysplasia and cancer was just 4 years. Among 13.7% of individuals, the interval was less than 1 year, suggesting an even shorter window of opportunity for screening.
Beyond this brief timeframe, low test sensitivity explains why screening efforts to date have fallen short, the investigators wrote.
Better tests are “urgently needed,” they added, while acknowledging the challenges inherent to this endeavor. Previous research has shown that precursor lesions in the pancreas are often less than 5 mm in diameter, making them extremely challenging to detect. An effective tool would need to identify solid precursor lesions (PanINs), and also need to simultaneously determine grade of dysplasia.
“Biomarkers could be the future in this matter,” the investigators suggested.
Dr. Koopmann and colleagues concluded by noting that more research is needed to characterize the pathophysiology of pancreatic cancer. On their part, “the current model will be validated, adjusted, and improved whenever new data from autopsy or prospective surveillance studies become available.”
The study was funded in part by Maag Lever Darm Stichting. The investigators disclosed no conflicts of interest.
, based on a microsimulation model.
To seize this opportunity, however, a greater understanding of natural disease course is needed, along with more sensitive screening tools, reported Brechtje D. M. Koopmann, MD, of Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues.
Previous studies have suggested that the window of opportunity for pancreatic cancer screening may span decades, with estimates ranging from 12 to 50 years, the investigators wrote. Their report was published in Gastroenterology.
“Unfortunately, the poor results of pancreatic cancer screening do not align with this assumption, leaving unanswered whether this large window of opportunity truly exists,” they noted. “Microsimulation modeling, combined with available, if limited data, can provide new information on the natural disease course.”
For the present study, the investigators used the Microsimulation Screening Analysis (MISCAN) model, which has guided development of screening programs around the world for cervical, breast, and colorectal cancer. The model incorporates natural disease course, screening, and demographic data, then uses observable inputs such as precursor lesion prevalence and cancer incidence to estimate unobservable outcomes like stage durations and precursor lesion onset.
Dr. Koopmann and colleagues programmed this model with Dutch pancreatic cancer incidence data and findings from Japanese autopsy cases without pancreatic cancer.
First, the model offered insights into precursor lesion prevalence.
The estimated prevalence of any cystic lesion in the pancreas was 6.1% for individuals 50 years of age and 29.6% for those 80 years of age. Solid precursor lesions (PanINs) were estimated to be mainly multifocal (three or more lesions) in individuals older than 80 years. By this age, almost 12% had at least two PanINs. For those lesions that eventually became cancerous, the mean time since cyst onset was estimated to be 8.8 years, and mean time since PanIN onset was 9.0 years.
However, less than 10% of cystic and PanIN lesions progress to become cancers. PanIN lesions are not visible on imaging, and therefore current screening focuses on finding cystic precursor lesions, although these represent only about 10% of pancreatic cancers.
“Given the low pancreatic cancer progression risk of cysts, evaluation of the efficiency of current surveillance guidelines is necessary,” the investigators noted.
Screening should instead focus on identifying high-grade dysplastic lesions, they suggested. While these lesions may have a very low estimated prevalence, at just 0.3% among individuals 90 years of age, they present the greatest risk of pancreatic cancer.
For precursor cysts exhibiting HGD that progressed to pancreatic cancer, the mean interval between dysplasia and cancer was just 4 years. Among 13.7% of individuals, the interval was less than 1 year, suggesting an even shorter window of opportunity for screening.
Beyond this brief timeframe, low test sensitivity explains why screening efforts to date have fallen short, the investigators wrote.
Better tests are “urgently needed,” they added, while acknowledging the challenges inherent to this endeavor. Previous research has shown that precursor lesions in the pancreas are often less than 5 mm in diameter, making them extremely challenging to detect. An effective tool would need to identify solid precursor lesions (PanINs), and also need to simultaneously determine grade of dysplasia.
“Biomarkers could be the future in this matter,” the investigators suggested.
Dr. Koopmann and colleagues concluded by noting that more research is needed to characterize the pathophysiology of pancreatic cancer. On their part, “the current model will be validated, adjusted, and improved whenever new data from autopsy or prospective surveillance studies become available.”
The study was funded in part by Maag Lever Darm Stichting. The investigators disclosed no conflicts of interest.
FROM GASTROENTEROLOGY
Many preoperative EAC biopsies fail to predict true tumor grade, leading to unnecessary esophagectomy
Inaccurate preoperative biopsy findings could mean that patients who are candidates for endoscopic resection (ER) are unnecessarily undergoing esophagectomy, a procedure with greater risks of morbidity and mortality, reported Ravi S. Shah, MD, of Cleveland Clinic, and colleagues.
“It is unclear how accurate tumor differentiation on endoscopic biopsies is and if it can be used for clinical decision-making,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “Given that tumors may be considerably heterogeneous in gland formation, the limited amount of tissue obtained from endoscopic forceps biopsies may not be representative of the entire tumor for pathologic grading, which may result in discrepant tumor grading between biopsy and resection specimens.”
While previous studies have compared esophagogastroduodenoscopy-guided biopsy results with histological findings after surgical resection, scant evidence is available to compare biopsy findings with both surgically and endoscopically resected tissue.
Despite this potential knowledge gap, “many patients with poorly differentiated EAC on preresection biopsy do not undergo ER, with the belief that the final resection pathology would be noncurative,” the investigators noted.
To help clarify how congruent pre- and postoperative biopsies are for both resection methods, Dr. Shah and colleagues conducted a retrospective study involving 346 EAC lesions. Samples were drawn from 121 ERs and 225 esophagectomies performed at two tertiary referral centers. Preoperative and postoperative findings were compared for accuracy and for level of agreement via Gwet’s AC2 interrater analysis.
For all evaluable lesions, preoperative biopsy had an accuracy of 68%, with a “substantial” agreement coefficient (Gwet’s AC2, 0.70; P less than .001). Accuracy in the esophagectomy group was similar, at 72%, again with “substantial” agreement (Gwet’s AC2, 0.74; P less than .001). For the ER group, however, accuracy was just 56%, with a “moderate” level of agreement (Gwet’s AC2, 0.60; P less than .001).
“We speculate that the discrepancy of tumor differentiation on endoscopic forceps biopsies and resection specimens is due to nonrepresentative sampling of tumors to accurately determine the percentage of gland formation and thus tumor grade,” the investigators noted.
Further analysis showed that 22.7% of moderately differentiated tumors were upgraded to poorly differentiated upon final histology. Conversely, 19.6% of poorly differentiated tumors were downgraded to moderately differentiated. Downgrading was even more common among T1a tumors, 40% of which were changed from poorly to moderately differentiated between pre- and postprocedural histology.
These latter findings concerning downgrading are particularly relevant for clinical decision-making, the investigators noted, as patients with poorly differentiated EAC on preoperative biopsy are typically sent for esophagectomy – a more invasive and riskier procedure – out of concern that ER will be noncurative.
“If poor differentiation was the only high-risk feature, these patients may have unnecessarily undergone esophagectomy,” Dr. Shah and colleagues wrote. “Especially in marginal surgical candidates, staging ER should be considered in patients with early esophageal cancer with preoperative biopsies showing poorly differentiated cancer.”
The investigators disclosed relationships with Medtronic, Lucid Diagnostics, Lumendi, and others.
Inaccurate preoperative biopsy findings could mean that patients who are candidates for endoscopic resection (ER) are unnecessarily undergoing esophagectomy, a procedure with greater risks of morbidity and mortality, reported Ravi S. Shah, MD, of Cleveland Clinic, and colleagues.
“It is unclear how accurate tumor differentiation on endoscopic biopsies is and if it can be used for clinical decision-making,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “Given that tumors may be considerably heterogeneous in gland formation, the limited amount of tissue obtained from endoscopic forceps biopsies may not be representative of the entire tumor for pathologic grading, which may result in discrepant tumor grading between biopsy and resection specimens.”
While previous studies have compared esophagogastroduodenoscopy-guided biopsy results with histological findings after surgical resection, scant evidence is available to compare biopsy findings with both surgically and endoscopically resected tissue.
Despite this potential knowledge gap, “many patients with poorly differentiated EAC on preresection biopsy do not undergo ER, with the belief that the final resection pathology would be noncurative,” the investigators noted.
To help clarify how congruent pre- and postoperative biopsies are for both resection methods, Dr. Shah and colleagues conducted a retrospective study involving 346 EAC lesions. Samples were drawn from 121 ERs and 225 esophagectomies performed at two tertiary referral centers. Preoperative and postoperative findings were compared for accuracy and for level of agreement via Gwet’s AC2 interrater analysis.
For all evaluable lesions, preoperative biopsy had an accuracy of 68%, with a “substantial” agreement coefficient (Gwet’s AC2, 0.70; P less than .001). Accuracy in the esophagectomy group was similar, at 72%, again with “substantial” agreement (Gwet’s AC2, 0.74; P less than .001). For the ER group, however, accuracy was just 56%, with a “moderate” level of agreement (Gwet’s AC2, 0.60; P less than .001).
“We speculate that the discrepancy of tumor differentiation on endoscopic forceps biopsies and resection specimens is due to nonrepresentative sampling of tumors to accurately determine the percentage of gland formation and thus tumor grade,” the investigators noted.
Further analysis showed that 22.7% of moderately differentiated tumors were upgraded to poorly differentiated upon final histology. Conversely, 19.6% of poorly differentiated tumors were downgraded to moderately differentiated. Downgrading was even more common among T1a tumors, 40% of which were changed from poorly to moderately differentiated between pre- and postprocedural histology.
These latter findings concerning downgrading are particularly relevant for clinical decision-making, the investigators noted, as patients with poorly differentiated EAC on preoperative biopsy are typically sent for esophagectomy – a more invasive and riskier procedure – out of concern that ER will be noncurative.
“If poor differentiation was the only high-risk feature, these patients may have unnecessarily undergone esophagectomy,” Dr. Shah and colleagues wrote. “Especially in marginal surgical candidates, staging ER should be considered in patients with early esophageal cancer with preoperative biopsies showing poorly differentiated cancer.”
The investigators disclosed relationships with Medtronic, Lucid Diagnostics, Lumendi, and others.
Inaccurate preoperative biopsy findings could mean that patients who are candidates for endoscopic resection (ER) are unnecessarily undergoing esophagectomy, a procedure with greater risks of morbidity and mortality, reported Ravi S. Shah, MD, of Cleveland Clinic, and colleagues.
“It is unclear how accurate tumor differentiation on endoscopic biopsies is and if it can be used for clinical decision-making,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “Given that tumors may be considerably heterogeneous in gland formation, the limited amount of tissue obtained from endoscopic forceps biopsies may not be representative of the entire tumor for pathologic grading, which may result in discrepant tumor grading between biopsy and resection specimens.”
While previous studies have compared esophagogastroduodenoscopy-guided biopsy results with histological findings after surgical resection, scant evidence is available to compare biopsy findings with both surgically and endoscopically resected tissue.
Despite this potential knowledge gap, “many patients with poorly differentiated EAC on preresection biopsy do not undergo ER, with the belief that the final resection pathology would be noncurative,” the investigators noted.
To help clarify how congruent pre- and postoperative biopsies are for both resection methods, Dr. Shah and colleagues conducted a retrospective study involving 346 EAC lesions. Samples were drawn from 121 ERs and 225 esophagectomies performed at two tertiary referral centers. Preoperative and postoperative findings were compared for accuracy and for level of agreement via Gwet’s AC2 interrater analysis.
For all evaluable lesions, preoperative biopsy had an accuracy of 68%, with a “substantial” agreement coefficient (Gwet’s AC2, 0.70; P less than .001). Accuracy in the esophagectomy group was similar, at 72%, again with “substantial” agreement (Gwet’s AC2, 0.74; P less than .001). For the ER group, however, accuracy was just 56%, with a “moderate” level of agreement (Gwet’s AC2, 0.60; P less than .001).
“We speculate that the discrepancy of tumor differentiation on endoscopic forceps biopsies and resection specimens is due to nonrepresentative sampling of tumors to accurately determine the percentage of gland formation and thus tumor grade,” the investigators noted.
Further analysis showed that 22.7% of moderately differentiated tumors were upgraded to poorly differentiated upon final histology. Conversely, 19.6% of poorly differentiated tumors were downgraded to moderately differentiated. Downgrading was even more common among T1a tumors, 40% of which were changed from poorly to moderately differentiated between pre- and postprocedural histology.
These latter findings concerning downgrading are particularly relevant for clinical decision-making, the investigators noted, as patients with poorly differentiated EAC on preoperative biopsy are typically sent for esophagectomy – a more invasive and riskier procedure – out of concern that ER will be noncurative.
“If poor differentiation was the only high-risk feature, these patients may have unnecessarily undergone esophagectomy,” Dr. Shah and colleagues wrote. “Especially in marginal surgical candidates, staging ER should be considered in patients with early esophageal cancer with preoperative biopsies showing poorly differentiated cancer.”
The investigators disclosed relationships with Medtronic, Lucid Diagnostics, Lumendi, and others.
FROM TECHNIQUES AND INNOVATIONS IN GASTROINTESTINAL ENDOSCOPY
Report cards, additional observer improve adenoma detection rate
Although multimodal interventions like extra training with periodic feedback showed some signs of improving ADR, withdrawal time monitoring was not significantly associated with a better detection rate, reported Anshul Arora, MD, of Western University, London, Ont., and colleagues.
“Given the increased risk of postcolonoscopy colorectal cancer associated with low ADR, improving [this performance metric] has become a major focus for quality improvement,” the investigators wrote in Clinical Gastroenterology and Hepatology.
They noted that “numerous strategies” have been evaluated for this purpose, which may be sorted into three groups: endoscopy unit–level interventions (i.e., system changes), procedure-targeted interventions (i.e., technique changes), and technology-based interventions.
“Of these categories, endoscopy unit–level interventions are perhaps the easiest to implement widely because they generally require fewer changes in the technical aspect of how a colonoscopy is performed,” the investigators wrote. “Thus, the objective of this study was to conduct a systematic review and meta-analysis to identify endoscopy unit–level interventions aimed at improving ADRs and their effectiveness.”
To this end, Dr. Arora and colleagues analyzed data from 34 randomized controlled trials and observational studies involving 1,501 endoscopists and 371,041 procedures. They evaluated the relationship between ADR and implementation of four interventions: a performance report card, a multimodal intervention (e.g., training sessions with periodic feedback), presence of an additional observer, and withdrawal time monitoring.
Provision of report cards was associated with the greatest improvement in ADR, at 28% (odds ratio, 1.28; 95% confidence interval, 1.13-1.45; P less than .001), followed by presence of an additional observer, which bumped ADR by 25% (OR, 1.25; 95% CI, 1.09-1.43; P = .002). The impact of multimodal interventions was “borderline significant,” the investigators wrote, with an 18% improvement in ADR (OR, 1.18; 95% CI, 1.00-1.40; P = .05). In contrast, withdrawal time monitoring showed no significant benefit (OR, 1.35; 95% CI, 0.93-1.96; P = .11).
In their discussion, Dr. Arora and colleagues offered guidance on the use of report cards, which were associated with the greatest improvement in ADR.
“We found that benchmarking individual endoscopists against their peers was important for improving ADR performance because this was the common thread among all report card–based interventions,” they wrote. “In terms of the method of delivery for feedback, only one study used public reporting of colonoscopy quality indicators, whereas the rest delivered report cards privately to physicians. This suggests that confidential feedback did not impede self-improvement, which is desirable to avoid stigmatization of low ADR performers.”
The findings also suggest that additional observers can boost ADR without specialized training.
“[The benefit of an additional observer] may be explained by the presence of a second set of eyes to identify polyps or, more pragmatically, by the Hawthorne effect, whereby endoscopists may be more careful because they know someone else is watching the screen,” the investigators wrote. “Regardless, extra training for the observer does not seem to be necessary because the three RCTs [evaluating this intervention] all used endoscopy nurses who did not receive any additional polyp detection training. Thus, endoscopy unit nurses should be encouraged to speak up should they see a polyp the endoscopist missed.”
The investigators disclosed no conflicts of interest.
The effectiveness of colonoscopy to prevent colorectal cancer depends on the quality of the exam. Adenoma detection rate (ADR) is a validated quality indicator, associated with lower risk of postcolonoscopy colorectal cancer. There are multiple interventions that can improve endoscopists’ ADR, but it is unclear which ones are higher yield than others. This study summarizes the existing studies on various interventions and finds the largest increase in ADR with the use of physician report cards. This is not surprising, as report cards both provide measurement and are an intervention for improvement.
Interestingly the included studies mostly used individual confidential report cards, and demonstrated an improvement in ADR. Having a second set of eyes looking at the monitor was also associated with increase in ADR. Whether it’s the observer picking up missed polyps, or the endoscopist doing a more thorough exam because someone else is watching the screen, is unclear. This is the same principle that current computer assisted detection (CADe) devices help with. While having a second observer may not be practical or cost effective, and CADe is expensive, the take-away is that there are multiple ways to improve ADR, and at the very least every physician should be receiving report cards or feedback on their quality indicators and working towards achieving and exceeding the minimum benchmarks.
Aasma Shaukat, MD, MPH, is the Robert M. and Mary H. Glickman professor of medicine, New York University Grossman School of Medicine where she also holds a professorship in population health. She serves as director of outcomes research in the division of gastroenterology and hepatology, and codirector of Translational Research Education and Careers (TREC). She disclosed serving as an adviser for Motus-GI and Iterative Health.
The effectiveness of colonoscopy to prevent colorectal cancer depends on the quality of the exam. Adenoma detection rate (ADR) is a validated quality indicator, associated with lower risk of postcolonoscopy colorectal cancer. There are multiple interventions that can improve endoscopists’ ADR, but it is unclear which ones are higher yield than others. This study summarizes the existing studies on various interventions and finds the largest increase in ADR with the use of physician report cards. This is not surprising, as report cards both provide measurement and are an intervention for improvement.
Interestingly the included studies mostly used individual confidential report cards, and demonstrated an improvement in ADR. Having a second set of eyes looking at the monitor was also associated with increase in ADR. Whether it’s the observer picking up missed polyps, or the endoscopist doing a more thorough exam because someone else is watching the screen, is unclear. This is the same principle that current computer assisted detection (CADe) devices help with. While having a second observer may not be practical or cost effective, and CADe is expensive, the take-away is that there are multiple ways to improve ADR, and at the very least every physician should be receiving report cards or feedback on their quality indicators and working towards achieving and exceeding the minimum benchmarks.
Aasma Shaukat, MD, MPH, is the Robert M. and Mary H. Glickman professor of medicine, New York University Grossman School of Medicine where she also holds a professorship in population health. She serves as director of outcomes research in the division of gastroenterology and hepatology, and codirector of Translational Research Education and Careers (TREC). She disclosed serving as an adviser for Motus-GI and Iterative Health.
The effectiveness of colonoscopy to prevent colorectal cancer depends on the quality of the exam. Adenoma detection rate (ADR) is a validated quality indicator, associated with lower risk of postcolonoscopy colorectal cancer. There are multiple interventions that can improve endoscopists’ ADR, but it is unclear which ones are higher yield than others. This study summarizes the existing studies on various interventions and finds the largest increase in ADR with the use of physician report cards. This is not surprising, as report cards both provide measurement and are an intervention for improvement.
Interestingly the included studies mostly used individual confidential report cards, and demonstrated an improvement in ADR. Having a second set of eyes looking at the monitor was also associated with increase in ADR. Whether it’s the observer picking up missed polyps, or the endoscopist doing a more thorough exam because someone else is watching the screen, is unclear. This is the same principle that current computer assisted detection (CADe) devices help with. While having a second observer may not be practical or cost effective, and CADe is expensive, the take-away is that there are multiple ways to improve ADR, and at the very least every physician should be receiving report cards or feedback on their quality indicators and working towards achieving and exceeding the minimum benchmarks.
Aasma Shaukat, MD, MPH, is the Robert M. and Mary H. Glickman professor of medicine, New York University Grossman School of Medicine where she also holds a professorship in population health. She serves as director of outcomes research in the division of gastroenterology and hepatology, and codirector of Translational Research Education and Careers (TREC). She disclosed serving as an adviser for Motus-GI and Iterative Health.
Although multimodal interventions like extra training with periodic feedback showed some signs of improving ADR, withdrawal time monitoring was not significantly associated with a better detection rate, reported Anshul Arora, MD, of Western University, London, Ont., and colleagues.
“Given the increased risk of postcolonoscopy colorectal cancer associated with low ADR, improving [this performance metric] has become a major focus for quality improvement,” the investigators wrote in Clinical Gastroenterology and Hepatology.
They noted that “numerous strategies” have been evaluated for this purpose, which may be sorted into three groups: endoscopy unit–level interventions (i.e., system changes), procedure-targeted interventions (i.e., technique changes), and technology-based interventions.
“Of these categories, endoscopy unit–level interventions are perhaps the easiest to implement widely because they generally require fewer changes in the technical aspect of how a colonoscopy is performed,” the investigators wrote. “Thus, the objective of this study was to conduct a systematic review and meta-analysis to identify endoscopy unit–level interventions aimed at improving ADRs and their effectiveness.”
To this end, Dr. Arora and colleagues analyzed data from 34 randomized controlled trials and observational studies involving 1,501 endoscopists and 371,041 procedures. They evaluated the relationship between ADR and implementation of four interventions: a performance report card, a multimodal intervention (e.g., training sessions with periodic feedback), presence of an additional observer, and withdrawal time monitoring.
Provision of report cards was associated with the greatest improvement in ADR, at 28% (odds ratio, 1.28; 95% confidence interval, 1.13-1.45; P less than .001), followed by presence of an additional observer, which bumped ADR by 25% (OR, 1.25; 95% CI, 1.09-1.43; P = .002). The impact of multimodal interventions was “borderline significant,” the investigators wrote, with an 18% improvement in ADR (OR, 1.18; 95% CI, 1.00-1.40; P = .05). In contrast, withdrawal time monitoring showed no significant benefit (OR, 1.35; 95% CI, 0.93-1.96; P = .11).
In their discussion, Dr. Arora and colleagues offered guidance on the use of report cards, which were associated with the greatest improvement in ADR.
“We found that benchmarking individual endoscopists against their peers was important for improving ADR performance because this was the common thread among all report card–based interventions,” they wrote. “In terms of the method of delivery for feedback, only one study used public reporting of colonoscopy quality indicators, whereas the rest delivered report cards privately to physicians. This suggests that confidential feedback did not impede self-improvement, which is desirable to avoid stigmatization of low ADR performers.”
The findings also suggest that additional observers can boost ADR without specialized training.
“[The benefit of an additional observer] may be explained by the presence of a second set of eyes to identify polyps or, more pragmatically, by the Hawthorne effect, whereby endoscopists may be more careful because they know someone else is watching the screen,” the investigators wrote. “Regardless, extra training for the observer does not seem to be necessary because the three RCTs [evaluating this intervention] all used endoscopy nurses who did not receive any additional polyp detection training. Thus, endoscopy unit nurses should be encouraged to speak up should they see a polyp the endoscopist missed.”
The investigators disclosed no conflicts of interest.
Although multimodal interventions like extra training with periodic feedback showed some signs of improving ADR, withdrawal time monitoring was not significantly associated with a better detection rate, reported Anshul Arora, MD, of Western University, London, Ont., and colleagues.
“Given the increased risk of postcolonoscopy colorectal cancer associated with low ADR, improving [this performance metric] has become a major focus for quality improvement,” the investigators wrote in Clinical Gastroenterology and Hepatology.
They noted that “numerous strategies” have been evaluated for this purpose, which may be sorted into three groups: endoscopy unit–level interventions (i.e., system changes), procedure-targeted interventions (i.e., technique changes), and technology-based interventions.
“Of these categories, endoscopy unit–level interventions are perhaps the easiest to implement widely because they generally require fewer changes in the technical aspect of how a colonoscopy is performed,” the investigators wrote. “Thus, the objective of this study was to conduct a systematic review and meta-analysis to identify endoscopy unit–level interventions aimed at improving ADRs and their effectiveness.”
To this end, Dr. Arora and colleagues analyzed data from 34 randomized controlled trials and observational studies involving 1,501 endoscopists and 371,041 procedures. They evaluated the relationship between ADR and implementation of four interventions: a performance report card, a multimodal intervention (e.g., training sessions with periodic feedback), presence of an additional observer, and withdrawal time monitoring.
Provision of report cards was associated with the greatest improvement in ADR, at 28% (odds ratio, 1.28; 95% confidence interval, 1.13-1.45; P less than .001), followed by presence of an additional observer, which bumped ADR by 25% (OR, 1.25; 95% CI, 1.09-1.43; P = .002). The impact of multimodal interventions was “borderline significant,” the investigators wrote, with an 18% improvement in ADR (OR, 1.18; 95% CI, 1.00-1.40; P = .05). In contrast, withdrawal time monitoring showed no significant benefit (OR, 1.35; 95% CI, 0.93-1.96; P = .11).
In their discussion, Dr. Arora and colleagues offered guidance on the use of report cards, which were associated with the greatest improvement in ADR.
“We found that benchmarking individual endoscopists against their peers was important for improving ADR performance because this was the common thread among all report card–based interventions,” they wrote. “In terms of the method of delivery for feedback, only one study used public reporting of colonoscopy quality indicators, whereas the rest delivered report cards privately to physicians. This suggests that confidential feedback did not impede self-improvement, which is desirable to avoid stigmatization of low ADR performers.”
The findings also suggest that additional observers can boost ADR without specialized training.
“[The benefit of an additional observer] may be explained by the presence of a second set of eyes to identify polyps or, more pragmatically, by the Hawthorne effect, whereby endoscopists may be more careful because they know someone else is watching the screen,” the investigators wrote. “Regardless, extra training for the observer does not seem to be necessary because the three RCTs [evaluating this intervention] all used endoscopy nurses who did not receive any additional polyp detection training. Thus, endoscopy unit nurses should be encouraged to speak up should they see a polyp the endoscopist missed.”
The investigators disclosed no conflicts of interest.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Experts offer guidance on GLP-1 receptor agonists prior to endoscopy
to support the success of endoscopic procedures, according to a new Clinical Practice Update from the American Gastroenterological Association.
Use of glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs) has been associated with delayed gastric emptying, which raises a clinical concern about performing endoscopic procedures, especially upper endoscopies in patients using these medications, wrote Jana G. Al Hashash, MD, MSc, of the Mayo Clinic, Jacksonville, Fla., and colleagues.
The Clinical Practice Update (CPU), published in Clinical Gastroenterology and Hepatology, reviews the evidence and provides expert advice for clinicians on the evolving landscape of patients taking GLP-1 receptor agonists prior to endoscopic procedures. The CPU reflects on the most recent literature and the experience of the authors, all experts in bariatric medicine and/or endoscopy.
The American Society of Anesthesiologists (ASA) issued guidance that reflects concerns for the risk of aspiration in sedated patients because of delayed gastric motility from the use of GLP-1 RAs. The ASA advises patients on daily doses of GLP-1 RAs to refrain from taking the medications on the day of a procedure; those on weekly dosing should hold the drugs for a week prior to surgery.
However, the ASA suggestions do not differentiate based on the indication for the drug or for the type of procedure, and questions remain as to whether these changes are necessary and/or effective, the CPU authors said. The ASA’s guidance is based mainly on expert opinion, as not enough published evidence on this topic exists for a robust review and formal guideline, they added.
Recently, a multisociety statement from the AGA, AASLD, ACG, ASGE, and NASPGHAN noted that widespread implementation of the ASA guidance could be associated with unintended harms to patients.
Therefore, the AGA CPU suggests an individualized approach to managing patients on GLP-1 RAs in a pre-endoscopic setting.
For patients on GLP-1 RAs for diabetes management, discontinuing prior to endoscopic may not be worth the potential risk. Also, consider not only the dose and frequency of the GLP-1 RAs but also other comorbidities, medications, and potential gastrointestinal side effects.
“If patients taking GLP-1 RAs solely for weight loss can be identified beforehand, a dose of the medication could be withheld prior to endoscopy with likely little harm, though this should not be considered mandatory or evidence-based,” the CPU authors wrote.
However, withholding a single dose of medication may not be enough for an individual’s gastric motility to return to normal, the authors emphasized.
Additionally, the ASA’s suggestions for holding GLP-1 RAs add complexity to periprocedural medication management, which may strain resources and delay care.
The AGA CPU offers the following guidance for patients on GLP-1 RAs prior to endoscopy:
In general, patients using GLP-1 RAs who have followed the standard perioperative procedures, usually an 8-hour solid-food fast and 2-hour liquid fast, and who do not have symptoms such as ongoing nausea, vomiting, or abdominal distension should proceed with upper and/or lower endoscopy.
For symptomatic patients who may experience negative clinical consequences of endoscopy if delayed, consider rapid-sequence intubation, but the authors acknowledge that this option may not be possible in most ambulatory or office-based endoscopy settings.
Finally, consider placing patients on a liquid diet the day before a sedated procedure instead of stopping GLP-1 RAs; this strategy is “more consistent with the holistic approach to preprocedural management of other similar condi-tions,” the authors said.
The current CPU endorses the multi-society statement that puts patient safety first and encourages AGA members to follow best practices when performing endoscopies on patients who are using GLP-1 RAs, in the absence of actionable data, the authors concluded.
The Clinical Practice Update received no outside funding. Lead author Dr. Al Hashash had no financial conflicts to disclose.
to support the success of endoscopic procedures, according to a new Clinical Practice Update from the American Gastroenterological Association.
Use of glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs) has been associated with delayed gastric emptying, which raises a clinical concern about performing endoscopic procedures, especially upper endoscopies in patients using these medications, wrote Jana G. Al Hashash, MD, MSc, of the Mayo Clinic, Jacksonville, Fla., and colleagues.
The Clinical Practice Update (CPU), published in Clinical Gastroenterology and Hepatology, reviews the evidence and provides expert advice for clinicians on the evolving landscape of patients taking GLP-1 receptor agonists prior to endoscopic procedures. The CPU reflects on the most recent literature and the experience of the authors, all experts in bariatric medicine and/or endoscopy.
The American Society of Anesthesiologists (ASA) issued guidance that reflects concerns for the risk of aspiration in sedated patients because of delayed gastric motility from the use of GLP-1 RAs. The ASA advises patients on daily doses of GLP-1 RAs to refrain from taking the medications on the day of a procedure; those on weekly dosing should hold the drugs for a week prior to surgery.
However, the ASA suggestions do not differentiate based on the indication for the drug or for the type of procedure, and questions remain as to whether these changes are necessary and/or effective, the CPU authors said. The ASA’s guidance is based mainly on expert opinion, as not enough published evidence on this topic exists for a robust review and formal guideline, they added.
Recently, a multisociety statement from the AGA, AASLD, ACG, ASGE, and NASPGHAN noted that widespread implementation of the ASA guidance could be associated with unintended harms to patients.
Therefore, the AGA CPU suggests an individualized approach to managing patients on GLP-1 RAs in a pre-endoscopic setting.
For patients on GLP-1 RAs for diabetes management, discontinuing prior to endoscopic may not be worth the potential risk. Also, consider not only the dose and frequency of the GLP-1 RAs but also other comorbidities, medications, and potential gastrointestinal side effects.
“If patients taking GLP-1 RAs solely for weight loss can be identified beforehand, a dose of the medication could be withheld prior to endoscopy with likely little harm, though this should not be considered mandatory or evidence-based,” the CPU authors wrote.
However, withholding a single dose of medication may not be enough for an individual’s gastric motility to return to normal, the authors emphasized.
Additionally, the ASA’s suggestions for holding GLP-1 RAs add complexity to periprocedural medication management, which may strain resources and delay care.
The AGA CPU offers the following guidance for patients on GLP-1 RAs prior to endoscopy:
In general, patients using GLP-1 RAs who have followed the standard perioperative procedures, usually an 8-hour solid-food fast and 2-hour liquid fast, and who do not have symptoms such as ongoing nausea, vomiting, or abdominal distension should proceed with upper and/or lower endoscopy.
For symptomatic patients who may experience negative clinical consequences of endoscopy if delayed, consider rapid-sequence intubation, but the authors acknowledge that this option may not be possible in most ambulatory or office-based endoscopy settings.
Finally, consider placing patients on a liquid diet the day before a sedated procedure instead of stopping GLP-1 RAs; this strategy is “more consistent with the holistic approach to preprocedural management of other similar condi-tions,” the authors said.
The current CPU endorses the multi-society statement that puts patient safety first and encourages AGA members to follow best practices when performing endoscopies on patients who are using GLP-1 RAs, in the absence of actionable data, the authors concluded.
The Clinical Practice Update received no outside funding. Lead author Dr. Al Hashash had no financial conflicts to disclose.
to support the success of endoscopic procedures, according to a new Clinical Practice Update from the American Gastroenterological Association.
Use of glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1 RAs) has been associated with delayed gastric emptying, which raises a clinical concern about performing endoscopic procedures, especially upper endoscopies in patients using these medications, wrote Jana G. Al Hashash, MD, MSc, of the Mayo Clinic, Jacksonville, Fla., and colleagues.
The Clinical Practice Update (CPU), published in Clinical Gastroenterology and Hepatology, reviews the evidence and provides expert advice for clinicians on the evolving landscape of patients taking GLP-1 receptor agonists prior to endoscopic procedures. The CPU reflects on the most recent literature and the experience of the authors, all experts in bariatric medicine and/or endoscopy.
The American Society of Anesthesiologists (ASA) issued guidance that reflects concerns for the risk of aspiration in sedated patients because of delayed gastric motility from the use of GLP-1 RAs. The ASA advises patients on daily doses of GLP-1 RAs to refrain from taking the medications on the day of a procedure; those on weekly dosing should hold the drugs for a week prior to surgery.
However, the ASA suggestions do not differentiate based on the indication for the drug or for the type of procedure, and questions remain as to whether these changes are necessary and/or effective, the CPU authors said. The ASA’s guidance is based mainly on expert opinion, as not enough published evidence on this topic exists for a robust review and formal guideline, they added.
Recently, a multisociety statement from the AGA, AASLD, ACG, ASGE, and NASPGHAN noted that widespread implementation of the ASA guidance could be associated with unintended harms to patients.
Therefore, the AGA CPU suggests an individualized approach to managing patients on GLP-1 RAs in a pre-endoscopic setting.
For patients on GLP-1 RAs for diabetes management, discontinuing prior to endoscopic may not be worth the potential risk. Also, consider not only the dose and frequency of the GLP-1 RAs but also other comorbidities, medications, and potential gastrointestinal side effects.
“If patients taking GLP-1 RAs solely for weight loss can be identified beforehand, a dose of the medication could be withheld prior to endoscopy with likely little harm, though this should not be considered mandatory or evidence-based,” the CPU authors wrote.
However, withholding a single dose of medication may not be enough for an individual’s gastric motility to return to normal, the authors emphasized.
Additionally, the ASA’s suggestions for holding GLP-1 RAs add complexity to periprocedural medication management, which may strain resources and delay care.
The AGA CPU offers the following guidance for patients on GLP-1 RAs prior to endoscopy:
In general, patients using GLP-1 RAs who have followed the standard perioperative procedures, usually an 8-hour solid-food fast and 2-hour liquid fast, and who do not have symptoms such as ongoing nausea, vomiting, or abdominal distension should proceed with upper and/or lower endoscopy.
For symptomatic patients who may experience negative clinical consequences of endoscopy if delayed, consider rapid-sequence intubation, but the authors acknowledge that this option may not be possible in most ambulatory or office-based endoscopy settings.
Finally, consider placing patients on a liquid diet the day before a sedated procedure instead of stopping GLP-1 RAs; this strategy is “more consistent with the holistic approach to preprocedural management of other similar condi-tions,” the authors said.
The current CPU endorses the multi-society statement that puts patient safety first and encourages AGA members to follow best practices when performing endoscopies on patients who are using GLP-1 RAs, in the absence of actionable data, the authors concluded.
The Clinical Practice Update received no outside funding. Lead author Dr. Al Hashash had no financial conflicts to disclose.
CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Nano drug delivery could overcome toxicity in HCC to enable safer, more effective therapy
leading to safer treatment and better outcomes, according to a recent review.
Nanomedicines homing in on the Wnt/beta-catenin signaling pathway could be particularly impactful, Mamatha Bhat, MD, PhD, a hepatologist and clinician-scientist at Toronto General Hospital Research Institute, and colleagues reported, as this is one of the most up-regulated pathways in HCC.
To date, however, agents addressing this pathway have been hindered by off-target toxicity, suggesting that more work is needed to develop the right payload for nanoparticle delivery, the investigators wrote in Gastro Hep Advances.
“Although nanotherapeutics offers an unmatched improvement in drug delivery, due to the limited impact and treatment-resistance demonstrated by the current systemic therapies, there is currently no approved nanomedicine for the treatment of HCC,” the investigators wrote. “Therefore, it is of utmost importance to dig deeper into understanding the signaling pathways that govern hepatocarcinogenesis and identify novel targets that can be used to develop more specific and targeted nanotherapies.”
Their review focused on the Wnt/beta-catenin signaling pathway, but first, Dr. Bhat and colleagues discussed the characteristics of inorganic versus lipid nanoparticles, as these differences can determine liver uptake.
Inorganic nanoparticles have a high surface-to-volume ratio, leading to increased surface charges that enhance cellular uptake. However, they are prone to oxidation, requiring surface modifications or short circulation times to prevent degradation. These nanoparticles are limited in delivering chemotherapeutic drugs and peptides, and are not suitable for encapsulating nucleic acids.
In contrast, lipid nanoparticles are preferred for targeted delivery in HCC, according to the investigators. They have a natural affinity for apolipoprotein E (apo E), resembling lipoproteins, which aids in specific liver cell targeting. When lipid nanoparticles enter the bloodstream, they interact with apo E–rich lipoproteins like HDL cholesterol and LDL cholesterol, leading to formation of complexes recognized by LDL cholesterol receptors on liver cells. This triggers receptor-mediated endocytosis, internalizing apo E–lipid nanoparticle complexes into HCC cells.
The other major variable is the selected treatment target. Dr. Bhat and colleagues made the case for the Wnt/beta-catenin signaling pathway based on alterations found in approximately two-thirds of patients with HCC.
“Aberrant activation of this pathway and mutations in genes encoding key components are characteristic to hepatocarcinogenesis and promote tumor growth and dedifferentiation,” they wrote.
Although beta-catenin itself makes for an obvious molecular target, especially considering known associations with drug resistance, its flat structure lacks deep binding pockets that would be suitable for small-molecule inhibitors, and any available pockets may be altered by numerous posttranscriptional modifications. Instead, beta-catenin could be indirectly modulated by nanoparticle-mediated siRNA therapy, as this would allow for precise delivery of siRNA to cancer cells, minimizing off-target toxicity.
Alternative approaches could involve targeting proteasomal degradation of beta-catenin, transcriptional coactivators of beta-catenin, or different oncogenes in HCC, all of which are described in further detail in the review, along with promising preclinical findings.
“With ongoing advancements in nanotechnology, there is optimism that it will continue to play a vital role in overcoming the challenges associated with HCC management and contribute to further advancements in therapeutic outcomes for patients,” the authors concluded.
One coauthor disclosed external funding by a Mitacs Elevate postdoctoral fellowship in collaboration with Highland Therapeutics. The remaining authors disclosed no conflicts of interest.
Hepatocellular Carcinoma (HCC) remains a major health problem associate with increasing prevalence and mortality rates worldwide. Around 50-60% of HCC patients are exposed to systemic therapies during their natural history. Atezolizumab plus bevacizumab (median OS: 19.2mo, ORR 30%), and durvalumab plus tremelimumab (median OS: 16.4mo, ORR: 20%) are considered first line treatment options for advanced HCC, and sorafenib or lenvatinib are recommended for patients with any contraindication for immune checkpoint inhibitors. These therapies are indicated for ‘all comers’ an no molecular markers /personalize medicine is currently available for this cancer. The lack of precision oncology relates to the fact that the most common mutations ( i.e TERT, TP53,CTNNB1) are unactionable targets. In this scenario, advances in precision oncology are an unmet medical need.
The Wnt/B-catenin signaling pathway is a master regulator of oncogenesis in HCC and defines one of the molecular subclasses characterized by CTNNB1 mutations (~25-30%) or AXIN1 mutations (~5-10%). Most of these tumors have an immune excluded/desert phenotype. Thus, targeting this pathway is expected to provide a primary antitumoral effect along with an immune-modulatory effect rescuing cases with an immune excluded phenotype.
In this review, the authors discuss the applicability of precision oncology in HCC targeting the WNT/B-catenin pathway by inhibiting the interaction with transcriptional coactivators of B-catenin such as CBP and TCF or by enhancing the proteasomal degradation of B-catenin, reducing pathway activation, with drugs like Tankyrase inhibitors and casein kinase 1a activators. These approaches are challenging due to its associated off-target toxicity and its complexity. To overcome these caveats, the author propose to utilization of nanotechnology to deliver Wnt inhibitors, an approach that currently requires further research to refine the most promising strategies and drugs suitable for clinical implementation.
Josep M. Llovet, MD, PhD, FAASLD, director, Mount Sinai Liver Cancer Program in New York, and head of translational research in the Liver Cancer Group, Liver Unit, IDIBAPS, Hospital Clínic Barcelona. Dr. Llovet receives research support from Bayer Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb and Ipsen.
Hepatocellular Carcinoma (HCC) remains a major health problem associate with increasing prevalence and mortality rates worldwide. Around 50-60% of HCC patients are exposed to systemic therapies during their natural history. Atezolizumab plus bevacizumab (median OS: 19.2mo, ORR 30%), and durvalumab plus tremelimumab (median OS: 16.4mo, ORR: 20%) are considered first line treatment options for advanced HCC, and sorafenib or lenvatinib are recommended for patients with any contraindication for immune checkpoint inhibitors. These therapies are indicated for ‘all comers’ an no molecular markers /personalize medicine is currently available for this cancer. The lack of precision oncology relates to the fact that the most common mutations ( i.e TERT, TP53,CTNNB1) are unactionable targets. In this scenario, advances in precision oncology are an unmet medical need.
The Wnt/B-catenin signaling pathway is a master regulator of oncogenesis in HCC and defines one of the molecular subclasses characterized by CTNNB1 mutations (~25-30%) or AXIN1 mutations (~5-10%). Most of these tumors have an immune excluded/desert phenotype. Thus, targeting this pathway is expected to provide a primary antitumoral effect along with an immune-modulatory effect rescuing cases with an immune excluded phenotype.
In this review, the authors discuss the applicability of precision oncology in HCC targeting the WNT/B-catenin pathway by inhibiting the interaction with transcriptional coactivators of B-catenin such as CBP and TCF or by enhancing the proteasomal degradation of B-catenin, reducing pathway activation, with drugs like Tankyrase inhibitors and casein kinase 1a activators. These approaches are challenging due to its associated off-target toxicity and its complexity. To overcome these caveats, the author propose to utilization of nanotechnology to deliver Wnt inhibitors, an approach that currently requires further research to refine the most promising strategies and drugs suitable for clinical implementation.
Josep M. Llovet, MD, PhD, FAASLD, director, Mount Sinai Liver Cancer Program in New York, and head of translational research in the Liver Cancer Group, Liver Unit, IDIBAPS, Hospital Clínic Barcelona. Dr. Llovet receives research support from Bayer Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb and Ipsen.
Hepatocellular Carcinoma (HCC) remains a major health problem associate with increasing prevalence and mortality rates worldwide. Around 50-60% of HCC patients are exposed to systemic therapies during their natural history. Atezolizumab plus bevacizumab (median OS: 19.2mo, ORR 30%), and durvalumab plus tremelimumab (median OS: 16.4mo, ORR: 20%) are considered first line treatment options for advanced HCC, and sorafenib or lenvatinib are recommended for patients with any contraindication for immune checkpoint inhibitors. These therapies are indicated for ‘all comers’ an no molecular markers /personalize medicine is currently available for this cancer. The lack of precision oncology relates to the fact that the most common mutations ( i.e TERT, TP53,CTNNB1) are unactionable targets. In this scenario, advances in precision oncology are an unmet medical need.
The Wnt/B-catenin signaling pathway is a master regulator of oncogenesis in HCC and defines one of the molecular subclasses characterized by CTNNB1 mutations (~25-30%) or AXIN1 mutations (~5-10%). Most of these tumors have an immune excluded/desert phenotype. Thus, targeting this pathway is expected to provide a primary antitumoral effect along with an immune-modulatory effect rescuing cases with an immune excluded phenotype.
In this review, the authors discuss the applicability of precision oncology in HCC targeting the WNT/B-catenin pathway by inhibiting the interaction with transcriptional coactivators of B-catenin such as CBP and TCF or by enhancing the proteasomal degradation of B-catenin, reducing pathway activation, with drugs like Tankyrase inhibitors and casein kinase 1a activators. These approaches are challenging due to its associated off-target toxicity and its complexity. To overcome these caveats, the author propose to utilization of nanotechnology to deliver Wnt inhibitors, an approach that currently requires further research to refine the most promising strategies and drugs suitable for clinical implementation.
Josep M. Llovet, MD, PhD, FAASLD, director, Mount Sinai Liver Cancer Program in New York, and head of translational research in the Liver Cancer Group, Liver Unit, IDIBAPS, Hospital Clínic Barcelona. Dr. Llovet receives research support from Bayer Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb and Ipsen.
leading to safer treatment and better outcomes, according to a recent review.
Nanomedicines homing in on the Wnt/beta-catenin signaling pathway could be particularly impactful, Mamatha Bhat, MD, PhD, a hepatologist and clinician-scientist at Toronto General Hospital Research Institute, and colleagues reported, as this is one of the most up-regulated pathways in HCC.
To date, however, agents addressing this pathway have been hindered by off-target toxicity, suggesting that more work is needed to develop the right payload for nanoparticle delivery, the investigators wrote in Gastro Hep Advances.
“Although nanotherapeutics offers an unmatched improvement in drug delivery, due to the limited impact and treatment-resistance demonstrated by the current systemic therapies, there is currently no approved nanomedicine for the treatment of HCC,” the investigators wrote. “Therefore, it is of utmost importance to dig deeper into understanding the signaling pathways that govern hepatocarcinogenesis and identify novel targets that can be used to develop more specific and targeted nanotherapies.”
Their review focused on the Wnt/beta-catenin signaling pathway, but first, Dr. Bhat and colleagues discussed the characteristics of inorganic versus lipid nanoparticles, as these differences can determine liver uptake.
Inorganic nanoparticles have a high surface-to-volume ratio, leading to increased surface charges that enhance cellular uptake. However, they are prone to oxidation, requiring surface modifications or short circulation times to prevent degradation. These nanoparticles are limited in delivering chemotherapeutic drugs and peptides, and are not suitable for encapsulating nucleic acids.
In contrast, lipid nanoparticles are preferred for targeted delivery in HCC, according to the investigators. They have a natural affinity for apolipoprotein E (apo E), resembling lipoproteins, which aids in specific liver cell targeting. When lipid nanoparticles enter the bloodstream, they interact with apo E–rich lipoproteins like HDL cholesterol and LDL cholesterol, leading to formation of complexes recognized by LDL cholesterol receptors on liver cells. This triggers receptor-mediated endocytosis, internalizing apo E–lipid nanoparticle complexes into HCC cells.
The other major variable is the selected treatment target. Dr. Bhat and colleagues made the case for the Wnt/beta-catenin signaling pathway based on alterations found in approximately two-thirds of patients with HCC.
“Aberrant activation of this pathway and mutations in genes encoding key components are characteristic to hepatocarcinogenesis and promote tumor growth and dedifferentiation,” they wrote.
Although beta-catenin itself makes for an obvious molecular target, especially considering known associations with drug resistance, its flat structure lacks deep binding pockets that would be suitable for small-molecule inhibitors, and any available pockets may be altered by numerous posttranscriptional modifications. Instead, beta-catenin could be indirectly modulated by nanoparticle-mediated siRNA therapy, as this would allow for precise delivery of siRNA to cancer cells, minimizing off-target toxicity.
Alternative approaches could involve targeting proteasomal degradation of beta-catenin, transcriptional coactivators of beta-catenin, or different oncogenes in HCC, all of which are described in further detail in the review, along with promising preclinical findings.
“With ongoing advancements in nanotechnology, there is optimism that it will continue to play a vital role in overcoming the challenges associated with HCC management and contribute to further advancements in therapeutic outcomes for patients,” the authors concluded.
One coauthor disclosed external funding by a Mitacs Elevate postdoctoral fellowship in collaboration with Highland Therapeutics. The remaining authors disclosed no conflicts of interest.
leading to safer treatment and better outcomes, according to a recent review.
Nanomedicines homing in on the Wnt/beta-catenin signaling pathway could be particularly impactful, Mamatha Bhat, MD, PhD, a hepatologist and clinician-scientist at Toronto General Hospital Research Institute, and colleagues reported, as this is one of the most up-regulated pathways in HCC.
To date, however, agents addressing this pathway have been hindered by off-target toxicity, suggesting that more work is needed to develop the right payload for nanoparticle delivery, the investigators wrote in Gastro Hep Advances.
“Although nanotherapeutics offers an unmatched improvement in drug delivery, due to the limited impact and treatment-resistance demonstrated by the current systemic therapies, there is currently no approved nanomedicine for the treatment of HCC,” the investigators wrote. “Therefore, it is of utmost importance to dig deeper into understanding the signaling pathways that govern hepatocarcinogenesis and identify novel targets that can be used to develop more specific and targeted nanotherapies.”
Their review focused on the Wnt/beta-catenin signaling pathway, but first, Dr. Bhat and colleagues discussed the characteristics of inorganic versus lipid nanoparticles, as these differences can determine liver uptake.
Inorganic nanoparticles have a high surface-to-volume ratio, leading to increased surface charges that enhance cellular uptake. However, they are prone to oxidation, requiring surface modifications or short circulation times to prevent degradation. These nanoparticles are limited in delivering chemotherapeutic drugs and peptides, and are not suitable for encapsulating nucleic acids.
In contrast, lipid nanoparticles are preferred for targeted delivery in HCC, according to the investigators. They have a natural affinity for apolipoprotein E (apo E), resembling lipoproteins, which aids in specific liver cell targeting. When lipid nanoparticles enter the bloodstream, they interact with apo E–rich lipoproteins like HDL cholesterol and LDL cholesterol, leading to formation of complexes recognized by LDL cholesterol receptors on liver cells. This triggers receptor-mediated endocytosis, internalizing apo E–lipid nanoparticle complexes into HCC cells.
The other major variable is the selected treatment target. Dr. Bhat and colleagues made the case for the Wnt/beta-catenin signaling pathway based on alterations found in approximately two-thirds of patients with HCC.
“Aberrant activation of this pathway and mutations in genes encoding key components are characteristic to hepatocarcinogenesis and promote tumor growth and dedifferentiation,” they wrote.
Although beta-catenin itself makes for an obvious molecular target, especially considering known associations with drug resistance, its flat structure lacks deep binding pockets that would be suitable for small-molecule inhibitors, and any available pockets may be altered by numerous posttranscriptional modifications. Instead, beta-catenin could be indirectly modulated by nanoparticle-mediated siRNA therapy, as this would allow for precise delivery of siRNA to cancer cells, minimizing off-target toxicity.
Alternative approaches could involve targeting proteasomal degradation of beta-catenin, transcriptional coactivators of beta-catenin, or different oncogenes in HCC, all of which are described in further detail in the review, along with promising preclinical findings.
“With ongoing advancements in nanotechnology, there is optimism that it will continue to play a vital role in overcoming the challenges associated with HCC management and contribute to further advancements in therapeutic outcomes for patients,” the authors concluded.
One coauthor disclosed external funding by a Mitacs Elevate postdoctoral fellowship in collaboration with Highland Therapeutics. The remaining authors disclosed no conflicts of interest.
FROM GASTRO HEP ADVANCES
Neutrophils may offer therapeutic target for Wilson’s disease
Inhibiting neutrophil function via transforming growth factor (TGF-beta 1) inhibition or methylation inhibition reduced parenchymal liver fibrosis and injury while improving liver function in a mouse model of Wilson’s disease, shows new research published in Cellular and Molecular Gastroenterology and Hepatology.
Also called progressive hepatolenticular degeneration, Wilson’s disease is an inherited nervous system disorder that can occur as a result of severe liver disease. It is caused by variants in the ATP7B gene which can lead to abnormalities in copper metabolism that lead to accumulation of the heavy metal in the liver and brain, resulting in damage to both organs. Approximately 60% of patients with Wilson’s disease present with hepatic syndromes, and of those 50%-60% go on to develop liver cirrhosis.
Current treatments aim to address metal deposition, but this approach is poorly tolerated by many patients, wrote investigators who were led by Junping Shi, MD, PhD, of the Institute of Hepatology and Metabolic Diseases, The Affiliated Hospital of Hangzhou Normal University, China.
“Drug interventions (such as copper chelators and zinc salts) reduce pathologic copper deposition, but side effects can be observed in up to 40% of patients during treatment and even after years of treatment, particularly nephropathy, autoimmune conditions, and skin changes,” the investigators wrote. “Liver transplantation is an effective treatment for Wilson’s disease, particularly for patients with end-stage liver disease, but donor shortages and lifelong immunosuppression limit its use. Therefore, alternative treatments with higher specificity in Wilson’s disease patients are urgently needed.”
The present study explored the underlying metabolic abnormalities in Wilson’s disease that result in liver injury and fibrosis, and related therapeutic approaches. Based on previous studies that have shown a relationship between persistent neutrophil infiltration and chronic tissue inflammation and damage, the investigators sought to explore the role of neutrophils in Wilson’s disease, with a focus on the N2 subtype.
First, they analyzed neutrophil populations in the livers of Atp7b–/– mice and atp7b–/– zebrafish, both of which are established animal models of Wilson’s disease. Compared with the wild-type comparison animals, the livers of disease model animals showed increased neutrophil infiltration, in terms of both count and density.
In one of several related experiments, administering a neutrophil agonist in the presence of copper led to significantly greater neutrophil infiltration in mutant versus wild-type fish, as well as greater increases in lipid droplets and disorganized tissue structure, which serve as markers of disease activity.
“Collectively, these data suggested that neutrophils infiltrated the liver and accelerated liver defects in Wilson’s disease,” the investigators wrote.
Additional experiments with the mouse model showed that pharmacologic ablation of N2 neutrophils via two approaches led to reduced liver fibrosis, offering a glimpse at therapeutic potential.
These findings were further supported by experiments involving a cellular model of Wilson’s disease with isolated bone marrow neutrophils. These analyses revealed the role of the TGF1–DNMT3A/STAT3 signaling axis in neutrophil polarization, and resultant liver disease progression, in Wilson’s disease.
“Neutrophil heterogeneity shows therapeutic potential, and pharmacologic modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in Wilson’s disease,” the investigators concluded, noting that TGF-beta 1, DNMT3A, or STAT3 could all serve as rational therapeutic targets.
Beyond Wilson’s disease, the findings may offer broader value for understanding the mechanisms driving other neutrophil-related diseases, as well as possible therapeutic approaches for those conditions, the authors added.
The authors disclosed no conflicts of interest.
The treatment of Wilson disease relies on use of chelators (D-pencilliamine; trientine) that promote urinary copper excretion and zinc, which blocks intestinal absorption.
These drugs, which must be taken continuously, are effective but are associated with significant side effects. Another chelator, bis-choline-tetrathiomolybdate (TTM), promotes biliary, rather than urinary copper excretion.
TTM improved neurological function in clinical trials; however, dose-dependent transaminase elevations were noted.
Thus, there is a need to identify new therapeutic approaches to reduce impact of copper toxicity in hepatocytes.
In the current issue of CMGH, Mi and colleagues utilize zebrafish and mouse models of Wilson disease to generate novel insights into the pathogenesis and molecular basis of liver injury and fibrosis caused by ATP7B mutations. In the zebrafish model, they first showed that fluorescently-labeled neutrophils accumulate in the livers of live, mutant animals, which are transparent, and thus, uniquely suited to these studies. Gene expression analyses showed that the liver neutrophils are metabolically active and sensitize hepatocytes to copper-induced injury, thus providing a therapeutic rational for neutrophil inhibition. Next, the authors confirmed these findings in the mouse model, showing specifically that the N2-neutrophil subtype predominated and correlated with the degree of liver injury. Subsequent gene expression studies in the mouse, combined with in vitro analysis of bone marrow-derived neutrophils, identified a molecular signaling pathway originating in hepatocytes that triggered N2 differentiation. This pathway, which was previously shown to drive N2 differentiation in cancer models, involves TGF-beta induced methylation (and hence repression) of a gene (SOCS3) that itself, blocks expression of STAT3, a gene that drives N2 differentiation. Importantly, liver injury and fibrosis were reduced in the mouse model by drugs that inhibit TGF-beta or DNA methylation, and hence N2 differentiation, or by directly blocking the activity of N2 neutrophils.
In summary, this new study provides novel insights into not only into the pathogenesis and potential treatment of Wilson disease, but also demonstrates how signaling pathways, such as the one involving TGFbeta-SOCS3-STAT3, are reiteratively used in a variety of pathologic contexts. Going forward, it will be important to determine whether this pharmacologically modifiable signaling pathway is activated in Wilson disease patients, and whether it impacts the pathogenesis of more common liver disorders.
Michael Pack, M.D., is professor of medicine at Perelman School of Medicine, University of Pennsylvania. He has no conflicts.
The treatment of Wilson disease relies on use of chelators (D-pencilliamine; trientine) that promote urinary copper excretion and zinc, which blocks intestinal absorption.
These drugs, which must be taken continuously, are effective but are associated with significant side effects. Another chelator, bis-choline-tetrathiomolybdate (TTM), promotes biliary, rather than urinary copper excretion.
TTM improved neurological function in clinical trials; however, dose-dependent transaminase elevations were noted.
Thus, there is a need to identify new therapeutic approaches to reduce impact of copper toxicity in hepatocytes.
In the current issue of CMGH, Mi and colleagues utilize zebrafish and mouse models of Wilson disease to generate novel insights into the pathogenesis and molecular basis of liver injury and fibrosis caused by ATP7B mutations. In the zebrafish model, they first showed that fluorescently-labeled neutrophils accumulate in the livers of live, mutant animals, which are transparent, and thus, uniquely suited to these studies. Gene expression analyses showed that the liver neutrophils are metabolically active and sensitize hepatocytes to copper-induced injury, thus providing a therapeutic rational for neutrophil inhibition. Next, the authors confirmed these findings in the mouse model, showing specifically that the N2-neutrophil subtype predominated and correlated with the degree of liver injury. Subsequent gene expression studies in the mouse, combined with in vitro analysis of bone marrow-derived neutrophils, identified a molecular signaling pathway originating in hepatocytes that triggered N2 differentiation. This pathway, which was previously shown to drive N2 differentiation in cancer models, involves TGF-beta induced methylation (and hence repression) of a gene (SOCS3) that itself, blocks expression of STAT3, a gene that drives N2 differentiation. Importantly, liver injury and fibrosis were reduced in the mouse model by drugs that inhibit TGF-beta or DNA methylation, and hence N2 differentiation, or by directly blocking the activity of N2 neutrophils.
In summary, this new study provides novel insights into not only into the pathogenesis and potential treatment of Wilson disease, but also demonstrates how signaling pathways, such as the one involving TGFbeta-SOCS3-STAT3, are reiteratively used in a variety of pathologic contexts. Going forward, it will be important to determine whether this pharmacologically modifiable signaling pathway is activated in Wilson disease patients, and whether it impacts the pathogenesis of more common liver disorders.
Michael Pack, M.D., is professor of medicine at Perelman School of Medicine, University of Pennsylvania. He has no conflicts.
The treatment of Wilson disease relies on use of chelators (D-pencilliamine; trientine) that promote urinary copper excretion and zinc, which blocks intestinal absorption.
These drugs, which must be taken continuously, are effective but are associated with significant side effects. Another chelator, bis-choline-tetrathiomolybdate (TTM), promotes biliary, rather than urinary copper excretion.
TTM improved neurological function in clinical trials; however, dose-dependent transaminase elevations were noted.
Thus, there is a need to identify new therapeutic approaches to reduce impact of copper toxicity in hepatocytes.
In the current issue of CMGH, Mi and colleagues utilize zebrafish and mouse models of Wilson disease to generate novel insights into the pathogenesis and molecular basis of liver injury and fibrosis caused by ATP7B mutations. In the zebrafish model, they first showed that fluorescently-labeled neutrophils accumulate in the livers of live, mutant animals, which are transparent, and thus, uniquely suited to these studies. Gene expression analyses showed that the liver neutrophils are metabolically active and sensitize hepatocytes to copper-induced injury, thus providing a therapeutic rational for neutrophil inhibition. Next, the authors confirmed these findings in the mouse model, showing specifically that the N2-neutrophil subtype predominated and correlated with the degree of liver injury. Subsequent gene expression studies in the mouse, combined with in vitro analysis of bone marrow-derived neutrophils, identified a molecular signaling pathway originating in hepatocytes that triggered N2 differentiation. This pathway, which was previously shown to drive N2 differentiation in cancer models, involves TGF-beta induced methylation (and hence repression) of a gene (SOCS3) that itself, blocks expression of STAT3, a gene that drives N2 differentiation. Importantly, liver injury and fibrosis were reduced in the mouse model by drugs that inhibit TGF-beta or DNA methylation, and hence N2 differentiation, or by directly blocking the activity of N2 neutrophils.
In summary, this new study provides novel insights into not only into the pathogenesis and potential treatment of Wilson disease, but also demonstrates how signaling pathways, such as the one involving TGFbeta-SOCS3-STAT3, are reiteratively used in a variety of pathologic contexts. Going forward, it will be important to determine whether this pharmacologically modifiable signaling pathway is activated in Wilson disease patients, and whether it impacts the pathogenesis of more common liver disorders.
Michael Pack, M.D., is professor of medicine at Perelman School of Medicine, University of Pennsylvania. He has no conflicts.
Inhibiting neutrophil function via transforming growth factor (TGF-beta 1) inhibition or methylation inhibition reduced parenchymal liver fibrosis and injury while improving liver function in a mouse model of Wilson’s disease, shows new research published in Cellular and Molecular Gastroenterology and Hepatology.
Also called progressive hepatolenticular degeneration, Wilson’s disease is an inherited nervous system disorder that can occur as a result of severe liver disease. It is caused by variants in the ATP7B gene which can lead to abnormalities in copper metabolism that lead to accumulation of the heavy metal in the liver and brain, resulting in damage to both organs. Approximately 60% of patients with Wilson’s disease present with hepatic syndromes, and of those 50%-60% go on to develop liver cirrhosis.
Current treatments aim to address metal deposition, but this approach is poorly tolerated by many patients, wrote investigators who were led by Junping Shi, MD, PhD, of the Institute of Hepatology and Metabolic Diseases, The Affiliated Hospital of Hangzhou Normal University, China.
“Drug interventions (such as copper chelators and zinc salts) reduce pathologic copper deposition, but side effects can be observed in up to 40% of patients during treatment and even after years of treatment, particularly nephropathy, autoimmune conditions, and skin changes,” the investigators wrote. “Liver transplantation is an effective treatment for Wilson’s disease, particularly for patients with end-stage liver disease, but donor shortages and lifelong immunosuppression limit its use. Therefore, alternative treatments with higher specificity in Wilson’s disease patients are urgently needed.”
The present study explored the underlying metabolic abnormalities in Wilson’s disease that result in liver injury and fibrosis, and related therapeutic approaches. Based on previous studies that have shown a relationship between persistent neutrophil infiltration and chronic tissue inflammation and damage, the investigators sought to explore the role of neutrophils in Wilson’s disease, with a focus on the N2 subtype.
First, they analyzed neutrophil populations in the livers of Atp7b–/– mice and atp7b–/– zebrafish, both of which are established animal models of Wilson’s disease. Compared with the wild-type comparison animals, the livers of disease model animals showed increased neutrophil infiltration, in terms of both count and density.
In one of several related experiments, administering a neutrophil agonist in the presence of copper led to significantly greater neutrophil infiltration in mutant versus wild-type fish, as well as greater increases in lipid droplets and disorganized tissue structure, which serve as markers of disease activity.
“Collectively, these data suggested that neutrophils infiltrated the liver and accelerated liver defects in Wilson’s disease,” the investigators wrote.
Additional experiments with the mouse model showed that pharmacologic ablation of N2 neutrophils via two approaches led to reduced liver fibrosis, offering a glimpse at therapeutic potential.
These findings were further supported by experiments involving a cellular model of Wilson’s disease with isolated bone marrow neutrophils. These analyses revealed the role of the TGF1–DNMT3A/STAT3 signaling axis in neutrophil polarization, and resultant liver disease progression, in Wilson’s disease.
“Neutrophil heterogeneity shows therapeutic potential, and pharmacologic modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in Wilson’s disease,” the investigators concluded, noting that TGF-beta 1, DNMT3A, or STAT3 could all serve as rational therapeutic targets.
Beyond Wilson’s disease, the findings may offer broader value for understanding the mechanisms driving other neutrophil-related diseases, as well as possible therapeutic approaches for those conditions, the authors added.
The authors disclosed no conflicts of interest.
Inhibiting neutrophil function via transforming growth factor (TGF-beta 1) inhibition or methylation inhibition reduced parenchymal liver fibrosis and injury while improving liver function in a mouse model of Wilson’s disease, shows new research published in Cellular and Molecular Gastroenterology and Hepatology.
Also called progressive hepatolenticular degeneration, Wilson’s disease is an inherited nervous system disorder that can occur as a result of severe liver disease. It is caused by variants in the ATP7B gene which can lead to abnormalities in copper metabolism that lead to accumulation of the heavy metal in the liver and brain, resulting in damage to both organs. Approximately 60% of patients with Wilson’s disease present with hepatic syndromes, and of those 50%-60% go on to develop liver cirrhosis.
Current treatments aim to address metal deposition, but this approach is poorly tolerated by many patients, wrote investigators who were led by Junping Shi, MD, PhD, of the Institute of Hepatology and Metabolic Diseases, The Affiliated Hospital of Hangzhou Normal University, China.
“Drug interventions (such as copper chelators and zinc salts) reduce pathologic copper deposition, but side effects can be observed in up to 40% of patients during treatment and even after years of treatment, particularly nephropathy, autoimmune conditions, and skin changes,” the investigators wrote. “Liver transplantation is an effective treatment for Wilson’s disease, particularly for patients with end-stage liver disease, but donor shortages and lifelong immunosuppression limit its use. Therefore, alternative treatments with higher specificity in Wilson’s disease patients are urgently needed.”
The present study explored the underlying metabolic abnormalities in Wilson’s disease that result in liver injury and fibrosis, and related therapeutic approaches. Based on previous studies that have shown a relationship between persistent neutrophil infiltration and chronic tissue inflammation and damage, the investigators sought to explore the role of neutrophils in Wilson’s disease, with a focus on the N2 subtype.
First, they analyzed neutrophil populations in the livers of Atp7b–/– mice and atp7b–/– zebrafish, both of which are established animal models of Wilson’s disease. Compared with the wild-type comparison animals, the livers of disease model animals showed increased neutrophil infiltration, in terms of both count and density.
In one of several related experiments, administering a neutrophil agonist in the presence of copper led to significantly greater neutrophil infiltration in mutant versus wild-type fish, as well as greater increases in lipid droplets and disorganized tissue structure, which serve as markers of disease activity.
“Collectively, these data suggested that neutrophils infiltrated the liver and accelerated liver defects in Wilson’s disease,” the investigators wrote.
Additional experiments with the mouse model showed that pharmacologic ablation of N2 neutrophils via two approaches led to reduced liver fibrosis, offering a glimpse at therapeutic potential.
These findings were further supported by experiments involving a cellular model of Wilson’s disease with isolated bone marrow neutrophils. These analyses revealed the role of the TGF1–DNMT3A/STAT3 signaling axis in neutrophil polarization, and resultant liver disease progression, in Wilson’s disease.
“Neutrophil heterogeneity shows therapeutic potential, and pharmacologic modulation of N2-neutrophil activity should be explored as an alternative therapeutic to improve liver function in Wilson’s disease,” the investigators concluded, noting that TGF-beta 1, DNMT3A, or STAT3 could all serve as rational therapeutic targets.
Beyond Wilson’s disease, the findings may offer broader value for understanding the mechanisms driving other neutrophil-related diseases, as well as possible therapeutic approaches for those conditions, the authors added.
The authors disclosed no conflicts of interest.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Two-thirds with microscopic colitis respond to bile acid sequestrants
, based on a recent retrospective study from the Mayo Clinic.
The findings support use of BAS in patients with microscopic colitis who fail first-line therapy, or have intolerance to those agents, wrote researchers who were led by Darrell S. Pardi, MD, AGAF, a gastroenterologist with Mayo Clinic, Rochester, Minn. To date, the American Gastroenterological Association (AGA) has refrained from issuing any recommendations for BAS monotherapy in microscopic colitis (MC), the study authors wrote, citing a lack of relevant data.
The AGA recommends budesonide as first-line therapy for patients with moderate to severe symptoms of microscopic colitis. However, the treatment is associated with a high rate of relapse (40%-81%) once the patient stops taking the drug. Its long-term use is associated with a risk of side effects.
“At present, there are no randomized controlled trials that have evaluated the efficacy of BAS monotherapy for MC,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Studies investigating the role of BAM [bile acid malabsorption] in MC are comprised of small cohorts and have shown inconsistent results. Patients without BAM may also respond to BAS therapy. Therefore, the role of BAM and treatment with BAS in MC merits further investigation.”
The study analyzed data from 282 patients (88.3% women) with microscopic colitis treated between 2010 to 2020. Bile acid malabsorption was defined by elevated serum 7⍺-hydroxy-4-cholesten-3-one or by fecal testing. After a median follow-up of 4.5 years, cholestyramine was the most prescribed BAS (64.9%), followed by colesevelam (21.6%) and colestipol (13.5%). Approximately half of the patients achieved a complete response (49.3%), while 16.3% had a partial response. Nonresponders accounted for 24.8% of the population, and 9.6% of patients did not tolerate BAS therapy. These outcomes were not significantly impacted by BAS dose or combination with other agents. Additional logistic regression analysis revealed no predictors of response.
After discontinuing BAS, 41.6% of patients had recurrence in a median of 21 weeks, ranging from 1 to 172 weeks.
“Consistent with prior studies evaluating the clinical course of MC and similar to the high rate of recurrence after discontinuation of budesonide, relapse was common after cessation of BAS therapy,” the investigators noted.
Still, the findings suggest that BAS is a valid second-line option with a favorable risk-benefit profile, and an elevated dose appears unnecessary to achieve clinical response.
“These results suggest that BAS may be considered as a treatment option in those that do not respond to first-line options or have intolerance to these agents,” the researchers wrote.
They suggested that BAS may be particularly useful as long-term maintenance therapy for patients wishing to avoid prolonged corticosteroid exposure.
“However, BAS have the potential to interfere with the administration and absorption of other medications, particularly in older populations with polypharmacy,” the researchers wrote. “Patients should thus be closely monitored for drug interactions, especially those taking concurrent medications. BAS should be administered separately from other medications to avoid the potential for drug interactions.”
Ideally, prospective studies will be conducted to confirm these findings, and to identify the subset of patients who are most likely to respond to BAS, the investigators concluded.
Dr. Pardi has grant funding from Pfizer, Vedanta, Seres, Finch, Applied Molecular Transport, and Takeda; and has consulted for Vedanta, Seres, Phantom Pharmaceuticals, Abbvie, Immunic, and Otsuka.
Despite being increasingly recognized and diagnosed, there remains a scantiness of studies addressing therapeutic options in microscopic colitis (MC). Oral budesonide is recommended as first-line option; however, there is a high relapse rate after budesonide discontinuation, some patients are intolerant, and there is concern for steroid toxicity associated with long-term exposure.
While the cause of MC remains elusive, there is a rationale to suggest that bile acids may play a role in disease pathogenesis. Not only are BA important signaling molecules, acting in inflammation and metabolism, but also prior small studies reported on BA malabsorption co-existing in MC, with variable response rates to BA sequestrants.
This retrospective large study of 282 patients with MC showed that almost two-thirds of patients will present a complete or partial response to BA sequestrant therapy (cholestyramine, colesevelam, and colestipol). For those that relapsed following BA therapy discontinuation, re-treatment was successful in the majority of cases.
Therapy was well tolerated, however caution is needed, as it can interfere with absorption of other medications, and in the long-term also with fat-soluble vitamins. It remains to be determined which patients could benefit the most from BA therapy, since no predictors of response were identified, nor was response associated with BA malabsorption. Nonetheless, this study shows that BA therapy could be an attractive option for steroid-dependent, steroid refractory or intolerant MC patients potentially worth trying before embarking on immunosuppressive or biological therapy. It also highlights the need for carefully conducted clinical trials exploring other options beyond budesonide for this chronic and debilitating condition.
Joana Torres, MD, PhD, is a consultant gastroenterologist at Hospital Beatriz Angelo and Hospital da Luz in Portugal and assistant professor in Uniersidade de Lisboa, Portugal. She has no conflicts.
Despite being increasingly recognized and diagnosed, there remains a scantiness of studies addressing therapeutic options in microscopic colitis (MC). Oral budesonide is recommended as first-line option; however, there is a high relapse rate after budesonide discontinuation, some patients are intolerant, and there is concern for steroid toxicity associated with long-term exposure.
While the cause of MC remains elusive, there is a rationale to suggest that bile acids may play a role in disease pathogenesis. Not only are BA important signaling molecules, acting in inflammation and metabolism, but also prior small studies reported on BA malabsorption co-existing in MC, with variable response rates to BA sequestrants.
This retrospective large study of 282 patients with MC showed that almost two-thirds of patients will present a complete or partial response to BA sequestrant therapy (cholestyramine, colesevelam, and colestipol). For those that relapsed following BA therapy discontinuation, re-treatment was successful in the majority of cases.
Therapy was well tolerated, however caution is needed, as it can interfere with absorption of other medications, and in the long-term also with fat-soluble vitamins. It remains to be determined which patients could benefit the most from BA therapy, since no predictors of response were identified, nor was response associated with BA malabsorption. Nonetheless, this study shows that BA therapy could be an attractive option for steroid-dependent, steroid refractory or intolerant MC patients potentially worth trying before embarking on immunosuppressive or biological therapy. It also highlights the need for carefully conducted clinical trials exploring other options beyond budesonide for this chronic and debilitating condition.
Joana Torres, MD, PhD, is a consultant gastroenterologist at Hospital Beatriz Angelo and Hospital da Luz in Portugal and assistant professor in Uniersidade de Lisboa, Portugal. She has no conflicts.
Despite being increasingly recognized and diagnosed, there remains a scantiness of studies addressing therapeutic options in microscopic colitis (MC). Oral budesonide is recommended as first-line option; however, there is a high relapse rate after budesonide discontinuation, some patients are intolerant, and there is concern for steroid toxicity associated with long-term exposure.
While the cause of MC remains elusive, there is a rationale to suggest that bile acids may play a role in disease pathogenesis. Not only are BA important signaling molecules, acting in inflammation and metabolism, but also prior small studies reported on BA malabsorption co-existing in MC, with variable response rates to BA sequestrants.
This retrospective large study of 282 patients with MC showed that almost two-thirds of patients will present a complete or partial response to BA sequestrant therapy (cholestyramine, colesevelam, and colestipol). For those that relapsed following BA therapy discontinuation, re-treatment was successful in the majority of cases.
Therapy was well tolerated, however caution is needed, as it can interfere with absorption of other medications, and in the long-term also with fat-soluble vitamins. It remains to be determined which patients could benefit the most from BA therapy, since no predictors of response were identified, nor was response associated with BA malabsorption. Nonetheless, this study shows that BA therapy could be an attractive option for steroid-dependent, steroid refractory or intolerant MC patients potentially worth trying before embarking on immunosuppressive or biological therapy. It also highlights the need for carefully conducted clinical trials exploring other options beyond budesonide for this chronic and debilitating condition.
Joana Torres, MD, PhD, is a consultant gastroenterologist at Hospital Beatriz Angelo and Hospital da Luz in Portugal and assistant professor in Uniersidade de Lisboa, Portugal. She has no conflicts.
, based on a recent retrospective study from the Mayo Clinic.
The findings support use of BAS in patients with microscopic colitis who fail first-line therapy, or have intolerance to those agents, wrote researchers who were led by Darrell S. Pardi, MD, AGAF, a gastroenterologist with Mayo Clinic, Rochester, Minn. To date, the American Gastroenterological Association (AGA) has refrained from issuing any recommendations for BAS monotherapy in microscopic colitis (MC), the study authors wrote, citing a lack of relevant data.
The AGA recommends budesonide as first-line therapy for patients with moderate to severe symptoms of microscopic colitis. However, the treatment is associated with a high rate of relapse (40%-81%) once the patient stops taking the drug. Its long-term use is associated with a risk of side effects.
“At present, there are no randomized controlled trials that have evaluated the efficacy of BAS monotherapy for MC,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Studies investigating the role of BAM [bile acid malabsorption] in MC are comprised of small cohorts and have shown inconsistent results. Patients without BAM may also respond to BAS therapy. Therefore, the role of BAM and treatment with BAS in MC merits further investigation.”
The study analyzed data from 282 patients (88.3% women) with microscopic colitis treated between 2010 to 2020. Bile acid malabsorption was defined by elevated serum 7⍺-hydroxy-4-cholesten-3-one or by fecal testing. After a median follow-up of 4.5 years, cholestyramine was the most prescribed BAS (64.9%), followed by colesevelam (21.6%) and colestipol (13.5%). Approximately half of the patients achieved a complete response (49.3%), while 16.3% had a partial response. Nonresponders accounted for 24.8% of the population, and 9.6% of patients did not tolerate BAS therapy. These outcomes were not significantly impacted by BAS dose or combination with other agents. Additional logistic regression analysis revealed no predictors of response.
After discontinuing BAS, 41.6% of patients had recurrence in a median of 21 weeks, ranging from 1 to 172 weeks.
“Consistent with prior studies evaluating the clinical course of MC and similar to the high rate of recurrence after discontinuation of budesonide, relapse was common after cessation of BAS therapy,” the investigators noted.
Still, the findings suggest that BAS is a valid second-line option with a favorable risk-benefit profile, and an elevated dose appears unnecessary to achieve clinical response.
“These results suggest that BAS may be considered as a treatment option in those that do not respond to first-line options or have intolerance to these agents,” the researchers wrote.
They suggested that BAS may be particularly useful as long-term maintenance therapy for patients wishing to avoid prolonged corticosteroid exposure.
“However, BAS have the potential to interfere with the administration and absorption of other medications, particularly in older populations with polypharmacy,” the researchers wrote. “Patients should thus be closely monitored for drug interactions, especially those taking concurrent medications. BAS should be administered separately from other medications to avoid the potential for drug interactions.”
Ideally, prospective studies will be conducted to confirm these findings, and to identify the subset of patients who are most likely to respond to BAS, the investigators concluded.
Dr. Pardi has grant funding from Pfizer, Vedanta, Seres, Finch, Applied Molecular Transport, and Takeda; and has consulted for Vedanta, Seres, Phantom Pharmaceuticals, Abbvie, Immunic, and Otsuka.
, based on a recent retrospective study from the Mayo Clinic.
The findings support use of BAS in patients with microscopic colitis who fail first-line therapy, or have intolerance to those agents, wrote researchers who were led by Darrell S. Pardi, MD, AGAF, a gastroenterologist with Mayo Clinic, Rochester, Minn. To date, the American Gastroenterological Association (AGA) has refrained from issuing any recommendations for BAS monotherapy in microscopic colitis (MC), the study authors wrote, citing a lack of relevant data.
The AGA recommends budesonide as first-line therapy for patients with moderate to severe symptoms of microscopic colitis. However, the treatment is associated with a high rate of relapse (40%-81%) once the patient stops taking the drug. Its long-term use is associated with a risk of side effects.
“At present, there are no randomized controlled trials that have evaluated the efficacy of BAS monotherapy for MC,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Studies investigating the role of BAM [bile acid malabsorption] in MC are comprised of small cohorts and have shown inconsistent results. Patients without BAM may also respond to BAS therapy. Therefore, the role of BAM and treatment with BAS in MC merits further investigation.”
The study analyzed data from 282 patients (88.3% women) with microscopic colitis treated between 2010 to 2020. Bile acid malabsorption was defined by elevated serum 7⍺-hydroxy-4-cholesten-3-one or by fecal testing. After a median follow-up of 4.5 years, cholestyramine was the most prescribed BAS (64.9%), followed by colesevelam (21.6%) and colestipol (13.5%). Approximately half of the patients achieved a complete response (49.3%), while 16.3% had a partial response. Nonresponders accounted for 24.8% of the population, and 9.6% of patients did not tolerate BAS therapy. These outcomes were not significantly impacted by BAS dose or combination with other agents. Additional logistic regression analysis revealed no predictors of response.
After discontinuing BAS, 41.6% of patients had recurrence in a median of 21 weeks, ranging from 1 to 172 weeks.
“Consistent with prior studies evaluating the clinical course of MC and similar to the high rate of recurrence after discontinuation of budesonide, relapse was common after cessation of BAS therapy,” the investigators noted.
Still, the findings suggest that BAS is a valid second-line option with a favorable risk-benefit profile, and an elevated dose appears unnecessary to achieve clinical response.
“These results suggest that BAS may be considered as a treatment option in those that do not respond to first-line options or have intolerance to these agents,” the researchers wrote.
They suggested that BAS may be particularly useful as long-term maintenance therapy for patients wishing to avoid prolonged corticosteroid exposure.
“However, BAS have the potential to interfere with the administration and absorption of other medications, particularly in older populations with polypharmacy,” the researchers wrote. “Patients should thus be closely monitored for drug interactions, especially those taking concurrent medications. BAS should be administered separately from other medications to avoid the potential for drug interactions.”
Ideally, prospective studies will be conducted to confirm these findings, and to identify the subset of patients who are most likely to respond to BAS, the investigators concluded.
Dr. Pardi has grant funding from Pfizer, Vedanta, Seres, Finch, Applied Molecular Transport, and Takeda; and has consulted for Vedanta, Seres, Phantom Pharmaceuticals, Abbvie, Immunic, and Otsuka.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Low-certainty evidence supports probiotics for IBS
or very low certainty, with many studies suffering from bias, according to a recent review and meta-analysis.
These shortcomings in the probiotic research landscape should be kept in mind when making treatment recommendations, reported researchers who were led by Alexander C. Ford, MBChB, of the Leeds Gastroenterology Institute, University of Leeds (England). They suggested these issues need to be addressed in the methodology of future clinical trials.
“Although multiple probiotics have been tested in IBS in randomized clinical trials, understanding of which probiotics may be beneficial is limited,” the investigators wrote in Gastroenterology.
They noted that previous efforts – including their own – to meta-analyze these findings have been hindered by a scarcity of trial data coupled with heterogeneity across probiotic strains, combinations, and doses, resulting in clinical uncertainty.
“Making recommendations concerning which probiotics, or combinations of probiotics, are beneficial according to IBS subtype or individual symptom has been difficult to date,” they wrote.
To narrow this knowledge gap, the researchers conducted an updated systematic review and meta-analysis with newly identified trials.
“There is continued interest in the role of probiotics in the management of IBS, as evidenced by the publication of more than 20 new randomized clinical trials since the prior version of this meta-analysis in 2018,” they wrote.
The new dataset included 82 RCTs comprising 10,332 patients with IBS. Along with safety, three separate efficacy endpoints were evaluated: global symptoms, abdominal pain, and abdominal bloating or distension.
For global symptoms, moderate-certainty evidence supported the efficacy of Escherichia coli strains; low-certainty data supported Lactobacillus plantarum 299V and other Lactobacillus strains; and very-low-certainty evidence supported Bacillus, LacClean Gold S, and Duolac 7s strains, and combination probiotics.
For abdominal pain, low-certainty evidence supported Bifidobacterium strains and Saccharomyces cerevisiae I-3856. Very-low-certainty data supported Lactobacillus, Saccharomyces, and Bacillus strains, and combination probiotics.
Very-low-certainty evidence supported the benefits of Bacillus strains and combination probiotics for alleviating abdominal bloating or distension.
In a safety analysis of 55 trials involving more than 7,000 patients, risk of adverse events was no higher for probiotics than placebo.
“Our analyses provide some support for the use of certain probiotics in IBS, and also for particular strains for specific symptoms,” the investigators wrote. “However, there is a paucity of data for their use in patients with IBS-C [IBS with constipation], with only seven RCTs reporting efficacy in this subtype, and no evidence of efficacy in any of these analyses. Their use in patients with IBS-C is, therefore, not supported by current evidence.”
A broader discussion in the publication called out the general lack of high certainty evidence in this area of clinical research.
“Only 24 of 82 eligible RCTs were low risk of bias across all domains, and there was significant heterogeneity between trials in many of our analyses, as well as evidence of publication bias, or other small study effects, in some of our analyses,” the researchers wrote. “The fact that few of the included studies were low risk of bias across all domains should be borne in mind when making treatment recommendations.”
The investigators disclosed relationships with Salix, Biocodex, 4D Pharma, and others.
IBS patients frequently inquire about probiotics. As a clinician, this can be difficult to address. A search of the literature yields numerous small trials. Turning to the guidelines does not help, as the AGA Clinical Practice Guidelines on Probiotics offer no recommendations for IBS because of the low quality of evidence. Nevertheless, we have patients who want to try probiotics. Some of these patients have had inadequate responses to first-line therapies and/or prefer a nonpharmacologic approach.
For example, the strain with the most trials was Lactobacillus plantarum 299V. The dose used (10 billion CFU once daily) is commercially available (Jarrow Formulas Ideal Bowel Support® LP299V®). Bacillus strains were also promising for global symptoms, abdominal pain and bloating. Two trials used the same strain and dose, Bacillus coagulans MTCC 5856, 2 billion CFU once daily, also commercially available (LactoSpore). Both can be purchased via major online retailers for $10-$13 for a 30-day supply. I am glad to have something to recommend however conditionally.
Elizabeth (Beth) Videlock, MD, PhD is assistant professor of medicine in the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California, Los Angeles, and a staff physician in gastroenterology in the Greater Los Angeles Veterans Affairs Healthcare System. She is co-lead of the neurodevelopmental and neurodegenerative diseases research program of the Goodman-Luskin Microbiome Center at UCLA. She has no relevant disclosures.
IBS patients frequently inquire about probiotics. As a clinician, this can be difficult to address. A search of the literature yields numerous small trials. Turning to the guidelines does not help, as the AGA Clinical Practice Guidelines on Probiotics offer no recommendations for IBS because of the low quality of evidence. Nevertheless, we have patients who want to try probiotics. Some of these patients have had inadequate responses to first-line therapies and/or prefer a nonpharmacologic approach.
For example, the strain with the most trials was Lactobacillus plantarum 299V. The dose used (10 billion CFU once daily) is commercially available (Jarrow Formulas Ideal Bowel Support® LP299V®). Bacillus strains were also promising for global symptoms, abdominal pain and bloating. Two trials used the same strain and dose, Bacillus coagulans MTCC 5856, 2 billion CFU once daily, also commercially available (LactoSpore). Both can be purchased via major online retailers for $10-$13 for a 30-day supply. I am glad to have something to recommend however conditionally.
Elizabeth (Beth) Videlock, MD, PhD is assistant professor of medicine in the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California, Los Angeles, and a staff physician in gastroenterology in the Greater Los Angeles Veterans Affairs Healthcare System. She is co-lead of the neurodevelopmental and neurodegenerative diseases research program of the Goodman-Luskin Microbiome Center at UCLA. She has no relevant disclosures.
IBS patients frequently inquire about probiotics. As a clinician, this can be difficult to address. A search of the literature yields numerous small trials. Turning to the guidelines does not help, as the AGA Clinical Practice Guidelines on Probiotics offer no recommendations for IBS because of the low quality of evidence. Nevertheless, we have patients who want to try probiotics. Some of these patients have had inadequate responses to first-line therapies and/or prefer a nonpharmacologic approach.
For example, the strain with the most trials was Lactobacillus plantarum 299V. The dose used (10 billion CFU once daily) is commercially available (Jarrow Formulas Ideal Bowel Support® LP299V®). Bacillus strains were also promising for global symptoms, abdominal pain and bloating. Two trials used the same strain and dose, Bacillus coagulans MTCC 5856, 2 billion CFU once daily, also commercially available (LactoSpore). Both can be purchased via major online retailers for $10-$13 for a 30-day supply. I am glad to have something to recommend however conditionally.
Elizabeth (Beth) Videlock, MD, PhD is assistant professor of medicine in the Vatche and Tamar Manoukian Division of Digestive Diseases at the University of California, Los Angeles, and a staff physician in gastroenterology in the Greater Los Angeles Veterans Affairs Healthcare System. She is co-lead of the neurodevelopmental and neurodegenerative diseases research program of the Goodman-Luskin Microbiome Center at UCLA. She has no relevant disclosures.
or very low certainty, with many studies suffering from bias, according to a recent review and meta-analysis.
These shortcomings in the probiotic research landscape should be kept in mind when making treatment recommendations, reported researchers who were led by Alexander C. Ford, MBChB, of the Leeds Gastroenterology Institute, University of Leeds (England). They suggested these issues need to be addressed in the methodology of future clinical trials.
“Although multiple probiotics have been tested in IBS in randomized clinical trials, understanding of which probiotics may be beneficial is limited,” the investigators wrote in Gastroenterology.
They noted that previous efforts – including their own – to meta-analyze these findings have been hindered by a scarcity of trial data coupled with heterogeneity across probiotic strains, combinations, and doses, resulting in clinical uncertainty.
“Making recommendations concerning which probiotics, or combinations of probiotics, are beneficial according to IBS subtype or individual symptom has been difficult to date,” they wrote.
To narrow this knowledge gap, the researchers conducted an updated systematic review and meta-analysis with newly identified trials.
“There is continued interest in the role of probiotics in the management of IBS, as evidenced by the publication of more than 20 new randomized clinical trials since the prior version of this meta-analysis in 2018,” they wrote.
The new dataset included 82 RCTs comprising 10,332 patients with IBS. Along with safety, three separate efficacy endpoints were evaluated: global symptoms, abdominal pain, and abdominal bloating or distension.
For global symptoms, moderate-certainty evidence supported the efficacy of Escherichia coli strains; low-certainty data supported Lactobacillus plantarum 299V and other Lactobacillus strains; and very-low-certainty evidence supported Bacillus, LacClean Gold S, and Duolac 7s strains, and combination probiotics.
For abdominal pain, low-certainty evidence supported Bifidobacterium strains and Saccharomyces cerevisiae I-3856. Very-low-certainty data supported Lactobacillus, Saccharomyces, and Bacillus strains, and combination probiotics.
Very-low-certainty evidence supported the benefits of Bacillus strains and combination probiotics for alleviating abdominal bloating or distension.
In a safety analysis of 55 trials involving more than 7,000 patients, risk of adverse events was no higher for probiotics than placebo.
“Our analyses provide some support for the use of certain probiotics in IBS, and also for particular strains for specific symptoms,” the investigators wrote. “However, there is a paucity of data for their use in patients with IBS-C [IBS with constipation], with only seven RCTs reporting efficacy in this subtype, and no evidence of efficacy in any of these analyses. Their use in patients with IBS-C is, therefore, not supported by current evidence.”
A broader discussion in the publication called out the general lack of high certainty evidence in this area of clinical research.
“Only 24 of 82 eligible RCTs were low risk of bias across all domains, and there was significant heterogeneity between trials in many of our analyses, as well as evidence of publication bias, or other small study effects, in some of our analyses,” the researchers wrote. “The fact that few of the included studies were low risk of bias across all domains should be borne in mind when making treatment recommendations.”
The investigators disclosed relationships with Salix, Biocodex, 4D Pharma, and others.
or very low certainty, with many studies suffering from bias, according to a recent review and meta-analysis.
These shortcomings in the probiotic research landscape should be kept in mind when making treatment recommendations, reported researchers who were led by Alexander C. Ford, MBChB, of the Leeds Gastroenterology Institute, University of Leeds (England). They suggested these issues need to be addressed in the methodology of future clinical trials.
“Although multiple probiotics have been tested in IBS in randomized clinical trials, understanding of which probiotics may be beneficial is limited,” the investigators wrote in Gastroenterology.
They noted that previous efforts – including their own – to meta-analyze these findings have been hindered by a scarcity of trial data coupled with heterogeneity across probiotic strains, combinations, and doses, resulting in clinical uncertainty.
“Making recommendations concerning which probiotics, or combinations of probiotics, are beneficial according to IBS subtype or individual symptom has been difficult to date,” they wrote.
To narrow this knowledge gap, the researchers conducted an updated systematic review and meta-analysis with newly identified trials.
“There is continued interest in the role of probiotics in the management of IBS, as evidenced by the publication of more than 20 new randomized clinical trials since the prior version of this meta-analysis in 2018,” they wrote.
The new dataset included 82 RCTs comprising 10,332 patients with IBS. Along with safety, three separate efficacy endpoints were evaluated: global symptoms, abdominal pain, and abdominal bloating or distension.
For global symptoms, moderate-certainty evidence supported the efficacy of Escherichia coli strains; low-certainty data supported Lactobacillus plantarum 299V and other Lactobacillus strains; and very-low-certainty evidence supported Bacillus, LacClean Gold S, and Duolac 7s strains, and combination probiotics.
For abdominal pain, low-certainty evidence supported Bifidobacterium strains and Saccharomyces cerevisiae I-3856. Very-low-certainty data supported Lactobacillus, Saccharomyces, and Bacillus strains, and combination probiotics.
Very-low-certainty evidence supported the benefits of Bacillus strains and combination probiotics for alleviating abdominal bloating or distension.
In a safety analysis of 55 trials involving more than 7,000 patients, risk of adverse events was no higher for probiotics than placebo.
“Our analyses provide some support for the use of certain probiotics in IBS, and also for particular strains for specific symptoms,” the investigators wrote. “However, there is a paucity of data for their use in patients with IBS-C [IBS with constipation], with only seven RCTs reporting efficacy in this subtype, and no evidence of efficacy in any of these analyses. Their use in patients with IBS-C is, therefore, not supported by current evidence.”
A broader discussion in the publication called out the general lack of high certainty evidence in this area of clinical research.
“Only 24 of 82 eligible RCTs were low risk of bias across all domains, and there was significant heterogeneity between trials in many of our analyses, as well as evidence of publication bias, or other small study effects, in some of our analyses,” the researchers wrote. “The fact that few of the included studies were low risk of bias across all domains should be borne in mind when making treatment recommendations.”
The investigators disclosed relationships with Salix, Biocodex, 4D Pharma, and others.
FROM GASTROENTEROLOGY