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Irisin Shows Potential as Alzheimer’s Disease Biomarker
, according to investigators.
Irisin, a hormone released by muscles during physical exercise, also negatively correlated with Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) in female patients, pointing to a sex-specific disease phenomenon, reported by co-lead authors Manuela Dicarlo, PhD, and Patrizia Pignataro, MSc, of the University of Bari “A. Moro,” Bari, Italy, and colleagues.
Regular physical exercise can slow cognitive decline in individuals at risk for or with Alzheimer’s disease, and irisin appears to play a key role in this process, the investigators wrote in Annals of Neurology. Previous studies have shown that increased irisin levels in the brain are associated with improved cognitive function and reduced amyloid beta levels, suggesting the hormone’s potential as a biomarker and therapeutic target for Alzheimer’s disease.
“Based on the protective effect of irisin in Alzheimer’s disease shown in animal and cell models, the goal of the present study was to investigate the levels of irisin in the biological fluids of a large cohort of patients biologically characterized according to the amyloid/tau/neurodegeneration (ATN) scheme of the National Institute on Aging–Alzheimer’s Association (NIA-AA),” Dr. Dicarlo and colleagues wrote. “We aimed to understand whether there may be variations of irisin levels across the disease stages, identified through the ATN system.”
Lower Levels of Irisin Seen in Patients With Alzheimer’s Disease
The study included 82 patients with Alzheimer’s disease, 44 individuals with mild cognitive impairment (MCI), and 20 with subjective memory complaints (SMC). Participants underwent comprehensive assessments, including neurological and neuropsychological exams, nutritional evaluations, MRI scans, and routine lab tests. Cognitive impairment severity was measured using the CDR-SOB and other metrics.
Blood and CSF samples were collected from all patients, the latter via lumbar puncture. These samples were analyzed for irisin levels and known Alzheimer’s disease biomarkers, including Abeta42, total tau (t-tau), and hyperphosphorylated tau (p-tau).
Mean CSF irisin levels were significantly lower among patients with Alzheimer’s disease than those with SMC (0.80 vs 1.23 pg/mL; P < .0001), and among those with MCI vs SMC (0.95 vs 1.23 pg/mL; P = .046). Among patients with Alzheimer’s disease, irisin levels were significantly lower among women than men (0.70 vs 0.96 pg/mL; P = .031).
Further analyses revealed positive correlations between CSF irisin level and Abeta42 in both males (r = 0.262; P < 005) and females (r = 0.379; P < .001). Conversely, in female patients, a significant negative correlation was found between CSF irisin level and CDR-SOB score (r = −0.234; P < .05).
Although a negative trend was observed between CSF irisin and total tau (t-tau) in the overall patient population (r = −0.144; P = 0.082), and more notably in female patients (r = −0.189; P = 0.084), these results were not statistically significant.
Plasma irisin levels were not significantly correlated with any of the other biomarkers.
Clinical Implications
This study “verifies that irisin levels do have a relationship to the Alzheimer’s disease process,” said Dylan Wint, MD, director of Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas.
In a written comment, Dr. Wint speculated that measuring irisin levels could theoretically help individualize physical exercise routines designed to combat cognitive decline.
“For example, maybe someone who is exercising but has a low irisin level would need to change the type of exercise they’re doing in order to optimally protect their brain health,” he said. “Or maybe they won’t get the same benefits for brain health as someone whose irisin shoots up every time they walk a flight of stairs.”
It’s “near-impossible to tell,” however, if irisin will be employed in clinical trials or real-world practice, he added.
“I don’t see this being a highly useful serum biomarker for Alzheimer’s disease itself because other serum biomarkers are so far ahead and have more face validity,” Dr. Wint said.
The route of collection could also cause challenges.
“In the United States, CSF-based biomarkers can be a difficult sell, especially for serial testing,” Dr. Wint said. “But we have usable serum biomarkers for Alzheimer’s disease only because we have had CSF biomarkers against which to evaluate them. They may develop a way to evaluate this in the serum.”
Dr. Dicarlo and colleagues suggested that more work is needed to determine the ultimate value of irisin measurement.“The true ability of irisin to represent a biomarker of disease progression and severity remains to be further investigated,” they concluded. “However, our findings might offer interesting perspectives toward the potential role of irisin in the modulation of AD pathology and can guide the exploration of medication targeting the irisin system.”
The study was supported by Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione, CIREMIC, the University of Bari, and Next Generation EU. The investigators and Dr. Wint disclosed no conflicts of interest.
, according to investigators.
Irisin, a hormone released by muscles during physical exercise, also negatively correlated with Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) in female patients, pointing to a sex-specific disease phenomenon, reported by co-lead authors Manuela Dicarlo, PhD, and Patrizia Pignataro, MSc, of the University of Bari “A. Moro,” Bari, Italy, and colleagues.
Regular physical exercise can slow cognitive decline in individuals at risk for or with Alzheimer’s disease, and irisin appears to play a key role in this process, the investigators wrote in Annals of Neurology. Previous studies have shown that increased irisin levels in the brain are associated with improved cognitive function and reduced amyloid beta levels, suggesting the hormone’s potential as a biomarker and therapeutic target for Alzheimer’s disease.
“Based on the protective effect of irisin in Alzheimer’s disease shown in animal and cell models, the goal of the present study was to investigate the levels of irisin in the biological fluids of a large cohort of patients biologically characterized according to the amyloid/tau/neurodegeneration (ATN) scheme of the National Institute on Aging–Alzheimer’s Association (NIA-AA),” Dr. Dicarlo and colleagues wrote. “We aimed to understand whether there may be variations of irisin levels across the disease stages, identified through the ATN system.”
Lower Levels of Irisin Seen in Patients With Alzheimer’s Disease
The study included 82 patients with Alzheimer’s disease, 44 individuals with mild cognitive impairment (MCI), and 20 with subjective memory complaints (SMC). Participants underwent comprehensive assessments, including neurological and neuropsychological exams, nutritional evaluations, MRI scans, and routine lab tests. Cognitive impairment severity was measured using the CDR-SOB and other metrics.
Blood and CSF samples were collected from all patients, the latter via lumbar puncture. These samples were analyzed for irisin levels and known Alzheimer’s disease biomarkers, including Abeta42, total tau (t-tau), and hyperphosphorylated tau (p-tau).
Mean CSF irisin levels were significantly lower among patients with Alzheimer’s disease than those with SMC (0.80 vs 1.23 pg/mL; P < .0001), and among those with MCI vs SMC (0.95 vs 1.23 pg/mL; P = .046). Among patients with Alzheimer’s disease, irisin levels were significantly lower among women than men (0.70 vs 0.96 pg/mL; P = .031).
Further analyses revealed positive correlations between CSF irisin level and Abeta42 in both males (r = 0.262; P < 005) and females (r = 0.379; P < .001). Conversely, in female patients, a significant negative correlation was found between CSF irisin level and CDR-SOB score (r = −0.234; P < .05).
Although a negative trend was observed between CSF irisin and total tau (t-tau) in the overall patient population (r = −0.144; P = 0.082), and more notably in female patients (r = −0.189; P = 0.084), these results were not statistically significant.
Plasma irisin levels were not significantly correlated with any of the other biomarkers.
Clinical Implications
This study “verifies that irisin levels do have a relationship to the Alzheimer’s disease process,” said Dylan Wint, MD, director of Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas.
In a written comment, Dr. Wint speculated that measuring irisin levels could theoretically help individualize physical exercise routines designed to combat cognitive decline.
“For example, maybe someone who is exercising but has a low irisin level would need to change the type of exercise they’re doing in order to optimally protect their brain health,” he said. “Or maybe they won’t get the same benefits for brain health as someone whose irisin shoots up every time they walk a flight of stairs.”
It’s “near-impossible to tell,” however, if irisin will be employed in clinical trials or real-world practice, he added.
“I don’t see this being a highly useful serum biomarker for Alzheimer’s disease itself because other serum biomarkers are so far ahead and have more face validity,” Dr. Wint said.
The route of collection could also cause challenges.
“In the United States, CSF-based biomarkers can be a difficult sell, especially for serial testing,” Dr. Wint said. “But we have usable serum biomarkers for Alzheimer’s disease only because we have had CSF biomarkers against which to evaluate them. They may develop a way to evaluate this in the serum.”
Dr. Dicarlo and colleagues suggested that more work is needed to determine the ultimate value of irisin measurement.“The true ability of irisin to represent a biomarker of disease progression and severity remains to be further investigated,” they concluded. “However, our findings might offer interesting perspectives toward the potential role of irisin in the modulation of AD pathology and can guide the exploration of medication targeting the irisin system.”
The study was supported by Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione, CIREMIC, the University of Bari, and Next Generation EU. The investigators and Dr. Wint disclosed no conflicts of interest.
, according to investigators.
Irisin, a hormone released by muscles during physical exercise, also negatively correlated with Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) in female patients, pointing to a sex-specific disease phenomenon, reported by co-lead authors Manuela Dicarlo, PhD, and Patrizia Pignataro, MSc, of the University of Bari “A. Moro,” Bari, Italy, and colleagues.
Regular physical exercise can slow cognitive decline in individuals at risk for or with Alzheimer’s disease, and irisin appears to play a key role in this process, the investigators wrote in Annals of Neurology. Previous studies have shown that increased irisin levels in the brain are associated with improved cognitive function and reduced amyloid beta levels, suggesting the hormone’s potential as a biomarker and therapeutic target for Alzheimer’s disease.
“Based on the protective effect of irisin in Alzheimer’s disease shown in animal and cell models, the goal of the present study was to investigate the levels of irisin in the biological fluids of a large cohort of patients biologically characterized according to the amyloid/tau/neurodegeneration (ATN) scheme of the National Institute on Aging–Alzheimer’s Association (NIA-AA),” Dr. Dicarlo and colleagues wrote. “We aimed to understand whether there may be variations of irisin levels across the disease stages, identified through the ATN system.”
Lower Levels of Irisin Seen in Patients With Alzheimer’s Disease
The study included 82 patients with Alzheimer’s disease, 44 individuals with mild cognitive impairment (MCI), and 20 with subjective memory complaints (SMC). Participants underwent comprehensive assessments, including neurological and neuropsychological exams, nutritional evaluations, MRI scans, and routine lab tests. Cognitive impairment severity was measured using the CDR-SOB and other metrics.
Blood and CSF samples were collected from all patients, the latter via lumbar puncture. These samples were analyzed for irisin levels and known Alzheimer’s disease biomarkers, including Abeta42, total tau (t-tau), and hyperphosphorylated tau (p-tau).
Mean CSF irisin levels were significantly lower among patients with Alzheimer’s disease than those with SMC (0.80 vs 1.23 pg/mL; P < .0001), and among those with MCI vs SMC (0.95 vs 1.23 pg/mL; P = .046). Among patients with Alzheimer’s disease, irisin levels were significantly lower among women than men (0.70 vs 0.96 pg/mL; P = .031).
Further analyses revealed positive correlations between CSF irisin level and Abeta42 in both males (r = 0.262; P < 005) and females (r = 0.379; P < .001). Conversely, in female patients, a significant negative correlation was found between CSF irisin level and CDR-SOB score (r = −0.234; P < .05).
Although a negative trend was observed between CSF irisin and total tau (t-tau) in the overall patient population (r = −0.144; P = 0.082), and more notably in female patients (r = −0.189; P = 0.084), these results were not statistically significant.
Plasma irisin levels were not significantly correlated with any of the other biomarkers.
Clinical Implications
This study “verifies that irisin levels do have a relationship to the Alzheimer’s disease process,” said Dylan Wint, MD, director of Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas.
In a written comment, Dr. Wint speculated that measuring irisin levels could theoretically help individualize physical exercise routines designed to combat cognitive decline.
“For example, maybe someone who is exercising but has a low irisin level would need to change the type of exercise they’re doing in order to optimally protect their brain health,” he said. “Or maybe they won’t get the same benefits for brain health as someone whose irisin shoots up every time they walk a flight of stairs.”
It’s “near-impossible to tell,” however, if irisin will be employed in clinical trials or real-world practice, he added.
“I don’t see this being a highly useful serum biomarker for Alzheimer’s disease itself because other serum biomarkers are so far ahead and have more face validity,” Dr. Wint said.
The route of collection could also cause challenges.
“In the United States, CSF-based biomarkers can be a difficult sell, especially for serial testing,” Dr. Wint said. “But we have usable serum biomarkers for Alzheimer’s disease only because we have had CSF biomarkers against which to evaluate them. They may develop a way to evaluate this in the serum.”
Dr. Dicarlo and colleagues suggested that more work is needed to determine the ultimate value of irisin measurement.“The true ability of irisin to represent a biomarker of disease progression and severity remains to be further investigated,” they concluded. “However, our findings might offer interesting perspectives toward the potential role of irisin in the modulation of AD pathology and can guide the exploration of medication targeting the irisin system.”
The study was supported by Regione Puglia and CNR for Tecnopolo per la Medicina di Precisione, CIREMIC, the University of Bari, and Next Generation EU. The investigators and Dr. Wint disclosed no conflicts of interest.
FROM ANNALS OF NEUROLOGY
ASTRO Releases New EBRT Guideline for Symptomatic Bone Mets
The guideline was needed to update previous recommendations and incorporate new high-quality evidence for the management of symptomatic bone metastases, Sara Alcorn, MD, PhD, of the University of Minnesota, Minneapolis, and colleagues wrote in Practical Radiation Oncology.
The focus was on the efficacy of EBRT in reducing pain, improving skeletal function, and enhancing quality of life, they wrote in the clinical practice guideline.
In developing their recommendations, the ASTRO task force reviewed evidence from 53 randomized controlled trials (RCTs) and 31 nonrandomized studies, and considered clinical experience.
Indications for Palliative Radiation
EBRT is strongly recommended for reducing pain from osseous metastasis and improving ambulatory status, sphincter function, and reducing pain in patients with spinal metastases causing compression of the spinal cord or cauda equina.
For patients with symptomatic bone metastases and an anticipated life expectancy of at least 4 weeks, EBRT is conditionally recommended to improve quality of life.
Implementation of other Treatments Alongside Palliative Radiation
Instead of RT alone, surgery with postoperative RT is conditionally recommended for patients with compression of the spinal cord or cauda equina.
Postoperative RT is strongly recommended for patients who have undergone surgery for non-spine bone metastases or spine metastases without involving spinal cord or cauda equina compression.
For patients with spinal bone metastases compressing the spinal cord or cauda equina, combining RT with dexamethasone is strongly recommended over RT alone.
Techniques, Dose-Fractionation, and Dose-Constraints for Initial Palliative Radiation
For patients with symptomatic bone metastases undergoing conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 3000 cGy in 10 fractions.
For patients with spinal bone metastases causing compression of the spinal cord or cauda equina who are not candidates for initial surgical decompression and are treated with conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 1600 cGy in 2 fractions, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions.
When selecting dose-fractionation, consider patient and disease factors such as prognosis and radiosensitivity, the authors wrote.
Highly conformal planning and delivery techniques, such as intensity-modulated radiation therapy, are conditionally recommended for patients with spinal bone metastases compressing the spinal cord or cauda equina who are receiving dose-escalated palliative RT.
The strongly recommended stereotactic body radiotherapy (SBRT) doses for patients with symptomatic bone metastases are 1200 to 1600 cGy in 1 fraction for non-spine metastases and 2400 cGy in 2 fractions for spine metastases. Other established SBRT dose and fractionation regimens with similar biologically effective doses may be considered based on patient tumor characteristics, normal tissue factors, and physician experience.
For patients with symptomatic bone metastases who have an ECOG PS of 0-2, are not undergoing surgical intervention, and have no neurological symptoms, SBRT is conditionally recommended over conventional palliative RT. Other factors to consider include life expectancy, tumor radiosensitivity, and metastatic disease burden, the guideline says.
Techniques, Dose-Fractionation, and Dose-Constraints for Palliative Reirradiation
For patients with spinal bone metastases requiring reirradiation to the same site, the strongly recommended conventional palliative RT regimens are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 2000 cGy in 8 fractions. When determining the RT dose-fractionation, consider the prior RT dose, time interval, and total spinal cord tolerance, the guideline says.
Treatment with SBRT is conditionally recommended for patients with spinal bone metastases needing reirradiation at the same site. When determining if SBRT is appropriate, consider patient factors such as urgency of treatment, prognosis, and radio-resistance. In addition, consider the prior RT dose, time interval, and total spinal cord tolerance when determining the RT dose-fractionation, the authors say.
The strongly recommended options for patients with symptomatic non-spine bone metastases needing reirradiation at the same site are single-fraction RT (800 cGy in 1 fraction) or multifraction conventional palliative RT (2000 cGy in 5 fractions or 2400 cGy in 6 fractions).
Impact of Techniques and Dose-fractionation on Quality of Life and Toxicity
For patients with bone metastases undergoing palliative radiation, it is strongly recommended to use a shared decision-making approach to determine the dose, fractionation, and supportive measures to optimize quality of life.
“Based on published data, the ASTRO task force’s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases,” the guideline panelists said.
Limitations
While the guideline provides comprehensive recommendations, the panelists underscored the importance of individualized treatment approaches. Future research is needed to address gaps in evidence, particularly regarding advanced RT techniques and reirradiation strategies.
Guideline development was funded by ASTRO, with the systematic evidence review funded by the Patient-Centered Outcomes Research Institute. The panelists disclosed relationships with AstraZeneca, Elekta, Teladoc, and others.
The guideline was needed to update previous recommendations and incorporate new high-quality evidence for the management of symptomatic bone metastases, Sara Alcorn, MD, PhD, of the University of Minnesota, Minneapolis, and colleagues wrote in Practical Radiation Oncology.
The focus was on the efficacy of EBRT in reducing pain, improving skeletal function, and enhancing quality of life, they wrote in the clinical practice guideline.
In developing their recommendations, the ASTRO task force reviewed evidence from 53 randomized controlled trials (RCTs) and 31 nonrandomized studies, and considered clinical experience.
Indications for Palliative Radiation
EBRT is strongly recommended for reducing pain from osseous metastasis and improving ambulatory status, sphincter function, and reducing pain in patients with spinal metastases causing compression of the spinal cord or cauda equina.
For patients with symptomatic bone metastases and an anticipated life expectancy of at least 4 weeks, EBRT is conditionally recommended to improve quality of life.
Implementation of other Treatments Alongside Palliative Radiation
Instead of RT alone, surgery with postoperative RT is conditionally recommended for patients with compression of the spinal cord or cauda equina.
Postoperative RT is strongly recommended for patients who have undergone surgery for non-spine bone metastases or spine metastases without involving spinal cord or cauda equina compression.
For patients with spinal bone metastases compressing the spinal cord or cauda equina, combining RT with dexamethasone is strongly recommended over RT alone.
Techniques, Dose-Fractionation, and Dose-Constraints for Initial Palliative Radiation
For patients with symptomatic bone metastases undergoing conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 3000 cGy in 10 fractions.
For patients with spinal bone metastases causing compression of the spinal cord or cauda equina who are not candidates for initial surgical decompression and are treated with conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 1600 cGy in 2 fractions, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions.
When selecting dose-fractionation, consider patient and disease factors such as prognosis and radiosensitivity, the authors wrote.
Highly conformal planning and delivery techniques, such as intensity-modulated radiation therapy, are conditionally recommended for patients with spinal bone metastases compressing the spinal cord or cauda equina who are receiving dose-escalated palliative RT.
The strongly recommended stereotactic body radiotherapy (SBRT) doses for patients with symptomatic bone metastases are 1200 to 1600 cGy in 1 fraction for non-spine metastases and 2400 cGy in 2 fractions for spine metastases. Other established SBRT dose and fractionation regimens with similar biologically effective doses may be considered based on patient tumor characteristics, normal tissue factors, and physician experience.
For patients with symptomatic bone metastases who have an ECOG PS of 0-2, are not undergoing surgical intervention, and have no neurological symptoms, SBRT is conditionally recommended over conventional palliative RT. Other factors to consider include life expectancy, tumor radiosensitivity, and metastatic disease burden, the guideline says.
Techniques, Dose-Fractionation, and Dose-Constraints for Palliative Reirradiation
For patients with spinal bone metastases requiring reirradiation to the same site, the strongly recommended conventional palliative RT regimens are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 2000 cGy in 8 fractions. When determining the RT dose-fractionation, consider the prior RT dose, time interval, and total spinal cord tolerance, the guideline says.
Treatment with SBRT is conditionally recommended for patients with spinal bone metastases needing reirradiation at the same site. When determining if SBRT is appropriate, consider patient factors such as urgency of treatment, prognosis, and radio-resistance. In addition, consider the prior RT dose, time interval, and total spinal cord tolerance when determining the RT dose-fractionation, the authors say.
The strongly recommended options for patients with symptomatic non-spine bone metastases needing reirradiation at the same site are single-fraction RT (800 cGy in 1 fraction) or multifraction conventional palliative RT (2000 cGy in 5 fractions or 2400 cGy in 6 fractions).
Impact of Techniques and Dose-fractionation on Quality of Life and Toxicity
For patients with bone metastases undergoing palliative radiation, it is strongly recommended to use a shared decision-making approach to determine the dose, fractionation, and supportive measures to optimize quality of life.
“Based on published data, the ASTRO task force’s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases,” the guideline panelists said.
Limitations
While the guideline provides comprehensive recommendations, the panelists underscored the importance of individualized treatment approaches. Future research is needed to address gaps in evidence, particularly regarding advanced RT techniques and reirradiation strategies.
Guideline development was funded by ASTRO, with the systematic evidence review funded by the Patient-Centered Outcomes Research Institute. The panelists disclosed relationships with AstraZeneca, Elekta, Teladoc, and others.
The guideline was needed to update previous recommendations and incorporate new high-quality evidence for the management of symptomatic bone metastases, Sara Alcorn, MD, PhD, of the University of Minnesota, Minneapolis, and colleagues wrote in Practical Radiation Oncology.
The focus was on the efficacy of EBRT in reducing pain, improving skeletal function, and enhancing quality of life, they wrote in the clinical practice guideline.
In developing their recommendations, the ASTRO task force reviewed evidence from 53 randomized controlled trials (RCTs) and 31 nonrandomized studies, and considered clinical experience.
Indications for Palliative Radiation
EBRT is strongly recommended for reducing pain from osseous metastasis and improving ambulatory status, sphincter function, and reducing pain in patients with spinal metastases causing compression of the spinal cord or cauda equina.
For patients with symptomatic bone metastases and an anticipated life expectancy of at least 4 weeks, EBRT is conditionally recommended to improve quality of life.
Implementation of other Treatments Alongside Palliative Radiation
Instead of RT alone, surgery with postoperative RT is conditionally recommended for patients with compression of the spinal cord or cauda equina.
Postoperative RT is strongly recommended for patients who have undergone surgery for non-spine bone metastases or spine metastases without involving spinal cord or cauda equina compression.
For patients with spinal bone metastases compressing the spinal cord or cauda equina, combining RT with dexamethasone is strongly recommended over RT alone.
Techniques, Dose-Fractionation, and Dose-Constraints for Initial Palliative Radiation
For patients with symptomatic bone metastases undergoing conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 3000 cGy in 10 fractions.
For patients with spinal bone metastases causing compression of the spinal cord or cauda equina who are not candidates for initial surgical decompression and are treated with conventional palliative RT, strongly recommended doses are 800 cGy in 1 fraction, 1600 cGy in 2 fractions, 2000 cGy in 5 fractions, or 3000 cGy in 10 fractions.
When selecting dose-fractionation, consider patient and disease factors such as prognosis and radiosensitivity, the authors wrote.
Highly conformal planning and delivery techniques, such as intensity-modulated radiation therapy, are conditionally recommended for patients with spinal bone metastases compressing the spinal cord or cauda equina who are receiving dose-escalated palliative RT.
The strongly recommended stereotactic body radiotherapy (SBRT) doses for patients with symptomatic bone metastases are 1200 to 1600 cGy in 1 fraction for non-spine metastases and 2400 cGy in 2 fractions for spine metastases. Other established SBRT dose and fractionation regimens with similar biologically effective doses may be considered based on patient tumor characteristics, normal tissue factors, and physician experience.
For patients with symptomatic bone metastases who have an ECOG PS of 0-2, are not undergoing surgical intervention, and have no neurological symptoms, SBRT is conditionally recommended over conventional palliative RT. Other factors to consider include life expectancy, tumor radiosensitivity, and metastatic disease burden, the guideline says.
Techniques, Dose-Fractionation, and Dose-Constraints for Palliative Reirradiation
For patients with spinal bone metastases requiring reirradiation to the same site, the strongly recommended conventional palliative RT regimens are 800 cGy in 1 fraction, 2000 cGy in 5 fractions, 2400 cGy in 6 fractions, or 2000 cGy in 8 fractions. When determining the RT dose-fractionation, consider the prior RT dose, time interval, and total spinal cord tolerance, the guideline says.
Treatment with SBRT is conditionally recommended for patients with spinal bone metastases needing reirradiation at the same site. When determining if SBRT is appropriate, consider patient factors such as urgency of treatment, prognosis, and radio-resistance. In addition, consider the prior RT dose, time interval, and total spinal cord tolerance when determining the RT dose-fractionation, the authors say.
The strongly recommended options for patients with symptomatic non-spine bone metastases needing reirradiation at the same site are single-fraction RT (800 cGy in 1 fraction) or multifraction conventional palliative RT (2000 cGy in 5 fractions or 2400 cGy in 6 fractions).
Impact of Techniques and Dose-fractionation on Quality of Life and Toxicity
For patients with bone metastases undergoing palliative radiation, it is strongly recommended to use a shared decision-making approach to determine the dose, fractionation, and supportive measures to optimize quality of life.
“Based on published data, the ASTRO task force’s recommendations inform best clinical practices on palliative RT for symptomatic bone metastases,” the guideline panelists said.
Limitations
While the guideline provides comprehensive recommendations, the panelists underscored the importance of individualized treatment approaches. Future research is needed to address gaps in evidence, particularly regarding advanced RT techniques and reirradiation strategies.
Guideline development was funded by ASTRO, with the systematic evidence review funded by the Patient-Centered Outcomes Research Institute. The panelists disclosed relationships with AstraZeneca, Elekta, Teladoc, and others.
FROM PRACTICAL RADIATION ONCOLOGY
ASCO Provides Guidance on CDK4/6 Inhibitors for Early Breast Cancer
TOPLINE:
METHODOLOGY:
- The guideline update was needed to incorporate new high-quality evidence for the adjuvant use of CDK4/6 inhibitors in early breast cancer.
- The ASCO guideline expert panel reviewed evidence from phase 3 trials, including the monarchE and NATALEE studies, focusing on the efficacy of abemaciclib and ribociclib in improving invasive disease-free survival (IDFS) and distant disease-free survival (DDFS).
TAKEAWAY:
- Abemaciclib for 2 years plus endocrine therapy (ET) for at least 5 years is recommended for patients with resected, hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, including those with at least four positive axillary lymph nodes (ALNs) or one to three positive ALNs plus additional high-risk features.
- Ribociclib (400 mg once daily, 3 weeks on, 1 week off) for 3 years plus ET is recommended for patients with stage II or III breast cancer who have a high risk of recurrence, based on the NATALEE trial.
- For patients meeting both monarchE and NATALEE criteria, abemaciclib is preferred due to longer follow-up, a deepening benefit over time, and FDA approval in the adjuvant setting.
- Ribociclib is recommended for patients who cannot tolerate abemaciclib due to contraindications such as high-grade diarrhea.
- Benefits, risks, costs, and individual patient preferences should be considered when deciding on adjuvant CDK4/6 inhibitor therapy.
IN PRACTICE:
This rapid recommendation update addresses the adjuvant use of CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer.
SOURCE:
The clinical practice guideline update, led by Rachel A. Freedman, from Dana-Farber Cancer Institute, Boston, was published in the Journal of Clinical Oncology.
LIMITATIONS:
The guideline panelists noted that the clinical benefits of adjuvant CDK4/6 inhibitor therapy may not extend to all patients eligible for the trials, particularly those at lower risk. There are insufficient data to specify which subgroups of patients may not warrant therapy, emphasizing the need for individualized treatment decisions. More data are needed to provide long-term efficacy data and more detailed guidance on which specific patient populations will benefit most from adjuvant CDK4/6 inhibitor therapy.
DISCLOSURES:
Guideline development was funded by the American Society of Clinical Oncology (ASCO). The panelists disclosed relationships with Firefly Health, Eisai, Novartis, and others.
TOPLINE:
METHODOLOGY:
- The guideline update was needed to incorporate new high-quality evidence for the adjuvant use of CDK4/6 inhibitors in early breast cancer.
- The ASCO guideline expert panel reviewed evidence from phase 3 trials, including the monarchE and NATALEE studies, focusing on the efficacy of abemaciclib and ribociclib in improving invasive disease-free survival (IDFS) and distant disease-free survival (DDFS).
TAKEAWAY:
- Abemaciclib for 2 years plus endocrine therapy (ET) for at least 5 years is recommended for patients with resected, hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, including those with at least four positive axillary lymph nodes (ALNs) or one to three positive ALNs plus additional high-risk features.
- Ribociclib (400 mg once daily, 3 weeks on, 1 week off) for 3 years plus ET is recommended for patients with stage II or III breast cancer who have a high risk of recurrence, based on the NATALEE trial.
- For patients meeting both monarchE and NATALEE criteria, abemaciclib is preferred due to longer follow-up, a deepening benefit over time, and FDA approval in the adjuvant setting.
- Ribociclib is recommended for patients who cannot tolerate abemaciclib due to contraindications such as high-grade diarrhea.
- Benefits, risks, costs, and individual patient preferences should be considered when deciding on adjuvant CDK4/6 inhibitor therapy.
IN PRACTICE:
This rapid recommendation update addresses the adjuvant use of CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer.
SOURCE:
The clinical practice guideline update, led by Rachel A. Freedman, from Dana-Farber Cancer Institute, Boston, was published in the Journal of Clinical Oncology.
LIMITATIONS:
The guideline panelists noted that the clinical benefits of adjuvant CDK4/6 inhibitor therapy may not extend to all patients eligible for the trials, particularly those at lower risk. There are insufficient data to specify which subgroups of patients may not warrant therapy, emphasizing the need for individualized treatment decisions. More data are needed to provide long-term efficacy data and more detailed guidance on which specific patient populations will benefit most from adjuvant CDK4/6 inhibitor therapy.
DISCLOSURES:
Guideline development was funded by the American Society of Clinical Oncology (ASCO). The panelists disclosed relationships with Firefly Health, Eisai, Novartis, and others.
TOPLINE:
METHODOLOGY:
- The guideline update was needed to incorporate new high-quality evidence for the adjuvant use of CDK4/6 inhibitors in early breast cancer.
- The ASCO guideline expert panel reviewed evidence from phase 3 trials, including the monarchE and NATALEE studies, focusing on the efficacy of abemaciclib and ribociclib in improving invasive disease-free survival (IDFS) and distant disease-free survival (DDFS).
TAKEAWAY:
- Abemaciclib for 2 years plus endocrine therapy (ET) for at least 5 years is recommended for patients with resected, hormone receptor–positive, HER2-negative, node-positive early breast cancer at high risk of recurrence, including those with at least four positive axillary lymph nodes (ALNs) or one to three positive ALNs plus additional high-risk features.
- Ribociclib (400 mg once daily, 3 weeks on, 1 week off) for 3 years plus ET is recommended for patients with stage II or III breast cancer who have a high risk of recurrence, based on the NATALEE trial.
- For patients meeting both monarchE and NATALEE criteria, abemaciclib is preferred due to longer follow-up, a deepening benefit over time, and FDA approval in the adjuvant setting.
- Ribociclib is recommended for patients who cannot tolerate abemaciclib due to contraindications such as high-grade diarrhea.
- Benefits, risks, costs, and individual patient preferences should be considered when deciding on adjuvant CDK4/6 inhibitor therapy.
IN PRACTICE:
This rapid recommendation update addresses the adjuvant use of CDK4/6 inhibitors abemaciclib and ribociclib in patients with stage II and III breast cancer.
SOURCE:
The clinical practice guideline update, led by Rachel A. Freedman, from Dana-Farber Cancer Institute, Boston, was published in the Journal of Clinical Oncology.
LIMITATIONS:
The guideline panelists noted that the clinical benefits of adjuvant CDK4/6 inhibitor therapy may not extend to all patients eligible for the trials, particularly those at lower risk. There are insufficient data to specify which subgroups of patients may not warrant therapy, emphasizing the need for individualized treatment decisions. More data are needed to provide long-term efficacy data and more detailed guidance on which specific patient populations will benefit most from adjuvant CDK4/6 inhibitor therapy.
DISCLOSURES:
Guideline development was funded by the American Society of Clinical Oncology (ASCO). The panelists disclosed relationships with Firefly Health, Eisai, Novartis, and others.
FROM JOURNAL OF CLINICAL ONCOLOGY
Could Aspirin Help Treat Breast Cancer?
These data are more robust than the efficacy signals from previous studies, meaning healthcare providers should not recommend aspirin as adjuvant therapy for breast cancer, reported lead author Wendy Y. Chen, MD, of Dana Farber Cancer Institute, Boston, and colleagues.
What Data Support Aspirin for Treating Breast Cancer?
“Multiple observational studies have reported a decreased risk of death among survivors of breast cancer who were regular aspirin users,” the investigators wrote in JAMA. “Even more compelling were data from randomized trials of aspirin for cardiovascular disease.”
This possible benefit was reported with mechanistic support, as aspirin’s anti-inflammatory and anti-platelet properties could theoretically control tumor growth, they added. Furthermore, aspirin impacts several cancer pathways currently targeted by agents approved by the US Food and Drug Administration (FDA).
“Collectively, evidence from laboratory and epidemiologic studies and randomized trials strongly suggested a role for aspirin to improve breast cancer outcomes, leading to [this new study, Alliance for Clinical Trials in Oncology (Alliance) A011502,] which, to our knowledge, is the first randomized, placebo-controlled trial of aspirin to report results among survivors of breast cancer,” Dr. Chen and colleagues wrote.
What Were The Key Findings From The A011502 Trial?
The A011502 trial enrolled 3,020 patients aged 18-70 years with ERBB2-negative breast cancer who had received standard therapy via routine clinical care. Eligibility required that chemotherapy and local therapy were complete, but ongoing endocrine therapy was allowed.
Participants were randomized in a 1:1 ratio to receive aspirin 300 mg per day or matching placebo for 5 years. The primary outcome was invasive disease-free survival, and the key secondary outcome was overall survival.
After a median follow-up of almost 3 years, at the first interim analysis, the study was suspended early due to statistical futility. By that timepoint, 253 invasive disease-free survival events occurred, of which 141 occurred in the aspirin group, compared with 112 in the placebo group, providing a hazard ratio of 1.27 (95% CI, 0.99-1.63) that was not statistically significant (P = .06). No statistically significant difference in overall survival was observed (hazard ratio, 1.19; 95% CI, 0.82-1.72). Safety profiles were similar across groups.
How Will This Study Change Practice?
In an accompanying editorial, Jeanne S. Mandelblatt, MD, of Georgetown Lombardi Institute for Cancer and Aging Research, Washington, and colleagues, praised the trial for its comprehensive approach, but they predicted that the negative result could spell friction for health care providers.
“[C]linicians may find it challenging to communicate with their patients about the negative result in the Alliance trial, because prior lay press articles, observational studies, and meta-analyses of cardiovascular trials suggested that aspirin may decrease breast cancer recurrence,” they wrote.
Dr. Mandelblatt and colleagues went on to explore broader implications beyond breast cancer, including considerations for communication of negative results in other medical specialties, discussions between clinicians and patients regarding aspirin use for non–breast cancer purposes, and questions about the timing of aspirin use and the role of age and biological aging.
How Might the Findings From the A011502 Trial Impact Future Research?
Finally, and “most critically,” the editorialists raised concerns about health equity, noting the limited diversity in trial participants and the potential exclusion of subgroups that might benefit from aspirin use, particularly those more likely to experience accelerated biological aging and disparities in cancer risk and outcomes due to systemic racism or adverse social determinants of health.
They concluded by emphasizing the need to consider the intersectionality of aging, cancer, and disparities in designing future trials to advance health equity.
This study was funded by the Department of Defense Breast Cancer Research Program and the National Cancer Institute of the National Institutes of Health. The research was also supported in part by Bayer, which provided the study drug. The investigators disclosed relationships with Novartis, Seagen, Orum Clinical, and others. The editorialists disclosed relationships with Cantex Pharmaceuticals, and Pfizer.
These data are more robust than the efficacy signals from previous studies, meaning healthcare providers should not recommend aspirin as adjuvant therapy for breast cancer, reported lead author Wendy Y. Chen, MD, of Dana Farber Cancer Institute, Boston, and colleagues.
What Data Support Aspirin for Treating Breast Cancer?
“Multiple observational studies have reported a decreased risk of death among survivors of breast cancer who were regular aspirin users,” the investigators wrote in JAMA. “Even more compelling were data from randomized trials of aspirin for cardiovascular disease.”
This possible benefit was reported with mechanistic support, as aspirin’s anti-inflammatory and anti-platelet properties could theoretically control tumor growth, they added. Furthermore, aspirin impacts several cancer pathways currently targeted by agents approved by the US Food and Drug Administration (FDA).
“Collectively, evidence from laboratory and epidemiologic studies and randomized trials strongly suggested a role for aspirin to improve breast cancer outcomes, leading to [this new study, Alliance for Clinical Trials in Oncology (Alliance) A011502,] which, to our knowledge, is the first randomized, placebo-controlled trial of aspirin to report results among survivors of breast cancer,” Dr. Chen and colleagues wrote.
What Were The Key Findings From The A011502 Trial?
The A011502 trial enrolled 3,020 patients aged 18-70 years with ERBB2-negative breast cancer who had received standard therapy via routine clinical care. Eligibility required that chemotherapy and local therapy were complete, but ongoing endocrine therapy was allowed.
Participants were randomized in a 1:1 ratio to receive aspirin 300 mg per day or matching placebo for 5 years. The primary outcome was invasive disease-free survival, and the key secondary outcome was overall survival.
After a median follow-up of almost 3 years, at the first interim analysis, the study was suspended early due to statistical futility. By that timepoint, 253 invasive disease-free survival events occurred, of which 141 occurred in the aspirin group, compared with 112 in the placebo group, providing a hazard ratio of 1.27 (95% CI, 0.99-1.63) that was not statistically significant (P = .06). No statistically significant difference in overall survival was observed (hazard ratio, 1.19; 95% CI, 0.82-1.72). Safety profiles were similar across groups.
How Will This Study Change Practice?
In an accompanying editorial, Jeanne S. Mandelblatt, MD, of Georgetown Lombardi Institute for Cancer and Aging Research, Washington, and colleagues, praised the trial for its comprehensive approach, but they predicted that the negative result could spell friction for health care providers.
“[C]linicians may find it challenging to communicate with their patients about the negative result in the Alliance trial, because prior lay press articles, observational studies, and meta-analyses of cardiovascular trials suggested that aspirin may decrease breast cancer recurrence,” they wrote.
Dr. Mandelblatt and colleagues went on to explore broader implications beyond breast cancer, including considerations for communication of negative results in other medical specialties, discussions between clinicians and patients regarding aspirin use for non–breast cancer purposes, and questions about the timing of aspirin use and the role of age and biological aging.
How Might the Findings From the A011502 Trial Impact Future Research?
Finally, and “most critically,” the editorialists raised concerns about health equity, noting the limited diversity in trial participants and the potential exclusion of subgroups that might benefit from aspirin use, particularly those more likely to experience accelerated biological aging and disparities in cancer risk and outcomes due to systemic racism or adverse social determinants of health.
They concluded by emphasizing the need to consider the intersectionality of aging, cancer, and disparities in designing future trials to advance health equity.
This study was funded by the Department of Defense Breast Cancer Research Program and the National Cancer Institute of the National Institutes of Health. The research was also supported in part by Bayer, which provided the study drug. The investigators disclosed relationships with Novartis, Seagen, Orum Clinical, and others. The editorialists disclosed relationships with Cantex Pharmaceuticals, and Pfizer.
These data are more robust than the efficacy signals from previous studies, meaning healthcare providers should not recommend aspirin as adjuvant therapy for breast cancer, reported lead author Wendy Y. Chen, MD, of Dana Farber Cancer Institute, Boston, and colleagues.
What Data Support Aspirin for Treating Breast Cancer?
“Multiple observational studies have reported a decreased risk of death among survivors of breast cancer who were regular aspirin users,” the investigators wrote in JAMA. “Even more compelling were data from randomized trials of aspirin for cardiovascular disease.”
This possible benefit was reported with mechanistic support, as aspirin’s anti-inflammatory and anti-platelet properties could theoretically control tumor growth, they added. Furthermore, aspirin impacts several cancer pathways currently targeted by agents approved by the US Food and Drug Administration (FDA).
“Collectively, evidence from laboratory and epidemiologic studies and randomized trials strongly suggested a role for aspirin to improve breast cancer outcomes, leading to [this new study, Alliance for Clinical Trials in Oncology (Alliance) A011502,] which, to our knowledge, is the first randomized, placebo-controlled trial of aspirin to report results among survivors of breast cancer,” Dr. Chen and colleagues wrote.
What Were The Key Findings From The A011502 Trial?
The A011502 trial enrolled 3,020 patients aged 18-70 years with ERBB2-negative breast cancer who had received standard therapy via routine clinical care. Eligibility required that chemotherapy and local therapy were complete, but ongoing endocrine therapy was allowed.
Participants were randomized in a 1:1 ratio to receive aspirin 300 mg per day or matching placebo for 5 years. The primary outcome was invasive disease-free survival, and the key secondary outcome was overall survival.
After a median follow-up of almost 3 years, at the first interim analysis, the study was suspended early due to statistical futility. By that timepoint, 253 invasive disease-free survival events occurred, of which 141 occurred in the aspirin group, compared with 112 in the placebo group, providing a hazard ratio of 1.27 (95% CI, 0.99-1.63) that was not statistically significant (P = .06). No statistically significant difference in overall survival was observed (hazard ratio, 1.19; 95% CI, 0.82-1.72). Safety profiles were similar across groups.
How Will This Study Change Practice?
In an accompanying editorial, Jeanne S. Mandelblatt, MD, of Georgetown Lombardi Institute for Cancer and Aging Research, Washington, and colleagues, praised the trial for its comprehensive approach, but they predicted that the negative result could spell friction for health care providers.
“[C]linicians may find it challenging to communicate with their patients about the negative result in the Alliance trial, because prior lay press articles, observational studies, and meta-analyses of cardiovascular trials suggested that aspirin may decrease breast cancer recurrence,” they wrote.
Dr. Mandelblatt and colleagues went on to explore broader implications beyond breast cancer, including considerations for communication of negative results in other medical specialties, discussions between clinicians and patients regarding aspirin use for non–breast cancer purposes, and questions about the timing of aspirin use and the role of age and biological aging.
How Might the Findings From the A011502 Trial Impact Future Research?
Finally, and “most critically,” the editorialists raised concerns about health equity, noting the limited diversity in trial participants and the potential exclusion of subgroups that might benefit from aspirin use, particularly those more likely to experience accelerated biological aging and disparities in cancer risk and outcomes due to systemic racism or adverse social determinants of health.
They concluded by emphasizing the need to consider the intersectionality of aging, cancer, and disparities in designing future trials to advance health equity.
This study was funded by the Department of Defense Breast Cancer Research Program and the National Cancer Institute of the National Institutes of Health. The research was also supported in part by Bayer, which provided the study drug. The investigators disclosed relationships with Novartis, Seagen, Orum Clinical, and others. The editorialists disclosed relationships with Cantex Pharmaceuticals, and Pfizer.
FROM JAMA
AGA Defines Diagnostic, Treatment Approach to Cannabinoid Hyperemesis Syndrome
.
CHS, which is triggered by chronic cannabis usage and manifests with GI and autonomic symptoms, is on the rise in the United States, yet underdiagnosis remains a challenge and clinical data are scarce, reported lead update panelist Alberto Rubio Tapia, MD, of Cleveland Clinic, Cleveland, Ohio, and colleagues.
“Although cannabis use has been reported for many decades, some of its unique adverse effects of nausea, vomiting, and abdominal pain, termed CHS, were noted relatively recently,” the panelists wrote in Gastroenterology. “The objective of this article was to help practitioners define the appropriate approach to the diagnosis and management of CHS.”
According to the update, the typical CHS patient is male with a years-long history of daily or near-daily cannabis use. Paradoxically, while cannabis use drives this condition, some patients with CHS report that cannabis use relieves their symptoms.The update describes CHS as a subtype of cyclical vomiting syndrome (CVS), and offers diagnostic criteria for CHS, reproduced below verbatim:
- Clinical features: stereotypical episodic vomiting resembling CVS in terms of onset, with frequency 3 or more times annually;
- Cannabis use patterns: duration of cannabis use more than 1 year before symptom onset; frequency more than 4 times per week, on average;
- Cannabis cessation: resolution of symptoms after a period of abstinence from cannabis use for at least 6 months, or at least equal to the total duration of 3 typical vomiting cycles in that patient.
As CHS is a subtype of CVS, the update also provides an outline and management guide for this broader condition, which is characterized by four phases: inter-episodic, prodromal, emetic, and recovery.
During the inter-episodic phase, patients will have minimal or no symptoms, although almost one third will describe dyspepsia or nausea. Prophylactic medications in this period include tricyclics, mitochondrial supplements like CoQ10 and vitamin B12, NK1 antagonists, and anticonvulsants.
The prodromal phase is characterized by abdominal pain and nausea with a duration of 30-90 minutes. During this time patients may have autonomic symptoms like sweating and feeling hot or cold. Psychological symptoms may include feelings of panic and being “out of control.” Abortive medications are appropriate during this period, according to the update, like triptans and antiemetics.
Next comes the emetic phase, in which patients exhibit “relentless vomiting,” retching, abdominal pain, neurological symptoms and extreme thirst. Because an empty stomach may provide relief, inducing emesis may be considered, along with rest in a quiet dark room and supportive care.
Finally, the vomiting subsides during the recovery phase, when it is possible to restart oral intake and resume normal activities.
While this framework may be useful when managing patients with CHS, intervention should be centered around cannabis cessation, according to the update.
“For long-term management, counseling to achieve marijuana cessation and tricyclic antidepressants, such as amitriptyline, are the mainstay of therapy,” Dr. Rubio Tapia and colleagues wrote.
Advising patients to stop cannabis “cold turkey” is not recommended, they added, as this may bring on withdrawal symptoms, and it tends to be ineffective in this population, which has a high recidivism rate.
“Co-management with a psychologist or psychiatrist may be helpful for patients who have a lack of response to standard therapies or extensive psychiatric comorbidity,” the panelists wrote. “Anxiety and depression are very common associated conditions.”
Dr. Rubio Tapia and colleagues concluded with a call for more research.
“Further understanding of CHS pathophysiology and evidence-based therapies are urgently needed,” they wrote.
This update was commissioned and approved by the AGA. The update panelists disclosed relationships with Evoke Pharma, RedHill Biopharma, Takeda, and others.
.
CHS, which is triggered by chronic cannabis usage and manifests with GI and autonomic symptoms, is on the rise in the United States, yet underdiagnosis remains a challenge and clinical data are scarce, reported lead update panelist Alberto Rubio Tapia, MD, of Cleveland Clinic, Cleveland, Ohio, and colleagues.
“Although cannabis use has been reported for many decades, some of its unique adverse effects of nausea, vomiting, and abdominal pain, termed CHS, were noted relatively recently,” the panelists wrote in Gastroenterology. “The objective of this article was to help practitioners define the appropriate approach to the diagnosis and management of CHS.”
According to the update, the typical CHS patient is male with a years-long history of daily or near-daily cannabis use. Paradoxically, while cannabis use drives this condition, some patients with CHS report that cannabis use relieves their symptoms.The update describes CHS as a subtype of cyclical vomiting syndrome (CVS), and offers diagnostic criteria for CHS, reproduced below verbatim:
- Clinical features: stereotypical episodic vomiting resembling CVS in terms of onset, with frequency 3 or more times annually;
- Cannabis use patterns: duration of cannabis use more than 1 year before symptom onset; frequency more than 4 times per week, on average;
- Cannabis cessation: resolution of symptoms after a period of abstinence from cannabis use for at least 6 months, or at least equal to the total duration of 3 typical vomiting cycles in that patient.
As CHS is a subtype of CVS, the update also provides an outline and management guide for this broader condition, which is characterized by four phases: inter-episodic, prodromal, emetic, and recovery.
During the inter-episodic phase, patients will have minimal or no symptoms, although almost one third will describe dyspepsia or nausea. Prophylactic medications in this period include tricyclics, mitochondrial supplements like CoQ10 and vitamin B12, NK1 antagonists, and anticonvulsants.
The prodromal phase is characterized by abdominal pain and nausea with a duration of 30-90 minutes. During this time patients may have autonomic symptoms like sweating and feeling hot or cold. Psychological symptoms may include feelings of panic and being “out of control.” Abortive medications are appropriate during this period, according to the update, like triptans and antiemetics.
Next comes the emetic phase, in which patients exhibit “relentless vomiting,” retching, abdominal pain, neurological symptoms and extreme thirst. Because an empty stomach may provide relief, inducing emesis may be considered, along with rest in a quiet dark room and supportive care.
Finally, the vomiting subsides during the recovery phase, when it is possible to restart oral intake and resume normal activities.
While this framework may be useful when managing patients with CHS, intervention should be centered around cannabis cessation, according to the update.
“For long-term management, counseling to achieve marijuana cessation and tricyclic antidepressants, such as amitriptyline, are the mainstay of therapy,” Dr. Rubio Tapia and colleagues wrote.
Advising patients to stop cannabis “cold turkey” is not recommended, they added, as this may bring on withdrawal symptoms, and it tends to be ineffective in this population, which has a high recidivism rate.
“Co-management with a psychologist or psychiatrist may be helpful for patients who have a lack of response to standard therapies or extensive psychiatric comorbidity,” the panelists wrote. “Anxiety and depression are very common associated conditions.”
Dr. Rubio Tapia and colleagues concluded with a call for more research.
“Further understanding of CHS pathophysiology and evidence-based therapies are urgently needed,” they wrote.
This update was commissioned and approved by the AGA. The update panelists disclosed relationships with Evoke Pharma, RedHill Biopharma, Takeda, and others.
.
CHS, which is triggered by chronic cannabis usage and manifests with GI and autonomic symptoms, is on the rise in the United States, yet underdiagnosis remains a challenge and clinical data are scarce, reported lead update panelist Alberto Rubio Tapia, MD, of Cleveland Clinic, Cleveland, Ohio, and colleagues.
“Although cannabis use has been reported for many decades, some of its unique adverse effects of nausea, vomiting, and abdominal pain, termed CHS, were noted relatively recently,” the panelists wrote in Gastroenterology. “The objective of this article was to help practitioners define the appropriate approach to the diagnosis and management of CHS.”
According to the update, the typical CHS patient is male with a years-long history of daily or near-daily cannabis use. Paradoxically, while cannabis use drives this condition, some patients with CHS report that cannabis use relieves their symptoms.The update describes CHS as a subtype of cyclical vomiting syndrome (CVS), and offers diagnostic criteria for CHS, reproduced below verbatim:
- Clinical features: stereotypical episodic vomiting resembling CVS in terms of onset, with frequency 3 or more times annually;
- Cannabis use patterns: duration of cannabis use more than 1 year before symptom onset; frequency more than 4 times per week, on average;
- Cannabis cessation: resolution of symptoms after a period of abstinence from cannabis use for at least 6 months, or at least equal to the total duration of 3 typical vomiting cycles in that patient.
As CHS is a subtype of CVS, the update also provides an outline and management guide for this broader condition, which is characterized by four phases: inter-episodic, prodromal, emetic, and recovery.
During the inter-episodic phase, patients will have minimal or no symptoms, although almost one third will describe dyspepsia or nausea. Prophylactic medications in this period include tricyclics, mitochondrial supplements like CoQ10 and vitamin B12, NK1 antagonists, and anticonvulsants.
The prodromal phase is characterized by abdominal pain and nausea with a duration of 30-90 minutes. During this time patients may have autonomic symptoms like sweating and feeling hot or cold. Psychological symptoms may include feelings of panic and being “out of control.” Abortive medications are appropriate during this period, according to the update, like triptans and antiemetics.
Next comes the emetic phase, in which patients exhibit “relentless vomiting,” retching, abdominal pain, neurological symptoms and extreme thirst. Because an empty stomach may provide relief, inducing emesis may be considered, along with rest in a quiet dark room and supportive care.
Finally, the vomiting subsides during the recovery phase, when it is possible to restart oral intake and resume normal activities.
While this framework may be useful when managing patients with CHS, intervention should be centered around cannabis cessation, according to the update.
“For long-term management, counseling to achieve marijuana cessation and tricyclic antidepressants, such as amitriptyline, are the mainstay of therapy,” Dr. Rubio Tapia and colleagues wrote.
Advising patients to stop cannabis “cold turkey” is not recommended, they added, as this may bring on withdrawal symptoms, and it tends to be ineffective in this population, which has a high recidivism rate.
“Co-management with a psychologist or psychiatrist may be helpful for patients who have a lack of response to standard therapies or extensive psychiatric comorbidity,” the panelists wrote. “Anxiety and depression are very common associated conditions.”
Dr. Rubio Tapia and colleagues concluded with a call for more research.
“Further understanding of CHS pathophysiology and evidence-based therapies are urgently needed,” they wrote.
This update was commissioned and approved by the AGA. The update panelists disclosed relationships with Evoke Pharma, RedHill Biopharma, Takeda, and others.
FROM GASTROENTEROLOGY
TRAIL-targeting Therapies Still Hold Promise in Cholangiocarcinoma
primarily due to the adaptive resistance and unexpected immune modulation, according to investigators.
Those prior studies evaluated a combination of immunotherapy and TRAIL agonism, but selective TRAIL antagonism shows greater potential via dual ligand/receptor (TRAIL/TRAIL-R) targeting to block immunosuppression, reported lead author Emilien J. Loeuillard, PhD, of Mayo Clinic, Rochester, Minnesota, and colleagues.
“The TRAIL/TRAIL-R system has garnered considerable interest in cancer biology, especially as a potential anticancer therapy,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “However, TRAIL-R agonists have had very limited anticancer activity in human beings, challenging this concept of TRAIL as an anticancer agent.”
This may be because they were working in the wrong direction, Dr. Loeuillard and colleagues suggested, citing recent work linking TRAIL with tumor proliferation and invasion, possibly via modification of the tumor immune microenvironment.
Exact mechanisms of modification, however, remain unclear. While TRAIL has been associated with tumor-promoting effects like induction of a promyeloid secretome in adenocarcinoma, it has also been linked with anticancer effects like activation of natural killer cells and cytotoxic T lymphocytes.
“Thus, the potency and hierarchy of TRAIL anticancer vs procancer processes in cancer biology has yet to be defined,” the investigators wrote.
While TRAIL ligation of cognate receptors has been previously investigated and shown to trigger proapoptotic signaling pathways, noncanonical TRAIL-mediated signaling remains largely unexplored, particularly in CCA.
The present study evaluated TRAIL biology in CCA using immunocompetent mouse models.
These experiments showed that noncanonical TRAIL signaling immunosuppresses the tumor microenvironment by increasing quantity and activity of myeloid-derived suppressor cells (MDSCs). Blocking noncanonical TRAIL signaling by selective deletion of TRAIL-R in immune cells had significantly reduced tumor volumes alongside fewer MDSCs, driven by FLICE inhibitory protein (cFLIP)-dependent nuclear factor kappa-B activation (NF-kappa-B) in MDSCs, which has antiapoptotic activity. While MDSCs present one possible target in this chain of immunosuppression, “therapeutic strategies for targeting MDSCs are limited,” the investigators wrote, noting that available myeloid modulators have fallen short in clinical trials.
Instead, cFLIP may be a convincing option, they suggested, as targeting cFLIP can sensitize cancer cells to proapoptotic TRAIL signaling. What’s more, cFLIP appears to protect MDSCs from TRAIL-mediated apoptosis, so taking out this barrier could render MDSCs susceptible to therapy.
“Our studies suggest that switching prosurvival/proliferation TRAIL signaling to canonical proapoptotic TRAIL signaling will promote MDSC apoptosis, which in turn has therapeutic implications for CCA suppression,” the investigators wrote.
Hope therefore remains for targeting TRAIL in patients with CCA, but with selective antagonism instead of agonism, as previously attempted.
“In summary, our findings support the role of selective therapeutic targeting of TRAIL-positive cancer cells in an effort to block TRAIL/TRAIL-R–mediated tumor immunosuppression,” Dr. Loeuillard and colleagues concluded.
This study was funded by the Cholangiocarcinoma Foundation and the Mayo Clinic Eagles 5th District Cancer Telethon Funds for Research Fellowship Program, the CTSA/National Center for Advancing Translational Science, the National Institutes of Health/National Cancer Institute, and others. The investigators disclosed no conflicts of interest.
The dismal response of cholangiocarcinoma to immune checkpoint inhibitors (ICI) is particularly concerning, as it impedes the adoption of combination regimens, now standard in most solid tumors. Strategies modulating selective genes involved in the tumor inflammatory environment and tumor cell viability, including those within the tumor necrosis factor superfamily, parallel the mechanism of action of ICI and present a double-edged sword due to the context-dependent pro- and/or anticancer effects of their canonical and/or phantom roles.
Recent investigations suggest that selectively antagonizing TRAIL via (TRAIL/TRAIL-R) targeting may be more effective than agonism. Dr. Ilyas’ group from Mayo Clinic delved into the potential of TRAIL in cancer biology, particularly in CCA, shedding light on the complexities of TRAIL’s role in cancer, where both procancer and anticancer effects are observed.
Further investigation is warranted to explore how TRAIL/TRAIL-R therapy can be effectively combined with other broad-spectrum and/or targeted therapies to maximize selective toxicity to CCA cells, sparing the nonmalignant tissue, thereby extending the lifespan of CCA patients as well as assessing its preventive potential in predisposed premalignant stages, including cholestasis patients.
Sungjin Ko, DVM, PhD, is assistant professor in the Division of Experimental Pathology at the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. He is also a member of the Pittsburgh Liver Research Center. He reported no conflicts of interest.
The dismal response of cholangiocarcinoma to immune checkpoint inhibitors (ICI) is particularly concerning, as it impedes the adoption of combination regimens, now standard in most solid tumors. Strategies modulating selective genes involved in the tumor inflammatory environment and tumor cell viability, including those within the tumor necrosis factor superfamily, parallel the mechanism of action of ICI and present a double-edged sword due to the context-dependent pro- and/or anticancer effects of their canonical and/or phantom roles.
Recent investigations suggest that selectively antagonizing TRAIL via (TRAIL/TRAIL-R) targeting may be more effective than agonism. Dr. Ilyas’ group from Mayo Clinic delved into the potential of TRAIL in cancer biology, particularly in CCA, shedding light on the complexities of TRAIL’s role in cancer, where both procancer and anticancer effects are observed.
Further investigation is warranted to explore how TRAIL/TRAIL-R therapy can be effectively combined with other broad-spectrum and/or targeted therapies to maximize selective toxicity to CCA cells, sparing the nonmalignant tissue, thereby extending the lifespan of CCA patients as well as assessing its preventive potential in predisposed premalignant stages, including cholestasis patients.
Sungjin Ko, DVM, PhD, is assistant professor in the Division of Experimental Pathology at the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. He is also a member of the Pittsburgh Liver Research Center. He reported no conflicts of interest.
The dismal response of cholangiocarcinoma to immune checkpoint inhibitors (ICI) is particularly concerning, as it impedes the adoption of combination regimens, now standard in most solid tumors. Strategies modulating selective genes involved in the tumor inflammatory environment and tumor cell viability, including those within the tumor necrosis factor superfamily, parallel the mechanism of action of ICI and present a double-edged sword due to the context-dependent pro- and/or anticancer effects of their canonical and/or phantom roles.
Recent investigations suggest that selectively antagonizing TRAIL via (TRAIL/TRAIL-R) targeting may be more effective than agonism. Dr. Ilyas’ group from Mayo Clinic delved into the potential of TRAIL in cancer biology, particularly in CCA, shedding light on the complexities of TRAIL’s role in cancer, where both procancer and anticancer effects are observed.
Further investigation is warranted to explore how TRAIL/TRAIL-R therapy can be effectively combined with other broad-spectrum and/or targeted therapies to maximize selective toxicity to CCA cells, sparing the nonmalignant tissue, thereby extending the lifespan of CCA patients as well as assessing its preventive potential in predisposed premalignant stages, including cholestasis patients.
Sungjin Ko, DVM, PhD, is assistant professor in the Division of Experimental Pathology at the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania. He is also a member of the Pittsburgh Liver Research Center. He reported no conflicts of interest.
primarily due to the adaptive resistance and unexpected immune modulation, according to investigators.
Those prior studies evaluated a combination of immunotherapy and TRAIL agonism, but selective TRAIL antagonism shows greater potential via dual ligand/receptor (TRAIL/TRAIL-R) targeting to block immunosuppression, reported lead author Emilien J. Loeuillard, PhD, of Mayo Clinic, Rochester, Minnesota, and colleagues.
“The TRAIL/TRAIL-R system has garnered considerable interest in cancer biology, especially as a potential anticancer therapy,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “However, TRAIL-R agonists have had very limited anticancer activity in human beings, challenging this concept of TRAIL as an anticancer agent.”
This may be because they were working in the wrong direction, Dr. Loeuillard and colleagues suggested, citing recent work linking TRAIL with tumor proliferation and invasion, possibly via modification of the tumor immune microenvironment.
Exact mechanisms of modification, however, remain unclear. While TRAIL has been associated with tumor-promoting effects like induction of a promyeloid secretome in adenocarcinoma, it has also been linked with anticancer effects like activation of natural killer cells and cytotoxic T lymphocytes.
“Thus, the potency and hierarchy of TRAIL anticancer vs procancer processes in cancer biology has yet to be defined,” the investigators wrote.
While TRAIL ligation of cognate receptors has been previously investigated and shown to trigger proapoptotic signaling pathways, noncanonical TRAIL-mediated signaling remains largely unexplored, particularly in CCA.
The present study evaluated TRAIL biology in CCA using immunocompetent mouse models.
These experiments showed that noncanonical TRAIL signaling immunosuppresses the tumor microenvironment by increasing quantity and activity of myeloid-derived suppressor cells (MDSCs). Blocking noncanonical TRAIL signaling by selective deletion of TRAIL-R in immune cells had significantly reduced tumor volumes alongside fewer MDSCs, driven by FLICE inhibitory protein (cFLIP)-dependent nuclear factor kappa-B activation (NF-kappa-B) in MDSCs, which has antiapoptotic activity. While MDSCs present one possible target in this chain of immunosuppression, “therapeutic strategies for targeting MDSCs are limited,” the investigators wrote, noting that available myeloid modulators have fallen short in clinical trials.
Instead, cFLIP may be a convincing option, they suggested, as targeting cFLIP can sensitize cancer cells to proapoptotic TRAIL signaling. What’s more, cFLIP appears to protect MDSCs from TRAIL-mediated apoptosis, so taking out this barrier could render MDSCs susceptible to therapy.
“Our studies suggest that switching prosurvival/proliferation TRAIL signaling to canonical proapoptotic TRAIL signaling will promote MDSC apoptosis, which in turn has therapeutic implications for CCA suppression,” the investigators wrote.
Hope therefore remains for targeting TRAIL in patients with CCA, but with selective antagonism instead of agonism, as previously attempted.
“In summary, our findings support the role of selective therapeutic targeting of TRAIL-positive cancer cells in an effort to block TRAIL/TRAIL-R–mediated tumor immunosuppression,” Dr. Loeuillard and colleagues concluded.
This study was funded by the Cholangiocarcinoma Foundation and the Mayo Clinic Eagles 5th District Cancer Telethon Funds for Research Fellowship Program, the CTSA/National Center for Advancing Translational Science, the National Institutes of Health/National Cancer Institute, and others. The investigators disclosed no conflicts of interest.
primarily due to the adaptive resistance and unexpected immune modulation, according to investigators.
Those prior studies evaluated a combination of immunotherapy and TRAIL agonism, but selective TRAIL antagonism shows greater potential via dual ligand/receptor (TRAIL/TRAIL-R) targeting to block immunosuppression, reported lead author Emilien J. Loeuillard, PhD, of Mayo Clinic, Rochester, Minnesota, and colleagues.
“The TRAIL/TRAIL-R system has garnered considerable interest in cancer biology, especially as a potential anticancer therapy,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. “However, TRAIL-R agonists have had very limited anticancer activity in human beings, challenging this concept of TRAIL as an anticancer agent.”
This may be because they were working in the wrong direction, Dr. Loeuillard and colleagues suggested, citing recent work linking TRAIL with tumor proliferation and invasion, possibly via modification of the tumor immune microenvironment.
Exact mechanisms of modification, however, remain unclear. While TRAIL has been associated with tumor-promoting effects like induction of a promyeloid secretome in adenocarcinoma, it has also been linked with anticancer effects like activation of natural killer cells and cytotoxic T lymphocytes.
“Thus, the potency and hierarchy of TRAIL anticancer vs procancer processes in cancer biology has yet to be defined,” the investigators wrote.
While TRAIL ligation of cognate receptors has been previously investigated and shown to trigger proapoptotic signaling pathways, noncanonical TRAIL-mediated signaling remains largely unexplored, particularly in CCA.
The present study evaluated TRAIL biology in CCA using immunocompetent mouse models.
These experiments showed that noncanonical TRAIL signaling immunosuppresses the tumor microenvironment by increasing quantity and activity of myeloid-derived suppressor cells (MDSCs). Blocking noncanonical TRAIL signaling by selective deletion of TRAIL-R in immune cells had significantly reduced tumor volumes alongside fewer MDSCs, driven by FLICE inhibitory protein (cFLIP)-dependent nuclear factor kappa-B activation (NF-kappa-B) in MDSCs, which has antiapoptotic activity. While MDSCs present one possible target in this chain of immunosuppression, “therapeutic strategies for targeting MDSCs are limited,” the investigators wrote, noting that available myeloid modulators have fallen short in clinical trials.
Instead, cFLIP may be a convincing option, they suggested, as targeting cFLIP can sensitize cancer cells to proapoptotic TRAIL signaling. What’s more, cFLIP appears to protect MDSCs from TRAIL-mediated apoptosis, so taking out this barrier could render MDSCs susceptible to therapy.
“Our studies suggest that switching prosurvival/proliferation TRAIL signaling to canonical proapoptotic TRAIL signaling will promote MDSC apoptosis, which in turn has therapeutic implications for CCA suppression,” the investigators wrote.
Hope therefore remains for targeting TRAIL in patients with CCA, but with selective antagonism instead of agonism, as previously attempted.
“In summary, our findings support the role of selective therapeutic targeting of TRAIL-positive cancer cells in an effort to block TRAIL/TRAIL-R–mediated tumor immunosuppression,” Dr. Loeuillard and colleagues concluded.
This study was funded by the Cholangiocarcinoma Foundation and the Mayo Clinic Eagles 5th District Cancer Telethon Funds for Research Fellowship Program, the CTSA/National Center for Advancing Translational Science, the National Institutes of Health/National Cancer Institute, and others. The investigators disclosed no conflicts of interest.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
IBD: Histologic Inflammation Linked With Lower Female Fertility
, according to a Swedish nationwide cohort study.
Reduced fertility was linked with histologic inflammation even in the absence of clinical disease activity, highlighting the importance of achieving deep remission in women planning pregnancy, reported lead author Karl Mårild, MD, PhD, of Sahlgrenska Academy, Gothenburg, Sweden, and colleagues.
“Reduced female fertility (ie, number of live births) is believed to be primarily confined to women with clinically active IBD, especially in Crohn’s disease (CD), where symptoms may inhibit sexual activity, and inflammation may affect the fallopian tubes and ovaries,” the investigators wrote in Gastroenterology. “Despite the increasing appreciation of histologic activity in IBD, its association with female fertility has not been clarified, including whether histologic activity in the absence of clinical disease activity impairs fertility.”
Dr. Mårild and colleagues aimed to address this knowledge gap by analyzing fertility rates and histologic inflammation or IBD activity in two cohorts of women with IBD aged 15-44 years. The first group included approximately 21,000 women with and without histologic inflammation from 1990 to 2016. The second group included approximately 25,000 women with or without IBD clinical activity from 2006 to 2020. In each group, the relationship between fertility and IBD was compared with fertility in matched general population comparator individuals.
This approach showed that clinical IBD activity was associated with an adjusted fertility rate ratio (aFRR) of 0.76 (95% CI, 0.72-0.79), which equates to one fewer child per six women with 10 years of clinical activity. Impacts on fertility were similar for UC (aFRR, 0.75) and CD (aFRR, 0.76).
“Fertility rates were notably reduced during periods of clinical IBD activity and, contrary to a generally accepted belief, equally reduced in clinically active UC and CD,” the investigators wrote. “Besides inflammation, clinically active IBD may reduce fertility through psychological mechanisms (eg, depression), dyspareunia (especially in perianal CD), bowel pain, urgency, and other symptoms that hinder sexual activity.”
Compared with histologic remission, histologic inflammation was also associated with reduced fertility (aFRR, 0.90). This means that in periods of histologic inflammation, 6.35 live births occurred per 100 person-years of follow-up, compared with 7.09 lives births for periods of histologic remission. This amounts to one fewer child per 14 women with 10 years of histologic inflammation.
Finally, the study revealed that, in women with clinically quiescent IBD, those with histologic inflammation had significantly reduced fertility, compared with those in histologic remission (aFRR, 0.85). This association persisted after controlling for contraceptive use.
“Even if histologic inflammation was associated with an overall modest fertility reduction … its impact on the individual might be substantial, with potential ramifications beyond reproductive health, given that reduced female fertility is linked to poor quality of life and mental health,” Dr. Mårild and colleagues wrote. “At a societal level, involuntary childlessness causes high and increasing costs, highlighting the need to focus on preventable causes of reduced fertility.”
The investigators suggested that inflammation may be driving infertility by reducing ovulation and fertilization, or by reducing endometrial receptivity, which increases risk of pregnancy loss.
“This is the first study, to our knowledge, to show reduced fertility during histologic inflammation in IBD compared to histologic remission,” the investigators wrote. “Our findings suggest that achieving histologic remission may improve the fertility of women with IBD, even in the absence of clinically defined disease activity.”
The investigators disclosed relationships with AbbVie, Pfizer, Janssen, and others.
The importance of controlling inflammation to ensure a healthy pregnancy cannot be overstated. With regard to fertility, the literature has emphasized that surgery has been the major risk factor for decreasing fertility in both ulcerative colitis and Crohn’s disease. Disease activity has been more influential on Crohn’s disease versus ulcerative colitis. Other factors such as voluntary childlessness, premature ovarian failure, and malnutrition can also play a role. There have been data to show that anti–tumor necrosis factor use increases the chances of successful implantation for women with sub-fertility who do not have concomitant IBD, perhaps by decreasing inflammation in the pelvis.
Sunanda Kane, MD, MSPH, AGAF, is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. She reports serving as a consultant to Boehringer Ingelheim, Bristol Myers Squibb, Fresenius Kabi, Gilead, Janssen, and Takeda. She is also Section Editor for IBD for UptoDate.
The importance of controlling inflammation to ensure a healthy pregnancy cannot be overstated. With regard to fertility, the literature has emphasized that surgery has been the major risk factor for decreasing fertility in both ulcerative colitis and Crohn’s disease. Disease activity has been more influential on Crohn’s disease versus ulcerative colitis. Other factors such as voluntary childlessness, premature ovarian failure, and malnutrition can also play a role. There have been data to show that anti–tumor necrosis factor use increases the chances of successful implantation for women with sub-fertility who do not have concomitant IBD, perhaps by decreasing inflammation in the pelvis.
Sunanda Kane, MD, MSPH, AGAF, is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. She reports serving as a consultant to Boehringer Ingelheim, Bristol Myers Squibb, Fresenius Kabi, Gilead, Janssen, and Takeda. She is also Section Editor for IBD for UptoDate.
The importance of controlling inflammation to ensure a healthy pregnancy cannot be overstated. With regard to fertility, the literature has emphasized that surgery has been the major risk factor for decreasing fertility in both ulcerative colitis and Crohn’s disease. Disease activity has been more influential on Crohn’s disease versus ulcerative colitis. Other factors such as voluntary childlessness, premature ovarian failure, and malnutrition can also play a role. There have been data to show that anti–tumor necrosis factor use increases the chances of successful implantation for women with sub-fertility who do not have concomitant IBD, perhaps by decreasing inflammation in the pelvis.
Sunanda Kane, MD, MSPH, AGAF, is based in the Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. She reports serving as a consultant to Boehringer Ingelheim, Bristol Myers Squibb, Fresenius Kabi, Gilead, Janssen, and Takeda. She is also Section Editor for IBD for UptoDate.
, according to a Swedish nationwide cohort study.
Reduced fertility was linked with histologic inflammation even in the absence of clinical disease activity, highlighting the importance of achieving deep remission in women planning pregnancy, reported lead author Karl Mårild, MD, PhD, of Sahlgrenska Academy, Gothenburg, Sweden, and colleagues.
“Reduced female fertility (ie, number of live births) is believed to be primarily confined to women with clinically active IBD, especially in Crohn’s disease (CD), where symptoms may inhibit sexual activity, and inflammation may affect the fallopian tubes and ovaries,” the investigators wrote in Gastroenterology. “Despite the increasing appreciation of histologic activity in IBD, its association with female fertility has not been clarified, including whether histologic activity in the absence of clinical disease activity impairs fertility.”
Dr. Mårild and colleagues aimed to address this knowledge gap by analyzing fertility rates and histologic inflammation or IBD activity in two cohorts of women with IBD aged 15-44 years. The first group included approximately 21,000 women with and without histologic inflammation from 1990 to 2016. The second group included approximately 25,000 women with or without IBD clinical activity from 2006 to 2020. In each group, the relationship between fertility and IBD was compared with fertility in matched general population comparator individuals.
This approach showed that clinical IBD activity was associated with an adjusted fertility rate ratio (aFRR) of 0.76 (95% CI, 0.72-0.79), which equates to one fewer child per six women with 10 years of clinical activity. Impacts on fertility were similar for UC (aFRR, 0.75) and CD (aFRR, 0.76).
“Fertility rates were notably reduced during periods of clinical IBD activity and, contrary to a generally accepted belief, equally reduced in clinically active UC and CD,” the investigators wrote. “Besides inflammation, clinically active IBD may reduce fertility through psychological mechanisms (eg, depression), dyspareunia (especially in perianal CD), bowel pain, urgency, and other symptoms that hinder sexual activity.”
Compared with histologic remission, histologic inflammation was also associated with reduced fertility (aFRR, 0.90). This means that in periods of histologic inflammation, 6.35 live births occurred per 100 person-years of follow-up, compared with 7.09 lives births for periods of histologic remission. This amounts to one fewer child per 14 women with 10 years of histologic inflammation.
Finally, the study revealed that, in women with clinically quiescent IBD, those with histologic inflammation had significantly reduced fertility, compared with those in histologic remission (aFRR, 0.85). This association persisted after controlling for contraceptive use.
“Even if histologic inflammation was associated with an overall modest fertility reduction … its impact on the individual might be substantial, with potential ramifications beyond reproductive health, given that reduced female fertility is linked to poor quality of life and mental health,” Dr. Mårild and colleagues wrote. “At a societal level, involuntary childlessness causes high and increasing costs, highlighting the need to focus on preventable causes of reduced fertility.”
The investigators suggested that inflammation may be driving infertility by reducing ovulation and fertilization, or by reducing endometrial receptivity, which increases risk of pregnancy loss.
“This is the first study, to our knowledge, to show reduced fertility during histologic inflammation in IBD compared to histologic remission,” the investigators wrote. “Our findings suggest that achieving histologic remission may improve the fertility of women with IBD, even in the absence of clinically defined disease activity.”
The investigators disclosed relationships with AbbVie, Pfizer, Janssen, and others.
, according to a Swedish nationwide cohort study.
Reduced fertility was linked with histologic inflammation even in the absence of clinical disease activity, highlighting the importance of achieving deep remission in women planning pregnancy, reported lead author Karl Mårild, MD, PhD, of Sahlgrenska Academy, Gothenburg, Sweden, and colleagues.
“Reduced female fertility (ie, number of live births) is believed to be primarily confined to women with clinically active IBD, especially in Crohn’s disease (CD), where symptoms may inhibit sexual activity, and inflammation may affect the fallopian tubes and ovaries,” the investigators wrote in Gastroenterology. “Despite the increasing appreciation of histologic activity in IBD, its association with female fertility has not been clarified, including whether histologic activity in the absence of clinical disease activity impairs fertility.”
Dr. Mårild and colleagues aimed to address this knowledge gap by analyzing fertility rates and histologic inflammation or IBD activity in two cohorts of women with IBD aged 15-44 years. The first group included approximately 21,000 women with and without histologic inflammation from 1990 to 2016. The second group included approximately 25,000 women with or without IBD clinical activity from 2006 to 2020. In each group, the relationship between fertility and IBD was compared with fertility in matched general population comparator individuals.
This approach showed that clinical IBD activity was associated with an adjusted fertility rate ratio (aFRR) of 0.76 (95% CI, 0.72-0.79), which equates to one fewer child per six women with 10 years of clinical activity. Impacts on fertility were similar for UC (aFRR, 0.75) and CD (aFRR, 0.76).
“Fertility rates were notably reduced during periods of clinical IBD activity and, contrary to a generally accepted belief, equally reduced in clinically active UC and CD,” the investigators wrote. “Besides inflammation, clinically active IBD may reduce fertility through psychological mechanisms (eg, depression), dyspareunia (especially in perianal CD), bowel pain, urgency, and other symptoms that hinder sexual activity.”
Compared with histologic remission, histologic inflammation was also associated with reduced fertility (aFRR, 0.90). This means that in periods of histologic inflammation, 6.35 live births occurred per 100 person-years of follow-up, compared with 7.09 lives births for periods of histologic remission. This amounts to one fewer child per 14 women with 10 years of histologic inflammation.
Finally, the study revealed that, in women with clinically quiescent IBD, those with histologic inflammation had significantly reduced fertility, compared with those in histologic remission (aFRR, 0.85). This association persisted after controlling for contraceptive use.
“Even if histologic inflammation was associated with an overall modest fertility reduction … its impact on the individual might be substantial, with potential ramifications beyond reproductive health, given that reduced female fertility is linked to poor quality of life and mental health,” Dr. Mårild and colleagues wrote. “At a societal level, involuntary childlessness causes high and increasing costs, highlighting the need to focus on preventable causes of reduced fertility.”
The investigators suggested that inflammation may be driving infertility by reducing ovulation and fertilization, or by reducing endometrial receptivity, which increases risk of pregnancy loss.
“This is the first study, to our knowledge, to show reduced fertility during histologic inflammation in IBD compared to histologic remission,” the investigators wrote. “Our findings suggest that achieving histologic remission may improve the fertility of women with IBD, even in the absence of clinically defined disease activity.”
The investigators disclosed relationships with AbbVie, Pfizer, Janssen, and others.
FROM GASTROENTEROLOGY
AGA Clinical Practice Update Describes High-Quality Upper Endoscopy
The update, authored by Satish Nagula, MD, of Icahn School of Medicine at Mount Sinai, New York, NY, and colleagues, includes nine pieces of best practice advice that address procedure optimization, evaluation of suspected premalignancy, and postprocedure follow-up evaluation.
“Defining what constitutes a high-quality esophagogastroduodenoscopy (EGD) poses somewhat of a challenge because the spectrum of indications and the breadth of benign and (pre)malignant disease pathology in the upper GI tract is very broad,” the update panelists wrote in Clinical Gastroenterology and Hepatology. “Standardizing the measures defining a high-quality upper endoscopic examination is one of the first steps for assessing quality.”
Preprocedure Recommendations
Dr. Nagula and colleagues first emphasized that EGD should be performed for an appropriate indication, citing a recent meta-analysis that found 21.7% of upper endoscopy procedures were performed for an inappropriate indication. Of note, diagnostic yields were 42% higher in procedures performed for an appropriate indication.
After ensuring an appropriate indication, the update also encourages clinicians to inform patients of the various benefits, risks, and alternatives of the procedure prior to providing consent.
Intraprocedure Recommendations
During the procedure, endoscopists should take several steps to ensure optimal visualization of tissues, according to the update.
First, a high-definition (HD) white-light endoscopy system should be employed.
“Although HD imaging is a standard feature of newer-generation endoscopes, legacy standard-definition scopes remain in use,” Dr. Nagula and colleagues noted. “Moreover, to provide true HD image resolution, each component of the system (eg, the endoscope video chip, the processor, the monitor, and transmission cables) must be HD compatible.”
This HD-compatible system should be coupled with image-enhancing technology to further improve lesion detection. In Barrett’s esophagus, the panelists noted, image enhancement can improve lesion detection as much as 20%.
They predicted that AI-assisted software may boost detection rates even higher: “Computer-aided detection and computer-aided diagnosis systems for upper endoscopy are still in the early phases of development but do show similar promise for improving the detection and characterization of upper GI tract neoplasia.”
Beyond selection of best available technologies, the update encourages more fundamental strategies to improve visualization, including mucosal cleansing and insufflation, with sufficient time spent inspecting the foregut mucosa via anterograde and retroflexed views.
Where appropriate, standardized biopsy protocols should be followed to evaluate and manage foregut conditions.
Postprocedure Recommendations
After the procedure, endoscopists should offer patients management recommendations based on the endoscopic findings and, if necessary, notify them that more recommendations may be forthcoming based on histopathology results, according to the update.
Similarly, endoscopists should follow established surveillance intervals for future procedures, with modifications made as needed, based on histopathology findings.
Document, Document, Document
Throughout the update, Dr. Nagula and colleagues repeatedly emphasize the importance of documentation, from preprocedural discussions with patients through planned surveillance schedules.
However, the recommendations are clear about “weighing the practical implications” of “onerous” documentation, particularly photodocumentation requirements. For instance, the authors note that “there are some scenarios in which more rigorous photodocumentation standards during upper endoscopy should be considered, such as patients with risk factors for neoplasia,” but at the very least “photodocumentation of any suspicious abnormalities, ideally with annotations, is strongly advised.”
Moving Toward Quality Standardization for Upper Endoscopy
“These best practice advice statements are intended to improve measurable clinical, patient-reported, and economic healthcare outcomes and are not meant to put an additional burden on endoscopists,” the panelists wrote. “Ideally, future research will set threshold indicators of adherence to these best practices that optimally are associated with these aforementioned objective outcomes.”
This update was commissioned and approved by AGA. The update panelists disclosed relationships with Covidien LP, Fujifilm USA, Mahana Therapeutics, and others.
The update, authored by Satish Nagula, MD, of Icahn School of Medicine at Mount Sinai, New York, NY, and colleagues, includes nine pieces of best practice advice that address procedure optimization, evaluation of suspected premalignancy, and postprocedure follow-up evaluation.
“Defining what constitutes a high-quality esophagogastroduodenoscopy (EGD) poses somewhat of a challenge because the spectrum of indications and the breadth of benign and (pre)malignant disease pathology in the upper GI tract is very broad,” the update panelists wrote in Clinical Gastroenterology and Hepatology. “Standardizing the measures defining a high-quality upper endoscopic examination is one of the first steps for assessing quality.”
Preprocedure Recommendations
Dr. Nagula and colleagues first emphasized that EGD should be performed for an appropriate indication, citing a recent meta-analysis that found 21.7% of upper endoscopy procedures were performed for an inappropriate indication. Of note, diagnostic yields were 42% higher in procedures performed for an appropriate indication.
After ensuring an appropriate indication, the update also encourages clinicians to inform patients of the various benefits, risks, and alternatives of the procedure prior to providing consent.
Intraprocedure Recommendations
During the procedure, endoscopists should take several steps to ensure optimal visualization of tissues, according to the update.
First, a high-definition (HD) white-light endoscopy system should be employed.
“Although HD imaging is a standard feature of newer-generation endoscopes, legacy standard-definition scopes remain in use,” Dr. Nagula and colleagues noted. “Moreover, to provide true HD image resolution, each component of the system (eg, the endoscope video chip, the processor, the monitor, and transmission cables) must be HD compatible.”
This HD-compatible system should be coupled with image-enhancing technology to further improve lesion detection. In Barrett’s esophagus, the panelists noted, image enhancement can improve lesion detection as much as 20%.
They predicted that AI-assisted software may boost detection rates even higher: “Computer-aided detection and computer-aided diagnosis systems for upper endoscopy are still in the early phases of development but do show similar promise for improving the detection and characterization of upper GI tract neoplasia.”
Beyond selection of best available technologies, the update encourages more fundamental strategies to improve visualization, including mucosal cleansing and insufflation, with sufficient time spent inspecting the foregut mucosa via anterograde and retroflexed views.
Where appropriate, standardized biopsy protocols should be followed to evaluate and manage foregut conditions.
Postprocedure Recommendations
After the procedure, endoscopists should offer patients management recommendations based on the endoscopic findings and, if necessary, notify them that more recommendations may be forthcoming based on histopathology results, according to the update.
Similarly, endoscopists should follow established surveillance intervals for future procedures, with modifications made as needed, based on histopathology findings.
Document, Document, Document
Throughout the update, Dr. Nagula and colleagues repeatedly emphasize the importance of documentation, from preprocedural discussions with patients through planned surveillance schedules.
However, the recommendations are clear about “weighing the practical implications” of “onerous” documentation, particularly photodocumentation requirements. For instance, the authors note that “there are some scenarios in which more rigorous photodocumentation standards during upper endoscopy should be considered, such as patients with risk factors for neoplasia,” but at the very least “photodocumentation of any suspicious abnormalities, ideally with annotations, is strongly advised.”
Moving Toward Quality Standardization for Upper Endoscopy
“These best practice advice statements are intended to improve measurable clinical, patient-reported, and economic healthcare outcomes and are not meant to put an additional burden on endoscopists,” the panelists wrote. “Ideally, future research will set threshold indicators of adherence to these best practices that optimally are associated with these aforementioned objective outcomes.”
This update was commissioned and approved by AGA. The update panelists disclosed relationships with Covidien LP, Fujifilm USA, Mahana Therapeutics, and others.
The update, authored by Satish Nagula, MD, of Icahn School of Medicine at Mount Sinai, New York, NY, and colleagues, includes nine pieces of best practice advice that address procedure optimization, evaluation of suspected premalignancy, and postprocedure follow-up evaluation.
“Defining what constitutes a high-quality esophagogastroduodenoscopy (EGD) poses somewhat of a challenge because the spectrum of indications and the breadth of benign and (pre)malignant disease pathology in the upper GI tract is very broad,” the update panelists wrote in Clinical Gastroenterology and Hepatology. “Standardizing the measures defining a high-quality upper endoscopic examination is one of the first steps for assessing quality.”
Preprocedure Recommendations
Dr. Nagula and colleagues first emphasized that EGD should be performed for an appropriate indication, citing a recent meta-analysis that found 21.7% of upper endoscopy procedures were performed for an inappropriate indication. Of note, diagnostic yields were 42% higher in procedures performed for an appropriate indication.
After ensuring an appropriate indication, the update also encourages clinicians to inform patients of the various benefits, risks, and alternatives of the procedure prior to providing consent.
Intraprocedure Recommendations
During the procedure, endoscopists should take several steps to ensure optimal visualization of tissues, according to the update.
First, a high-definition (HD) white-light endoscopy system should be employed.
“Although HD imaging is a standard feature of newer-generation endoscopes, legacy standard-definition scopes remain in use,” Dr. Nagula and colleagues noted. “Moreover, to provide true HD image resolution, each component of the system (eg, the endoscope video chip, the processor, the monitor, and transmission cables) must be HD compatible.”
This HD-compatible system should be coupled with image-enhancing technology to further improve lesion detection. In Barrett’s esophagus, the panelists noted, image enhancement can improve lesion detection as much as 20%.
They predicted that AI-assisted software may boost detection rates even higher: “Computer-aided detection and computer-aided diagnosis systems for upper endoscopy are still in the early phases of development but do show similar promise for improving the detection and characterization of upper GI tract neoplasia.”
Beyond selection of best available technologies, the update encourages more fundamental strategies to improve visualization, including mucosal cleansing and insufflation, with sufficient time spent inspecting the foregut mucosa via anterograde and retroflexed views.
Where appropriate, standardized biopsy protocols should be followed to evaluate and manage foregut conditions.
Postprocedure Recommendations
After the procedure, endoscopists should offer patients management recommendations based on the endoscopic findings and, if necessary, notify them that more recommendations may be forthcoming based on histopathology results, according to the update.
Similarly, endoscopists should follow established surveillance intervals for future procedures, with modifications made as needed, based on histopathology findings.
Document, Document, Document
Throughout the update, Dr. Nagula and colleagues repeatedly emphasize the importance of documentation, from preprocedural discussions with patients through planned surveillance schedules.
However, the recommendations are clear about “weighing the practical implications” of “onerous” documentation, particularly photodocumentation requirements. For instance, the authors note that “there are some scenarios in which more rigorous photodocumentation standards during upper endoscopy should be considered, such as patients with risk factors for neoplasia,” but at the very least “photodocumentation of any suspicious abnormalities, ideally with annotations, is strongly advised.”
Moving Toward Quality Standardization for Upper Endoscopy
“These best practice advice statements are intended to improve measurable clinical, patient-reported, and economic healthcare outcomes and are not meant to put an additional burden on endoscopists,” the panelists wrote. “Ideally, future research will set threshold indicators of adherence to these best practices that optimally are associated with these aforementioned objective outcomes.”
This update was commissioned and approved by AGA. The update panelists disclosed relationships with Covidien LP, Fujifilm USA, Mahana Therapeutics, and others.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Power-Washing Moves Beyond Home Improvement, Into Gastroenterology
Power-washing is no longer just for blasting grimy driveways and stripping flaky paint. It’s good for work inside the gut, too.
In a proof-of-concept study, a “novel systematically directed high-pressure liquid spray,” delivered via the ERBEJET flexible probe, showed promise for collecting cytology specimens from the stomachs of patients undergoing endoscopy for gastric cancer screening or surveillance, reported lead author Charles J. Lightdale, MD, of Columbia University Irving Medical Center, New York City, and colleagues.
“Systematic random biopsies (updated Sydney protocol) have been recommended to increase detection of gastric intestinal metaplasia (GIM) and dysplasia,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “However, random biopsies can be laborious, time consuming, costly, and susceptible to sampling error owing to the large surface area of the stomach.”
Power-washing, in contrast, with the pressure dial turned to 10 bar, involves spraying the gut in a systematic fashion “using sweeping and painting motions” to dislodge cells from the mucosa. These specimens are then suctioned from the resultant pools of liquid, mixed 1:1 with 10% formalin, and shipped to the lab.
Boom! Cytology!
Just to be sure, however, the nine patients involved in the study also underwent standard-of-care biopsy collection from areas of interest, followed by random sampling according to the updated Sydney protocol. Two of the patients were power-washed again 12 months later for endoscopic surveillance.
Power-washing added 7-10 minutes to standard endoscopy time and generated 60-100 mL of liquid for collection. Post suction, a closer look at the gastric mucosa revealed “scattered superficial erosions,” while blood loss was deemed “minimal.” The procedure appeared well tolerated, with no aspiration or esophageal reflux during endoscopy, or adverse events reported by patients after 1 week of follow-up.
Cytopathology samples were deemed satisfactory and yielded “multiple strips and large clusters of cells.” These were sufficient to diagnose GIM in three patients and reactive glandular changes with inflammation in one patient, with findings confirmed on biopsy. In contrast, the power-washed cells from one patient were “highly suspicious” for dysplasia, but biopsies were negative.
Although the study was too small for a reliable comparison with the Sydney protocol, Dr. Lightdale and colleagues concluded that the power-wash approach deserves further investigation.
“ and to reduce morbidity and mortality from gastric cancer,” they wrote.
The investigators predicted that power-washing is likely safe in most patients, although it may be unsuitable for those with noncorrectable coagulopathies or in patients who cannot stop anticoagulants. Postsurgical patients, on the other hand, should tolerate the procedure just fine.
Patients with risk of gastric cancer “might be an important group” for evaluating the power-wash procedure, the investigators wrote, noting that combining the approach with artificial intelligence could one day yield even better results.
In the meantime, Dr. Lightdale and colleagues — like so many weekend warriors wielding a power-washer — are going to see if a different nozzle will take their work to the next level.
“We are actively studying a catheter with a broader stream and the potential to increase efficiency and decrease procedure time,” they wrote. “Another catheter design might allow for simultaneous spray and suction, so that cytology samples from specific regions of the stomach could be separately analyzed.”
This study was funded by Dalio Philanthropies, the Price Family Foundation, and the Frederic and Patricia Salerno Foundation. The investigators disclosed relationships with Boston Scientific, Interscope, Medtronic, and others.
The optimal surveillance endoscopic modality for gastric intestinal metaplasia (GIM) is yet to be determined. Although the updated Sydney System, a comprehensive endoscopic biopsy protocol, has been advocated for GIM mapping, challenges are the heterogeneous distribution of GIM, suboptimal diagnostic accuracy of endoscopy to detect GIM, and the cost burden of multiple biopsies.
This study by Lightdale et al. demonstrated the technical feasibility and safety of obtaining cytology for the detection of gastric intestinal metaplasia by using a systemic endoscopy-guided high-pressure spray “power-wash” method. In this study, all cytophathology samples in nine subjects were deemed satisfactory for evaluation. All three subjects who were cytology positive for GIM on H&E stain and confirmed with positive immunohistochemistry (IHC) showed GIM on biopsy, and one subject had cells highly suspicious for dysplasia on cytology but biopsy was negative. Although all patients showed multiple superficial erosions after power-wash, bleeding was minimal and no adverse events related to power-wash were observed.
Applying cytology for detection of GIM appears promising as the way of collecting samples from the large surface area of the stomach. As clinicians, however, we are still left with some challenges. Even if cells collected are suspicious for dysplasia/neoplasia by this power-wash method, it would not be useful unless we precisely localize the area as we can not provide a focal curative endoscopic treatment. It is critical to increase the yield of localization of cytology sampling. Further research is also needed to standardize the cytopathologic diagnostic criteria of GIM and cost-effectiveness of the cytology-based approach compared to the current gold-standard biopsy protocol for the diagnosis of GIM.
Yutaka Tomizawa, MD, MSc, is a therapeutic endoscopist and clinical associate professor of medicine, Division of Gastroenterology, University of Washington, Seattle. He has no conflicts related to this report.
The optimal surveillance endoscopic modality for gastric intestinal metaplasia (GIM) is yet to be determined. Although the updated Sydney System, a comprehensive endoscopic biopsy protocol, has been advocated for GIM mapping, challenges are the heterogeneous distribution of GIM, suboptimal diagnostic accuracy of endoscopy to detect GIM, and the cost burden of multiple biopsies.
This study by Lightdale et al. demonstrated the technical feasibility and safety of obtaining cytology for the detection of gastric intestinal metaplasia by using a systemic endoscopy-guided high-pressure spray “power-wash” method. In this study, all cytophathology samples in nine subjects were deemed satisfactory for evaluation. All three subjects who were cytology positive for GIM on H&E stain and confirmed with positive immunohistochemistry (IHC) showed GIM on biopsy, and one subject had cells highly suspicious for dysplasia on cytology but biopsy was negative. Although all patients showed multiple superficial erosions after power-wash, bleeding was minimal and no adverse events related to power-wash were observed.
Applying cytology for detection of GIM appears promising as the way of collecting samples from the large surface area of the stomach. As clinicians, however, we are still left with some challenges. Even if cells collected are suspicious for dysplasia/neoplasia by this power-wash method, it would not be useful unless we precisely localize the area as we can not provide a focal curative endoscopic treatment. It is critical to increase the yield of localization of cytology sampling. Further research is also needed to standardize the cytopathologic diagnostic criteria of GIM and cost-effectiveness of the cytology-based approach compared to the current gold-standard biopsy protocol for the diagnosis of GIM.
Yutaka Tomizawa, MD, MSc, is a therapeutic endoscopist and clinical associate professor of medicine, Division of Gastroenterology, University of Washington, Seattle. He has no conflicts related to this report.
The optimal surveillance endoscopic modality for gastric intestinal metaplasia (GIM) is yet to be determined. Although the updated Sydney System, a comprehensive endoscopic biopsy protocol, has been advocated for GIM mapping, challenges are the heterogeneous distribution of GIM, suboptimal diagnostic accuracy of endoscopy to detect GIM, and the cost burden of multiple biopsies.
This study by Lightdale et al. demonstrated the technical feasibility and safety of obtaining cytology for the detection of gastric intestinal metaplasia by using a systemic endoscopy-guided high-pressure spray “power-wash” method. In this study, all cytophathology samples in nine subjects were deemed satisfactory for evaluation. All three subjects who were cytology positive for GIM on H&E stain and confirmed with positive immunohistochemistry (IHC) showed GIM on biopsy, and one subject had cells highly suspicious for dysplasia on cytology but biopsy was negative. Although all patients showed multiple superficial erosions after power-wash, bleeding was minimal and no adverse events related to power-wash were observed.
Applying cytology for detection of GIM appears promising as the way of collecting samples from the large surface area of the stomach. As clinicians, however, we are still left with some challenges. Even if cells collected are suspicious for dysplasia/neoplasia by this power-wash method, it would not be useful unless we precisely localize the area as we can not provide a focal curative endoscopic treatment. It is critical to increase the yield of localization of cytology sampling. Further research is also needed to standardize the cytopathologic diagnostic criteria of GIM and cost-effectiveness of the cytology-based approach compared to the current gold-standard biopsy protocol for the diagnosis of GIM.
Yutaka Tomizawa, MD, MSc, is a therapeutic endoscopist and clinical associate professor of medicine, Division of Gastroenterology, University of Washington, Seattle. He has no conflicts related to this report.
Power-washing is no longer just for blasting grimy driveways and stripping flaky paint. It’s good for work inside the gut, too.
In a proof-of-concept study, a “novel systematically directed high-pressure liquid spray,” delivered via the ERBEJET flexible probe, showed promise for collecting cytology specimens from the stomachs of patients undergoing endoscopy for gastric cancer screening or surveillance, reported lead author Charles J. Lightdale, MD, of Columbia University Irving Medical Center, New York City, and colleagues.
“Systematic random biopsies (updated Sydney protocol) have been recommended to increase detection of gastric intestinal metaplasia (GIM) and dysplasia,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “However, random biopsies can be laborious, time consuming, costly, and susceptible to sampling error owing to the large surface area of the stomach.”
Power-washing, in contrast, with the pressure dial turned to 10 bar, involves spraying the gut in a systematic fashion “using sweeping and painting motions” to dislodge cells from the mucosa. These specimens are then suctioned from the resultant pools of liquid, mixed 1:1 with 10% formalin, and shipped to the lab.
Boom! Cytology!
Just to be sure, however, the nine patients involved in the study also underwent standard-of-care biopsy collection from areas of interest, followed by random sampling according to the updated Sydney protocol. Two of the patients were power-washed again 12 months later for endoscopic surveillance.
Power-washing added 7-10 minutes to standard endoscopy time and generated 60-100 mL of liquid for collection. Post suction, a closer look at the gastric mucosa revealed “scattered superficial erosions,” while blood loss was deemed “minimal.” The procedure appeared well tolerated, with no aspiration or esophageal reflux during endoscopy, or adverse events reported by patients after 1 week of follow-up.
Cytopathology samples were deemed satisfactory and yielded “multiple strips and large clusters of cells.” These were sufficient to diagnose GIM in three patients and reactive glandular changes with inflammation in one patient, with findings confirmed on biopsy. In contrast, the power-washed cells from one patient were “highly suspicious” for dysplasia, but biopsies were negative.
Although the study was too small for a reliable comparison with the Sydney protocol, Dr. Lightdale and colleagues concluded that the power-wash approach deserves further investigation.
“ and to reduce morbidity and mortality from gastric cancer,” they wrote.
The investigators predicted that power-washing is likely safe in most patients, although it may be unsuitable for those with noncorrectable coagulopathies or in patients who cannot stop anticoagulants. Postsurgical patients, on the other hand, should tolerate the procedure just fine.
Patients with risk of gastric cancer “might be an important group” for evaluating the power-wash procedure, the investigators wrote, noting that combining the approach with artificial intelligence could one day yield even better results.
In the meantime, Dr. Lightdale and colleagues — like so many weekend warriors wielding a power-washer — are going to see if a different nozzle will take their work to the next level.
“We are actively studying a catheter with a broader stream and the potential to increase efficiency and decrease procedure time,” they wrote. “Another catheter design might allow for simultaneous spray and suction, so that cytology samples from specific regions of the stomach could be separately analyzed.”
This study was funded by Dalio Philanthropies, the Price Family Foundation, and the Frederic and Patricia Salerno Foundation. The investigators disclosed relationships with Boston Scientific, Interscope, Medtronic, and others.
Power-washing is no longer just for blasting grimy driveways and stripping flaky paint. It’s good for work inside the gut, too.
In a proof-of-concept study, a “novel systematically directed high-pressure liquid spray,” delivered via the ERBEJET flexible probe, showed promise for collecting cytology specimens from the stomachs of patients undergoing endoscopy for gastric cancer screening or surveillance, reported lead author Charles J. Lightdale, MD, of Columbia University Irving Medical Center, New York City, and colleagues.
“Systematic random biopsies (updated Sydney protocol) have been recommended to increase detection of gastric intestinal metaplasia (GIM) and dysplasia,” the investigators wrote in Techniques and Innovations in Gastrointestinal Endoscopy. “However, random biopsies can be laborious, time consuming, costly, and susceptible to sampling error owing to the large surface area of the stomach.”
Power-washing, in contrast, with the pressure dial turned to 10 bar, involves spraying the gut in a systematic fashion “using sweeping and painting motions” to dislodge cells from the mucosa. These specimens are then suctioned from the resultant pools of liquid, mixed 1:1 with 10% formalin, and shipped to the lab.
Boom! Cytology!
Just to be sure, however, the nine patients involved in the study also underwent standard-of-care biopsy collection from areas of interest, followed by random sampling according to the updated Sydney protocol. Two of the patients were power-washed again 12 months later for endoscopic surveillance.
Power-washing added 7-10 minutes to standard endoscopy time and generated 60-100 mL of liquid for collection. Post suction, a closer look at the gastric mucosa revealed “scattered superficial erosions,” while blood loss was deemed “minimal.” The procedure appeared well tolerated, with no aspiration or esophageal reflux during endoscopy, or adverse events reported by patients after 1 week of follow-up.
Cytopathology samples were deemed satisfactory and yielded “multiple strips and large clusters of cells.” These were sufficient to diagnose GIM in three patients and reactive glandular changes with inflammation in one patient, with findings confirmed on biopsy. In contrast, the power-washed cells from one patient were “highly suspicious” for dysplasia, but biopsies were negative.
Although the study was too small for a reliable comparison with the Sydney protocol, Dr. Lightdale and colleagues concluded that the power-wash approach deserves further investigation.
“ and to reduce morbidity and mortality from gastric cancer,” they wrote.
The investigators predicted that power-washing is likely safe in most patients, although it may be unsuitable for those with noncorrectable coagulopathies or in patients who cannot stop anticoagulants. Postsurgical patients, on the other hand, should tolerate the procedure just fine.
Patients with risk of gastric cancer “might be an important group” for evaluating the power-wash procedure, the investigators wrote, noting that combining the approach with artificial intelligence could one day yield even better results.
In the meantime, Dr. Lightdale and colleagues — like so many weekend warriors wielding a power-washer — are going to see if a different nozzle will take their work to the next level.
“We are actively studying a catheter with a broader stream and the potential to increase efficiency and decrease procedure time,” they wrote. “Another catheter design might allow for simultaneous spray and suction, so that cytology samples from specific regions of the stomach could be separately analyzed.”
This study was funded by Dalio Philanthropies, the Price Family Foundation, and the Frederic and Patricia Salerno Foundation. The investigators disclosed relationships with Boston Scientific, Interscope, Medtronic, and others.
FROM TECHNIQUES AND INNOVATIONS IN GASTROINTESTINAL ENDOSCOPY
Real-World HDV Study Characterizes Responses to Bulevirtide
, based on real-world experience.
These findings suggest that longer follow-up is needed to determine the optimal treatment duration for bulevirtide monotherapy, reported lead author Alexander Killer, MD, of Heinrich Heine University Düsseldorf, Germany, and colleagues.
Bulevirtide was conditionally approved by the European Medicines Agency in 2020 and is on track for full marketing approval in Europe, but it remains unavailable in the United States, where Gilead, the manufacturer, has faced regulatory hurdles.
In the MYR202 and 301 clinical trials, bulevirtide significantly reduced HDV-RNA levels in 54% of patients after 24 weeks, and reduced viremia while normalizing ALT in 48% of patients after 48 weeks.
“Given its standalone status and good treatment tolerance even in patients with compensated cirrhosis, this represents a step change in the treatment of HDV-coinfected individuals,” Dr. Killer and colleagues wrote in Gastro Hep Advances.
Yet dynamics of response and clinical predictors of treatment outcome remain unclear, prompting Dr. Killer and colleagues to conduct the present retrospective study. The dataset included 15 patients who received bulevirtide for at least 1 year at a single center in Germany.
The analysis focused on monthly changes in biochemical and virologic parameters. The investigators also screened for clinical factors that might predict responses to therapy.
Treatment response rate and safety profile aligned with data from clinical trials, suggesting that bulevirtide is safe and effective in a real-world setting.
Patients typically achieved ALT normalization 2-6 months into therapy, followed by virologic response at least 6 months after starting treatment, with one-third of patients requiring at least 1 year to achieve HDV-RNA negativity.
“Of note, normalization of ALT under bulevirtide treatment occurs earlier than the decline of HDV-RNA levels, which contrasts with the response seen to nucleos(t)ide analog treatment in hepatitis B,” the investigators wrote. They suggested that this may be due to bulevirtide’s distinct mechanism of action.
Severe hepatitis was associated with lower response rates in the first year. Possible predictors of delayed response included low body mass index and high alpha-fetoprotein.
Of note, two patients had ALT normalization without virologic response.
“It is unclear whether these patients actually have worse outcomes in terms of overall success than patients with a combined response, especially since these patients experienced a decline of more than 1 log,” Dr. Killer and colleagues wrote, noting that a 1 log reduction is considered an intermediate virologic response, and hepatitis B virus (HBV) studies have shown that severe liver events are prevented by early ALT normalization. “Therefore, it does not seem appropriate to categorize patients with biochemical responses as ‘treatment nonresponders’ [according to FDA criteria].”
The investigators called for longer observational studies to determine the optimal duration of bulevirtide monotherapy.
This study was funded by the Ministry of Culture and Science of the State of North Rhine-Westphalia and the German Research Foundation. The investigators disclosed relationships with Novartis, GSK, AbbVie, and others.
, based on real-world experience.
These findings suggest that longer follow-up is needed to determine the optimal treatment duration for bulevirtide monotherapy, reported lead author Alexander Killer, MD, of Heinrich Heine University Düsseldorf, Germany, and colleagues.
Bulevirtide was conditionally approved by the European Medicines Agency in 2020 and is on track for full marketing approval in Europe, but it remains unavailable in the United States, where Gilead, the manufacturer, has faced regulatory hurdles.
In the MYR202 and 301 clinical trials, bulevirtide significantly reduced HDV-RNA levels in 54% of patients after 24 weeks, and reduced viremia while normalizing ALT in 48% of patients after 48 weeks.
“Given its standalone status and good treatment tolerance even in patients with compensated cirrhosis, this represents a step change in the treatment of HDV-coinfected individuals,” Dr. Killer and colleagues wrote in Gastro Hep Advances.
Yet dynamics of response and clinical predictors of treatment outcome remain unclear, prompting Dr. Killer and colleagues to conduct the present retrospective study. The dataset included 15 patients who received bulevirtide for at least 1 year at a single center in Germany.
The analysis focused on monthly changes in biochemical and virologic parameters. The investigators also screened for clinical factors that might predict responses to therapy.
Treatment response rate and safety profile aligned with data from clinical trials, suggesting that bulevirtide is safe and effective in a real-world setting.
Patients typically achieved ALT normalization 2-6 months into therapy, followed by virologic response at least 6 months after starting treatment, with one-third of patients requiring at least 1 year to achieve HDV-RNA negativity.
“Of note, normalization of ALT under bulevirtide treatment occurs earlier than the decline of HDV-RNA levels, which contrasts with the response seen to nucleos(t)ide analog treatment in hepatitis B,” the investigators wrote. They suggested that this may be due to bulevirtide’s distinct mechanism of action.
Severe hepatitis was associated with lower response rates in the first year. Possible predictors of delayed response included low body mass index and high alpha-fetoprotein.
Of note, two patients had ALT normalization without virologic response.
“It is unclear whether these patients actually have worse outcomes in terms of overall success than patients with a combined response, especially since these patients experienced a decline of more than 1 log,” Dr. Killer and colleagues wrote, noting that a 1 log reduction is considered an intermediate virologic response, and hepatitis B virus (HBV) studies have shown that severe liver events are prevented by early ALT normalization. “Therefore, it does not seem appropriate to categorize patients with biochemical responses as ‘treatment nonresponders’ [according to FDA criteria].”
The investigators called for longer observational studies to determine the optimal duration of bulevirtide monotherapy.
This study was funded by the Ministry of Culture and Science of the State of North Rhine-Westphalia and the German Research Foundation. The investigators disclosed relationships with Novartis, GSK, AbbVie, and others.
, based on real-world experience.
These findings suggest that longer follow-up is needed to determine the optimal treatment duration for bulevirtide monotherapy, reported lead author Alexander Killer, MD, of Heinrich Heine University Düsseldorf, Germany, and colleagues.
Bulevirtide was conditionally approved by the European Medicines Agency in 2020 and is on track for full marketing approval in Europe, but it remains unavailable in the United States, where Gilead, the manufacturer, has faced regulatory hurdles.
In the MYR202 and 301 clinical trials, bulevirtide significantly reduced HDV-RNA levels in 54% of patients after 24 weeks, and reduced viremia while normalizing ALT in 48% of patients after 48 weeks.
“Given its standalone status and good treatment tolerance even in patients with compensated cirrhosis, this represents a step change in the treatment of HDV-coinfected individuals,” Dr. Killer and colleagues wrote in Gastro Hep Advances.
Yet dynamics of response and clinical predictors of treatment outcome remain unclear, prompting Dr. Killer and colleagues to conduct the present retrospective study. The dataset included 15 patients who received bulevirtide for at least 1 year at a single center in Germany.
The analysis focused on monthly changes in biochemical and virologic parameters. The investigators also screened for clinical factors that might predict responses to therapy.
Treatment response rate and safety profile aligned with data from clinical trials, suggesting that bulevirtide is safe and effective in a real-world setting.
Patients typically achieved ALT normalization 2-6 months into therapy, followed by virologic response at least 6 months after starting treatment, with one-third of patients requiring at least 1 year to achieve HDV-RNA negativity.
“Of note, normalization of ALT under bulevirtide treatment occurs earlier than the decline of HDV-RNA levels, which contrasts with the response seen to nucleos(t)ide analog treatment in hepatitis B,” the investigators wrote. They suggested that this may be due to bulevirtide’s distinct mechanism of action.
Severe hepatitis was associated with lower response rates in the first year. Possible predictors of delayed response included low body mass index and high alpha-fetoprotein.
Of note, two patients had ALT normalization without virologic response.
“It is unclear whether these patients actually have worse outcomes in terms of overall success than patients with a combined response, especially since these patients experienced a decline of more than 1 log,” Dr. Killer and colleagues wrote, noting that a 1 log reduction is considered an intermediate virologic response, and hepatitis B virus (HBV) studies have shown that severe liver events are prevented by early ALT normalization. “Therefore, it does not seem appropriate to categorize patients with biochemical responses as ‘treatment nonresponders’ [according to FDA criteria].”
The investigators called for longer observational studies to determine the optimal duration of bulevirtide monotherapy.
This study was funded by the Ministry of Culture and Science of the State of North Rhine-Westphalia and the German Research Foundation. The investigators disclosed relationships with Novartis, GSK, AbbVie, and others.
FROM GASTRO HEP ADVANCES