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Supplement combo buffers against PD neurodegeneration in rodent model
NEW YORK – A combination of nutrients offered protection against neurodegeneration in a rodent model of parkinsonism, according to a new study.
The findings pave the way for human studies to explore whether nutritional supplementation in early Parkinson’s disease (PD) can modify the disease course, said Azza Ali, PhD, speaking at the International Conference on Parkinson’s Disease and Movement Disorders.
The rodent study found improvement in a broad array of behavioral, biochemical, and histopathologic measures in rats who were dosed with a combination of whole foods known to have constituents beneficial in other disease states.
Dr. Ali, who is head of the department of pharmacology and toxicology at Al-Azzah University, Cairo, said that the element manganese ingested in excessive amounts is neurotoxic to both humans and rodents. Many elements of manganism, or manganese poisoning, she said, mimic PD in both species. She added that, in humans, “Chronic exposures to low levels of manganese may progressively extend the site of manganese deposition and toxicity to the entire area of the basal ganglia,” and that this chronic exposure can be a risk factor for PD.
Manganese-induced oxidative stress, with subsequent neuroinflammation, DNA damage, and cell apoptosis and necrosis, is a logical target for therapy by means of nutritional supplementation, said Dr. Ali.
Dr. Ali and her collaborators selected several supplements to test against both control rats fed a usual diet and those in whom manganism had been induced via a 17-day run-in period of manganese supplementation.
Wheatgrass has active constituents, including chlorophyll, vitamins, minerals, enzymes, and amino acids, and has been studied in a variety of inflammatory conditions, said Dr. Ali. Cocoa is a natural source of flavonoids and was another nutrient selected for study.
Coenzyme Q10 (CoQ10) “acts as an antioxidant that scavenges free radicals and ... protects the stability of cell membranes,” and is key to mitochondrial bioenergetics, Dr. Ali said. Finally, pomegranate contains vitamins and minerals, as well as phenolic compounds that have been studied in diabetes and Alzheimer’s disease, she said.
The study’s primary aim was to assess the neuroprotective effects of each of these four supplements singly and in combination against manganese-induced parkinsonism in rats, with a secondary aim of comparing the efficacy of each substance against the others and against the combination taken together.
The PD rats were divided into five groups, with four groups each receiving one of the supplements, and one group receiving all four in combination. The normal controls – who were dosed with saline rather than manganese – made up the sixth group of rodents studied.
After 28 days, all groups were put through a series of behavioral tests. The investigators also drew blood to assess levels of a variety of neurotransmitters, inflammatory markers, and hormones. Finally, the animals were sacrificed for histopathologic examination of the cerebral cortex, the hippocampus, and the striatum, all areas where PD-related neurodegeneration are seen.
Compared with the control rats, the manganese-dosed rats showed significantly abnormal behavior, with longer latency shown on the classic swimming test and worse working memory performance in a maze test. In most cases, though, giving a PD model rat each supplement individually resulted in significant improvements in the behavioral tests. The PD model rats given the full combination of supplements showed performance essentially equal to the control rats, Dr. Ali said. Turning to the many biochemical parameters measured in the rodent study, Dr. Ali said that the supplements all ameliorated, but did not normalize, the proinflammatory effects of manganese. Tumor necrosis factor–alpha and interleukin 1–beta levels fell by about one half with all kinds of supplementation – a significant effect – but levels still far exceeded those seen in the control rats, she said.
Dopamine and norepinephrine levels rose markedly with supplement administration as well, though serotonin levels did not. With combination therapy, both dopamine and norepinephrine values, as well as those of gamma-aminobutyric acid and glutamate, approached those of controls, said Dr. Ali.
Histology of the control rats’ brains, as expected, showed no abnormal changes in the areas examined. The manganese-dosed rats showed a variety of degenerative changes, including diffuse nuclear pyknosis, and eosinophilic plaque formation within the striatum. The brains of the rats fed the individual supplements showed essentially the same amount of degeneration. However, Dr. Ali noted, rats fed the combination therapy had brain tissue that essentially looked like that of the control rats, with “no histopathological alteration” in any area examined.
A more fine-grained examination of the data showed that overall, “Cocoa and pomegranate showed more pronounced protection against neuronal degeneration and behavioral impairments induced by manganese than wheatgrass or CoQ10,” Dr. Ali said.
Still, the combination of nutrients offered “maximum protection” against manganese-induced parkinsonism, she said. “This combination of nutrients could be a meaningful approach to reduce motor and nonmotor symptoms of Parkinson’s disease, and warrants further study in human subjects.”
Dr. Ali reported no relevant financial disclosures.
NEW YORK – A combination of nutrients offered protection against neurodegeneration in a rodent model of parkinsonism, according to a new study.
The findings pave the way for human studies to explore whether nutritional supplementation in early Parkinson’s disease (PD) can modify the disease course, said Azza Ali, PhD, speaking at the International Conference on Parkinson’s Disease and Movement Disorders.
The rodent study found improvement in a broad array of behavioral, biochemical, and histopathologic measures in rats who were dosed with a combination of whole foods known to have constituents beneficial in other disease states.
Dr. Ali, who is head of the department of pharmacology and toxicology at Al-Azzah University, Cairo, said that the element manganese ingested in excessive amounts is neurotoxic to both humans and rodents. Many elements of manganism, or manganese poisoning, she said, mimic PD in both species. She added that, in humans, “Chronic exposures to low levels of manganese may progressively extend the site of manganese deposition and toxicity to the entire area of the basal ganglia,” and that this chronic exposure can be a risk factor for PD.
Manganese-induced oxidative stress, with subsequent neuroinflammation, DNA damage, and cell apoptosis and necrosis, is a logical target for therapy by means of nutritional supplementation, said Dr. Ali.
Dr. Ali and her collaborators selected several supplements to test against both control rats fed a usual diet and those in whom manganism had been induced via a 17-day run-in period of manganese supplementation.
Wheatgrass has active constituents, including chlorophyll, vitamins, minerals, enzymes, and amino acids, and has been studied in a variety of inflammatory conditions, said Dr. Ali. Cocoa is a natural source of flavonoids and was another nutrient selected for study.
Coenzyme Q10 (CoQ10) “acts as an antioxidant that scavenges free radicals and ... protects the stability of cell membranes,” and is key to mitochondrial bioenergetics, Dr. Ali said. Finally, pomegranate contains vitamins and minerals, as well as phenolic compounds that have been studied in diabetes and Alzheimer’s disease, she said.
The study’s primary aim was to assess the neuroprotective effects of each of these four supplements singly and in combination against manganese-induced parkinsonism in rats, with a secondary aim of comparing the efficacy of each substance against the others and against the combination taken together.
The PD rats were divided into five groups, with four groups each receiving one of the supplements, and one group receiving all four in combination. The normal controls – who were dosed with saline rather than manganese – made up the sixth group of rodents studied.
After 28 days, all groups were put through a series of behavioral tests. The investigators also drew blood to assess levels of a variety of neurotransmitters, inflammatory markers, and hormones. Finally, the animals were sacrificed for histopathologic examination of the cerebral cortex, the hippocampus, and the striatum, all areas where PD-related neurodegeneration are seen.
Compared with the control rats, the manganese-dosed rats showed significantly abnormal behavior, with longer latency shown on the classic swimming test and worse working memory performance in a maze test. In most cases, though, giving a PD model rat each supplement individually resulted in significant improvements in the behavioral tests. The PD model rats given the full combination of supplements showed performance essentially equal to the control rats, Dr. Ali said. Turning to the many biochemical parameters measured in the rodent study, Dr. Ali said that the supplements all ameliorated, but did not normalize, the proinflammatory effects of manganese. Tumor necrosis factor–alpha and interleukin 1–beta levels fell by about one half with all kinds of supplementation – a significant effect – but levels still far exceeded those seen in the control rats, she said.
Dopamine and norepinephrine levels rose markedly with supplement administration as well, though serotonin levels did not. With combination therapy, both dopamine and norepinephrine values, as well as those of gamma-aminobutyric acid and glutamate, approached those of controls, said Dr. Ali.
Histology of the control rats’ brains, as expected, showed no abnormal changes in the areas examined. The manganese-dosed rats showed a variety of degenerative changes, including diffuse nuclear pyknosis, and eosinophilic plaque formation within the striatum. The brains of the rats fed the individual supplements showed essentially the same amount of degeneration. However, Dr. Ali noted, rats fed the combination therapy had brain tissue that essentially looked like that of the control rats, with “no histopathological alteration” in any area examined.
A more fine-grained examination of the data showed that overall, “Cocoa and pomegranate showed more pronounced protection against neuronal degeneration and behavioral impairments induced by manganese than wheatgrass or CoQ10,” Dr. Ali said.
Still, the combination of nutrients offered “maximum protection” against manganese-induced parkinsonism, she said. “This combination of nutrients could be a meaningful approach to reduce motor and nonmotor symptoms of Parkinson’s disease, and warrants further study in human subjects.”
Dr. Ali reported no relevant financial disclosures.
NEW YORK – A combination of nutrients offered protection against neurodegeneration in a rodent model of parkinsonism, according to a new study.
The findings pave the way for human studies to explore whether nutritional supplementation in early Parkinson’s disease (PD) can modify the disease course, said Azza Ali, PhD, speaking at the International Conference on Parkinson’s Disease and Movement Disorders.
The rodent study found improvement in a broad array of behavioral, biochemical, and histopathologic measures in rats who were dosed with a combination of whole foods known to have constituents beneficial in other disease states.
Dr. Ali, who is head of the department of pharmacology and toxicology at Al-Azzah University, Cairo, said that the element manganese ingested in excessive amounts is neurotoxic to both humans and rodents. Many elements of manganism, or manganese poisoning, she said, mimic PD in both species. She added that, in humans, “Chronic exposures to low levels of manganese may progressively extend the site of manganese deposition and toxicity to the entire area of the basal ganglia,” and that this chronic exposure can be a risk factor for PD.
Manganese-induced oxidative stress, with subsequent neuroinflammation, DNA damage, and cell apoptosis and necrosis, is a logical target for therapy by means of nutritional supplementation, said Dr. Ali.
Dr. Ali and her collaborators selected several supplements to test against both control rats fed a usual diet and those in whom manganism had been induced via a 17-day run-in period of manganese supplementation.
Wheatgrass has active constituents, including chlorophyll, vitamins, minerals, enzymes, and amino acids, and has been studied in a variety of inflammatory conditions, said Dr. Ali. Cocoa is a natural source of flavonoids and was another nutrient selected for study.
Coenzyme Q10 (CoQ10) “acts as an antioxidant that scavenges free radicals and ... protects the stability of cell membranes,” and is key to mitochondrial bioenergetics, Dr. Ali said. Finally, pomegranate contains vitamins and minerals, as well as phenolic compounds that have been studied in diabetes and Alzheimer’s disease, she said.
The study’s primary aim was to assess the neuroprotective effects of each of these four supplements singly and in combination against manganese-induced parkinsonism in rats, with a secondary aim of comparing the efficacy of each substance against the others and against the combination taken together.
The PD rats were divided into five groups, with four groups each receiving one of the supplements, and one group receiving all four in combination. The normal controls – who were dosed with saline rather than manganese – made up the sixth group of rodents studied.
After 28 days, all groups were put through a series of behavioral tests. The investigators also drew blood to assess levels of a variety of neurotransmitters, inflammatory markers, and hormones. Finally, the animals were sacrificed for histopathologic examination of the cerebral cortex, the hippocampus, and the striatum, all areas where PD-related neurodegeneration are seen.
Compared with the control rats, the manganese-dosed rats showed significantly abnormal behavior, with longer latency shown on the classic swimming test and worse working memory performance in a maze test. In most cases, though, giving a PD model rat each supplement individually resulted in significant improvements in the behavioral tests. The PD model rats given the full combination of supplements showed performance essentially equal to the control rats, Dr. Ali said. Turning to the many biochemical parameters measured in the rodent study, Dr. Ali said that the supplements all ameliorated, but did not normalize, the proinflammatory effects of manganese. Tumor necrosis factor–alpha and interleukin 1–beta levels fell by about one half with all kinds of supplementation – a significant effect – but levels still far exceeded those seen in the control rats, she said.
Dopamine and norepinephrine levels rose markedly with supplement administration as well, though serotonin levels did not. With combination therapy, both dopamine and norepinephrine values, as well as those of gamma-aminobutyric acid and glutamate, approached those of controls, said Dr. Ali.
Histology of the control rats’ brains, as expected, showed no abnormal changes in the areas examined. The manganese-dosed rats showed a variety of degenerative changes, including diffuse nuclear pyknosis, and eosinophilic plaque formation within the striatum. The brains of the rats fed the individual supplements showed essentially the same amount of degeneration. However, Dr. Ali noted, rats fed the combination therapy had brain tissue that essentially looked like that of the control rats, with “no histopathological alteration” in any area examined.
A more fine-grained examination of the data showed that overall, “Cocoa and pomegranate showed more pronounced protection against neuronal degeneration and behavioral impairments induced by manganese than wheatgrass or CoQ10,” Dr. Ali said.
Still, the combination of nutrients offered “maximum protection” against manganese-induced parkinsonism, she said. “This combination of nutrients could be a meaningful approach to reduce motor and nonmotor symptoms of Parkinson’s disease, and warrants further study in human subjects.”
Dr. Ali reported no relevant financial disclosures.
REPORTING FROM ICPDMD 2018
Sensory feedback modalities tackle gait, balance problems in PD
NEW YORK – Sending sensory feedback upstream to patients with Parkinson’s disease (PD) may offer a low-risk, nonpharmaceutical method to retain and improve motor function. These interventions may be especially helpful in the subpopulation of patients who are intolerant to exercise, with a growing body of evidence showing sustained benefit for newer sensory stimulation techniques.
“In a healthy person, movement is the seamless integration of sensory and motor systems,” said Ben Weinstock, DPT, speaking at the International Conference on Parkinson’s Disease and Movement Disorders, pointing out that movement stimulates the senses, and sensory stimulation improves movement.
By contrast, patients with PD experience more than just problems with motor function. Patients with PD and sensory or autonomic dysfunction may find these disturbances contributing to motor dysfunction, said Dr. Weinstock, who treats patients with PD and a variety of complex medical conditions in his private practice.
Some of the hallmark features of PD are movement related: the cogwheel rigidity, bradykinesia, and freezing all contribute to poor balance and a fear of falling. Commonly, PD patients also experience fatigue and alterations in cognition and mood.
However, afferent small-fiber neuropathies and centrally mediated mechanisms in PD can also disturb sensory input: Vestibular function, equilibrium, proprioception, and light and deep touch may all be affected, Dr. Weinstock said.
Autonomic dysfunction can be an underappreciated feature of PD, but such manifestations as orthostatic hypotension and poor thermal regulation can have significant negative impact on quality of life for an individual with PD.
Perhaps the gravest variant of autonomic dysregulation, however, is the cardiac denervation that frequently accompanies PD, said Dr. Weinstock. “Although there is a belief that intensive exercise helps people with PD, many individuals are actually exercise intolerant because of loss of cardiac norepinephrine,” he said (J Neurochem. 2014;131[2]:219-228). “A person with PD who is exercise intolerant is at risk” of syncope, falls, and even serious cardiac events during exercise, he noted.
Cardiovascular dysautonomia in PD has been documented in serial 18F-dopamine PET scans, showing progressive reduction in uptake over the course of several years in individual patients (Neurobiol Dis. 2012 June;46[3]:572-80). Similarly, studies have shown lower cardiac radiotracer uptake in patients with PD, compared with normal controls, he said (NPJ Parkinsons Dis. 2017. doi: 10.1038/S41531-017-0017-1).
It’s not easy to determine what level of nonmotor dysfunction a given patient has at a particular point in disease progression, said Dr. Weinstock.
“There is no correlation between motor and nonmotor deterioration,” he said. “Somebody might be newly diagnosed with just a mild tremor and still have significant cardiac denervation.”
Weighing how to help an exercise-intolerant patient with PD means taking into consideration the known risks and side effect profile of PD medications, Dr. Weinstock pointed out. Increasing medications, or beginning a new drug therapy, can mean increased risk for unwanted psychiatric side effects and ototoxicity, among other potential ill effects.
Similarly, the decision to implant deep brain stimulation is not to be taken lightly, since depression can begin or worsen, and any surgical procedure carries risks.
For Dr. Weinstock, using strategies to improve sensory input are “a valid option for people with PD.” Such a strategy is safe, and even brief bouts of stimulation “can have significant, beneficial effects,” he said. “The overall goal is to avoid sedentary behavior,” with its accompanying ills, he said.
Dr. Weinstock noted that he uses different strategies to stimulate the various senses, including bright light therapy, which can help regulate circadian rhythms and promote appropriate melatonin secretion, improving sleep and upping daytime wakefulness.
Another visual strategy when working on gait is to use surface lines, a checkerboard pattern, or other targets that provide a visual goal for step length, which typically shortens with PD progression. Though more high-tech options exist, Dr. Weinstock suggested patients begin with just laying lines of masking tape along the floor to mark the target gait length. “Usually the cheap technique is a good test to see if it’s going to work,” he said.
An auditory strategy to improve the gait cycle is use of a metronome or other rhythmic auditory stimulation; music can be helpful in this regard and as a general cognitive and emotional stimulus, said Dr. Weinstock.
“Loss of smell is an early sign of Parkinson’s,” said Dr. Weinstock, and taste also can be dulled. Though offering tasty meals could help reduce risk of malnutrition in PD patients, “It remains to be seen if aromatherapy can lead to neural plasticity and reverse smell loss in PD.”
Vestibular rehabilitation techniques can help not just with balance, but also with helping to lift mood and improve functional activities, according to one study (Arq Neuropsiquiatr 2009;67[2-A]:219-23).
Other ways to provide proprioceptive feedback include the use of orthotics and textured insoles and the use of a weighted vest. Dr. Weinstock also gives consideration to skin taping, which may give patients useful feedback about their bodies’ position in space, he said.
Intriguing results have been seen with acupuncture, acupressure, and electroacupuncture for PD patients, said Dr. Weinstock. In particular, a technique called automated mechanical pressure stimulation uses a bootlike device to provide mechanical stimulation to points at the head of the great toe and on the ball of the foot at the head of the first metatarsal bone.
One functional magnetic resonance imaging (fMRI) study showed acutely increased resting state functional connectivity after such stimulation, in comparison with a sham procedure that also applied pressure, but over a broader area, he said.
After the stimulation procedure used in the study, the patients who received actual stimulation also saw improved ability to initiate voluntary movements, less tremor and rigidity, and less gait freezing (PLoS One. 2015 Oct 15. doi: 10.1371/journal.pone.0137977).
Other studies of the mechanical stimulation device showed similar results, with some showing that repeated sessions helped maintain these and other benefits, such as improved walking velocity, stride length, and Timed Up and Go results – an assessment of fall risk (Int J Rehabil Res. 2015 Sep;38[3]:238-45). Treatment with the device, dubbed Gondola, is most widely available in Italy, where clinical trials are ongoing.
Stimulation to an acupuncture point located on the proximal lateral leg, near the head of the fibula, showed improvements in gait parameters and in fMRI-assessed brain connectivity as well, noted Dr. Weinstock (CNS Neurosci Ther. 2012 Sep;18[9]:781-90).
“There’s a growing amount of evidence that various types of sensory stimulation can have significant benefits for people with Parkinson’s Disease, especially for those who are exercise intolerant,” said Dr. Weinstock.
Dr. Weinstock reported no relevant disclosures.
[email protected]
NEW YORK – Sending sensory feedback upstream to patients with Parkinson’s disease (PD) may offer a low-risk, nonpharmaceutical method to retain and improve motor function. These interventions may be especially helpful in the subpopulation of patients who are intolerant to exercise, with a growing body of evidence showing sustained benefit for newer sensory stimulation techniques.
“In a healthy person, movement is the seamless integration of sensory and motor systems,” said Ben Weinstock, DPT, speaking at the International Conference on Parkinson’s Disease and Movement Disorders, pointing out that movement stimulates the senses, and sensory stimulation improves movement.
By contrast, patients with PD experience more than just problems with motor function. Patients with PD and sensory or autonomic dysfunction may find these disturbances contributing to motor dysfunction, said Dr. Weinstock, who treats patients with PD and a variety of complex medical conditions in his private practice.
Some of the hallmark features of PD are movement related: the cogwheel rigidity, bradykinesia, and freezing all contribute to poor balance and a fear of falling. Commonly, PD patients also experience fatigue and alterations in cognition and mood.
However, afferent small-fiber neuropathies and centrally mediated mechanisms in PD can also disturb sensory input: Vestibular function, equilibrium, proprioception, and light and deep touch may all be affected, Dr. Weinstock said.
Autonomic dysfunction can be an underappreciated feature of PD, but such manifestations as orthostatic hypotension and poor thermal regulation can have significant negative impact on quality of life for an individual with PD.
Perhaps the gravest variant of autonomic dysregulation, however, is the cardiac denervation that frequently accompanies PD, said Dr. Weinstock. “Although there is a belief that intensive exercise helps people with PD, many individuals are actually exercise intolerant because of loss of cardiac norepinephrine,” he said (J Neurochem. 2014;131[2]:219-228). “A person with PD who is exercise intolerant is at risk” of syncope, falls, and even serious cardiac events during exercise, he noted.
Cardiovascular dysautonomia in PD has been documented in serial 18F-dopamine PET scans, showing progressive reduction in uptake over the course of several years in individual patients (Neurobiol Dis. 2012 June;46[3]:572-80). Similarly, studies have shown lower cardiac radiotracer uptake in patients with PD, compared with normal controls, he said (NPJ Parkinsons Dis. 2017. doi: 10.1038/S41531-017-0017-1).
It’s not easy to determine what level of nonmotor dysfunction a given patient has at a particular point in disease progression, said Dr. Weinstock.
“There is no correlation between motor and nonmotor deterioration,” he said. “Somebody might be newly diagnosed with just a mild tremor and still have significant cardiac denervation.”
Weighing how to help an exercise-intolerant patient with PD means taking into consideration the known risks and side effect profile of PD medications, Dr. Weinstock pointed out. Increasing medications, or beginning a new drug therapy, can mean increased risk for unwanted psychiatric side effects and ototoxicity, among other potential ill effects.
Similarly, the decision to implant deep brain stimulation is not to be taken lightly, since depression can begin or worsen, and any surgical procedure carries risks.
For Dr. Weinstock, using strategies to improve sensory input are “a valid option for people with PD.” Such a strategy is safe, and even brief bouts of stimulation “can have significant, beneficial effects,” he said. “The overall goal is to avoid sedentary behavior,” with its accompanying ills, he said.
Dr. Weinstock noted that he uses different strategies to stimulate the various senses, including bright light therapy, which can help regulate circadian rhythms and promote appropriate melatonin secretion, improving sleep and upping daytime wakefulness.
Another visual strategy when working on gait is to use surface lines, a checkerboard pattern, or other targets that provide a visual goal for step length, which typically shortens with PD progression. Though more high-tech options exist, Dr. Weinstock suggested patients begin with just laying lines of masking tape along the floor to mark the target gait length. “Usually the cheap technique is a good test to see if it’s going to work,” he said.
An auditory strategy to improve the gait cycle is use of a metronome or other rhythmic auditory stimulation; music can be helpful in this regard and as a general cognitive and emotional stimulus, said Dr. Weinstock.
“Loss of smell is an early sign of Parkinson’s,” said Dr. Weinstock, and taste also can be dulled. Though offering tasty meals could help reduce risk of malnutrition in PD patients, “It remains to be seen if aromatherapy can lead to neural plasticity and reverse smell loss in PD.”
Vestibular rehabilitation techniques can help not just with balance, but also with helping to lift mood and improve functional activities, according to one study (Arq Neuropsiquiatr 2009;67[2-A]:219-23).
Other ways to provide proprioceptive feedback include the use of orthotics and textured insoles and the use of a weighted vest. Dr. Weinstock also gives consideration to skin taping, which may give patients useful feedback about their bodies’ position in space, he said.
Intriguing results have been seen with acupuncture, acupressure, and electroacupuncture for PD patients, said Dr. Weinstock. In particular, a technique called automated mechanical pressure stimulation uses a bootlike device to provide mechanical stimulation to points at the head of the great toe and on the ball of the foot at the head of the first metatarsal bone.
One functional magnetic resonance imaging (fMRI) study showed acutely increased resting state functional connectivity after such stimulation, in comparison with a sham procedure that also applied pressure, but over a broader area, he said.
After the stimulation procedure used in the study, the patients who received actual stimulation also saw improved ability to initiate voluntary movements, less tremor and rigidity, and less gait freezing (PLoS One. 2015 Oct 15. doi: 10.1371/journal.pone.0137977).
Other studies of the mechanical stimulation device showed similar results, with some showing that repeated sessions helped maintain these and other benefits, such as improved walking velocity, stride length, and Timed Up and Go results – an assessment of fall risk (Int J Rehabil Res. 2015 Sep;38[3]:238-45). Treatment with the device, dubbed Gondola, is most widely available in Italy, where clinical trials are ongoing.
Stimulation to an acupuncture point located on the proximal lateral leg, near the head of the fibula, showed improvements in gait parameters and in fMRI-assessed brain connectivity as well, noted Dr. Weinstock (CNS Neurosci Ther. 2012 Sep;18[9]:781-90).
“There’s a growing amount of evidence that various types of sensory stimulation can have significant benefits for people with Parkinson’s Disease, especially for those who are exercise intolerant,” said Dr. Weinstock.
Dr. Weinstock reported no relevant disclosures.
[email protected]
NEW YORK – Sending sensory feedback upstream to patients with Parkinson’s disease (PD) may offer a low-risk, nonpharmaceutical method to retain and improve motor function. These interventions may be especially helpful in the subpopulation of patients who are intolerant to exercise, with a growing body of evidence showing sustained benefit for newer sensory stimulation techniques.
“In a healthy person, movement is the seamless integration of sensory and motor systems,” said Ben Weinstock, DPT, speaking at the International Conference on Parkinson’s Disease and Movement Disorders, pointing out that movement stimulates the senses, and sensory stimulation improves movement.
By contrast, patients with PD experience more than just problems with motor function. Patients with PD and sensory or autonomic dysfunction may find these disturbances contributing to motor dysfunction, said Dr. Weinstock, who treats patients with PD and a variety of complex medical conditions in his private practice.
Some of the hallmark features of PD are movement related: the cogwheel rigidity, bradykinesia, and freezing all contribute to poor balance and a fear of falling. Commonly, PD patients also experience fatigue and alterations in cognition and mood.
However, afferent small-fiber neuropathies and centrally mediated mechanisms in PD can also disturb sensory input: Vestibular function, equilibrium, proprioception, and light and deep touch may all be affected, Dr. Weinstock said.
Autonomic dysfunction can be an underappreciated feature of PD, but such manifestations as orthostatic hypotension and poor thermal regulation can have significant negative impact on quality of life for an individual with PD.
Perhaps the gravest variant of autonomic dysregulation, however, is the cardiac denervation that frequently accompanies PD, said Dr. Weinstock. “Although there is a belief that intensive exercise helps people with PD, many individuals are actually exercise intolerant because of loss of cardiac norepinephrine,” he said (J Neurochem. 2014;131[2]:219-228). “A person with PD who is exercise intolerant is at risk” of syncope, falls, and even serious cardiac events during exercise, he noted.
Cardiovascular dysautonomia in PD has been documented in serial 18F-dopamine PET scans, showing progressive reduction in uptake over the course of several years in individual patients (Neurobiol Dis. 2012 June;46[3]:572-80). Similarly, studies have shown lower cardiac radiotracer uptake in patients with PD, compared with normal controls, he said (NPJ Parkinsons Dis. 2017. doi: 10.1038/S41531-017-0017-1).
It’s not easy to determine what level of nonmotor dysfunction a given patient has at a particular point in disease progression, said Dr. Weinstock.
“There is no correlation between motor and nonmotor deterioration,” he said. “Somebody might be newly diagnosed with just a mild tremor and still have significant cardiac denervation.”
Weighing how to help an exercise-intolerant patient with PD means taking into consideration the known risks and side effect profile of PD medications, Dr. Weinstock pointed out. Increasing medications, or beginning a new drug therapy, can mean increased risk for unwanted psychiatric side effects and ototoxicity, among other potential ill effects.
Similarly, the decision to implant deep brain stimulation is not to be taken lightly, since depression can begin or worsen, and any surgical procedure carries risks.
For Dr. Weinstock, using strategies to improve sensory input are “a valid option for people with PD.” Such a strategy is safe, and even brief bouts of stimulation “can have significant, beneficial effects,” he said. “The overall goal is to avoid sedentary behavior,” with its accompanying ills, he said.
Dr. Weinstock noted that he uses different strategies to stimulate the various senses, including bright light therapy, which can help regulate circadian rhythms and promote appropriate melatonin secretion, improving sleep and upping daytime wakefulness.
Another visual strategy when working on gait is to use surface lines, a checkerboard pattern, or other targets that provide a visual goal for step length, which typically shortens with PD progression. Though more high-tech options exist, Dr. Weinstock suggested patients begin with just laying lines of masking tape along the floor to mark the target gait length. “Usually the cheap technique is a good test to see if it’s going to work,” he said.
An auditory strategy to improve the gait cycle is use of a metronome or other rhythmic auditory stimulation; music can be helpful in this regard and as a general cognitive and emotional stimulus, said Dr. Weinstock.
“Loss of smell is an early sign of Parkinson’s,” said Dr. Weinstock, and taste also can be dulled. Though offering tasty meals could help reduce risk of malnutrition in PD patients, “It remains to be seen if aromatherapy can lead to neural plasticity and reverse smell loss in PD.”
Vestibular rehabilitation techniques can help not just with balance, but also with helping to lift mood and improve functional activities, according to one study (Arq Neuropsiquiatr 2009;67[2-A]:219-23).
Other ways to provide proprioceptive feedback include the use of orthotics and textured insoles and the use of a weighted vest. Dr. Weinstock also gives consideration to skin taping, which may give patients useful feedback about their bodies’ position in space, he said.
Intriguing results have been seen with acupuncture, acupressure, and electroacupuncture for PD patients, said Dr. Weinstock. In particular, a technique called automated mechanical pressure stimulation uses a bootlike device to provide mechanical stimulation to points at the head of the great toe and on the ball of the foot at the head of the first metatarsal bone.
One functional magnetic resonance imaging (fMRI) study showed acutely increased resting state functional connectivity after such stimulation, in comparison with a sham procedure that also applied pressure, but over a broader area, he said.
After the stimulation procedure used in the study, the patients who received actual stimulation also saw improved ability to initiate voluntary movements, less tremor and rigidity, and less gait freezing (PLoS One. 2015 Oct 15. doi: 10.1371/journal.pone.0137977).
Other studies of the mechanical stimulation device showed similar results, with some showing that repeated sessions helped maintain these and other benefits, such as improved walking velocity, stride length, and Timed Up and Go results – an assessment of fall risk (Int J Rehabil Res. 2015 Sep;38[3]:238-45). Treatment with the device, dubbed Gondola, is most widely available in Italy, where clinical trials are ongoing.
Stimulation to an acupuncture point located on the proximal lateral leg, near the head of the fibula, showed improvements in gait parameters and in fMRI-assessed brain connectivity as well, noted Dr. Weinstock (CNS Neurosci Ther. 2012 Sep;18[9]:781-90).
“There’s a growing amount of evidence that various types of sensory stimulation can have significant benefits for people with Parkinson’s Disease, especially for those who are exercise intolerant,” said Dr. Weinstock.
Dr. Weinstock reported no relevant disclosures.
[email protected]
EXPERT ANALYSIS FROM ICPDMD 2018
MS cognitive decline buffered by early high vitamin D levels
BERLIN – , according to a recent study.
“Higher vitamin D in the first years after [clinically isolated syndrome] was associated with better cognitive function and lower neuronal injury at year 11,” said Marianna Cortese, MD, presenting her findings during a late-breaking abstracts session at the annual congress of the European Society for Education and Treatment in Multiple Sclerosis.
“Vitamin D supplementation during the early years with the disease might be neuroprotective,” she said.
According to Dr. Cortese, 40%-70% of patients with MS will experience cognitive decline across their disease course; there is no currently known specific treatment for cognitive decline.
Smoking, low levels of vitamin D [as 25(OH)D], and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS, and have been associated with more active MS and progressive disease, but whether these factors predict cognitive status had not been known, said Dr. Cortese of the Harvard T.H. Chan School of Public Health.
Accordingly, she said, investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.
The study is an observational study that followed 278 participants with clinically isolated syndrome (CIS) in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled trial of interferon beta-1b for early treatment of clinically isolated syndrome. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.
“To minimize reverse causation, we used exposure status in the first 2 years after CIS to predict progression outcomes at year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline, and at study months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used for EBV seropositivity.
In terms of outcome measurements, the cognitive performance measure used in the study was the Paced Auditory Serial Addition Test, a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study years 1, 2, 5, and 11. At study year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.
In multivariable analysis, the study design adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease seen on baseline magnetic resonance imaging, body mass index, and whether the patient was treated with steroids during the initial CIS.
“Higher quintiles of mean vitamin D levels during the first 2 years were associated with lower odds of scoring worse on the PASAT at year 11,” said Dr. Cortese (P-trend = .028). The significant trend across the quintiles “suggests a dose-response relationship,” she said.* For vitamin D levels over the first 5 years, the P-trend was .049. Dr. Cortese explained that “scoring worse” meant scoring below the median.
Looking at the effect of early vitamin D levels another way, incremental increases of 50 nmol/L of mean 25(OH)D in study months 6-24 predicted 65% lower odds of having a PASAT score below the median at year 11 (P = .027). “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.
Turning to the effect of smoking on cognitive function at year 11, Dr. Cortese explained that cotinine levels obtained during the first 2 years were all used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker (N = 125). If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the small number of patients (N = 9) who were very heavy smokers, with cotinine levels over 191 ng/mL.
“Smokers – compared to nonsmokers – had a significantly lower standardized PASAT score at year 11,” said Dr. Cortese (P trend = .042 in age- and sex-adjusted analysis; P-trend = .056 in full multivariable analysis). “Actually, smokers had an up to 0.6-standard deviation-lower PASAT score at year 11 when we looked at heavy smokers. ...This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.”
Dr. Cortese pointed out that early smoking, again, showed a dose-response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients.”
Epstein-Barr antibodies were not associated with cognitive function at year 11, according to the analysis (P-trend = .93).
“The findings of neuroaxonal injury at year 11 using serum neurofilament light-chain measures corroborated the main findings on cognitive function at year 11,” said Dr. Cortese.
For a 50-nmol higher vitamin D level within the first 5 years, neurofilament light chain levels at year 11 were 20% lower, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first 5 years had neurofilament light chain levels 20% higher than other participants: “So they did worse. They had more neuroaxonal loss,” said Dr. Cortese. No association was seen between neurofilament light chain levels at year 11 and early EBV status, she said.
Though just cognitive function data from BENEFIT-11 were reported by Dr. Cortese, she said that radiologic and other clinical data are also being studied and will be reported in the future.
Dr. Cortese reported that she had no conflicts of interest. Several coauthors reported financial relationships with multiple pharmaceutical companies. The study was supported by the National Institutes of Health and the National Multiple Sclerosis Society, with clinical support from Bayer HealthCare.
SOURCE: Cortese M et al. ECTRIMS 2018, Late breaking abstracts session.
*Correction, 10/25/18: An earlier version of this article mischaracterized the relationship between vitamin D scores during the first 2 years and PASAT scores at year 11.
BERLIN – , according to a recent study.
“Higher vitamin D in the first years after [clinically isolated syndrome] was associated with better cognitive function and lower neuronal injury at year 11,” said Marianna Cortese, MD, presenting her findings during a late-breaking abstracts session at the annual congress of the European Society for Education and Treatment in Multiple Sclerosis.
“Vitamin D supplementation during the early years with the disease might be neuroprotective,” she said.
According to Dr. Cortese, 40%-70% of patients with MS will experience cognitive decline across their disease course; there is no currently known specific treatment for cognitive decline.
Smoking, low levels of vitamin D [as 25(OH)D], and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS, and have been associated with more active MS and progressive disease, but whether these factors predict cognitive status had not been known, said Dr. Cortese of the Harvard T.H. Chan School of Public Health.
Accordingly, she said, investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.
The study is an observational study that followed 278 participants with clinically isolated syndrome (CIS) in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled trial of interferon beta-1b for early treatment of clinically isolated syndrome. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.
“To minimize reverse causation, we used exposure status in the first 2 years after CIS to predict progression outcomes at year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline, and at study months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used for EBV seropositivity.
In terms of outcome measurements, the cognitive performance measure used in the study was the Paced Auditory Serial Addition Test, a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study years 1, 2, 5, and 11. At study year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.
In multivariable analysis, the study design adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease seen on baseline magnetic resonance imaging, body mass index, and whether the patient was treated with steroids during the initial CIS.
“Higher quintiles of mean vitamin D levels during the first 2 years were associated with lower odds of scoring worse on the PASAT at year 11,” said Dr. Cortese (P-trend = .028). The significant trend across the quintiles “suggests a dose-response relationship,” she said.* For vitamin D levels over the first 5 years, the P-trend was .049. Dr. Cortese explained that “scoring worse” meant scoring below the median.
Looking at the effect of early vitamin D levels another way, incremental increases of 50 nmol/L of mean 25(OH)D in study months 6-24 predicted 65% lower odds of having a PASAT score below the median at year 11 (P = .027). “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.
Turning to the effect of smoking on cognitive function at year 11, Dr. Cortese explained that cotinine levels obtained during the first 2 years were all used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker (N = 125). If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the small number of patients (N = 9) who were very heavy smokers, with cotinine levels over 191 ng/mL.
“Smokers – compared to nonsmokers – had a significantly lower standardized PASAT score at year 11,” said Dr. Cortese (P trend = .042 in age- and sex-adjusted analysis; P-trend = .056 in full multivariable analysis). “Actually, smokers had an up to 0.6-standard deviation-lower PASAT score at year 11 when we looked at heavy smokers. ...This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.”
Dr. Cortese pointed out that early smoking, again, showed a dose-response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients.”
Epstein-Barr antibodies were not associated with cognitive function at year 11, according to the analysis (P-trend = .93).
“The findings of neuroaxonal injury at year 11 using serum neurofilament light-chain measures corroborated the main findings on cognitive function at year 11,” said Dr. Cortese.
For a 50-nmol higher vitamin D level within the first 5 years, neurofilament light chain levels at year 11 were 20% lower, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first 5 years had neurofilament light chain levels 20% higher than other participants: “So they did worse. They had more neuroaxonal loss,” said Dr. Cortese. No association was seen between neurofilament light chain levels at year 11 and early EBV status, she said.
Though just cognitive function data from BENEFIT-11 were reported by Dr. Cortese, she said that radiologic and other clinical data are also being studied and will be reported in the future.
Dr. Cortese reported that she had no conflicts of interest. Several coauthors reported financial relationships with multiple pharmaceutical companies. The study was supported by the National Institutes of Health and the National Multiple Sclerosis Society, with clinical support from Bayer HealthCare.
SOURCE: Cortese M et al. ECTRIMS 2018, Late breaking abstracts session.
*Correction, 10/25/18: An earlier version of this article mischaracterized the relationship between vitamin D scores during the first 2 years and PASAT scores at year 11.
BERLIN – , according to a recent study.
“Higher vitamin D in the first years after [clinically isolated syndrome] was associated with better cognitive function and lower neuronal injury at year 11,” said Marianna Cortese, MD, presenting her findings during a late-breaking abstracts session at the annual congress of the European Society for Education and Treatment in Multiple Sclerosis.
“Vitamin D supplementation during the early years with the disease might be neuroprotective,” she said.
According to Dr. Cortese, 40%-70% of patients with MS will experience cognitive decline across their disease course; there is no currently known specific treatment for cognitive decline.
Smoking, low levels of vitamin D [as 25(OH)D], and Epstein-Barr virus (EBV) seropositivity are known risk factors for MS, and have been associated with more active MS and progressive disease, but whether these factors predict cognitive status had not been known, said Dr. Cortese of the Harvard T.H. Chan School of Public Health.
Accordingly, she said, investigators in the BENEFIT-11 trial sought to determine whether low vitamin D levels, smoking status, and EBV seropositivity detected early after the first disease manifestation in MS would affect later cognitive function.
The study is an observational study that followed 278 participants with clinically isolated syndrome (CIS) in the original BENEFIT trial, which was a randomized, double-blind, placebo-controlled trial of interferon beta-1b for early treatment of clinically isolated syndrome. The primary goal of BENEFIT-11, said Dr. Cortese, was to assess the effects of early treatment on long-term outcomes.
“To minimize reverse causation, we used exposure status in the first 2 years after CIS to predict progression outcomes at year 11,” explained Dr. Cortese. The investigators obtained biomarkers at baseline, and at study months 6, 12, and 24. Cotinine was used as a biomarker for current or recent nicotine exposure. Serum 25(OH)D levels were used to determine vitamin D levels, and immunoglobulin G levels for EBV antigen-1 were used for EBV seropositivity.
In terms of outcome measurements, the cognitive performance measure used in the study was the Paced Auditory Serial Addition Test, a validated test of processing speed, attention, and working memory, said Dr. Cortese. This test was performed at enrollment, and at study years 1, 2, 5, and 11. At study year 11, neuroaxonal injury was measured using serum neurofilament light chain levels.
In multivariable analysis, the study design adjusted for baseline age and sex, treatment allocation at baseline, unifocal versus multifocal disease seen on baseline magnetic resonance imaging, body mass index, and whether the patient was treated with steroids during the initial CIS.
“Higher quintiles of mean vitamin D levels during the first 2 years were associated with lower odds of scoring worse on the PASAT at year 11,” said Dr. Cortese (P-trend = .028). The significant trend across the quintiles “suggests a dose-response relationship,” she said.* For vitamin D levels over the first 5 years, the P-trend was .049. Dr. Cortese explained that “scoring worse” meant scoring below the median.
Looking at the effect of early vitamin D levels another way, incremental increases of 50 nmol/L of mean 25(OH)D in study months 6-24 predicted 65% lower odds of having a PASAT score below the median at year 11 (P = .027). “Within-person increases in vitamin D during the study were also significantly associated with a better PASAT score when we used the repeated measurement in a linear mixed model,” said Dr. Cortese.
Turning to the effect of smoking on cognitive function at year 11, Dr. Cortese explained that cotinine levels obtained during the first 2 years were all used to determine smoking status. If all levels were below 10 ng/mL, the participant was designated a nonsmoker (N = 125). If any levels were above 25 ng/mL, that patient was classified as a smoker. The investigators also looked at the small number of patients (N = 9) who were very heavy smokers, with cotinine levels over 191 ng/mL.
“Smokers – compared to nonsmokers – had a significantly lower standardized PASAT score at year 11,” said Dr. Cortese (P trend = .042 in age- and sex-adjusted analysis; P-trend = .056 in full multivariable analysis). “Actually, smokers had an up to 0.6-standard deviation-lower PASAT score at year 11 when we looked at heavy smokers. ...This difference corresponds to about 5 points of the PASAT, so I would say [the score is] clinically meaningful.”
Dr. Cortese pointed out that early smoking, again, showed a dose-response relationship with later cognitive status. “It continues to be important to encourage smoking cessation for patients.”
Epstein-Barr antibodies were not associated with cognitive function at year 11, according to the analysis (P-trend = .93).
“The findings of neuroaxonal injury at year 11 using serum neurofilament light-chain measures corroborated the main findings on cognitive function at year 11,” said Dr. Cortese.
For a 50-nmol higher vitamin D level within the first 5 years, neurofilament light chain levels at year 11 were 20% lower, said Dr. Cortese. Conversely, patients who had cotinine levels higher than 25 ng/mL during the first 5 years had neurofilament light chain levels 20% higher than other participants: “So they did worse. They had more neuroaxonal loss,” said Dr. Cortese. No association was seen between neurofilament light chain levels at year 11 and early EBV status, she said.
Though just cognitive function data from BENEFIT-11 were reported by Dr. Cortese, she said that radiologic and other clinical data are also being studied and will be reported in the future.
Dr. Cortese reported that she had no conflicts of interest. Several coauthors reported financial relationships with multiple pharmaceutical companies. The study was supported by the National Institutes of Health and the National Multiple Sclerosis Society, with clinical support from Bayer HealthCare.
SOURCE: Cortese M et al. ECTRIMS 2018, Late breaking abstracts session.
*Correction, 10/25/18: An earlier version of this article mischaracterized the relationship between vitamin D scores during the first 2 years and PASAT scores at year 11.
REPORTING FROM ECTRIMS 2018
Key clinical point: Higher early levels of vitamin D were associated with better later cognitive status in MS.
Major finding: Higher quintiles of baseline 25(OH)D were associated with higher PASAT scores (P-trend = .028).
Study details: Longitudinal observational study of 278 BENEFIT participants with CIS.
Disclosures: Dr. Cortese reported that she had no conflicts of interest. Several coauthors reported financial relationships with multiple pharmaceutical companies. The study was supported by the National Institutes of Health and the National Multiple Sclerosis Society, with clinical support from Bayer HealthCare.
Source: Cortese M et al. ECTRIMS 2018, Late breaking abstracts session.
Low spinal cord volume linked to higher MS disability
BERLIN – Spinal cord volume deficits in patients with multiple sclerosis may contribute to clinical disability that appears out of proportion to lesion load on brain imaging, according to new research.
In a pool of 362 patients with mild to moderate MS-related disability but identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes when compared against those with disability scores in the mild range (P less than .001).
Though brain MRI is a key tool used to track disease severity and progression in MS, some patients have relatively high disability but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in MS patients with pronounced dissociation between intracerebral lesion load and disability, Michaela Andelova, MD, said in an interview during a poster session at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Dr. Andelova, of Charles University, Prague, said that she and her colleagues hypothesized that spinal cord volume would differ between patients who had varying levels of disability, despite identical white matter lesion load.
To test this, she and her colleagues looked at records of 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability, and also by extent of cerebral T2 hyperintense lesion load. The investigators identified a group of patients (n = 53) whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5; this was the low lesion load/high disability (LLHD) group.
Dr. Andelova and her colleagues then identified another group of patients (n = 71) who had a volume of T2-weighted hyperintensities that was greater than 9 mL, but whose EDSS score was less than 1.5. This was the high lesion load/low disability (HLLD) group.
The remaining patients (n = 1,121), who did not have these paradoxical associations, were analyzed separately.
For all patients, mean upper cervical cord area (MUCCA) was also measured. Using images acquired by a 3 T MRI scanner, MUCCA was calculated as the mean sum of spinal cord area in 21 slices centered at the C3/4 intervertebral disk, using an in-house, semiautomated method.
“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of thalamus and callosum, and smaller lateral ventricles than [the] HLLD group,” wrote Dr. Andelova and her collaborators.
However, the LLHD patients had MUCCA values that were significantly lower than the other groups: The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. This difference was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller, at 80.40 mm2 (P = .023 versus nonparadoxical patients, and P = .007 versus HLLD patients).
Looking at the data another way, Dr. Andelova and her colleagues compared 362 evenly divided patients with moderate disability (EDSS 3.5-6.5) with matched patients who had mild MS-related disability (EDSS less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the moderate disability group (78.86 versus 84.44 mm2; P less than .001).
In addition to having identical lesions loads, the mild and moderate disability groups didn’t differ significantly in normalized total brain volume or regional brain volumes. The group with moderate disability did have slightly less white matter volume (P = .039), Dr. Andelova pointed out.
All differences found between groups retained statistical significance even after adjustment for such potential confounders as age, sex, and duration of disease, Dr. Andelova said.
“Reduced spinal cord volume may explain part of the clinical-radiological paradox in patients who have high disability despite low intracranial lesion load,” Dr. Andelova and her collaborators wrote. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”
Further work looking more precisely at cerebral lesion distribution and quantitative MRI investigation of lesion distribution is in the works for Dr. Andelova and her collaborators. They are hoping to see some association between various distribution patterns and accelerated spinal atrophy.
The research was supported by the Czech government. Dr. Andelova and several of her collaborators reported financial relationships with pharmaceutical companies.
SOURCE: Andelova M et al. Mult Scler. 2018;24(Suppl 2):211, Abstract P477.
BERLIN – Spinal cord volume deficits in patients with multiple sclerosis may contribute to clinical disability that appears out of proportion to lesion load on brain imaging, according to new research.
In a pool of 362 patients with mild to moderate MS-related disability but identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes when compared against those with disability scores in the mild range (P less than .001).
Though brain MRI is a key tool used to track disease severity and progression in MS, some patients have relatively high disability but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in MS patients with pronounced dissociation between intracerebral lesion load and disability, Michaela Andelova, MD, said in an interview during a poster session at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Dr. Andelova, of Charles University, Prague, said that she and her colleagues hypothesized that spinal cord volume would differ between patients who had varying levels of disability, despite identical white matter lesion load.
To test this, she and her colleagues looked at records of 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability, and also by extent of cerebral T2 hyperintense lesion load. The investigators identified a group of patients (n = 53) whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5; this was the low lesion load/high disability (LLHD) group.
Dr. Andelova and her colleagues then identified another group of patients (n = 71) who had a volume of T2-weighted hyperintensities that was greater than 9 mL, but whose EDSS score was less than 1.5. This was the high lesion load/low disability (HLLD) group.
The remaining patients (n = 1,121), who did not have these paradoxical associations, were analyzed separately.
For all patients, mean upper cervical cord area (MUCCA) was also measured. Using images acquired by a 3 T MRI scanner, MUCCA was calculated as the mean sum of spinal cord area in 21 slices centered at the C3/4 intervertebral disk, using an in-house, semiautomated method.
“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of thalamus and callosum, and smaller lateral ventricles than [the] HLLD group,” wrote Dr. Andelova and her collaborators.
However, the LLHD patients had MUCCA values that were significantly lower than the other groups: The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. This difference was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller, at 80.40 mm2 (P = .023 versus nonparadoxical patients, and P = .007 versus HLLD patients).
Looking at the data another way, Dr. Andelova and her colleagues compared 362 evenly divided patients with moderate disability (EDSS 3.5-6.5) with matched patients who had mild MS-related disability (EDSS less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the moderate disability group (78.86 versus 84.44 mm2; P less than .001).
In addition to having identical lesions loads, the mild and moderate disability groups didn’t differ significantly in normalized total brain volume or regional brain volumes. The group with moderate disability did have slightly less white matter volume (P = .039), Dr. Andelova pointed out.
All differences found between groups retained statistical significance even after adjustment for such potential confounders as age, sex, and duration of disease, Dr. Andelova said.
“Reduced spinal cord volume may explain part of the clinical-radiological paradox in patients who have high disability despite low intracranial lesion load,” Dr. Andelova and her collaborators wrote. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”
Further work looking more precisely at cerebral lesion distribution and quantitative MRI investigation of lesion distribution is in the works for Dr. Andelova and her collaborators. They are hoping to see some association between various distribution patterns and accelerated spinal atrophy.
The research was supported by the Czech government. Dr. Andelova and several of her collaborators reported financial relationships with pharmaceutical companies.
SOURCE: Andelova M et al. Mult Scler. 2018;24(Suppl 2):211, Abstract P477.
BERLIN – Spinal cord volume deficits in patients with multiple sclerosis may contribute to clinical disability that appears out of proportion to lesion load on brain imaging, according to new research.
In a pool of 362 patients with mild to moderate MS-related disability but identical white matter lesion load identified by MRI, those with higher disability had significantly lower spinal cord volumes when compared against those with disability scores in the mild range (P less than .001).
Though brain MRI is a key tool used to track disease severity and progression in MS, some patients have relatively high disability but a low burden of white matter intracerebral lesions on MRI. Little is known about spinal cord volume in MS patients with pronounced dissociation between intracerebral lesion load and disability, Michaela Andelova, MD, said in an interview during a poster session at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis.
Dr. Andelova, of Charles University, Prague, said that she and her colleagues hypothesized that spinal cord volume would differ between patients who had varying levels of disability, despite identical white matter lesion load.
To test this, she and her colleagues looked at records of 1,245 patients with relapsing-remitting MS. They divided them into three groups by severity of clinical disability, and also by extent of cerebral T2 hyperintense lesion load. The investigators identified a group of patients (n = 53) whose total volume of T2-weighted hyperintense lesions was less than 3 mL, but whose Expanded Disability Status Scale (EDSS) scores were at least 3.5; this was the low lesion load/high disability (LLHD) group.
Dr. Andelova and her colleagues then identified another group of patients (n = 71) who had a volume of T2-weighted hyperintensities that was greater than 9 mL, but whose EDSS score was less than 1.5. This was the high lesion load/low disability (HLLD) group.
The remaining patients (n = 1,121), who did not have these paradoxical associations, were analyzed separately.
For all patients, mean upper cervical cord area (MUCCA) was also measured. Using images acquired by a 3 T MRI scanner, MUCCA was calculated as the mean sum of spinal cord area in 21 slices centered at the C3/4 intervertebral disk, using an in-house, semiautomated method.
“Despite higher disability, LLHD patients demonstrated significantly higher normalized total brain volume, higher normalized volumes of thalamus and callosum, and smaller lateral ventricles than [the] HLLD group,” wrote Dr. Andelova and her collaborators.
However, the LLHD patients had MUCCA values that were significantly lower than the other groups: The nonparadoxical group’s mean MUCCA was 84.02 mm2, while the HLLD group had a mean MUCCA of 85.75 mm2. This difference was not statistically significant. By contrast, the LLHD group’s mean MUCCA was significantly smaller, at 80.40 mm2 (P = .023 versus nonparadoxical patients, and P = .007 versus HLLD patients).
Looking at the data another way, Dr. Andelova and her colleagues compared 362 evenly divided patients with moderate disability (EDSS 3.5-6.5) with matched patients who had mild MS-related disability (EDSS less than 3) and identical cerebral lesion loads. They found that MUCCA was significantly smaller in the moderate disability group (78.86 versus 84.44 mm2; P less than .001).
In addition to having identical lesions loads, the mild and moderate disability groups didn’t differ significantly in normalized total brain volume or regional brain volumes. The group with moderate disability did have slightly less white matter volume (P = .039), Dr. Andelova pointed out.
All differences found between groups retained statistical significance even after adjustment for such potential confounders as age, sex, and duration of disease, Dr. Andelova said.
“Reduced spinal cord volume may explain part of the clinical-radiological paradox in patients who have high disability despite low intracranial lesion load,” Dr. Andelova and her collaborators wrote. “In line with this finding, relatively preserved spinal cord volume may be associated with functional reserve and less physical disability in patients with low disability despite high cerebral lesion load.”
Further work looking more precisely at cerebral lesion distribution and quantitative MRI investigation of lesion distribution is in the works for Dr. Andelova and her collaborators. They are hoping to see some association between various distribution patterns and accelerated spinal atrophy.
The research was supported by the Czech government. Dr. Andelova and several of her collaborators reported financial relationships with pharmaceutical companies.
SOURCE: Andelova M et al. Mult Scler. 2018;24(Suppl 2):211, Abstract P477.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: Moderate disability patients had lower spinal cord volumes than did those with mild disability but a similar intracerebral lesion load.
Study details: Retrospective study of 1,245 patients with relapsing-remitting MS.
Disclosures: The study was sponsored by a grant from the Czech government. Several authors, including Dr. Andelova, reported multiple financial relationships with pharmaceutical companies.
Source: Andelova M et al. Mult Scler. 2018;24(Suppl 2):211, Abstract P477.
No elevated cancer risk with MS therapies in COMBAT-MS data
BERLIN – The risk of cancer – and breast cancer in particular – was not elevated above background levels in a large cohort of multiple sclerosis patients taking disease-modifying therapies.
Those findings from the large Nordic cohort study COMBAT-MS stand in contrast to previous work showing an elevated cancer risk for some monoclonal antibodies.
After statistical adjustment and use of rituximab (Rituxan) as the standard, the hazard ratio (HR) for any malignancy with fingolimod (Gilenya) was 1.74 (95% confidence interval, 0.92-3.28). For natalizumab (Tysabri), the malignancy HR was 1.06 (95% CI, 0.53-2.10), said Peter Alping, a PhD student in the department of clinical neuroscience at the Karolinska Institute, Stockholm.
Only limited data exist for real-world multiple sclerosis (MS) cohorts who have been exposed to novel disease-modifying therapies, said Mr. Alping, presenting the findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Rituximab has been studied in patients with rheumatoid arthritis, but the treatment regimens differ, as do patient characteristics, he noted. However, surveillance for risk of malignancy is important in these therapies, he said, “since modern disease-modifying therapies exert a more profound effect on the immune system, and we know that the immune system is vital in fighting and preventing cancers.”
The anti-CD20 monoclonal antibody ocrelizumab was studied in the ORATORIO trial. “There, they saw an imbalance in the numbers of breast cancers between the ocrelizumab and placebo groups,” said Mr. Alping, with raw data showing four breast cancers in the ocrelizumab population. However, this would translate to 26.1 cancers per 10,000 person-years, as opposed to the zero breast cancers seen in the placebo group (N Engl J Med. 2017;376:209-20).
“To what degree is cancer risk a concern with novel [disease-modifying therapy] use in MS?” Mr. Alping asked.
To answer the question, he and his colleagues from the Karolinska Institute sought to compare the risk of cancer in MS patients who were treated with rituximab, fingolimod, and natalizumab.
To do this, they conducted a nationwide cohort study using the Swedish MS registry, looking at treatment episodes between 2011 and 2016. In Sweden, the MS registry is also linked to the overall patient registry, as well as registries for cancer and prescription drug use. In addition, patient data are linked to national census data.
Mr. Alping and his colleagues looked at data for the first instance of use for an MS patient of rituximab, natalizumab, and/or fingolimod between the years 2011 and 2016. Then, they matched patient records from the general population by age, sex, and geographic location, enrolling the matched controls at the same time point as the MS match entered the study.
Patients treated with mitoxantrone, those who emigrated, and those who died during the study period were excluded from the study.
The statistical analysis, Mr. Alping said, used an ever-treated approach and didn’t attempt to weight exposure duration or dose. However, statistical adjustments were made for patient and control demographics and medical history, for any previous history of cancer, and for MS disease characteristics.
At baseline, 1,558 patients had been treated with fingolimod, 1,761 with natalizumab, and 3,012 with rituximab. A little less than one-third of the patients (26.3%-31.6%) were male, and the mean age was 35-43 years. Most patients (66%-86%) had undergone one or two previous therapies. The mean Expanded Disability Status Scale (EDSS) score was 2.20-2.88. Few patients (0.9%-1.7%) had any history of previous cancer.
Overall, the incidence of cancer in the MS cohort ranged from 23.09 per 10,000 person-years for rituximab ever-takers to 46.28 for those who had ever taken fingolimod. Among the general population, rates of any malignancy were 29.62 per 10,000 person-years.
Looking just at breast cancer, rates in the MS cohort ranged from 2.19 to 2.92/10,000 person-years. For the general population, the rate was 12.07/10,000 person-years.
However, using a Cox regression analysis employing MS-specific covariates and using rituximab as the reference, Mr. Alping and his colleagues calculated an inverse proportion-weighted hazard ratio for any malignancy under the various treatment conditions. Using this analysis, the HR for any cancer with fingolimod was 1.74 (95% CI, 0.92-3.28). For natalizumab, the malignancy HR was 1.06 (95% CI, 0.53-2.10).
Among just women taking rituximab, 2,274 therapy starts occurred, and one breast cancer was seen in 4,050 person-years. This yielded an incidence of 2.32 cancers per 10,000 person-years (95% CI, 0.06-12.9). This contrasts with the adjusted incidence rate in the general female population of 11.06 breast cancers per 10,000 person-years.
Looking at all the therapy episodes captured in the cohort study, there were 6,660 incidences of therapy initiation, and 52 malignancies were seen over 17,283 person-years, Mr. Alping said.
“For malignant cancer of any type, we found no increased risk for rituximab, compared to fingolimod and natalizumab,” Mr. Alping said, pointing to the wide confidence intervals in all the adjusted data. The incidence of breast cancer in women who have taken rituximab, he said, is “comparable to, or possibly lower than, that of the general female population, and lower than the incidence rate reported in the ORATORIO trial for ocrelizumab.
“The overall cancer risk and risk of breast cancer might not be major concerns short term when treating MS patients with rituximab relative to other disease-modifying therapies,” he said.
The study was partially funded by the Patient-Centered Outcomes Research Institute. Mr. Alping reported no conflicts of interest. One study author reported relationships with several pharmaceutical companies.
[email protected]
SOURCE: Alping P et al. Mult Scler. 2018;24(Suppl 2):36. Abstract 89.
BERLIN – The risk of cancer – and breast cancer in particular – was not elevated above background levels in a large cohort of multiple sclerosis patients taking disease-modifying therapies.
Those findings from the large Nordic cohort study COMBAT-MS stand in contrast to previous work showing an elevated cancer risk for some monoclonal antibodies.
After statistical adjustment and use of rituximab (Rituxan) as the standard, the hazard ratio (HR) for any malignancy with fingolimod (Gilenya) was 1.74 (95% confidence interval, 0.92-3.28). For natalizumab (Tysabri), the malignancy HR was 1.06 (95% CI, 0.53-2.10), said Peter Alping, a PhD student in the department of clinical neuroscience at the Karolinska Institute, Stockholm.
Only limited data exist for real-world multiple sclerosis (MS) cohorts who have been exposed to novel disease-modifying therapies, said Mr. Alping, presenting the findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Rituximab has been studied in patients with rheumatoid arthritis, but the treatment regimens differ, as do patient characteristics, he noted. However, surveillance for risk of malignancy is important in these therapies, he said, “since modern disease-modifying therapies exert a more profound effect on the immune system, and we know that the immune system is vital in fighting and preventing cancers.”
The anti-CD20 monoclonal antibody ocrelizumab was studied in the ORATORIO trial. “There, they saw an imbalance in the numbers of breast cancers between the ocrelizumab and placebo groups,” said Mr. Alping, with raw data showing four breast cancers in the ocrelizumab population. However, this would translate to 26.1 cancers per 10,000 person-years, as opposed to the zero breast cancers seen in the placebo group (N Engl J Med. 2017;376:209-20).
“To what degree is cancer risk a concern with novel [disease-modifying therapy] use in MS?” Mr. Alping asked.
To answer the question, he and his colleagues from the Karolinska Institute sought to compare the risk of cancer in MS patients who were treated with rituximab, fingolimod, and natalizumab.
To do this, they conducted a nationwide cohort study using the Swedish MS registry, looking at treatment episodes between 2011 and 2016. In Sweden, the MS registry is also linked to the overall patient registry, as well as registries for cancer and prescription drug use. In addition, patient data are linked to national census data.
Mr. Alping and his colleagues looked at data for the first instance of use for an MS patient of rituximab, natalizumab, and/or fingolimod between the years 2011 and 2016. Then, they matched patient records from the general population by age, sex, and geographic location, enrolling the matched controls at the same time point as the MS match entered the study.
Patients treated with mitoxantrone, those who emigrated, and those who died during the study period were excluded from the study.
The statistical analysis, Mr. Alping said, used an ever-treated approach and didn’t attempt to weight exposure duration or dose. However, statistical adjustments were made for patient and control demographics and medical history, for any previous history of cancer, and for MS disease characteristics.
At baseline, 1,558 patients had been treated with fingolimod, 1,761 with natalizumab, and 3,012 with rituximab. A little less than one-third of the patients (26.3%-31.6%) were male, and the mean age was 35-43 years. Most patients (66%-86%) had undergone one or two previous therapies. The mean Expanded Disability Status Scale (EDSS) score was 2.20-2.88. Few patients (0.9%-1.7%) had any history of previous cancer.
Overall, the incidence of cancer in the MS cohort ranged from 23.09 per 10,000 person-years for rituximab ever-takers to 46.28 for those who had ever taken fingolimod. Among the general population, rates of any malignancy were 29.62 per 10,000 person-years.
Looking just at breast cancer, rates in the MS cohort ranged from 2.19 to 2.92/10,000 person-years. For the general population, the rate was 12.07/10,000 person-years.
However, using a Cox regression analysis employing MS-specific covariates and using rituximab as the reference, Mr. Alping and his colleagues calculated an inverse proportion-weighted hazard ratio for any malignancy under the various treatment conditions. Using this analysis, the HR for any cancer with fingolimod was 1.74 (95% CI, 0.92-3.28). For natalizumab, the malignancy HR was 1.06 (95% CI, 0.53-2.10).
Among just women taking rituximab, 2,274 therapy starts occurred, and one breast cancer was seen in 4,050 person-years. This yielded an incidence of 2.32 cancers per 10,000 person-years (95% CI, 0.06-12.9). This contrasts with the adjusted incidence rate in the general female population of 11.06 breast cancers per 10,000 person-years.
Looking at all the therapy episodes captured in the cohort study, there were 6,660 incidences of therapy initiation, and 52 malignancies were seen over 17,283 person-years, Mr. Alping said.
“For malignant cancer of any type, we found no increased risk for rituximab, compared to fingolimod and natalizumab,” Mr. Alping said, pointing to the wide confidence intervals in all the adjusted data. The incidence of breast cancer in women who have taken rituximab, he said, is “comparable to, or possibly lower than, that of the general female population, and lower than the incidence rate reported in the ORATORIO trial for ocrelizumab.
“The overall cancer risk and risk of breast cancer might not be major concerns short term when treating MS patients with rituximab relative to other disease-modifying therapies,” he said.
The study was partially funded by the Patient-Centered Outcomes Research Institute. Mr. Alping reported no conflicts of interest. One study author reported relationships with several pharmaceutical companies.
[email protected]
SOURCE: Alping P et al. Mult Scler. 2018;24(Suppl 2):36. Abstract 89.
BERLIN – The risk of cancer – and breast cancer in particular – was not elevated above background levels in a large cohort of multiple sclerosis patients taking disease-modifying therapies.
Those findings from the large Nordic cohort study COMBAT-MS stand in contrast to previous work showing an elevated cancer risk for some monoclonal antibodies.
After statistical adjustment and use of rituximab (Rituxan) as the standard, the hazard ratio (HR) for any malignancy with fingolimod (Gilenya) was 1.74 (95% confidence interval, 0.92-3.28). For natalizumab (Tysabri), the malignancy HR was 1.06 (95% CI, 0.53-2.10), said Peter Alping, a PhD student in the department of clinical neuroscience at the Karolinska Institute, Stockholm.
Only limited data exist for real-world multiple sclerosis (MS) cohorts who have been exposed to novel disease-modifying therapies, said Mr. Alping, presenting the findings at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. Rituximab has been studied in patients with rheumatoid arthritis, but the treatment regimens differ, as do patient characteristics, he noted. However, surveillance for risk of malignancy is important in these therapies, he said, “since modern disease-modifying therapies exert a more profound effect on the immune system, and we know that the immune system is vital in fighting and preventing cancers.”
The anti-CD20 monoclonal antibody ocrelizumab was studied in the ORATORIO trial. “There, they saw an imbalance in the numbers of breast cancers between the ocrelizumab and placebo groups,” said Mr. Alping, with raw data showing four breast cancers in the ocrelizumab population. However, this would translate to 26.1 cancers per 10,000 person-years, as opposed to the zero breast cancers seen in the placebo group (N Engl J Med. 2017;376:209-20).
“To what degree is cancer risk a concern with novel [disease-modifying therapy] use in MS?” Mr. Alping asked.
To answer the question, he and his colleagues from the Karolinska Institute sought to compare the risk of cancer in MS patients who were treated with rituximab, fingolimod, and natalizumab.
To do this, they conducted a nationwide cohort study using the Swedish MS registry, looking at treatment episodes between 2011 and 2016. In Sweden, the MS registry is also linked to the overall patient registry, as well as registries for cancer and prescription drug use. In addition, patient data are linked to national census data.
Mr. Alping and his colleagues looked at data for the first instance of use for an MS patient of rituximab, natalizumab, and/or fingolimod between the years 2011 and 2016. Then, they matched patient records from the general population by age, sex, and geographic location, enrolling the matched controls at the same time point as the MS match entered the study.
Patients treated with mitoxantrone, those who emigrated, and those who died during the study period were excluded from the study.
The statistical analysis, Mr. Alping said, used an ever-treated approach and didn’t attempt to weight exposure duration or dose. However, statistical adjustments were made for patient and control demographics and medical history, for any previous history of cancer, and for MS disease characteristics.
At baseline, 1,558 patients had been treated with fingolimod, 1,761 with natalizumab, and 3,012 with rituximab. A little less than one-third of the patients (26.3%-31.6%) were male, and the mean age was 35-43 years. Most patients (66%-86%) had undergone one or two previous therapies. The mean Expanded Disability Status Scale (EDSS) score was 2.20-2.88. Few patients (0.9%-1.7%) had any history of previous cancer.
Overall, the incidence of cancer in the MS cohort ranged from 23.09 per 10,000 person-years for rituximab ever-takers to 46.28 for those who had ever taken fingolimod. Among the general population, rates of any malignancy were 29.62 per 10,000 person-years.
Looking just at breast cancer, rates in the MS cohort ranged from 2.19 to 2.92/10,000 person-years. For the general population, the rate was 12.07/10,000 person-years.
However, using a Cox regression analysis employing MS-specific covariates and using rituximab as the reference, Mr. Alping and his colleagues calculated an inverse proportion-weighted hazard ratio for any malignancy under the various treatment conditions. Using this analysis, the HR for any cancer with fingolimod was 1.74 (95% CI, 0.92-3.28). For natalizumab, the malignancy HR was 1.06 (95% CI, 0.53-2.10).
Among just women taking rituximab, 2,274 therapy starts occurred, and one breast cancer was seen in 4,050 person-years. This yielded an incidence of 2.32 cancers per 10,000 person-years (95% CI, 0.06-12.9). This contrasts with the adjusted incidence rate in the general female population of 11.06 breast cancers per 10,000 person-years.
Looking at all the therapy episodes captured in the cohort study, there were 6,660 incidences of therapy initiation, and 52 malignancies were seen over 17,283 person-years, Mr. Alping said.
“For malignant cancer of any type, we found no increased risk for rituximab, compared to fingolimod and natalizumab,” Mr. Alping said, pointing to the wide confidence intervals in all the adjusted data. The incidence of breast cancer in women who have taken rituximab, he said, is “comparable to, or possibly lower than, that of the general female population, and lower than the incidence rate reported in the ORATORIO trial for ocrelizumab.
“The overall cancer risk and risk of breast cancer might not be major concerns short term when treating MS patients with rituximab relative to other disease-modifying therapies,” he said.
The study was partially funded by the Patient-Centered Outcomes Research Institute. Mr. Alping reported no conflicts of interest. One study author reported relationships with several pharmaceutical companies.
[email protected]
SOURCE: Alping P et al. Mult Scler. 2018;24(Suppl 2):36. Abstract 89.
REPORTING FROM ECTRIMS 2018
Key clinical point:
Major finding: The hazard ratios for fingolimod and natalizumab versus rituximab were 1.74 and 1.06, respectively, with confidence intervals crossing 1.
Study details: Case-matched observational cohort study of 6,331 DMT-taking patients with MS.
Disclosures: The study was sponsored in part by the Patient-Centered Outcomes Research Institute. Mr. Alping reported no disclosures; one study author reported financial relationships with multiple pharmaceutical companies.
Source: Alping P et al. Mult Scler. 2018;24(Suppl 2):36. Abstract 89.
No signal for CV, breast effects with bioidentical vaginal estrogen for dyspareunia
that would suggest significant systemic absorption.
The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.
These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.
TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.
The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.
Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.
The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.
In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m2. African American women made up 12% of the study; the remainder of the women were white.
In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.
Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.
Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.
Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.
Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.
“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.
The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.
SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.
that would suggest significant systemic absorption.
The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.
These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.
TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.
The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.
Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.
The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.
In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m2. African American women made up 12% of the study; the remainder of the women were white.
In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.
Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.
Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.
Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.
Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.
“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.
The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.
SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.
that would suggest significant systemic absorption.
The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.
These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.
TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.
The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.
Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.
The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.
In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m2. African American women made up 12% of the study; the remainder of the women were white.
In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.
Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.
Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.
Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.
Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.
“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.
The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.
SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.
FROM NAMS 2018
Key clinical point: Safety data from clinical trials of a bioidentical vaginal estrogen for dyspareunia in menopausal women showed no signs of CV or breast risks.
Major finding: There were no cardiovascular events or thrombotic episodes among menopausal women with dyspareunia treated with TX-004HR.
Study details: Randomized, double-blind, placebo-controlled trial of 784 menopausal women with moderate to severe dyspareunia.
Disclosures: The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin reported financial relationships with several pharmaceutical companies, including TherapeuticsMD.
Source: Larkin L et al. NAMS 2018, Thursday concurrent session 1.
With more mindfulness, menopausal symptoms wane
An observational Furthermore, mindfulness had the greatest positive effect on menopausal symptoms for those women with the highest self-reported stress levels.
“In this cross-sectional study, mindfulness was associated with lower menopausal symptom burden. In women with higher stress, the magnitude of association between mindfulness and menopausal symptoms appeared more robust,” said Richa Sood, MD, speaking at the annual meeting of the North American Menopause Society.
Menopausal symptoms can exist alongside many other midlife issues because women often are trying to keep many balls in the air: This age group may be facing aging parents, a household with teenagers, and work-related pressures, she noted.
Thus, menopausal symptoms can be amplified by stressors. New mood problems – or worsening of preexisting ones – can interfere with work productivity and negatively affect relationships. Life satisfaction can take a steep dive during midlife for some women, said Dr. Sood of the Mayo Clinic, Rochester, Minn.
Could mindfulness be effective for stress management in this complex landscape of physiological and lifespan changes? “Mindfulness is paying attention,” said Dr. Sood. Practitioners of mindfulness focus on purposeful attention, staying in the present moment, and avoiding judgment.
Mindfulness may work as a stress-management tool for a variety of reasons, said Dr. Sood. The technique can help retrain people with tendencies for emotional reactivity in stressful situations; additionally, the focus on the present and on observation, rather than judgment, may help avoid maladaptive rumination.
To see how mindfulness in everyday life could affect the burden of menopausal symptoms, Dr. Sood and her collaborators designed an observational, cross-sectional study of 1,744 women aged 40-64 years.
The investigators used three scales in their assessments. The first, the Menopause Rating Scale (MRS), is an 11-item scale ranging from 0 to 44 that assesses psychological, somatovegetative, and urogenital domains. The second, the Perceived Stress Scale 4 (PSS-4), is a four-item scale that is a global measure of stress over the last 4 weeks, with tallied scores in the 0-16 range. Finally, the Mindful Attention Awareness Scale (MAAS) is a 15-item scale that captures how frequently respondents are in a mindful state during their daily life, with higher scores meaning more mindfulness.
The 1,744 women were seen in a women’s health clinic over the period of one year. Participants were a mean 53.4 years old (standard deviation, 6.1 years). Almost all were white (93%), most were married (82.7%), and most also had at least a 4-year college degree (64.6%) and were employed (65.3%).
The investigators mapped each scale against each of the others, which yielded three plots. In the first, higher MAAS scores were correlated with lower MRS scores (correlation, –0.49; P less than .001), which means that more time in a mindful state was associated with less severe menopausal symptoms.
In the second plot, lower MRS scores were associated with lower PSS-4 scores (correlation, 0.55; P less than .001). The last plot mapped PSS-4 scores against MAAS scores, showing that higher MAAS scores were correlated with lower PSS-4 scores, which means that more time in a mindful state was also associated with less perceived stress (correlation, –0.53; P less than .001).
Most of these associations remained statistically significant after multivariable linear regression analysis and breaking out the subscales of the MRS. Only the association between higher MAAS scores and the somatovegetative domain of the PSS-4 lost significance (P = 0.44).
Next, Dr. Sood and her collaborators probed how higher perceived stress, as measured by higher PSS-4 scores, altered the effects that mindful activity had on menopausal symptoms (as measured by the MRS).
The effect of mindfulness became stronger in the milieu of higher perceived stress. At a relatively low PSS-4 value of 4, the MRS score dropped 1.53 points for each one-point increase in the MAAS total score. However, with a PSS-4 score of 12, the decrease in MRS was 2.27 points for each one-point increase in MAAS, and with the maximum perceived stress score of 16, the MRS fell 2.64 points for each one-point increase in the MAAS score.
These findings are set against the backdrop of previous literature linking mindfulness to positive health behaviors and outcomes, she said, noting that work looking specifically at mindfulness-based stress reduction in peri- and postmenopausal women showed a halving of symptoms and improved quality of life.
Dr. Sood said that the present study was observational only, noting that it looked only at time spent in a mindful state in an untrained cohort of women in midlife. “Trait, or dispositional, mindfulness appears to be protective against stress and symptoms in midlife women,” she commented. “More mindful women may be choosing to shift their attention to more pleasant aspects of life, rather than their symptoms.”
“If you allow me to speculate a bit,” Dr. Sood continued, “the underpinnings of psychological symptoms rest in threat-focused attention and emotional reactivity – so the mindfulness approach appears to fit very well to impact such a change.”
Mindfulness, she added, “might be a tool to impact the emotional component of the overall experience, thereby decreasing the total suffering.” However, she noted that what’s needed are studies with a more heterogeneous population, as well as ones designed to tease out causality. Still, “the current study adds to the wealth of data supporting the role of mindfulness in various settings for impacting positive change in health and behaviors.”
Dr. Sood reported that she has ownership stake in the Global Center for Resiliency and Well-Being.
SOURCE: Sood R et al. NAMS 2018, Top-Scoring Abstract Session.
An observational Furthermore, mindfulness had the greatest positive effect on menopausal symptoms for those women with the highest self-reported stress levels.
“In this cross-sectional study, mindfulness was associated with lower menopausal symptom burden. In women with higher stress, the magnitude of association between mindfulness and menopausal symptoms appeared more robust,” said Richa Sood, MD, speaking at the annual meeting of the North American Menopause Society.
Menopausal symptoms can exist alongside many other midlife issues because women often are trying to keep many balls in the air: This age group may be facing aging parents, a household with teenagers, and work-related pressures, she noted.
Thus, menopausal symptoms can be amplified by stressors. New mood problems – or worsening of preexisting ones – can interfere with work productivity and negatively affect relationships. Life satisfaction can take a steep dive during midlife for some women, said Dr. Sood of the Mayo Clinic, Rochester, Minn.
Could mindfulness be effective for stress management in this complex landscape of physiological and lifespan changes? “Mindfulness is paying attention,” said Dr. Sood. Practitioners of mindfulness focus on purposeful attention, staying in the present moment, and avoiding judgment.
Mindfulness may work as a stress-management tool for a variety of reasons, said Dr. Sood. The technique can help retrain people with tendencies for emotional reactivity in stressful situations; additionally, the focus on the present and on observation, rather than judgment, may help avoid maladaptive rumination.
To see how mindfulness in everyday life could affect the burden of menopausal symptoms, Dr. Sood and her collaborators designed an observational, cross-sectional study of 1,744 women aged 40-64 years.
The investigators used three scales in their assessments. The first, the Menopause Rating Scale (MRS), is an 11-item scale ranging from 0 to 44 that assesses psychological, somatovegetative, and urogenital domains. The second, the Perceived Stress Scale 4 (PSS-4), is a four-item scale that is a global measure of stress over the last 4 weeks, with tallied scores in the 0-16 range. Finally, the Mindful Attention Awareness Scale (MAAS) is a 15-item scale that captures how frequently respondents are in a mindful state during their daily life, with higher scores meaning more mindfulness.
The 1,744 women were seen in a women’s health clinic over the period of one year. Participants were a mean 53.4 years old (standard deviation, 6.1 years). Almost all were white (93%), most were married (82.7%), and most also had at least a 4-year college degree (64.6%) and were employed (65.3%).
The investigators mapped each scale against each of the others, which yielded three plots. In the first, higher MAAS scores were correlated with lower MRS scores (correlation, –0.49; P less than .001), which means that more time in a mindful state was associated with less severe menopausal symptoms.
In the second plot, lower MRS scores were associated with lower PSS-4 scores (correlation, 0.55; P less than .001). The last plot mapped PSS-4 scores against MAAS scores, showing that higher MAAS scores were correlated with lower PSS-4 scores, which means that more time in a mindful state was also associated with less perceived stress (correlation, –0.53; P less than .001).
Most of these associations remained statistically significant after multivariable linear regression analysis and breaking out the subscales of the MRS. Only the association between higher MAAS scores and the somatovegetative domain of the PSS-4 lost significance (P = 0.44).
Next, Dr. Sood and her collaborators probed how higher perceived stress, as measured by higher PSS-4 scores, altered the effects that mindful activity had on menopausal symptoms (as measured by the MRS).
The effect of mindfulness became stronger in the milieu of higher perceived stress. At a relatively low PSS-4 value of 4, the MRS score dropped 1.53 points for each one-point increase in the MAAS total score. However, with a PSS-4 score of 12, the decrease in MRS was 2.27 points for each one-point increase in MAAS, and with the maximum perceived stress score of 16, the MRS fell 2.64 points for each one-point increase in the MAAS score.
These findings are set against the backdrop of previous literature linking mindfulness to positive health behaviors and outcomes, she said, noting that work looking specifically at mindfulness-based stress reduction in peri- and postmenopausal women showed a halving of symptoms and improved quality of life.
Dr. Sood said that the present study was observational only, noting that it looked only at time spent in a mindful state in an untrained cohort of women in midlife. “Trait, or dispositional, mindfulness appears to be protective against stress and symptoms in midlife women,” she commented. “More mindful women may be choosing to shift their attention to more pleasant aspects of life, rather than their symptoms.”
“If you allow me to speculate a bit,” Dr. Sood continued, “the underpinnings of psychological symptoms rest in threat-focused attention and emotional reactivity – so the mindfulness approach appears to fit very well to impact such a change.”
Mindfulness, she added, “might be a tool to impact the emotional component of the overall experience, thereby decreasing the total suffering.” However, she noted that what’s needed are studies with a more heterogeneous population, as well as ones designed to tease out causality. Still, “the current study adds to the wealth of data supporting the role of mindfulness in various settings for impacting positive change in health and behaviors.”
Dr. Sood reported that she has ownership stake in the Global Center for Resiliency and Well-Being.
SOURCE: Sood R et al. NAMS 2018, Top-Scoring Abstract Session.
An observational Furthermore, mindfulness had the greatest positive effect on menopausal symptoms for those women with the highest self-reported stress levels.
“In this cross-sectional study, mindfulness was associated with lower menopausal symptom burden. In women with higher stress, the magnitude of association between mindfulness and menopausal symptoms appeared more robust,” said Richa Sood, MD, speaking at the annual meeting of the North American Menopause Society.
Menopausal symptoms can exist alongside many other midlife issues because women often are trying to keep many balls in the air: This age group may be facing aging parents, a household with teenagers, and work-related pressures, she noted.
Thus, menopausal symptoms can be amplified by stressors. New mood problems – or worsening of preexisting ones – can interfere with work productivity and negatively affect relationships. Life satisfaction can take a steep dive during midlife for some women, said Dr. Sood of the Mayo Clinic, Rochester, Minn.
Could mindfulness be effective for stress management in this complex landscape of physiological and lifespan changes? “Mindfulness is paying attention,” said Dr. Sood. Practitioners of mindfulness focus on purposeful attention, staying in the present moment, and avoiding judgment.
Mindfulness may work as a stress-management tool for a variety of reasons, said Dr. Sood. The technique can help retrain people with tendencies for emotional reactivity in stressful situations; additionally, the focus on the present and on observation, rather than judgment, may help avoid maladaptive rumination.
To see how mindfulness in everyday life could affect the burden of menopausal symptoms, Dr. Sood and her collaborators designed an observational, cross-sectional study of 1,744 women aged 40-64 years.
The investigators used three scales in their assessments. The first, the Menopause Rating Scale (MRS), is an 11-item scale ranging from 0 to 44 that assesses psychological, somatovegetative, and urogenital domains. The second, the Perceived Stress Scale 4 (PSS-4), is a four-item scale that is a global measure of stress over the last 4 weeks, with tallied scores in the 0-16 range. Finally, the Mindful Attention Awareness Scale (MAAS) is a 15-item scale that captures how frequently respondents are in a mindful state during their daily life, with higher scores meaning more mindfulness.
The 1,744 women were seen in a women’s health clinic over the period of one year. Participants were a mean 53.4 years old (standard deviation, 6.1 years). Almost all were white (93%), most were married (82.7%), and most also had at least a 4-year college degree (64.6%) and were employed (65.3%).
The investigators mapped each scale against each of the others, which yielded three plots. In the first, higher MAAS scores were correlated with lower MRS scores (correlation, –0.49; P less than .001), which means that more time in a mindful state was associated with less severe menopausal symptoms.
In the second plot, lower MRS scores were associated with lower PSS-4 scores (correlation, 0.55; P less than .001). The last plot mapped PSS-4 scores against MAAS scores, showing that higher MAAS scores were correlated with lower PSS-4 scores, which means that more time in a mindful state was also associated with less perceived stress (correlation, –0.53; P less than .001).
Most of these associations remained statistically significant after multivariable linear regression analysis and breaking out the subscales of the MRS. Only the association between higher MAAS scores and the somatovegetative domain of the PSS-4 lost significance (P = 0.44).
Next, Dr. Sood and her collaborators probed how higher perceived stress, as measured by higher PSS-4 scores, altered the effects that mindful activity had on menopausal symptoms (as measured by the MRS).
The effect of mindfulness became stronger in the milieu of higher perceived stress. At a relatively low PSS-4 value of 4, the MRS score dropped 1.53 points for each one-point increase in the MAAS total score. However, with a PSS-4 score of 12, the decrease in MRS was 2.27 points for each one-point increase in MAAS, and with the maximum perceived stress score of 16, the MRS fell 2.64 points for each one-point increase in the MAAS score.
These findings are set against the backdrop of previous literature linking mindfulness to positive health behaviors and outcomes, she said, noting that work looking specifically at mindfulness-based stress reduction in peri- and postmenopausal women showed a halving of symptoms and improved quality of life.
Dr. Sood said that the present study was observational only, noting that it looked only at time spent in a mindful state in an untrained cohort of women in midlife. “Trait, or dispositional, mindfulness appears to be protective against stress and symptoms in midlife women,” she commented. “More mindful women may be choosing to shift their attention to more pleasant aspects of life, rather than their symptoms.”
“If you allow me to speculate a bit,” Dr. Sood continued, “the underpinnings of psychological symptoms rest in threat-focused attention and emotional reactivity – so the mindfulness approach appears to fit very well to impact such a change.”
Mindfulness, she added, “might be a tool to impact the emotional component of the overall experience, thereby decreasing the total suffering.” However, she noted that what’s needed are studies with a more heterogeneous population, as well as ones designed to tease out causality. Still, “the current study adds to the wealth of data supporting the role of mindfulness in various settings for impacting positive change in health and behaviors.”
Dr. Sood reported that she has ownership stake in the Global Center for Resiliency and Well-Being.
SOURCE: Sood R et al. NAMS 2018, Top-Scoring Abstract Session.
FROM NAMS 2018
Key clinical point: Time spent in a mindful state was associated with fewer menopause symptoms.
Major finding: With maximum stress, each 1-point increase in mindfulness was associated with a 2.64-point drop in menopausal symptoms.
Study details: A cross-sectional, single-center study of 1,744 women aged 40-64 years.
Disclosures: Dr. Sood reported that she has ownership stake in the Global Center for Resiliency and Well-Being.
Source: Sood R et al. NAMS 2018, Top-Scoring Abstract Session.
For dyspareunia, intravaginal prasterone may work best soon after menopause
Neither age nor previous hormone therapy had statistically significant associations with the effect of intravaginal prasterone on dyspareunia severity, according to a new subgroup analysis of clinical trial data. In a trend that did not reach statistical significance, though, said David F. Archer, MD.
“This was an unexpected finding,” he said in an interview.
In a subgroup analysis of data from two clinical trials of intravaginal prasterone (Intrarosa), Dr. Archer and his colleagues sought to investigate whether age, time since menopause, or any previous use of hormone replacement therapy influenced prasterone’s efficacy in treating dyspareunia.
Dr. Archer and his collaborators pooled data from two prospective, randomized, double-blind, placebo-controlled trials (NCT02013544 and NCT01256684) of intravaginal prasterone dosed at 0.50%, 6.5 mg once daily for 12 weeks; he presented the subgroup analyses at the annual meeting of the North American Menopause Society in San Diego.
For each subgroup, Dr. Archer, a professor of obstetrics and gynecology at Eastern Virginia Medical School, Norfolk, and his coinvestigators compared the mean differences in dyspareunia severity score of women who received prasterone and those who received placebo.
All subgroup analyses used the endpoint of improvement in moderate to severe dyspareunia or whether dyspareunia was the most bothersome symptoms for the women participating in the study. The investigators began by looking at the subgroup of 460 women who were 56 years and older at baseline and compared them with the 180 younger participants.
The 283 older participants who received prasterone saw a decrease of 0.36 points in a dyspareunia severity score versus a 0.44 point decrease for the 123 women aged 55 and younger who received prasterone, a nonsignificant difference between subgroups. The decrease compared with placebo-takers was significant in both cases, however (P = .0003 and P =.0031, respectively).
Looking at time since menopause, Dr. Archer and his collaborators divided participants into 33 individuals who were 1 or 2 years post menopause, 86 women who were 3-5 years post menopause, and 521 women who had experienced menopause at least 6 years before study baseline.
In this analysis, 22 of the earliest postmenopause women received prasterone, seeing a 1.59 point drop in dyspareunia severity. For the 59 women in the prasterone study arms who were 3-5 year past menopause, the decrease from baseline was 0.59 points. Finally, among the 325 women who received prasterone and experienced menopause 6 or more years ago, the decrease was 0.27 points.
Although there was a numeric difference in the change in dyspareunia score severity among these groups, the differences were not statistically significant, said Dr. Archer. Again, though, those who took prasterone had a significant reduction in dyspareunia severity scores when compared with those taking placebo (P less than .0001, P = .0136, and P = .0024, respectively).
In the prasterone study arms, 184 had previously used hormone therapy, and 222 had not. After 12 weeks of intravaginal prasterone, there was no statistically significant difference between the two subgroups, with a decreases in dyspareunia severity scores of 0.45 and 0.32, respectively. The decreases in severity scores when compared with those among women who took placebo were again statistically significant for both subgroups, however (P = .0002 and P = .0057, respectively).
Prasterone is a steroid that is also known as dehydroepiandrosterone (DHEA) and is an endogenous hormone that is a precursor for estrogens and androgens. Prasterone’s mechanism of action to reduce vulvar and vaginal atrophy is not completely understood, according to the Food and Drug Administration.
“The nonstatistically significant smaller effect on dyspareunia observed when treatment is initiated after a longer period after menopause suggests that a longer treatment period could be needed to achieve optimal benefit and that treatment of dyspareunia should be initiated as early as possible after menopause,” said Dr. Archer.
Dr. Archer reported grant support from and consulting relationships with several pharmaceutical companies, including Endoceutics, the producer of Intrarosa intravaginal prasterone.
Neither age nor previous hormone therapy had statistically significant associations with the effect of intravaginal prasterone on dyspareunia severity, according to a new subgroup analysis of clinical trial data. In a trend that did not reach statistical significance, though, said David F. Archer, MD.
“This was an unexpected finding,” he said in an interview.
In a subgroup analysis of data from two clinical trials of intravaginal prasterone (Intrarosa), Dr. Archer and his colleagues sought to investigate whether age, time since menopause, or any previous use of hormone replacement therapy influenced prasterone’s efficacy in treating dyspareunia.
Dr. Archer and his collaborators pooled data from two prospective, randomized, double-blind, placebo-controlled trials (NCT02013544 and NCT01256684) of intravaginal prasterone dosed at 0.50%, 6.5 mg once daily for 12 weeks; he presented the subgroup analyses at the annual meeting of the North American Menopause Society in San Diego.
For each subgroup, Dr. Archer, a professor of obstetrics and gynecology at Eastern Virginia Medical School, Norfolk, and his coinvestigators compared the mean differences in dyspareunia severity score of women who received prasterone and those who received placebo.
All subgroup analyses used the endpoint of improvement in moderate to severe dyspareunia or whether dyspareunia was the most bothersome symptoms for the women participating in the study. The investigators began by looking at the subgroup of 460 women who were 56 years and older at baseline and compared them with the 180 younger participants.
The 283 older participants who received prasterone saw a decrease of 0.36 points in a dyspareunia severity score versus a 0.44 point decrease for the 123 women aged 55 and younger who received prasterone, a nonsignificant difference between subgroups. The decrease compared with placebo-takers was significant in both cases, however (P = .0003 and P =.0031, respectively).
Looking at time since menopause, Dr. Archer and his collaborators divided participants into 33 individuals who were 1 or 2 years post menopause, 86 women who were 3-5 years post menopause, and 521 women who had experienced menopause at least 6 years before study baseline.
In this analysis, 22 of the earliest postmenopause women received prasterone, seeing a 1.59 point drop in dyspareunia severity. For the 59 women in the prasterone study arms who were 3-5 year past menopause, the decrease from baseline was 0.59 points. Finally, among the 325 women who received prasterone and experienced menopause 6 or more years ago, the decrease was 0.27 points.
Although there was a numeric difference in the change in dyspareunia score severity among these groups, the differences were not statistically significant, said Dr. Archer. Again, though, those who took prasterone had a significant reduction in dyspareunia severity scores when compared with those taking placebo (P less than .0001, P = .0136, and P = .0024, respectively).
In the prasterone study arms, 184 had previously used hormone therapy, and 222 had not. After 12 weeks of intravaginal prasterone, there was no statistically significant difference between the two subgroups, with a decreases in dyspareunia severity scores of 0.45 and 0.32, respectively. The decreases in severity scores when compared with those among women who took placebo were again statistically significant for both subgroups, however (P = .0002 and P = .0057, respectively).
Prasterone is a steroid that is also known as dehydroepiandrosterone (DHEA) and is an endogenous hormone that is a precursor for estrogens and androgens. Prasterone’s mechanism of action to reduce vulvar and vaginal atrophy is not completely understood, according to the Food and Drug Administration.
“The nonstatistically significant smaller effect on dyspareunia observed when treatment is initiated after a longer period after menopause suggests that a longer treatment period could be needed to achieve optimal benefit and that treatment of dyspareunia should be initiated as early as possible after menopause,” said Dr. Archer.
Dr. Archer reported grant support from and consulting relationships with several pharmaceutical companies, including Endoceutics, the producer of Intrarosa intravaginal prasterone.
Neither age nor previous hormone therapy had statistically significant associations with the effect of intravaginal prasterone on dyspareunia severity, according to a new subgroup analysis of clinical trial data. In a trend that did not reach statistical significance, though, said David F. Archer, MD.
“This was an unexpected finding,” he said in an interview.
In a subgroup analysis of data from two clinical trials of intravaginal prasterone (Intrarosa), Dr. Archer and his colleagues sought to investigate whether age, time since menopause, or any previous use of hormone replacement therapy influenced prasterone’s efficacy in treating dyspareunia.
Dr. Archer and his collaborators pooled data from two prospective, randomized, double-blind, placebo-controlled trials (NCT02013544 and NCT01256684) of intravaginal prasterone dosed at 0.50%, 6.5 mg once daily for 12 weeks; he presented the subgroup analyses at the annual meeting of the North American Menopause Society in San Diego.
For each subgroup, Dr. Archer, a professor of obstetrics and gynecology at Eastern Virginia Medical School, Norfolk, and his coinvestigators compared the mean differences in dyspareunia severity score of women who received prasterone and those who received placebo.
All subgroup analyses used the endpoint of improvement in moderate to severe dyspareunia or whether dyspareunia was the most bothersome symptoms for the women participating in the study. The investigators began by looking at the subgroup of 460 women who were 56 years and older at baseline and compared them with the 180 younger participants.
The 283 older participants who received prasterone saw a decrease of 0.36 points in a dyspareunia severity score versus a 0.44 point decrease for the 123 women aged 55 and younger who received prasterone, a nonsignificant difference between subgroups. The decrease compared with placebo-takers was significant in both cases, however (P = .0003 and P =.0031, respectively).
Looking at time since menopause, Dr. Archer and his collaborators divided participants into 33 individuals who were 1 or 2 years post menopause, 86 women who were 3-5 years post menopause, and 521 women who had experienced menopause at least 6 years before study baseline.
In this analysis, 22 of the earliest postmenopause women received prasterone, seeing a 1.59 point drop in dyspareunia severity. For the 59 women in the prasterone study arms who were 3-5 year past menopause, the decrease from baseline was 0.59 points. Finally, among the 325 women who received prasterone and experienced menopause 6 or more years ago, the decrease was 0.27 points.
Although there was a numeric difference in the change in dyspareunia score severity among these groups, the differences were not statistically significant, said Dr. Archer. Again, though, those who took prasterone had a significant reduction in dyspareunia severity scores when compared with those taking placebo (P less than .0001, P = .0136, and P = .0024, respectively).
In the prasterone study arms, 184 had previously used hormone therapy, and 222 had not. After 12 weeks of intravaginal prasterone, there was no statistically significant difference between the two subgroups, with a decreases in dyspareunia severity scores of 0.45 and 0.32, respectively. The decreases in severity scores when compared with those among women who took placebo were again statistically significant for both subgroups, however (P = .0002 and P = .0057, respectively).
Prasterone is a steroid that is also known as dehydroepiandrosterone (DHEA) and is an endogenous hormone that is a precursor for estrogens and androgens. Prasterone’s mechanism of action to reduce vulvar and vaginal atrophy is not completely understood, according to the Food and Drug Administration.
“The nonstatistically significant smaller effect on dyspareunia observed when treatment is initiated after a longer period after menopause suggests that a longer treatment period could be needed to achieve optimal benefit and that treatment of dyspareunia should be initiated as early as possible after menopause,” said Dr. Archer.
Dr. Archer reported grant support from and consulting relationships with several pharmaceutical companies, including Endoceutics, the producer of Intrarosa intravaginal prasterone.
FROM NAMS 2018
Key clinical point: Dyspareunia improvement was numerically, but not statistically, better soon after menopause.
Major finding: Dyspareunia scores dropped 1.59 points for those within 2 years of menopause, and 0.27 points for those 6 or more years post menopause.
Study details: Subgroup analysis of 640 postmenopausal women taking part in two clinical trials.
Disclosures: Dr. Archer reported receiving support from several pharmaceutical companies, including Endoceutics, the manufacturer of Intrarosa intravaginal prasterone.
For solitary renal tumors, RFA looks good at 10 years
Radiofrequency ablation (RFA) of small renal tumors is safe and effective, and is associated with high rates of disease-free survival, according to a study that followed patients for up to 10 years.
In 106 patients who had a total of 112 tumors and who were followed for a median 79 months, 10 recurrences were seen, after an initial procedural success rate of 97%.
Over a 6-year period, Kaplan-Meier disease-free survival (DFS) was 89%, and cancer-specific survival (CSS) was 96%. In the subgroup followed for 10 years, DFS was 82%, CSS was 94%, and overall survival (OS) was 49%.
Tumors were, on average, small (mean 2.5 cm), but for patients whose tumors were larger than 3 cm, the DFS rate fell to 68%. Patients were included in the study if they had a solitary renal mass; those who had metastatic renal cell carcinoma (RCC) or a hereditary kidney cancer syndrome were excluded.
Brett Johnson, MD, and his collaborators from the University of Texas Southwestern, Dallas, noted that an additional 29 patients received RFA but also had partial nephrectomy; these patients were excluded. “Healthier patients with larger tumors may have been advised to undergo partial nephrectomy, thereby selecting for more comorbid patients for RFA,” they noted in discussing their findings. The report was published in The Journal of Urology
Within these parameters, Dr. Johnson and his colleagues conducted a retrospective review of clinic patients whose renal tumors were successfully treated with RFA between the years 2000 and 2007. Patients were followed with yearly imaging, and were considered to have a recurrence if contrast enhancement was seen within the ablation zone at any point after a negative imaging study.
Of the 10 recurrences that were seen, eight were local and two were local and metastatic. An additional patient developed metastatic RCC without evidence of local recurrence; all patients with metastases died of their disease, said Dr. Johnson and his coauthors.
For patients whose tumors recurred, the mean initial tumor size was 3.2 cm, compared with 2.4 cm in those whose tumors didn’t recur (P = .005). Looking at the tumor size data another way, tumor size “was an independent risk factor for cancer recurrence,” with an odds ratio of 3.01 (P = .025), wrote Dr. Johnson and his collaborators.
They noted that it was not routine practice for biopsies to be performed during the initial study period; the seven patients with recurrences who had biopsy data all had clear cell RCC. Median time to local recurrence was 26 months, with no recurrences seen after 5 years.
At the time of the initial procedure, patients were a mean 63.1 years old. The relatively low OS in the subgroup with 10 years of follow-up was likely related to advancing age.
In the subgroup analysis of patients for whom 10-year data were available, the investigators used only data from patients whose initial tumors were biopsied when calculating CSS and metastasis-free survival; these rates were both 94% for those analyzed.
“Age, gender, and time of follow-up had no statistically significant effect on disease-free recurrence” in a univariate analysis, said Dr. Johnson and his colleagues.
“Nephron sparing surgery is the gold standard for treatment of small renal masses,” and the study bolsters the safety and durable efficacy of RFA by using actual survival data rather than actuarial disease survival, said the investigators.
The current study is unique in having such a long duration of follow-up and a subgroup of individuals with 10 years of annual imaging data. In addition, experienced urologists at a single site all used a uniform technique to perform thermal ablation on solitary tumors, noted Dr. Johnson and his coauthors. Successful ablations were followed only by surveillance, in keeping with current American Urological Association recommendations.
However, the study’s retrospective, nonrandomized nature introduces the possibility of selection bias, and variations in follow-up protocols may be a source of ascertainment bias, they said.
The authors reported no conflicts of interest and no outside sources of funding.
SOURCE: Johnson B et al. J Urol. 2018. doi:10.1016/j.juro.2018.08.045.
Radiofrequency ablation (RFA) of small renal tumors is safe and effective, and is associated with high rates of disease-free survival, according to a study that followed patients for up to 10 years.
In 106 patients who had a total of 112 tumors and who were followed for a median 79 months, 10 recurrences were seen, after an initial procedural success rate of 97%.
Over a 6-year period, Kaplan-Meier disease-free survival (DFS) was 89%, and cancer-specific survival (CSS) was 96%. In the subgroup followed for 10 years, DFS was 82%, CSS was 94%, and overall survival (OS) was 49%.
Tumors were, on average, small (mean 2.5 cm), but for patients whose tumors were larger than 3 cm, the DFS rate fell to 68%. Patients were included in the study if they had a solitary renal mass; those who had metastatic renal cell carcinoma (RCC) or a hereditary kidney cancer syndrome were excluded.
Brett Johnson, MD, and his collaborators from the University of Texas Southwestern, Dallas, noted that an additional 29 patients received RFA but also had partial nephrectomy; these patients were excluded. “Healthier patients with larger tumors may have been advised to undergo partial nephrectomy, thereby selecting for more comorbid patients for RFA,” they noted in discussing their findings. The report was published in The Journal of Urology
Within these parameters, Dr. Johnson and his colleagues conducted a retrospective review of clinic patients whose renal tumors were successfully treated with RFA between the years 2000 and 2007. Patients were followed with yearly imaging, and were considered to have a recurrence if contrast enhancement was seen within the ablation zone at any point after a negative imaging study.
Of the 10 recurrences that were seen, eight were local and two were local and metastatic. An additional patient developed metastatic RCC without evidence of local recurrence; all patients with metastases died of their disease, said Dr. Johnson and his coauthors.
For patients whose tumors recurred, the mean initial tumor size was 3.2 cm, compared with 2.4 cm in those whose tumors didn’t recur (P = .005). Looking at the tumor size data another way, tumor size “was an independent risk factor for cancer recurrence,” with an odds ratio of 3.01 (P = .025), wrote Dr. Johnson and his collaborators.
They noted that it was not routine practice for biopsies to be performed during the initial study period; the seven patients with recurrences who had biopsy data all had clear cell RCC. Median time to local recurrence was 26 months, with no recurrences seen after 5 years.
At the time of the initial procedure, patients were a mean 63.1 years old. The relatively low OS in the subgroup with 10 years of follow-up was likely related to advancing age.
In the subgroup analysis of patients for whom 10-year data were available, the investigators used only data from patients whose initial tumors were biopsied when calculating CSS and metastasis-free survival; these rates were both 94% for those analyzed.
“Age, gender, and time of follow-up had no statistically significant effect on disease-free recurrence” in a univariate analysis, said Dr. Johnson and his colleagues.
“Nephron sparing surgery is the gold standard for treatment of small renal masses,” and the study bolsters the safety and durable efficacy of RFA by using actual survival data rather than actuarial disease survival, said the investigators.
The current study is unique in having such a long duration of follow-up and a subgroup of individuals with 10 years of annual imaging data. In addition, experienced urologists at a single site all used a uniform technique to perform thermal ablation on solitary tumors, noted Dr. Johnson and his coauthors. Successful ablations were followed only by surveillance, in keeping with current American Urological Association recommendations.
However, the study’s retrospective, nonrandomized nature introduces the possibility of selection bias, and variations in follow-up protocols may be a source of ascertainment bias, they said.
The authors reported no conflicts of interest and no outside sources of funding.
SOURCE: Johnson B et al. J Urol. 2018. doi:10.1016/j.juro.2018.08.045.
Radiofrequency ablation (RFA) of small renal tumors is safe and effective, and is associated with high rates of disease-free survival, according to a study that followed patients for up to 10 years.
In 106 patients who had a total of 112 tumors and who were followed for a median 79 months, 10 recurrences were seen, after an initial procedural success rate of 97%.
Over a 6-year period, Kaplan-Meier disease-free survival (DFS) was 89%, and cancer-specific survival (CSS) was 96%. In the subgroup followed for 10 years, DFS was 82%, CSS was 94%, and overall survival (OS) was 49%.
Tumors were, on average, small (mean 2.5 cm), but for patients whose tumors were larger than 3 cm, the DFS rate fell to 68%. Patients were included in the study if they had a solitary renal mass; those who had metastatic renal cell carcinoma (RCC) or a hereditary kidney cancer syndrome were excluded.
Brett Johnson, MD, and his collaborators from the University of Texas Southwestern, Dallas, noted that an additional 29 patients received RFA but also had partial nephrectomy; these patients were excluded. “Healthier patients with larger tumors may have been advised to undergo partial nephrectomy, thereby selecting for more comorbid patients for RFA,” they noted in discussing their findings. The report was published in The Journal of Urology
Within these parameters, Dr. Johnson and his colleagues conducted a retrospective review of clinic patients whose renal tumors were successfully treated with RFA between the years 2000 and 2007. Patients were followed with yearly imaging, and were considered to have a recurrence if contrast enhancement was seen within the ablation zone at any point after a negative imaging study.
Of the 10 recurrences that were seen, eight were local and two were local and metastatic. An additional patient developed metastatic RCC without evidence of local recurrence; all patients with metastases died of their disease, said Dr. Johnson and his coauthors.
For patients whose tumors recurred, the mean initial tumor size was 3.2 cm, compared with 2.4 cm in those whose tumors didn’t recur (P = .005). Looking at the tumor size data another way, tumor size “was an independent risk factor for cancer recurrence,” with an odds ratio of 3.01 (P = .025), wrote Dr. Johnson and his collaborators.
They noted that it was not routine practice for biopsies to be performed during the initial study period; the seven patients with recurrences who had biopsy data all had clear cell RCC. Median time to local recurrence was 26 months, with no recurrences seen after 5 years.
At the time of the initial procedure, patients were a mean 63.1 years old. The relatively low OS in the subgroup with 10 years of follow-up was likely related to advancing age.
In the subgroup analysis of patients for whom 10-year data were available, the investigators used only data from patients whose initial tumors were biopsied when calculating CSS and metastasis-free survival; these rates were both 94% for those analyzed.
“Age, gender, and time of follow-up had no statistically significant effect on disease-free recurrence” in a univariate analysis, said Dr. Johnson and his colleagues.
“Nephron sparing surgery is the gold standard for treatment of small renal masses,” and the study bolsters the safety and durable efficacy of RFA by using actual survival data rather than actuarial disease survival, said the investigators.
The current study is unique in having such a long duration of follow-up and a subgroup of individuals with 10 years of annual imaging data. In addition, experienced urologists at a single site all used a uniform technique to perform thermal ablation on solitary tumors, noted Dr. Johnson and his coauthors. Successful ablations were followed only by surveillance, in keeping with current American Urological Association recommendations.
However, the study’s retrospective, nonrandomized nature introduces the possibility of selection bias, and variations in follow-up protocols may be a source of ascertainment bias, they said.
The authors reported no conflicts of interest and no outside sources of funding.
SOURCE: Johnson B et al. J Urol. 2018. doi:10.1016/j.juro.2018.08.045.
FROM THE JOURNAL OF UROLOGY
Key clinical point: Radiofrequency ablation of small renal tumors is safe and effective.
Major finding: In 106 patients with small renal masses, disease-free survival was 89% at 6 years post procedure.
Study details: Retrospective cohort study of 106 patients with 112 tumors, followed up to 10 years.
Disclosures: The authors reported no conflicts of interest and no outside sources of funding.
Source: Johnson B et al. J Urol. 2018. doi: 10.1016/j.juro.2018.08.045.
DEA moves Epidiolex to schedule V, clearing the way for marketing
Epidiolex, a cannabis-derived product approved earlier this year by the Food and Drug Administration for the treatment of childhood seizure syndromes, has been reclassified by the Drug Enforcement Administration. This paves the way for the manufacturer to begin marketing Epidiolex, which is expected to be on the market within 6 weeks.
GW Pharmaceuticals, in a Sept. 27 press release announcing the rescheduling of the company’s oral cannabidiol (CBD) solution, said that .
The final rescheduling order from the DEA is limited to drugs approved by the FDA that contain cannabis-derived CBD and no more than 0.1% tetrahydrocannabinols. In practice, this means that the rescheduling currently applies only to Epidiolex, since this is the only formulation of CBD that has received FDA approval.
“We are pleased that the DEA has placed Epidiolex in the lowest restriction schedule, because it will help ensure that patients with LGS [Lennox-Gastaut syndrome] and Dravet syndrome, two of the most debilitating forms of epilepsy, can access this important new treatment option through their physicians,” said GW Pharmaceutical’s chief executive officer Justin Gover in a statement from the company announcing the reclassification.
During the FDA advisory committee meeting for the approval of Epidiolex to treat LGS and Dravet syndromes, both the FDA and GW Pharmaceuticals assessed the abuse potential for CBD as very low, since it does not contain tetrahydrocannabinol, the primary psychoactive component of cannabis.
All other marijuana products are currently classified as schedule I drugs, along with such illegal substances as heroin and cocaine.
Epidiolex had received fast track and rare pediatric designations from the FDA for LGS and Dravet syndrome; the approval was based on three pivotal randomized, double-blind, placebo-controlled clinical trials. The drug met its primary endpoint of reduced seizure frequency in all trials when added to standard of care for patients with drug-resistant LGS and Dravet syndrome.
Safety evaluations assessed data from 1,756 patients, finding that the 20 deaths seen during the study period were not clearly linked to Epidiolex and not unexpected for children with severe seizure disorders.
In supplementary information accompanying the order, the DEA’s acting administrator, Uttam Dhillon, noted that the FDA’s approval of Epidiolex means that “it has a currently accepted medical use in treatment for purposes of the CSA [Controlled Substances Act]. Accordingly, Epidiolex no longer meets the criteria for placement in schedule I of the CSA.” Schedule I drugs, by definition, do not have a currently accepted medical use.
Schedule V drugs, according to the DEA’s website, are currently defined as “drugs with lower potential for abuse than schedule IV and consist of preparations containing limited quantities of certain narcotics.” Other schedule V drugs include cough medicine with less than 200 mg of codeine/100 mL, antidiarrheal medications, pregabalin (Lyrica), and the antiepileptics brivaracetam (Briviact) and lacosamide (Vimpat). “Schedule V drugs represents the least potential for abuse,” according to the website.
Epidiolex is indicated for adjunctive treatment of seizures in patients with LGS or Dravet syndrome aged 2 years and older. Initial dosing recommendations are to titrate to a dose of 10 mg/kg/day, with dose adjustments permissible up to 20 mg/kg/day depending on clinical response and tolerability. The manufacturer has also submitted a marketing agreement to the European Medicines Agency and has received orphan drug designation for Epidiolex in the treatment of another seizure disorder, tuberous sclerosis complex.
Epidiolex, a cannabis-derived product approved earlier this year by the Food and Drug Administration for the treatment of childhood seizure syndromes, has been reclassified by the Drug Enforcement Administration. This paves the way for the manufacturer to begin marketing Epidiolex, which is expected to be on the market within 6 weeks.
GW Pharmaceuticals, in a Sept. 27 press release announcing the rescheduling of the company’s oral cannabidiol (CBD) solution, said that .
The final rescheduling order from the DEA is limited to drugs approved by the FDA that contain cannabis-derived CBD and no more than 0.1% tetrahydrocannabinols. In practice, this means that the rescheduling currently applies only to Epidiolex, since this is the only formulation of CBD that has received FDA approval.
“We are pleased that the DEA has placed Epidiolex in the lowest restriction schedule, because it will help ensure that patients with LGS [Lennox-Gastaut syndrome] and Dravet syndrome, two of the most debilitating forms of epilepsy, can access this important new treatment option through their physicians,” said GW Pharmaceutical’s chief executive officer Justin Gover in a statement from the company announcing the reclassification.
During the FDA advisory committee meeting for the approval of Epidiolex to treat LGS and Dravet syndromes, both the FDA and GW Pharmaceuticals assessed the abuse potential for CBD as very low, since it does not contain tetrahydrocannabinol, the primary psychoactive component of cannabis.
All other marijuana products are currently classified as schedule I drugs, along with such illegal substances as heroin and cocaine.
Epidiolex had received fast track and rare pediatric designations from the FDA for LGS and Dravet syndrome; the approval was based on three pivotal randomized, double-blind, placebo-controlled clinical trials. The drug met its primary endpoint of reduced seizure frequency in all trials when added to standard of care for patients with drug-resistant LGS and Dravet syndrome.
Safety evaluations assessed data from 1,756 patients, finding that the 20 deaths seen during the study period were not clearly linked to Epidiolex and not unexpected for children with severe seizure disorders.
In supplementary information accompanying the order, the DEA’s acting administrator, Uttam Dhillon, noted that the FDA’s approval of Epidiolex means that “it has a currently accepted medical use in treatment for purposes of the CSA [Controlled Substances Act]. Accordingly, Epidiolex no longer meets the criteria for placement in schedule I of the CSA.” Schedule I drugs, by definition, do not have a currently accepted medical use.
Schedule V drugs, according to the DEA’s website, are currently defined as “drugs with lower potential for abuse than schedule IV and consist of preparations containing limited quantities of certain narcotics.” Other schedule V drugs include cough medicine with less than 200 mg of codeine/100 mL, antidiarrheal medications, pregabalin (Lyrica), and the antiepileptics brivaracetam (Briviact) and lacosamide (Vimpat). “Schedule V drugs represents the least potential for abuse,” according to the website.
Epidiolex is indicated for adjunctive treatment of seizures in patients with LGS or Dravet syndrome aged 2 years and older. Initial dosing recommendations are to titrate to a dose of 10 mg/kg/day, with dose adjustments permissible up to 20 mg/kg/day depending on clinical response and tolerability. The manufacturer has also submitted a marketing agreement to the European Medicines Agency and has received orphan drug designation for Epidiolex in the treatment of another seizure disorder, tuberous sclerosis complex.
Epidiolex, a cannabis-derived product approved earlier this year by the Food and Drug Administration for the treatment of childhood seizure syndromes, has been reclassified by the Drug Enforcement Administration. This paves the way for the manufacturer to begin marketing Epidiolex, which is expected to be on the market within 6 weeks.
GW Pharmaceuticals, in a Sept. 27 press release announcing the rescheduling of the company’s oral cannabidiol (CBD) solution, said that .
The final rescheduling order from the DEA is limited to drugs approved by the FDA that contain cannabis-derived CBD and no more than 0.1% tetrahydrocannabinols. In practice, this means that the rescheduling currently applies only to Epidiolex, since this is the only formulation of CBD that has received FDA approval.
“We are pleased that the DEA has placed Epidiolex in the lowest restriction schedule, because it will help ensure that patients with LGS [Lennox-Gastaut syndrome] and Dravet syndrome, two of the most debilitating forms of epilepsy, can access this important new treatment option through their physicians,” said GW Pharmaceutical’s chief executive officer Justin Gover in a statement from the company announcing the reclassification.
During the FDA advisory committee meeting for the approval of Epidiolex to treat LGS and Dravet syndromes, both the FDA and GW Pharmaceuticals assessed the abuse potential for CBD as very low, since it does not contain tetrahydrocannabinol, the primary psychoactive component of cannabis.
All other marijuana products are currently classified as schedule I drugs, along with such illegal substances as heroin and cocaine.
Epidiolex had received fast track and rare pediatric designations from the FDA for LGS and Dravet syndrome; the approval was based on three pivotal randomized, double-blind, placebo-controlled clinical trials. The drug met its primary endpoint of reduced seizure frequency in all trials when added to standard of care for patients with drug-resistant LGS and Dravet syndrome.
Safety evaluations assessed data from 1,756 patients, finding that the 20 deaths seen during the study period were not clearly linked to Epidiolex and not unexpected for children with severe seizure disorders.
In supplementary information accompanying the order, the DEA’s acting administrator, Uttam Dhillon, noted that the FDA’s approval of Epidiolex means that “it has a currently accepted medical use in treatment for purposes of the CSA [Controlled Substances Act]. Accordingly, Epidiolex no longer meets the criteria for placement in schedule I of the CSA.” Schedule I drugs, by definition, do not have a currently accepted medical use.
Schedule V drugs, according to the DEA’s website, are currently defined as “drugs with lower potential for abuse than schedule IV and consist of preparations containing limited quantities of certain narcotics.” Other schedule V drugs include cough medicine with less than 200 mg of codeine/100 mL, antidiarrheal medications, pregabalin (Lyrica), and the antiepileptics brivaracetam (Briviact) and lacosamide (Vimpat). “Schedule V drugs represents the least potential for abuse,” according to the website.
Epidiolex is indicated for adjunctive treatment of seizures in patients with LGS or Dravet syndrome aged 2 years and older. Initial dosing recommendations are to titrate to a dose of 10 mg/kg/day, with dose adjustments permissible up to 20 mg/kg/day depending on clinical response and tolerability. The manufacturer has also submitted a marketing agreement to the European Medicines Agency and has received orphan drug designation for Epidiolex in the treatment of another seizure disorder, tuberous sclerosis complex.
