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Panel votes against universal blood donor screens for Zika virus
SILVER SPRING, MD – Universal testing of individual blood donations for the presence of Zika virus was unanimously rejected by voting members of the Food and Drug Administration’s Blood Products Advisory Committee at a December 1 meeting.
Universal individual donor testing, while comprehensive, is resource intensive and places a burden on the blood system that is not outweighed by the benefits, 10 of the 11 committee members concluded. The other committee member could not be reached by phone for this vote.
The committee instead recommended by a vote of 10 to 1 that mini-pool nucleic acid testing (MP-NAT) be performed in all states and territories with known cases of Zika virus infection and the presence of A. aegypti mosquitoes, as well as in states and territories with a high number of travelers from areas with Zika virus infections. Also, the committee members agreed that a trigger needs to be defined for when to undertake universal individual donor nucleic acid testing (ID-NAT) in those areas.
Additionally, the committee agreed that it was not necessary to maintain a Zika virus-negative blood inventory for at-risk patients, such as pregnant women and newborns. Zika virus, a vector-borne disease carried by the Aedes aegypti and Aedes albopictus mosquitoes, has also been transmitted via sexual contact and blood transfusion. Infection has been linked to fetal loss and microcephaly in the offspring of infected pregnant women. Other neurological disorders, including Guillain-Barré Syndrome, also have been linked to Zika virus infection.
Noting the complexity of managing an inventory of tested and non-tested blood, the committee rejected the separate inventory approach by a vote of 9 to 2.*
The panel was clearly divided on the possibility of eliminating all Zika virus testing in some states and territories; 5 members supported this measure, 4 opposed it, and 2 abstained from voting.
The panel unanimously rejected using screening questionnaires to determine whether to selectively test individual at-risk donors in areas with active vector-borne Zika virus infections. This option was considered particularly troublesome, they agreed, because it relies on the use of nonspecific, insensitive, and error-prone questionnaires.
Some level of Zika virus testing is needed to safeguard blood products, the committee said. Eliminating all Zika virus testing of blood products would open the door for infections via transfusion and would diminish preparedness against a potential epidemic, they unanimously determined.
Prior to voting, the committee listened to presentations on the epidemiology of Zika virus infections, the effectiveness of screening tests, and the risk for transmission via transfusion.
Carolyn Gould, MD, of the Centers for Disease Control and Prevention, Atlanta, reported that the number of laboratory-confirmed Zika virus infections in 2016 was 4,830 for travelers to endemic areas and 224 for locally-acquired cases. In 2017, those numbers dropped to 344 confirmed cases for travelers and 2 for locally-acquired cases.
More than 4 million blood donations in the United States and Puerto Rico have been screened for Zika virus RNA using the cobas assay, which is now FDA approved. The overall confirmed positive rate of Zika virus is 0.0007% in donations from the continental United States (29 positive results in 4,341,770 donations) and 0.326% in donations from Puerto Rico (356 out of 111,808 donations) based on data obtained from May 23, 2016 to October 7, 2017, according to Tony Hardiman, Blood Screening, Life Cycle Leader at Roche Molecular Systems.
Of the Zika virus-positive donors who were available for follow up, 23 of 27 had traveled to Zika-active areas, including 3 cases associated with domestic travel to Florida. “I was surprised that 4 of the 29 were from Cuba, but it does seem, as we just saw, (that) an increasing number are coming out from Cuba, from travel to Cuba,” Mr. Hardiman said during his presentation to the committee.
Findings concerning viral RNA duration in blood and other body fluids were presented by Michael Busch, MD of the University of California, San Francisco, who spoke during the public hearing portion of the meeting.**
According to Dr. Busch, blood is likely not infectious to others once donors develop Zika virus-neutralizing antibodies and their viral load levels become very low.
Based on his review of various studies, Dr. Busch concluded that mini-pool testing options with triggers for individual testing are appropriate and effective for detecting Zika virus in endemic areas.
“In Puerto Rico, within a day of picking up a mini-pool positive [result}, we would have ID-NAT in place,” Dr. Busch said. “The mini-pool testing is picking up 90% of those at highest risk.”
The committee recommendations serve as guidance to the FDA, which is not obligated to follow the committee’s recommendations.
*Correction 12/14/17: An earlier version of this story misstated the vote on maintaining a Zika virus-negative blood inventory for at-risk patients. The advisory committee voted against that approach.
**Correction 12/14/17: Dr. Michael Busch's name was misstated in an earlier version of this article.
SILVER SPRING, MD – Universal testing of individual blood donations for the presence of Zika virus was unanimously rejected by voting members of the Food and Drug Administration’s Blood Products Advisory Committee at a December 1 meeting.
Universal individual donor testing, while comprehensive, is resource intensive and places a burden on the blood system that is not outweighed by the benefits, 10 of the 11 committee members concluded. The other committee member could not be reached by phone for this vote.
The committee instead recommended by a vote of 10 to 1 that mini-pool nucleic acid testing (MP-NAT) be performed in all states and territories with known cases of Zika virus infection and the presence of A. aegypti mosquitoes, as well as in states and territories with a high number of travelers from areas with Zika virus infections. Also, the committee members agreed that a trigger needs to be defined for when to undertake universal individual donor nucleic acid testing (ID-NAT) in those areas.
Additionally, the committee agreed that it was not necessary to maintain a Zika virus-negative blood inventory for at-risk patients, such as pregnant women and newborns. Zika virus, a vector-borne disease carried by the Aedes aegypti and Aedes albopictus mosquitoes, has also been transmitted via sexual contact and blood transfusion. Infection has been linked to fetal loss and microcephaly in the offspring of infected pregnant women. Other neurological disorders, including Guillain-Barré Syndrome, also have been linked to Zika virus infection.
Noting the complexity of managing an inventory of tested and non-tested blood, the committee rejected the separate inventory approach by a vote of 9 to 2.*
The panel was clearly divided on the possibility of eliminating all Zika virus testing in some states and territories; 5 members supported this measure, 4 opposed it, and 2 abstained from voting.
The panel unanimously rejected using screening questionnaires to determine whether to selectively test individual at-risk donors in areas with active vector-borne Zika virus infections. This option was considered particularly troublesome, they agreed, because it relies on the use of nonspecific, insensitive, and error-prone questionnaires.
Some level of Zika virus testing is needed to safeguard blood products, the committee said. Eliminating all Zika virus testing of blood products would open the door for infections via transfusion and would diminish preparedness against a potential epidemic, they unanimously determined.
Prior to voting, the committee listened to presentations on the epidemiology of Zika virus infections, the effectiveness of screening tests, and the risk for transmission via transfusion.
Carolyn Gould, MD, of the Centers for Disease Control and Prevention, Atlanta, reported that the number of laboratory-confirmed Zika virus infections in 2016 was 4,830 for travelers to endemic areas and 224 for locally-acquired cases. In 2017, those numbers dropped to 344 confirmed cases for travelers and 2 for locally-acquired cases.
More than 4 million blood donations in the United States and Puerto Rico have been screened for Zika virus RNA using the cobas assay, which is now FDA approved. The overall confirmed positive rate of Zika virus is 0.0007% in donations from the continental United States (29 positive results in 4,341,770 donations) and 0.326% in donations from Puerto Rico (356 out of 111,808 donations) based on data obtained from May 23, 2016 to October 7, 2017, according to Tony Hardiman, Blood Screening, Life Cycle Leader at Roche Molecular Systems.
Of the Zika virus-positive donors who were available for follow up, 23 of 27 had traveled to Zika-active areas, including 3 cases associated with domestic travel to Florida. “I was surprised that 4 of the 29 were from Cuba, but it does seem, as we just saw, (that) an increasing number are coming out from Cuba, from travel to Cuba,” Mr. Hardiman said during his presentation to the committee.
Findings concerning viral RNA duration in blood and other body fluids were presented by Michael Busch, MD of the University of California, San Francisco, who spoke during the public hearing portion of the meeting.**
According to Dr. Busch, blood is likely not infectious to others once donors develop Zika virus-neutralizing antibodies and their viral load levels become very low.
Based on his review of various studies, Dr. Busch concluded that mini-pool testing options with triggers for individual testing are appropriate and effective for detecting Zika virus in endemic areas.
“In Puerto Rico, within a day of picking up a mini-pool positive [result}, we would have ID-NAT in place,” Dr. Busch said. “The mini-pool testing is picking up 90% of those at highest risk.”
The committee recommendations serve as guidance to the FDA, which is not obligated to follow the committee’s recommendations.
*Correction 12/14/17: An earlier version of this story misstated the vote on maintaining a Zika virus-negative blood inventory for at-risk patients. The advisory committee voted against that approach.
**Correction 12/14/17: Dr. Michael Busch's name was misstated in an earlier version of this article.
SILVER SPRING, MD – Universal testing of individual blood donations for the presence of Zika virus was unanimously rejected by voting members of the Food and Drug Administration’s Blood Products Advisory Committee at a December 1 meeting.
Universal individual donor testing, while comprehensive, is resource intensive and places a burden on the blood system that is not outweighed by the benefits, 10 of the 11 committee members concluded. The other committee member could not be reached by phone for this vote.
The committee instead recommended by a vote of 10 to 1 that mini-pool nucleic acid testing (MP-NAT) be performed in all states and territories with known cases of Zika virus infection and the presence of A. aegypti mosquitoes, as well as in states and territories with a high number of travelers from areas with Zika virus infections. Also, the committee members agreed that a trigger needs to be defined for when to undertake universal individual donor nucleic acid testing (ID-NAT) in those areas.
Additionally, the committee agreed that it was not necessary to maintain a Zika virus-negative blood inventory for at-risk patients, such as pregnant women and newborns. Zika virus, a vector-borne disease carried by the Aedes aegypti and Aedes albopictus mosquitoes, has also been transmitted via sexual contact and blood transfusion. Infection has been linked to fetal loss and microcephaly in the offspring of infected pregnant women. Other neurological disorders, including Guillain-Barré Syndrome, also have been linked to Zika virus infection.
Noting the complexity of managing an inventory of tested and non-tested blood, the committee rejected the separate inventory approach by a vote of 9 to 2.*
The panel was clearly divided on the possibility of eliminating all Zika virus testing in some states and territories; 5 members supported this measure, 4 opposed it, and 2 abstained from voting.
The panel unanimously rejected using screening questionnaires to determine whether to selectively test individual at-risk donors in areas with active vector-borne Zika virus infections. This option was considered particularly troublesome, they agreed, because it relies on the use of nonspecific, insensitive, and error-prone questionnaires.
Some level of Zika virus testing is needed to safeguard blood products, the committee said. Eliminating all Zika virus testing of blood products would open the door for infections via transfusion and would diminish preparedness against a potential epidemic, they unanimously determined.
Prior to voting, the committee listened to presentations on the epidemiology of Zika virus infections, the effectiveness of screening tests, and the risk for transmission via transfusion.
Carolyn Gould, MD, of the Centers for Disease Control and Prevention, Atlanta, reported that the number of laboratory-confirmed Zika virus infections in 2016 was 4,830 for travelers to endemic areas and 224 for locally-acquired cases. In 2017, those numbers dropped to 344 confirmed cases for travelers and 2 for locally-acquired cases.
More than 4 million blood donations in the United States and Puerto Rico have been screened for Zika virus RNA using the cobas assay, which is now FDA approved. The overall confirmed positive rate of Zika virus is 0.0007% in donations from the continental United States (29 positive results in 4,341,770 donations) and 0.326% in donations from Puerto Rico (356 out of 111,808 donations) based on data obtained from May 23, 2016 to October 7, 2017, according to Tony Hardiman, Blood Screening, Life Cycle Leader at Roche Molecular Systems.
Of the Zika virus-positive donors who were available for follow up, 23 of 27 had traveled to Zika-active areas, including 3 cases associated with domestic travel to Florida. “I was surprised that 4 of the 29 were from Cuba, but it does seem, as we just saw, (that) an increasing number are coming out from Cuba, from travel to Cuba,” Mr. Hardiman said during his presentation to the committee.
Findings concerning viral RNA duration in blood and other body fluids were presented by Michael Busch, MD of the University of California, San Francisco, who spoke during the public hearing portion of the meeting.**
According to Dr. Busch, blood is likely not infectious to others once donors develop Zika virus-neutralizing antibodies and their viral load levels become very low.
Based on his review of various studies, Dr. Busch concluded that mini-pool testing options with triggers for individual testing are appropriate and effective for detecting Zika virus in endemic areas.
“In Puerto Rico, within a day of picking up a mini-pool positive [result}, we would have ID-NAT in place,” Dr. Busch said. “The mini-pool testing is picking up 90% of those at highest risk.”
The committee recommendations serve as guidance to the FDA, which is not obligated to follow the committee’s recommendations.
*Correction 12/14/17: An earlier version of this story misstated the vote on maintaining a Zika virus-negative blood inventory for at-risk patients. The advisory committee voted against that approach.
**Correction 12/14/17: Dr. Michael Busch's name was misstated in an earlier version of this article.
AT AN FDA ADVISORY COMMITTEE MEETING
Walking has beneficial cognitive effects in amyloid-positive older adults
BOSTON – Walking appears to moderate cognitive decline in people with elevated brain amyloid, a 4-year observational study has determined.
Among a group of cognitively normal older adults with beta-amyloid brain plaques, those who walked the most experienced significantly less decline in memory and thinking than those who didn’t walk much, Dylan Kirn reported at the Clinical Trials on Alzheimer’s Disease conference. Walking didn’t affect any of the hallmark biomarkers of Alzheimer’s disease, such as brain glucose utilization, amyloid accumulation, or hippocampal volume, but it was associated with significantly better cognitive scores on a composite measure of memory over time.
“We should be careful in interpreting these data, because this is an observational cohort and we can’t make claims regarding causality or the mechanism by which physical activity may be influencing cognitive decline,” said Mr. Kirn of the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, Boston. “But I find these results interesting and novel, and I think they support further investigation.”
The walking study comprised 255 subjects with a mean age of 73 years. They were highly educated, with a mean of 16 years’ schooling. About 24% were amyloid-positive by PET imaging. All were cognitively normal, with a Clinical Dementia Rating scale score of 0. Activity was established at baseline with a pedometer, which was worn for 7 consecutive days; only those who walked at least 100 steps per day were included in the analysis.
In addition to amyloid PET imaging, subjects also underwent a 18F-fluorodeoxyglucose (FDG) PET scan to assess brain glucose utilization, and MRI to measure hippocampal volume changes and assess white matter hyperintensities (WMHs). Changes in all of these biomarkers can herald the onset of Alzheimer’s.
The primary outcome was the relationship between physical activity as measured by number of walking steps per day and changes on the Preclinical Alzheimer’s Cognitive Composite (PACC) test. This relatively new cognitive scale is an increasingly popular item in clinical trials. The PACC is a composite of the Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale–Revised, the Mini Mental State Exam, the Total Recall score from the Free and Cued Selective Reminding Test, and the Delayed Recall score on the Logical Memory IIa sub-test from the Wechsler Memory Scale. It correlates well with amyloid accumulation in the brain, Mr. Kirn said.
The cohort was followed for up to 6 years (median of 4), and PACC scores were calculated annually. The investigators looked at the relationship between walking at baseline and PACC decline over the study period in two multivariate models: One controlling for age, sex, and years of education, and the second for those variables plus the biomarkers of cortical WMHs, bilateral hippocampal volume (HV), and FDG-PET in brain regions typically affected by Alzheimer’s.
Physical activity was divided into tertiles by the average number of steps per day over the 7-day measuring period: Mean (5,616 steps), one standard deviation above mean (high; 8,482 steps), and one standard deviation below mean (low, 2,751 steps). Amyloid-positive patients were further divided into those with high brain amyloid load and those with low amyloid brain load.
There were no significant relationships between any of the biomarkers and any level of physical activity in either of the analyses, Mr. Kirn said. However, when looking at the time-linked changes in the PACC, significant differences did emerge. Subjects who walked at least the mean number of steps per day were much more likely to maintain a stable cognitive score, while those who walked the fewest steps declined about a quarter of a point on the PACC. The difference in decline between the high activity and low activity subjects was statistically significant, even when the investigators controlled for amyloid burden and the other hallmark Alzheimer’s biomarkers.
The level of physical activity at baseline was a particularly strong predictor of cognitive health among amyloid-positive subjects. Those in the high-activity group maintained a steady score on the PACC. Those in the mean activity group declined slightly, and those in the low activity group showed a sharp decline, losing almost a full point on the PACC by the end of follow-up.
In the amyloid-negative group, there was no association between cognition and activity. All the groups improved their PACC scores over the study period, probably reflecting a practice effect, Mr. Kirn said.
Finally, he split the amyloid-positive group into subjects with low and high brain amyloid levels. “We observed that physical activity was significantly predictive of cognitive decline in high-amyloid participants, but not in low-amyloid participants,” he said. “Individuals with high amyloid and low physical activity at baseline had the steepest decline in cognition over time. But in those with high amyloid and high physical activity at baseline, we didn’t see a tremendous amount of decline.”
The study suggests that pedometers may have a place in stratifying patients for clinical trials, or assessing cognitive risk in elderly subjects. “Most studies that have looked at physical activity and dementia use a self-reported activity level, so the results have been varied,” Mr. Kirn said. “These findings support consideration of objectively measured physical activity in clinical research, and perhaps in stratification for risk of cognitive decline.”
He had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
BOSTON – Walking appears to moderate cognitive decline in people with elevated brain amyloid, a 4-year observational study has determined.
Among a group of cognitively normal older adults with beta-amyloid brain plaques, those who walked the most experienced significantly less decline in memory and thinking than those who didn’t walk much, Dylan Kirn reported at the Clinical Trials on Alzheimer’s Disease conference. Walking didn’t affect any of the hallmark biomarkers of Alzheimer’s disease, such as brain glucose utilization, amyloid accumulation, or hippocampal volume, but it was associated with significantly better cognitive scores on a composite measure of memory over time.
“We should be careful in interpreting these data, because this is an observational cohort and we can’t make claims regarding causality or the mechanism by which physical activity may be influencing cognitive decline,” said Mr. Kirn of the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, Boston. “But I find these results interesting and novel, and I think they support further investigation.”
The walking study comprised 255 subjects with a mean age of 73 years. They were highly educated, with a mean of 16 years’ schooling. About 24% were amyloid-positive by PET imaging. All were cognitively normal, with a Clinical Dementia Rating scale score of 0. Activity was established at baseline with a pedometer, which was worn for 7 consecutive days; only those who walked at least 100 steps per day were included in the analysis.
In addition to amyloid PET imaging, subjects also underwent a 18F-fluorodeoxyglucose (FDG) PET scan to assess brain glucose utilization, and MRI to measure hippocampal volume changes and assess white matter hyperintensities (WMHs). Changes in all of these biomarkers can herald the onset of Alzheimer’s.
The primary outcome was the relationship between physical activity as measured by number of walking steps per day and changes on the Preclinical Alzheimer’s Cognitive Composite (PACC) test. This relatively new cognitive scale is an increasingly popular item in clinical trials. The PACC is a composite of the Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale–Revised, the Mini Mental State Exam, the Total Recall score from the Free and Cued Selective Reminding Test, and the Delayed Recall score on the Logical Memory IIa sub-test from the Wechsler Memory Scale. It correlates well with amyloid accumulation in the brain, Mr. Kirn said.
The cohort was followed for up to 6 years (median of 4), and PACC scores were calculated annually. The investigators looked at the relationship between walking at baseline and PACC decline over the study period in two multivariate models: One controlling for age, sex, and years of education, and the second for those variables plus the biomarkers of cortical WMHs, bilateral hippocampal volume (HV), and FDG-PET in brain regions typically affected by Alzheimer’s.
Physical activity was divided into tertiles by the average number of steps per day over the 7-day measuring period: Mean (5,616 steps), one standard deviation above mean (high; 8,482 steps), and one standard deviation below mean (low, 2,751 steps). Amyloid-positive patients were further divided into those with high brain amyloid load and those with low amyloid brain load.
There were no significant relationships between any of the biomarkers and any level of physical activity in either of the analyses, Mr. Kirn said. However, when looking at the time-linked changes in the PACC, significant differences did emerge. Subjects who walked at least the mean number of steps per day were much more likely to maintain a stable cognitive score, while those who walked the fewest steps declined about a quarter of a point on the PACC. The difference in decline between the high activity and low activity subjects was statistically significant, even when the investigators controlled for amyloid burden and the other hallmark Alzheimer’s biomarkers.
The level of physical activity at baseline was a particularly strong predictor of cognitive health among amyloid-positive subjects. Those in the high-activity group maintained a steady score on the PACC. Those in the mean activity group declined slightly, and those in the low activity group showed a sharp decline, losing almost a full point on the PACC by the end of follow-up.
In the amyloid-negative group, there was no association between cognition and activity. All the groups improved their PACC scores over the study period, probably reflecting a practice effect, Mr. Kirn said.
Finally, he split the amyloid-positive group into subjects with low and high brain amyloid levels. “We observed that physical activity was significantly predictive of cognitive decline in high-amyloid participants, but not in low-amyloid participants,” he said. “Individuals with high amyloid and low physical activity at baseline had the steepest decline in cognition over time. But in those with high amyloid and high physical activity at baseline, we didn’t see a tremendous amount of decline.”
The study suggests that pedometers may have a place in stratifying patients for clinical trials, or assessing cognitive risk in elderly subjects. “Most studies that have looked at physical activity and dementia use a self-reported activity level, so the results have been varied,” Mr. Kirn said. “These findings support consideration of objectively measured physical activity in clinical research, and perhaps in stratification for risk of cognitive decline.”
He had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
BOSTON – Walking appears to moderate cognitive decline in people with elevated brain amyloid, a 4-year observational study has determined.
Among a group of cognitively normal older adults with beta-amyloid brain plaques, those who walked the most experienced significantly less decline in memory and thinking than those who didn’t walk much, Dylan Kirn reported at the Clinical Trials on Alzheimer’s Disease conference. Walking didn’t affect any of the hallmark biomarkers of Alzheimer’s disease, such as brain glucose utilization, amyloid accumulation, or hippocampal volume, but it was associated with significantly better cognitive scores on a composite measure of memory over time.
“We should be careful in interpreting these data, because this is an observational cohort and we can’t make claims regarding causality or the mechanism by which physical activity may be influencing cognitive decline,” said Mr. Kirn of the Athinoula A. Martinos Center for Biomedical Imaging at Massachusetts General Hospital, Boston. “But I find these results interesting and novel, and I think they support further investigation.”
The walking study comprised 255 subjects with a mean age of 73 years. They were highly educated, with a mean of 16 years’ schooling. About 24% were amyloid-positive by PET imaging. All were cognitively normal, with a Clinical Dementia Rating scale score of 0. Activity was established at baseline with a pedometer, which was worn for 7 consecutive days; only those who walked at least 100 steps per day were included in the analysis.
In addition to amyloid PET imaging, subjects also underwent a 18F-fluorodeoxyglucose (FDG) PET scan to assess brain glucose utilization, and MRI to measure hippocampal volume changes and assess white matter hyperintensities (WMHs). Changes in all of these biomarkers can herald the onset of Alzheimer’s.
The primary outcome was the relationship between physical activity as measured by number of walking steps per day and changes on the Preclinical Alzheimer’s Cognitive Composite (PACC) test. This relatively new cognitive scale is an increasingly popular item in clinical trials. The PACC is a composite of the Digit Symbol Substitution Test score from the Wechsler Adult Intelligence Scale–Revised, the Mini Mental State Exam, the Total Recall score from the Free and Cued Selective Reminding Test, and the Delayed Recall score on the Logical Memory IIa sub-test from the Wechsler Memory Scale. It correlates well with amyloid accumulation in the brain, Mr. Kirn said.
The cohort was followed for up to 6 years (median of 4), and PACC scores were calculated annually. The investigators looked at the relationship between walking at baseline and PACC decline over the study period in two multivariate models: One controlling for age, sex, and years of education, and the second for those variables plus the biomarkers of cortical WMHs, bilateral hippocampal volume (HV), and FDG-PET in brain regions typically affected by Alzheimer’s.
Physical activity was divided into tertiles by the average number of steps per day over the 7-day measuring period: Mean (5,616 steps), one standard deviation above mean (high; 8,482 steps), and one standard deviation below mean (low, 2,751 steps). Amyloid-positive patients were further divided into those with high brain amyloid load and those with low amyloid brain load.
There were no significant relationships between any of the biomarkers and any level of physical activity in either of the analyses, Mr. Kirn said. However, when looking at the time-linked changes in the PACC, significant differences did emerge. Subjects who walked at least the mean number of steps per day were much more likely to maintain a stable cognitive score, while those who walked the fewest steps declined about a quarter of a point on the PACC. The difference in decline between the high activity and low activity subjects was statistically significant, even when the investigators controlled for amyloid burden and the other hallmark Alzheimer’s biomarkers.
The level of physical activity at baseline was a particularly strong predictor of cognitive health among amyloid-positive subjects. Those in the high-activity group maintained a steady score on the PACC. Those in the mean activity group declined slightly, and those in the low activity group showed a sharp decline, losing almost a full point on the PACC by the end of follow-up.
In the amyloid-negative group, there was no association between cognition and activity. All the groups improved their PACC scores over the study period, probably reflecting a practice effect, Mr. Kirn said.
Finally, he split the amyloid-positive group into subjects with low and high brain amyloid levels. “We observed that physical activity was significantly predictive of cognitive decline in high-amyloid participants, but not in low-amyloid participants,” he said. “Individuals with high amyloid and low physical activity at baseline had the steepest decline in cognition over time. But in those with high amyloid and high physical activity at baseline, we didn’t see a tremendous amount of decline.”
The study suggests that pedometers may have a place in stratifying patients for clinical trials, or assessing cognitive risk in elderly subjects. “Most studies that have looked at physical activity and dementia use a self-reported activity level, so the results have been varied,” Mr. Kirn said. “These findings support consideration of objectively measured physical activity in clinical research, and perhaps in stratification for risk of cognitive decline.”
He had no financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @Alz_Gal
AT CTAD
Key clinical point:
Major finding: Subjects with high amyloid burden who walked the least declined by almost 1 point on the PACC score; high-amyloid subjects who walked the most stayed at their baseline score.
Data source: A prospective, observational study comprising 255 elderly subjects with normal cognition.
Disclosures: The presenter had no financial disclosures.
Benefit of dabigatran over warfarin persists in AF patient subgroups undergoing PCI
ANAHEIM, CALIF. – The benefit of dabigatran dual therapy versus warfarin triple therapy after percutaneous coronary intervention in patients with atrial fibrillation was consistent whether patients had drug-eluting or bare-metal stents, concomitant treatment with ticagrelor or clopidogrel, or acute coronary syndrome or stable disease as the indication for PCI, according to a subgroup analysis of the RE-DUAL PCI trial.
The trial, presented at the American Heart Association scientific sessions, randomized 2,725 patients to triple therapy with warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin – the triple therapy group – or dabigatran 110 mg or 150 mg twice daily plus clopidogrel or ticagrelor – the dual therapy groups (N Engl J Med. 2017 Oct 19;377[16]:1513-24).
After a mean follow-up 14 months, the incidence of the major or clinically relevant nonmajor bleeding was 15.4% in the 110-mg dual-therapy group (hazard ratio, 0.52; 95% CI, 0.42-0.63; P less than .001) and 20.2% in the 150-mg dual-therapy group (HR, 0.72; 95% CI, 0.58-0.88; P less than .001), versus about 26% with triple-therapy.
The incidence of the composite efficacy endpoint – death, unplanned revascularization, myocardial infarction, stroke, or systemic embolism – was 13.7% in the two dual-therapy groups versus 13.4% with triple-therapy (HR, 1.04; 95% CI, 0.84-1.29; P = .005).
The investigators found consistent results when they analyzed their prespecified subgroups.
Drug-eluting stents were placed in 83% of patients; the rest had bare metal stents (BMS). The groups were well-balanced, except BMS patients were again more likely to be new to oral anticoagulation. Bleeding, thromboembolic events, and mortality were consistent with the main results regardless of the stent type, Most of the subjects were on clopidogrel, with just 12% on ticagrelor in both the dabigatran and warfarin groups. Ticagrelor patients were more likely to have ACS as their PCI indication and be new to oral anticoagulation. Ticagrelor patients were also more clinically complex, with a higher bleeding risk. Even so, they had relative bleeding risk reduction and efficacy results with dabigatran that were consistent with the overall finding, Dr. Oldgren said.
Patients were eligible for RE-DUAL PCI (Evaluation of Dual Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with AF That Undergo a PCI with Stenting) if they had nonvalvular atrial fibrillation and a successful PCI within 120 hours. Those with bioprosthetic or mechanical heart valves, severe renal insufficiency, or other major comorbidities were excluded.
The trial was funded by Boehringer Ingelheim, the maker of dabigatran. Several investigators were employees. Dr. Oldgren is an adviser to Boehringer Ingelheim. Other authors reported financial ties to the company as well.
ANAHEIM, CALIF. – The benefit of dabigatran dual therapy versus warfarin triple therapy after percutaneous coronary intervention in patients with atrial fibrillation was consistent whether patients had drug-eluting or bare-metal stents, concomitant treatment with ticagrelor or clopidogrel, or acute coronary syndrome or stable disease as the indication for PCI, according to a subgroup analysis of the RE-DUAL PCI trial.
The trial, presented at the American Heart Association scientific sessions, randomized 2,725 patients to triple therapy with warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin – the triple therapy group – or dabigatran 110 mg or 150 mg twice daily plus clopidogrel or ticagrelor – the dual therapy groups (N Engl J Med. 2017 Oct 19;377[16]:1513-24).
After a mean follow-up 14 months, the incidence of the major or clinically relevant nonmajor bleeding was 15.4% in the 110-mg dual-therapy group (hazard ratio, 0.52; 95% CI, 0.42-0.63; P less than .001) and 20.2% in the 150-mg dual-therapy group (HR, 0.72; 95% CI, 0.58-0.88; P less than .001), versus about 26% with triple-therapy.
The incidence of the composite efficacy endpoint – death, unplanned revascularization, myocardial infarction, stroke, or systemic embolism – was 13.7% in the two dual-therapy groups versus 13.4% with triple-therapy (HR, 1.04; 95% CI, 0.84-1.29; P = .005).
The investigators found consistent results when they analyzed their prespecified subgroups.
Drug-eluting stents were placed in 83% of patients; the rest had bare metal stents (BMS). The groups were well-balanced, except BMS patients were again more likely to be new to oral anticoagulation. Bleeding, thromboembolic events, and mortality were consistent with the main results regardless of the stent type, Most of the subjects were on clopidogrel, with just 12% on ticagrelor in both the dabigatran and warfarin groups. Ticagrelor patients were more likely to have ACS as their PCI indication and be new to oral anticoagulation. Ticagrelor patients were also more clinically complex, with a higher bleeding risk. Even so, they had relative bleeding risk reduction and efficacy results with dabigatran that were consistent with the overall finding, Dr. Oldgren said.
Patients were eligible for RE-DUAL PCI (Evaluation of Dual Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with AF That Undergo a PCI with Stenting) if they had nonvalvular atrial fibrillation and a successful PCI within 120 hours. Those with bioprosthetic or mechanical heart valves, severe renal insufficiency, or other major comorbidities were excluded.
The trial was funded by Boehringer Ingelheim, the maker of dabigatran. Several investigators were employees. Dr. Oldgren is an adviser to Boehringer Ingelheim. Other authors reported financial ties to the company as well.
ANAHEIM, CALIF. – The benefit of dabigatran dual therapy versus warfarin triple therapy after percutaneous coronary intervention in patients with atrial fibrillation was consistent whether patients had drug-eluting or bare-metal stents, concomitant treatment with ticagrelor or clopidogrel, or acute coronary syndrome or stable disease as the indication for PCI, according to a subgroup analysis of the RE-DUAL PCI trial.
The trial, presented at the American Heart Association scientific sessions, randomized 2,725 patients to triple therapy with warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin – the triple therapy group – or dabigatran 110 mg or 150 mg twice daily plus clopidogrel or ticagrelor – the dual therapy groups (N Engl J Med. 2017 Oct 19;377[16]:1513-24).
After a mean follow-up 14 months, the incidence of the major or clinically relevant nonmajor bleeding was 15.4% in the 110-mg dual-therapy group (hazard ratio, 0.52; 95% CI, 0.42-0.63; P less than .001) and 20.2% in the 150-mg dual-therapy group (HR, 0.72; 95% CI, 0.58-0.88; P less than .001), versus about 26% with triple-therapy.
The incidence of the composite efficacy endpoint – death, unplanned revascularization, myocardial infarction, stroke, or systemic embolism – was 13.7% in the two dual-therapy groups versus 13.4% with triple-therapy (HR, 1.04; 95% CI, 0.84-1.29; P = .005).
The investigators found consistent results when they analyzed their prespecified subgroups.
Drug-eluting stents were placed in 83% of patients; the rest had bare metal stents (BMS). The groups were well-balanced, except BMS patients were again more likely to be new to oral anticoagulation. Bleeding, thromboembolic events, and mortality were consistent with the main results regardless of the stent type, Most of the subjects were on clopidogrel, with just 12% on ticagrelor in both the dabigatran and warfarin groups. Ticagrelor patients were more likely to have ACS as their PCI indication and be new to oral anticoagulation. Ticagrelor patients were also more clinically complex, with a higher bleeding risk. Even so, they had relative bleeding risk reduction and efficacy results with dabigatran that were consistent with the overall finding, Dr. Oldgren said.
Patients were eligible for RE-DUAL PCI (Evaluation of Dual Therapy with Dabigatran vs. Triple Therapy with Warfarin in Patients with AF That Undergo a PCI with Stenting) if they had nonvalvular atrial fibrillation and a successful PCI within 120 hours. Those with bioprosthetic or mechanical heart valves, severe renal insufficiency, or other major comorbidities were excluded.
The trial was funded by Boehringer Ingelheim, the maker of dabigatran. Several investigators were employees. Dr. Oldgren is an adviser to Boehringer Ingelheim. Other authors reported financial ties to the company as well.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: After a mean follow-up of 14 months, the incidence of major or clinically relevant nonmajor bleeding was 15.4% in the 110-mg dual-therapy group (HR, 0.52; 95% CI, 0.42-0.63, P less than .001) and 20.2% in the 150-mg dual-therapy group (HR, 0.72; 95% CI, 0.58-0.88; P less than .001), versus about 26% with triple-therapy.
Data source: Subgroup analysis of RE-DUAL PCI trial
Disclosures: The trial was funded by Boehringer Ingelheim, the maker of dabigatran. Several investigators were employees. Authors disclosed various financial ties to the company.
Plek2 may be therapeutic target in MPNs
New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).
Plek2 was previously shown to be involved in red blood cell production.
Now, researchers have found Plek2 is upregulated in patients with JAK2V617F-positive MPNs.
And loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes in a mouse model.
Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.
The researchers found that Plek2 was significantly upregulated in patients with JAK2V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.
Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.
The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.
Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”
“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.
Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.
Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.
“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”
“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.” 
New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).
Plek2 was previously shown to be involved in red blood cell production.
Now, researchers have found Plek2 is upregulated in patients with JAK2V617F-positive MPNs.
And loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes in a mouse model.
Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.
The researchers found that Plek2 was significantly upregulated in patients with JAK2V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.
Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.
The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.
Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”
“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.
Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.
Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.
“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”
“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”
New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).
Plek2 was previously shown to be involved in red blood cell production.
Now, researchers have found Plek2 is upregulated in patients with JAK2V617F-positive MPNs.
And loss of Plek2 ameliorated JAK2V617F-induced myeloproliferative phenotypes in a mouse model.
Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.
The researchers found that Plek2 was significantly upregulated in patients with JAK2V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.
Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.
The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.
Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”
“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.
Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.
Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.
“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”
“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”
Which Is Junk: The Aspartame, or the Science?
A DIETARY DIAGNOSIS
I’m a hospital CEO and came across an NP colleague’s issue of Clinician Reviews; your September editorial on aspartame (2017;27[9]:6-7) caught my eye. While mine is another “n = 1” experience with the effects of aspartame, it was life-changing.
About 10 years ago, my former wife’s seizures suddenly increased in frequency after a fairly lengthy period without them. The problem was severe enough that she was faced with losing her ability to drive a car.
I had a good business relationship with the Massachusetts General Hospital and sought help from a prominent neurologist there. He asked us to keep a dietary journal before the appointment.
Though he ordered routine diagnostic tests, the journal told him all he needed to know: He told her to eliminate aspartame from her diet. It felt like a miracle when the seizures disappeared—no longer did I need to maintain bumpers on every sharp edge in the house!
Since this experience, I read every article that I can about this chemical additive and was interested to learn of your experiences.
Doug Jones
Ellsworth, ME
THE SCIENCE IS JUNK
I had to write because I can’t believe they allowed you to publish such a ridiculous article based on junk science. Anecdotal reports have no place in medicine. Aspartame is one of the most studied food items around. Many of these claims about the alleged danger of aspartame have been debunked by real scientists.
I am very disappointed.
Darlene Elliott, MSN, RN, CNP
Albuquerque, NM
STOP IGNORING THE BODY OF KNOWLEDGE
Thank you for addressing an issue that I believe to be of great importance. There is a huge body of knowledge that the medical community is ignoring regarding the correlation between diet and health in general, in particular the diabetes epidemic. As NPs, we are in a great position to lead.
I encourage you to read Jason Fung’s book, The Obesity Code. The entire book is eye popping, but chapter 15 (“The Diet Soda Delusion”) is particularly pertinent. He has the most thorough understanding of carbohydrate metabolism of all the authors I have read. However, Gary Taubes and Eric Westman have also published valuable resources; their books have changed my life, and I believe their knowledge could apply to many of our patients. If doctors will not embrace science, perhaps NPs will.
Martha DelGiudice, CNM
Smithtown, NY
MAYBE IT'S US …
Every time the “fasten seat belt” sign comes on, the ride gets very bumpy—so from now on, I’m going to ignore it. Aspartame “tricks our brain,” does it? What about agency? Or are we just passive leaves in the air blown about by gusts of aspartame?
Robert Pearlman, PA
Providence, RI
FAST TRACK FROM SWEET TO SOUR
Thank you for shedding light on the dangers of aspartame! My personal experience with it has not been good: One night, after drinking a large quantity of artificially sweetened powdered iced tea, I began to feel numb and experienced strange nerve sensations. I quickly learned that it is a migraine trigger for me. I now avoid aspartame and all other artificial sweeteners.
As a clinical dietitian (and NP), I’ve realized that fake food just doesn’t cut it for the body. Another issue in the dietary realm is that of folic acid. Yes, fortification has done wonders for preventing neural tube defects. But did you know that the folic acid put in our grains is a chemical that our bodies have to methylate to folinic acid, and that more than half of us do not do that well? This means excess synthetic folic acid is floating around in our bodies and brains, attributing to seizures, ADD, ADHD, migraines, miscarriages, etc.
I try to avoid eating foods with added folic acid. Talk about difficult! It means eating a lot of organic grains, whole grains, and natural vitamins with natural methylfolate to prevent anemia. Our bodies are designed to eat natural foods; the more processed something is, the more likely it is to be harmful to us.
Caroline Conneen, C-FNP, RD, IBCLC
Fredericksburg, VA
FAKE FOOD, NOT OUR FRIEND
My husband was habitually drinking flavored seltzer sweetened with aspartame when he became anxious, irritable, and developed insomnia. As soon as he stopped consuming it, the adverse effects dissipated. Since then, he has been astute about reading labels, and we do not support the use of any artificial sweeteners.
I believe aspartame should be taken off the market. The Internet is full of articles that report adverse effects from it. It seems more people are trying to avoid it. As an FNP and PMHNP, I educate my clients about aspartame and how it can exacerbate preexisting problems and contribute to insomnia, mood disorders, and panic/anxiety disorders.
I appreciate your scientific information about aspartame. We need to talk more about this chemical food additive; it is not our friend.
SUCRALOSE, ASPARTAME … ARE THE EFFECTS ONE AND THE SAME?
I have had negative thoughts concerning artificial sweeteners, including sucralose, which seems to be commonly used these days. I do not like the way I feel after ingesting these substances; it’s hard to describe—I just don’t feel right. I wonder if one answer lies in genomics and an individual’s inability to metabolize it? And to think of the byproducts you describe. Thank you for bringing this topic to light.
Anna Simon, CRNP
Allentown, PA
A DIETARY DIAGNOSIS
I’m a hospital CEO and came across an NP colleague’s issue of Clinician Reviews; your September editorial on aspartame (2017;27[9]:6-7) caught my eye. While mine is another “n = 1” experience with the effects of aspartame, it was life-changing.
About 10 years ago, my former wife’s seizures suddenly increased in frequency after a fairly lengthy period without them. The problem was severe enough that she was faced with losing her ability to drive a car.
I had a good business relationship with the Massachusetts General Hospital and sought help from a prominent neurologist there. He asked us to keep a dietary journal before the appointment.
Though he ordered routine diagnostic tests, the journal told him all he needed to know: He told her to eliminate aspartame from her diet. It felt like a miracle when the seizures disappeared—no longer did I need to maintain bumpers on every sharp edge in the house!
Since this experience, I read every article that I can about this chemical additive and was interested to learn of your experiences.
Doug Jones
Ellsworth, ME
THE SCIENCE IS JUNK
I had to write because I can’t believe they allowed you to publish such a ridiculous article based on junk science. Anecdotal reports have no place in medicine. Aspartame is one of the most studied food items around. Many of these claims about the alleged danger of aspartame have been debunked by real scientists.
I am very disappointed.
Darlene Elliott, MSN, RN, CNP
Albuquerque, NM
STOP IGNORING THE BODY OF KNOWLEDGE
Thank you for addressing an issue that I believe to be of great importance. There is a huge body of knowledge that the medical community is ignoring regarding the correlation between diet and health in general, in particular the diabetes epidemic. As NPs, we are in a great position to lead.
I encourage you to read Jason Fung’s book, The Obesity Code. The entire book is eye popping, but chapter 15 (“The Diet Soda Delusion”) is particularly pertinent. He has the most thorough understanding of carbohydrate metabolism of all the authors I have read. However, Gary Taubes and Eric Westman have also published valuable resources; their books have changed my life, and I believe their knowledge could apply to many of our patients. If doctors will not embrace science, perhaps NPs will.
Martha DelGiudice, CNM
Smithtown, NY
MAYBE IT'S US …
Every time the “fasten seat belt” sign comes on, the ride gets very bumpy—so from now on, I’m going to ignore it. Aspartame “tricks our brain,” does it? What about agency? Or are we just passive leaves in the air blown about by gusts of aspartame?
Robert Pearlman, PA
Providence, RI
FAST TRACK FROM SWEET TO SOUR
Thank you for shedding light on the dangers of aspartame! My personal experience with it has not been good: One night, after drinking a large quantity of artificially sweetened powdered iced tea, I began to feel numb and experienced strange nerve sensations. I quickly learned that it is a migraine trigger for me. I now avoid aspartame and all other artificial sweeteners.
As a clinical dietitian (and NP), I’ve realized that fake food just doesn’t cut it for the body. Another issue in the dietary realm is that of folic acid. Yes, fortification has done wonders for preventing neural tube defects. But did you know that the folic acid put in our grains is a chemical that our bodies have to methylate to folinic acid, and that more than half of us do not do that well? This means excess synthetic folic acid is floating around in our bodies and brains, attributing to seizures, ADD, ADHD, migraines, miscarriages, etc.
I try to avoid eating foods with added folic acid. Talk about difficult! It means eating a lot of organic grains, whole grains, and natural vitamins with natural methylfolate to prevent anemia. Our bodies are designed to eat natural foods; the more processed something is, the more likely it is to be harmful to us.
Caroline Conneen, C-FNP, RD, IBCLC
Fredericksburg, VA
FAKE FOOD, NOT OUR FRIEND
My husband was habitually drinking flavored seltzer sweetened with aspartame when he became anxious, irritable, and developed insomnia. As soon as he stopped consuming it, the adverse effects dissipated. Since then, he has been astute about reading labels, and we do not support the use of any artificial sweeteners.
I believe aspartame should be taken off the market. The Internet is full of articles that report adverse effects from it. It seems more people are trying to avoid it. As an FNP and PMHNP, I educate my clients about aspartame and how it can exacerbate preexisting problems and contribute to insomnia, mood disorders, and panic/anxiety disorders.
I appreciate your scientific information about aspartame. We need to talk more about this chemical food additive; it is not our friend.
SUCRALOSE, ASPARTAME … ARE THE EFFECTS ONE AND THE SAME?
I have had negative thoughts concerning artificial sweeteners, including sucralose, which seems to be commonly used these days. I do not like the way I feel after ingesting these substances; it’s hard to describe—I just don’t feel right. I wonder if one answer lies in genomics and an individual’s inability to metabolize it? And to think of the byproducts you describe. Thank you for bringing this topic to light.
Anna Simon, CRNP
Allentown, PA
A DIETARY DIAGNOSIS
I’m a hospital CEO and came across an NP colleague’s issue of Clinician Reviews; your September editorial on aspartame (2017;27[9]:6-7) caught my eye. While mine is another “n = 1” experience with the effects of aspartame, it was life-changing.
About 10 years ago, my former wife’s seizures suddenly increased in frequency after a fairly lengthy period without them. The problem was severe enough that she was faced with losing her ability to drive a car.
I had a good business relationship with the Massachusetts General Hospital and sought help from a prominent neurologist there. He asked us to keep a dietary journal before the appointment.
Though he ordered routine diagnostic tests, the journal told him all he needed to know: He told her to eliminate aspartame from her diet. It felt like a miracle when the seizures disappeared—no longer did I need to maintain bumpers on every sharp edge in the house!
Since this experience, I read every article that I can about this chemical additive and was interested to learn of your experiences.
Doug Jones
Ellsworth, ME
THE SCIENCE IS JUNK
I had to write because I can’t believe they allowed you to publish such a ridiculous article based on junk science. Anecdotal reports have no place in medicine. Aspartame is one of the most studied food items around. Many of these claims about the alleged danger of aspartame have been debunked by real scientists.
I am very disappointed.
Darlene Elliott, MSN, RN, CNP
Albuquerque, NM
STOP IGNORING THE BODY OF KNOWLEDGE
Thank you for addressing an issue that I believe to be of great importance. There is a huge body of knowledge that the medical community is ignoring regarding the correlation between diet and health in general, in particular the diabetes epidemic. As NPs, we are in a great position to lead.
I encourage you to read Jason Fung’s book, The Obesity Code. The entire book is eye popping, but chapter 15 (“The Diet Soda Delusion”) is particularly pertinent. He has the most thorough understanding of carbohydrate metabolism of all the authors I have read. However, Gary Taubes and Eric Westman have also published valuable resources; their books have changed my life, and I believe their knowledge could apply to many of our patients. If doctors will not embrace science, perhaps NPs will.
Martha DelGiudice, CNM
Smithtown, NY
MAYBE IT'S US …
Every time the “fasten seat belt” sign comes on, the ride gets very bumpy—so from now on, I’m going to ignore it. Aspartame “tricks our brain,” does it? What about agency? Or are we just passive leaves in the air blown about by gusts of aspartame?
Robert Pearlman, PA
Providence, RI
FAST TRACK FROM SWEET TO SOUR
Thank you for shedding light on the dangers of aspartame! My personal experience with it has not been good: One night, after drinking a large quantity of artificially sweetened powdered iced tea, I began to feel numb and experienced strange nerve sensations. I quickly learned that it is a migraine trigger for me. I now avoid aspartame and all other artificial sweeteners.
As a clinical dietitian (and NP), I’ve realized that fake food just doesn’t cut it for the body. Another issue in the dietary realm is that of folic acid. Yes, fortification has done wonders for preventing neural tube defects. But did you know that the folic acid put in our grains is a chemical that our bodies have to methylate to folinic acid, and that more than half of us do not do that well? This means excess synthetic folic acid is floating around in our bodies and brains, attributing to seizures, ADD, ADHD, migraines, miscarriages, etc.
I try to avoid eating foods with added folic acid. Talk about difficult! It means eating a lot of organic grains, whole grains, and natural vitamins with natural methylfolate to prevent anemia. Our bodies are designed to eat natural foods; the more processed something is, the more likely it is to be harmful to us.
Caroline Conneen, C-FNP, RD, IBCLC
Fredericksburg, VA
FAKE FOOD, NOT OUR FRIEND
My husband was habitually drinking flavored seltzer sweetened with aspartame when he became anxious, irritable, and developed insomnia. As soon as he stopped consuming it, the adverse effects dissipated. Since then, he has been astute about reading labels, and we do not support the use of any artificial sweeteners.
I believe aspartame should be taken off the market. The Internet is full of articles that report adverse effects from it. It seems more people are trying to avoid it. As an FNP and PMHNP, I educate my clients about aspartame and how it can exacerbate preexisting problems and contribute to insomnia, mood disorders, and panic/anxiety disorders.
I appreciate your scientific information about aspartame. We need to talk more about this chemical food additive; it is not our friend.
SUCRALOSE, ASPARTAME … ARE THE EFFECTS ONE AND THE SAME?
I have had negative thoughts concerning artificial sweeteners, including sucralose, which seems to be commonly used these days. I do not like the way I feel after ingesting these substances; it’s hard to describe—I just don’t feel right. I wonder if one answer lies in genomics and an individual’s inability to metabolize it? And to think of the byproducts you describe. Thank you for bringing this topic to light.
Anna Simon, CRNP
Allentown, PA
Sleep apnea treatment may reduce risk of epileptic seizures
WASHINGTON – In patients with epilepsy, treatment of obstructive sleep apnea with continuous positive airway pressure may lead to substantial and sustained reductions in seizure activity, according to data presented at the annual meeting of the American Epilepsy Society.
The reduction in seizure activity with continuous positive airway pressure (cPAP) in patients with epilepsy contributes to other evidence that poor sleep quality is an important but preventable risk factor for seizures, according to Thapanee Somboon, MD, a research fellow at the Sleep Disorders Center at the Cleveland Clinic in Ohio.
In this study, which was characterized as the largest yet to evaluate the effect of cPAP on seizure activity, all 197 patients had epilepsy but only 122 had obstructive sleep apnea (OSA). Of those with OSA, 73 were treated with cPAP and 49 were not. An additional 75 patients with epilepsy but no OSA were also treated with cPAP. Seizure activity in all groups was evaluated over a period of 1 year.
Treatment success, defined as no seizure activity or at least a 50% reduction from baseline in seizure activity, was achieved in 85% of those with OSA treated with cPAP, 55% of those with OSA that did not receive cPAP, and 65% of those who were treated with cPAP but did not have OSA.
The difference was even greater among those with seizure activity in the 6 months prior to cPAP use. In these, a 50% or greater reduction in seizure activity was achieved in 63% of those with OSA treated with cPAP but in only 14% of those with OSA that did not receive cPAP. In the group without OSA, 44% achieved a 50% or greater reduction in seizure activity from baseline on cPAP.
“Epilepsy patients without OSA also appeared to benefit from cPAP, although prospective data are needed to further explore this observation,” Dr. Somboon said.
All patients remained on antiepileptic drugs over the course of study, and the drug levels were not different between groups, according to Dr. Somboon. About half of all three groups were seizure free in the 6 months prior to cPAP. Those with OSA who received cPAP had a higher body mass index than did those who were not treated (34.6 vs. 31.1; P less than .001), but they were of similar age (47.6 vs. 47.9 years). Those without OSA who were treated with cPAP had a lower BMI (27.5; P less than .001) and were 10 years younger than were those with OSA (37.7 years; P less than .001). About two-thirds of all three groups had a history of focal seizures.
When expressed as odds ratios (OR), those treated for OSA had almost 10 times the likelihood of treatment success at 1 year (OR, 9.58; P less than .001), although being seizure free in the 6 months prior to cPAP had a 20-fold increased likelihood of treatment success (OR, 20.88; P less than .001).
Sleep disturbances and OSA are more common in patients with epilepsy than age-matched controls, according to Dr. Somboon, who cited published studies substantiating these statements. She noted that there are also previously published studies associating improved sleep hygiene, including improved sleep hygiene achieved with cPAP, with a reduced risk of seizure activity in epilepsy patients. However, at present there are no guideline recommendations for screening patients with epilepsy for OSA or other causes of impaired sleep, according to Dr. Somboon.
Although Dr. Somboon acknowledged that the data collected in this study cannot provide a definitive link between cPAP treatment, improved sleep, and reduced risk of seizure activity, this study does support these associations in the context of other evidence.
“We think clinicians should routinely screen patients with epilepsy for OSA and consider cPAP as a strategy to reduce seizure risk,” she said.
Dr. Somboon reported no financial relationships relevant to the study.
WASHINGTON – In patients with epilepsy, treatment of obstructive sleep apnea with continuous positive airway pressure may lead to substantial and sustained reductions in seizure activity, according to data presented at the annual meeting of the American Epilepsy Society.
The reduction in seizure activity with continuous positive airway pressure (cPAP) in patients with epilepsy contributes to other evidence that poor sleep quality is an important but preventable risk factor for seizures, according to Thapanee Somboon, MD, a research fellow at the Sleep Disorders Center at the Cleveland Clinic in Ohio.
In this study, which was characterized as the largest yet to evaluate the effect of cPAP on seizure activity, all 197 patients had epilepsy but only 122 had obstructive sleep apnea (OSA). Of those with OSA, 73 were treated with cPAP and 49 were not. An additional 75 patients with epilepsy but no OSA were also treated with cPAP. Seizure activity in all groups was evaluated over a period of 1 year.
Treatment success, defined as no seizure activity or at least a 50% reduction from baseline in seizure activity, was achieved in 85% of those with OSA treated with cPAP, 55% of those with OSA that did not receive cPAP, and 65% of those who were treated with cPAP but did not have OSA.
The difference was even greater among those with seizure activity in the 6 months prior to cPAP use. In these, a 50% or greater reduction in seizure activity was achieved in 63% of those with OSA treated with cPAP but in only 14% of those with OSA that did not receive cPAP. In the group without OSA, 44% achieved a 50% or greater reduction in seizure activity from baseline on cPAP.
“Epilepsy patients without OSA also appeared to benefit from cPAP, although prospective data are needed to further explore this observation,” Dr. Somboon said.
All patients remained on antiepileptic drugs over the course of study, and the drug levels were not different between groups, according to Dr. Somboon. About half of all three groups were seizure free in the 6 months prior to cPAP. Those with OSA who received cPAP had a higher body mass index than did those who were not treated (34.6 vs. 31.1; P less than .001), but they were of similar age (47.6 vs. 47.9 years). Those without OSA who were treated with cPAP had a lower BMI (27.5; P less than .001) and were 10 years younger than were those with OSA (37.7 years; P less than .001). About two-thirds of all three groups had a history of focal seizures.
When expressed as odds ratios (OR), those treated for OSA had almost 10 times the likelihood of treatment success at 1 year (OR, 9.58; P less than .001), although being seizure free in the 6 months prior to cPAP had a 20-fold increased likelihood of treatment success (OR, 20.88; P less than .001).
Sleep disturbances and OSA are more common in patients with epilepsy than age-matched controls, according to Dr. Somboon, who cited published studies substantiating these statements. She noted that there are also previously published studies associating improved sleep hygiene, including improved sleep hygiene achieved with cPAP, with a reduced risk of seizure activity in epilepsy patients. However, at present there are no guideline recommendations for screening patients with epilepsy for OSA or other causes of impaired sleep, according to Dr. Somboon.
Although Dr. Somboon acknowledged that the data collected in this study cannot provide a definitive link between cPAP treatment, improved sleep, and reduced risk of seizure activity, this study does support these associations in the context of other evidence.
“We think clinicians should routinely screen patients with epilepsy for OSA and consider cPAP as a strategy to reduce seizure risk,” she said.
Dr. Somboon reported no financial relationships relevant to the study.
WASHINGTON – In patients with epilepsy, treatment of obstructive sleep apnea with continuous positive airway pressure may lead to substantial and sustained reductions in seizure activity, according to data presented at the annual meeting of the American Epilepsy Society.
The reduction in seizure activity with continuous positive airway pressure (cPAP) in patients with epilepsy contributes to other evidence that poor sleep quality is an important but preventable risk factor for seizures, according to Thapanee Somboon, MD, a research fellow at the Sleep Disorders Center at the Cleveland Clinic in Ohio.
In this study, which was characterized as the largest yet to evaluate the effect of cPAP on seizure activity, all 197 patients had epilepsy but only 122 had obstructive sleep apnea (OSA). Of those with OSA, 73 were treated with cPAP and 49 were not. An additional 75 patients with epilepsy but no OSA were also treated with cPAP. Seizure activity in all groups was evaluated over a period of 1 year.
Treatment success, defined as no seizure activity or at least a 50% reduction from baseline in seizure activity, was achieved in 85% of those with OSA treated with cPAP, 55% of those with OSA that did not receive cPAP, and 65% of those who were treated with cPAP but did not have OSA.
The difference was even greater among those with seizure activity in the 6 months prior to cPAP use. In these, a 50% or greater reduction in seizure activity was achieved in 63% of those with OSA treated with cPAP but in only 14% of those with OSA that did not receive cPAP. In the group without OSA, 44% achieved a 50% or greater reduction in seizure activity from baseline on cPAP.
“Epilepsy patients without OSA also appeared to benefit from cPAP, although prospective data are needed to further explore this observation,” Dr. Somboon said.
All patients remained on antiepileptic drugs over the course of study, and the drug levels were not different between groups, according to Dr. Somboon. About half of all three groups were seizure free in the 6 months prior to cPAP. Those with OSA who received cPAP had a higher body mass index than did those who were not treated (34.6 vs. 31.1; P less than .001), but they were of similar age (47.6 vs. 47.9 years). Those without OSA who were treated with cPAP had a lower BMI (27.5; P less than .001) and were 10 years younger than were those with OSA (37.7 years; P less than .001). About two-thirds of all three groups had a history of focal seizures.
When expressed as odds ratios (OR), those treated for OSA had almost 10 times the likelihood of treatment success at 1 year (OR, 9.58; P less than .001), although being seizure free in the 6 months prior to cPAP had a 20-fold increased likelihood of treatment success (OR, 20.88; P less than .001).
Sleep disturbances and OSA are more common in patients with epilepsy than age-matched controls, according to Dr. Somboon, who cited published studies substantiating these statements. She noted that there are also previously published studies associating improved sleep hygiene, including improved sleep hygiene achieved with cPAP, with a reduced risk of seizure activity in epilepsy patients. However, at present there are no guideline recommendations for screening patients with epilepsy for OSA or other causes of impaired sleep, according to Dr. Somboon.
Although Dr. Somboon acknowledged that the data collected in this study cannot provide a definitive link between cPAP treatment, improved sleep, and reduced risk of seizure activity, this study does support these associations in the context of other evidence.
“We think clinicians should routinely screen patients with epilepsy for OSA and consider cPAP as a strategy to reduce seizure risk,” she said.
Dr. Somboon reported no financial relationships relevant to the study.
AT AES 2017
Key clinical point:
Major finding: In epilepsy patients and OSA, seizure activity was reduced by at least half in 63% of those treated with cPAP versus 14% of those who were not (P less than .001).
Data source: A retrospective study of 197 patients with epilepsy.
Disclosures: The presenter reported no financial relationships relevant to the study.
Intense urine output monitoring beneficial in ICU
Intense monitoring of urine output could be a useful tool in detecting acute kidney injury (AKI), according to a study conducted at the University of Pittsburgh.
Kui Jin, MD, of the University of Pittsburgh and his associates found that, after adjustment for baseline characteristics, intensive monitoring of urine output (UO) was associated with higher rates of AKI, with an odds ratio of 1.22. Intensive UO monitoring also was strongly associated with improved 30-day survival among patients developing AKI.
This retrospective cohort study included 15,724 adult patients admitted to the center’s ICUs during 2000-2008. All patients had either their UO or serum creatinine (SC) monitored. These patients were then divided into subcohorts that were monitored at one of two different intensities. UO intensive monitoring was defined by hourly recordings, with gaps no greater than 3 hours for the first 48 hours after ICU admission. The group receiving less intensive UO monitoring comprised patients who did not meet intensive monitoring criteria, regardless of their UO in the 7 days following ICU admission. The patients who had their SC intensively monitored had 3 calendar days of samples taken after their ICU admissions. Those who did not meet SC intensive monitoring criteria were placed into the less intensive SC monitoring group.
To understand the effect of the monitoring strategies on detecting the development of AKI, the researchers determined each patient’s baseline, admission, and reference serum creatinine levels. Baseline creatinine was defined as the lowest value in the year prior to hospital admission. Reference creatinine was the baseline creatinine, if available, or the lowest creatinine level recorded within 24 hours after ICU admission. A third method for determining reference creatinine levels was used for some patients, which involved making an estimation based on the Modification of Diet in Renal Disease equation for serum creatinine.
The crude rates of stage 2-3 AKI 7 days after admission to the ICU were similar between patients from both groups that had their UO monitored; 62.5% of intensive and 63.9% of less intensive patients displayed symptoms. After the researchers adjusted for baseline characteristics, however, intensive monitoring of UO was associated with greater rates of stage 2-3 AKI (OR, 1.22; P less than .001). Crude rates were higher in the patients who received intensive monitoring for SC, compared with patients who received less intensive monitoring for SC. Ultimately, Dr. Jin and his associates found that, when caring for patients with or without AKI, fluid management is one of the most important factors. Patients who underwent intensive UO monitoring received less fluid in their first 24 hours (3.6 L) in the ICU, compared with patients who received less intense UO monitoring (4.2 L). Patients who received intensive monitoring of their UO also were less likely to use vasopressors (29.9% vs. 43.3%; P less than .001), suggesting these patients were more hemodynamically stable. Further, the percentage of patients at or above 10% of fluid overload was lower in the group who received intensive monitoring of their UO (2.49% vs. 5.68%; P less than .001), during the first 72 hours in the ICU.
“Our results should help inform clinical decisions and ICU policy around frequency of monitoring of UO, especially for patients at high risk of AKI,” Dr. Jin and his colleagues wrote.
None of the authors had financial disclosures to report. Partial funding was provided by a research grant from C.R. Bard.
Intense monitoring of urine output could be a useful tool in detecting acute kidney injury (AKI), according to a study conducted at the University of Pittsburgh.
Kui Jin, MD, of the University of Pittsburgh and his associates found that, after adjustment for baseline characteristics, intensive monitoring of urine output (UO) was associated with higher rates of AKI, with an odds ratio of 1.22. Intensive UO monitoring also was strongly associated with improved 30-day survival among patients developing AKI.
This retrospective cohort study included 15,724 adult patients admitted to the center’s ICUs during 2000-2008. All patients had either their UO or serum creatinine (SC) monitored. These patients were then divided into subcohorts that were monitored at one of two different intensities. UO intensive monitoring was defined by hourly recordings, with gaps no greater than 3 hours for the first 48 hours after ICU admission. The group receiving less intensive UO monitoring comprised patients who did not meet intensive monitoring criteria, regardless of their UO in the 7 days following ICU admission. The patients who had their SC intensively monitored had 3 calendar days of samples taken after their ICU admissions. Those who did not meet SC intensive monitoring criteria were placed into the less intensive SC monitoring group.
To understand the effect of the monitoring strategies on detecting the development of AKI, the researchers determined each patient’s baseline, admission, and reference serum creatinine levels. Baseline creatinine was defined as the lowest value in the year prior to hospital admission. Reference creatinine was the baseline creatinine, if available, or the lowest creatinine level recorded within 24 hours after ICU admission. A third method for determining reference creatinine levels was used for some patients, which involved making an estimation based on the Modification of Diet in Renal Disease equation for serum creatinine.
The crude rates of stage 2-3 AKI 7 days after admission to the ICU were similar between patients from both groups that had their UO monitored; 62.5% of intensive and 63.9% of less intensive patients displayed symptoms. After the researchers adjusted for baseline characteristics, however, intensive monitoring of UO was associated with greater rates of stage 2-3 AKI (OR, 1.22; P less than .001). Crude rates were higher in the patients who received intensive monitoring for SC, compared with patients who received less intensive monitoring for SC. Ultimately, Dr. Jin and his associates found that, when caring for patients with or without AKI, fluid management is one of the most important factors. Patients who underwent intensive UO monitoring received less fluid in their first 24 hours (3.6 L) in the ICU, compared with patients who received less intense UO monitoring (4.2 L). Patients who received intensive monitoring of their UO also were less likely to use vasopressors (29.9% vs. 43.3%; P less than .001), suggesting these patients were more hemodynamically stable. Further, the percentage of patients at or above 10% of fluid overload was lower in the group who received intensive monitoring of their UO (2.49% vs. 5.68%; P less than .001), during the first 72 hours in the ICU.
“Our results should help inform clinical decisions and ICU policy around frequency of monitoring of UO, especially for patients at high risk of AKI,” Dr. Jin and his colleagues wrote.
None of the authors had financial disclosures to report. Partial funding was provided by a research grant from C.R. Bard.
Intense monitoring of urine output could be a useful tool in detecting acute kidney injury (AKI), according to a study conducted at the University of Pittsburgh.
Kui Jin, MD, of the University of Pittsburgh and his associates found that, after adjustment for baseline characteristics, intensive monitoring of urine output (UO) was associated with higher rates of AKI, with an odds ratio of 1.22. Intensive UO monitoring also was strongly associated with improved 30-day survival among patients developing AKI.
This retrospective cohort study included 15,724 adult patients admitted to the center’s ICUs during 2000-2008. All patients had either their UO or serum creatinine (SC) monitored. These patients were then divided into subcohorts that were monitored at one of two different intensities. UO intensive monitoring was defined by hourly recordings, with gaps no greater than 3 hours for the first 48 hours after ICU admission. The group receiving less intensive UO monitoring comprised patients who did not meet intensive monitoring criteria, regardless of their UO in the 7 days following ICU admission. The patients who had their SC intensively monitored had 3 calendar days of samples taken after their ICU admissions. Those who did not meet SC intensive monitoring criteria were placed into the less intensive SC monitoring group.
To understand the effect of the monitoring strategies on detecting the development of AKI, the researchers determined each patient’s baseline, admission, and reference serum creatinine levels. Baseline creatinine was defined as the lowest value in the year prior to hospital admission. Reference creatinine was the baseline creatinine, if available, or the lowest creatinine level recorded within 24 hours after ICU admission. A third method for determining reference creatinine levels was used for some patients, which involved making an estimation based on the Modification of Diet in Renal Disease equation for serum creatinine.
The crude rates of stage 2-3 AKI 7 days after admission to the ICU were similar between patients from both groups that had their UO monitored; 62.5% of intensive and 63.9% of less intensive patients displayed symptoms. After the researchers adjusted for baseline characteristics, however, intensive monitoring of UO was associated with greater rates of stage 2-3 AKI (OR, 1.22; P less than .001). Crude rates were higher in the patients who received intensive monitoring for SC, compared with patients who received less intensive monitoring for SC. Ultimately, Dr. Jin and his associates found that, when caring for patients with or without AKI, fluid management is one of the most important factors. Patients who underwent intensive UO monitoring received less fluid in their first 24 hours (3.6 L) in the ICU, compared with patients who received less intense UO monitoring (4.2 L). Patients who received intensive monitoring of their UO also were less likely to use vasopressors (29.9% vs. 43.3%; P less than .001), suggesting these patients were more hemodynamically stable. Further, the percentage of patients at or above 10% of fluid overload was lower in the group who received intensive monitoring of their UO (2.49% vs. 5.68%; P less than .001), during the first 72 hours in the ICU.
“Our results should help inform clinical decisions and ICU policy around frequency of monitoring of UO, especially for patients at high risk of AKI,” Dr. Jin and his colleagues wrote.
None of the authors had financial disclosures to report. Partial funding was provided by a research grant from C.R. Bard.
FROM CHEST
Key clinical point:
Major finding: AKI was more likely to be seen in patients who received intensive monitoring of their urine output (OR,1.22; P less than .001).
Data source: Retrospective cohort study at a single academic medical center of 15,724 adult patients admitted to the center’s ICUs during 2000-2008.
Disclosures: None of the authors had financial disclosures to report. Partial funding was provided by a research grant from C.R. Bard.
Ectopic pregnancies predicted by easy-to-use risk stratification model
SAN ANTONIO – An easy-to-use risk stratification tool accurately predicted which pregnancies of unknown location were ectopic pregnancies by using a model validated by retrospective chart review.
Reeva Makhijani, MD, and her colleagues built the tool using a composite of risk factors to create a “generalized additive model,” or GAM, in combination with beta HCG levels. They presented the results during a poster session at the annual meeting of the American Society for Reproductive Medicine.
The model showed that a prior history of ectopic pregnancy (EP) (P = .0045), a history of pelvic surgery (P = .397), and a presentation of vaginal bleeding (P = .0003) all significantly increased the risk of EP.
Another statistical measure, the area under the receiver operating curve (AUC), helps estimate the likelihood of EP according to beta-HCG levels. When the initial beta-HCG was considered together with the ratio of the initial beta HCG to the presenting beta-HCG, the AUC was 0.889. For the initial beta-HCG level alone, the AUC was 0.793, while for the ratio alone, the AUC was 0.88. Higher AUC figures indicate more predictive power.
Dr. Makhijani, an ob.gyn. resident physician at Brown University, Providence, R.I., and her colleagues have built a prototype of a computer application that calculates risk of EP when the significant risk factors and lab values are entered.
After reviewing the electronic medical records of 800 patients who had pregnancies of unknown location (PUL), in the final analysis Dr. Makhijani and her coauthors included 398 patients whose medical histories allowed assessment of risk factors and whose record included at least two beta-HCG values taken 36-72 hours apart. The investigators also excluded patients with molar pregnancies, ruptured EPs, or who had undergone surgery before a second beta-HCG was obtained.
Of the 398 patients, 40 (10%) were eventually found to have EP, while 168 (42%) had an intrauterine pregnancy, and 190 (48%) were diagnosed with spontaneous abortion.
The patients were about 27 years old on average, and just over half (n = 224) were parous. Vaginal bleeding was a presenting sign in 233 patients, and 284 had abdominal pain. Of those with EP, 34 of 40 had vaginal bleeding, and 25 of 40 had abdominal pain.
In addition to the three factors found to have significant association with EP, the investigators initially considered a number of other patient characteristics, including age, parity, and presentation with abdominal pain. Additional risk factors examined included history of infertility, pelvic inflammatory disease, sexually transmitted disease, intrauterine device placement, and diethylstilbestrol (DES) exposure. None of these were significantly associated with risk of EP.
“Our model can be translated into an easy-to-use risk stratification tool that can accurately predict the risk of EP,” said Dr. Makhijani and her coauthors. “This tool could potentially be used by clinicians and ob.gyn. residencies nationally as [pregnancies of unknown location] are a very common management scenario.”
Dr. Makhijani reported having no disclosures and no outside sources of funding.
koakes@frontlinemedcom.com
On Twitter @karioakes
SAN ANTONIO – An easy-to-use risk stratification tool accurately predicted which pregnancies of unknown location were ectopic pregnancies by using a model validated by retrospective chart review.
Reeva Makhijani, MD, and her colleagues built the tool using a composite of risk factors to create a “generalized additive model,” or GAM, in combination with beta HCG levels. They presented the results during a poster session at the annual meeting of the American Society for Reproductive Medicine.
The model showed that a prior history of ectopic pregnancy (EP) (P = .0045), a history of pelvic surgery (P = .397), and a presentation of vaginal bleeding (P = .0003) all significantly increased the risk of EP.
Another statistical measure, the area under the receiver operating curve (AUC), helps estimate the likelihood of EP according to beta-HCG levels. When the initial beta-HCG was considered together with the ratio of the initial beta HCG to the presenting beta-HCG, the AUC was 0.889. For the initial beta-HCG level alone, the AUC was 0.793, while for the ratio alone, the AUC was 0.88. Higher AUC figures indicate more predictive power.
Dr. Makhijani, an ob.gyn. resident physician at Brown University, Providence, R.I., and her colleagues have built a prototype of a computer application that calculates risk of EP when the significant risk factors and lab values are entered.
After reviewing the electronic medical records of 800 patients who had pregnancies of unknown location (PUL), in the final analysis Dr. Makhijani and her coauthors included 398 patients whose medical histories allowed assessment of risk factors and whose record included at least two beta-HCG values taken 36-72 hours apart. The investigators also excluded patients with molar pregnancies, ruptured EPs, or who had undergone surgery before a second beta-HCG was obtained.
Of the 398 patients, 40 (10%) were eventually found to have EP, while 168 (42%) had an intrauterine pregnancy, and 190 (48%) were diagnosed with spontaneous abortion.
The patients were about 27 years old on average, and just over half (n = 224) were parous. Vaginal bleeding was a presenting sign in 233 patients, and 284 had abdominal pain. Of those with EP, 34 of 40 had vaginal bleeding, and 25 of 40 had abdominal pain.
In addition to the three factors found to have significant association with EP, the investigators initially considered a number of other patient characteristics, including age, parity, and presentation with abdominal pain. Additional risk factors examined included history of infertility, pelvic inflammatory disease, sexually transmitted disease, intrauterine device placement, and diethylstilbestrol (DES) exposure. None of these were significantly associated with risk of EP.
“Our model can be translated into an easy-to-use risk stratification tool that can accurately predict the risk of EP,” said Dr. Makhijani and her coauthors. “This tool could potentially be used by clinicians and ob.gyn. residencies nationally as [pregnancies of unknown location] are a very common management scenario.”
Dr. Makhijani reported having no disclosures and no outside sources of funding.
koakes@frontlinemedcom.com
On Twitter @karioakes
SAN ANTONIO – An easy-to-use risk stratification tool accurately predicted which pregnancies of unknown location were ectopic pregnancies by using a model validated by retrospective chart review.
Reeva Makhijani, MD, and her colleagues built the tool using a composite of risk factors to create a “generalized additive model,” or GAM, in combination with beta HCG levels. They presented the results during a poster session at the annual meeting of the American Society for Reproductive Medicine.
The model showed that a prior history of ectopic pregnancy (EP) (P = .0045), a history of pelvic surgery (P = .397), and a presentation of vaginal bleeding (P = .0003) all significantly increased the risk of EP.
Another statistical measure, the area under the receiver operating curve (AUC), helps estimate the likelihood of EP according to beta-HCG levels. When the initial beta-HCG was considered together with the ratio of the initial beta HCG to the presenting beta-HCG, the AUC was 0.889. For the initial beta-HCG level alone, the AUC was 0.793, while for the ratio alone, the AUC was 0.88. Higher AUC figures indicate more predictive power.
Dr. Makhijani, an ob.gyn. resident physician at Brown University, Providence, R.I., and her colleagues have built a prototype of a computer application that calculates risk of EP when the significant risk factors and lab values are entered.
After reviewing the electronic medical records of 800 patients who had pregnancies of unknown location (PUL), in the final analysis Dr. Makhijani and her coauthors included 398 patients whose medical histories allowed assessment of risk factors and whose record included at least two beta-HCG values taken 36-72 hours apart. The investigators also excluded patients with molar pregnancies, ruptured EPs, or who had undergone surgery before a second beta-HCG was obtained.
Of the 398 patients, 40 (10%) were eventually found to have EP, while 168 (42%) had an intrauterine pregnancy, and 190 (48%) were diagnosed with spontaneous abortion.
The patients were about 27 years old on average, and just over half (n = 224) were parous. Vaginal bleeding was a presenting sign in 233 patients, and 284 had abdominal pain. Of those with EP, 34 of 40 had vaginal bleeding, and 25 of 40 had abdominal pain.
In addition to the three factors found to have significant association with EP, the investigators initially considered a number of other patient characteristics, including age, parity, and presentation with abdominal pain. Additional risk factors examined included history of infertility, pelvic inflammatory disease, sexually transmitted disease, intrauterine device placement, and diethylstilbestrol (DES) exposure. None of these were significantly associated with risk of EP.
“Our model can be translated into an easy-to-use risk stratification tool that can accurately predict the risk of EP,” said Dr. Makhijani and her coauthors. “This tool could potentially be used by clinicians and ob.gyn. residencies nationally as [pregnancies of unknown location] are a very common management scenario.”
Dr. Makhijani reported having no disclosures and no outside sources of funding.
koakes@frontlinemedcom.com
On Twitter @karioakes
AT ASRM 2017
Key clinical point:
Major finding: Incorporating initial and serial beta-HCGs yielded an AUC of 0.889 for predicting ectopic pregnancy.
Data source: A retrospective chart review of 398 patients with pregnancy of unknown location.
Disclosures: The presenter reported having no relevant disclosures and no outside sources of funding.
NIH goes straight to pregnant women in new research project
Research on pregnancy is now being crowdsourced, with pregnant women being asked in a new federal research project to “tell researchers and health care providers what pregnancy is really like.”
The project, PregSource, was launched in November by the National Institute of Child Health and Human Development (NICHD). Women who join PregSource (https://pregsource.nih.gov) are asked to chart changes to their weight, sleep, mood, morning sickness, and physical activity and to answer monthly online surveys about their pregnancy experiences, symptoms, and complications. It is hoped that resulting de-identified data will help inform future studies and improve maternal care, NICHD officials said.
“We had come to the recognition that we – the scientific community – lack a comprehensive database about how pregnancy affects women in the modern world,” said Caroline Signore, MD, MPH, deputy director of NICHD’s division of extramural research and principal investigator of PregSource.
“We spend a lot of time talking about the complications of pregnancy, but we don’t know a whole lot about the baseline experiences. . .the experiential trends of pregnancy” such as how many women experience morning sickness and for how long, and how pregnancy affects sleep patterns, she said.
By crowdsourcing to pregnant women themselves – by asking them to voluntarily offer data and make observations, “we’re researching on a large scale and doing so relatively cost effectively,” said Dr. Signore, an ob.gyn. “Women who are interested in contributing to science can [do so] on their own terms. They can visit PregSource on their own time and enter as much data as they want.”
Hal E. Lawrence III, MD, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists, called the project “groundbreaking” and said that NICHD should have “no problem” meeting its initial target of 100,000 pregnant women. “This is different from the other pregnancy apps,” he said. “This is more of a reporting and an informative [site], which the others aren’t.”
ACOG is one of about a dozen partnering organizations – along with the American Academy of Pediatrics and the American College of Nurse-Midwives – that have worked with NICHD on shaping the project and contributing content for a resource library that PregSource participants will have access to.
The project is currently in a “soft-launch phase,” Dr. Signore said, and will step up its outreach to women and providers in January.
Along with the current series of “trackers” and monthly questionnaires (in addition to questionnaires about prepregnancy health), women who indicate that they have physical disabilities or certain complications or conditions such as diabetes will be asked to participate in additional information-gathering modules. And once the project has amassed enough data, women will be able to compare specific experiences with those of other participants.
“A woman who’s 5 months’ pregnant and completes questions on nausea and vomiting, say, can click a button and see how everyone else who’s been in PregSource at this time has answered that question,” Dr. Signore said. “Or a woman who indicates she’s having a lot of heartburn at 27 weeks can learn about how many other women are having heartburn. We think this will be valuable for women, because [they’re] always wondering, ‘Is my experience unique?’ ”
NICHD officials said they hope women will share with their ob.gyns. or other providers the charts from their PregSource trackers, such as those plotting the individual’s weight gain against Institute of Medicine-recommended weight gain ranges. “We like to think that PregSource will promote conversations and shared decision making. . .and hopefully that it will improve that individual woman’s outcomes,” Dr. Signore said.
Indeed, said Uma M. Reddy, MD, MPH, project scientist for the NICHD’s Maternal-Fetal Medicine Units (MFMU) Network, women who use PregSource’s trackers should be “more in tune with their pregnancies” and with staying healthy. She and other experts touted PregSource at the recent biennial meeting of the Diabetes in Pregnancy Study Group.
The NICHD also plans to gently nudge women toward any relevant clinical studies underway in their locales “by simply notifying the women and making the information available to them,” Dr. Signore said. In addition, the project will invite women to track their experiences for several years after childbirth so more data can be generated on associations between pregnancy and child and maternal health. “Just as with the whole project, we’re trying to take into account the benefit-burden ratio and hope that women will continue to see value,” she said.
The NICHD-sponsored project will not sell or share any personal information to a third party, and participants will not receive any ads or product announcements. Data from the project – all of it de-identified – will be shared with approved researchers for their own analyses.
“We see it being already equipped to answer [existing] questions and to probe relationships” between pregnancy characteristics and complications, for instance, Dr. Signore said. “But it also could be a hypothesis-generating resource.”
A Spanish version will come “once we know we’ve optimized functionality and syntax,” she said. And overall, the NICHD is ready for growth, both in numbers of participants and in content.
ACOG is rooting for its success, Dr. Lawrence said. “We’ll have to wait and see how the results help us, but I’ll tell you one thing, having no data will never help us.”
Research on pregnancy is now being crowdsourced, with pregnant women being asked in a new federal research project to “tell researchers and health care providers what pregnancy is really like.”
The project, PregSource, was launched in November by the National Institute of Child Health and Human Development (NICHD). Women who join PregSource (https://pregsource.nih.gov) are asked to chart changes to their weight, sleep, mood, morning sickness, and physical activity and to answer monthly online surveys about their pregnancy experiences, symptoms, and complications. It is hoped that resulting de-identified data will help inform future studies and improve maternal care, NICHD officials said.
“We had come to the recognition that we – the scientific community – lack a comprehensive database about how pregnancy affects women in the modern world,” said Caroline Signore, MD, MPH, deputy director of NICHD’s division of extramural research and principal investigator of PregSource.
“We spend a lot of time talking about the complications of pregnancy, but we don’t know a whole lot about the baseline experiences. . .the experiential trends of pregnancy” such as how many women experience morning sickness and for how long, and how pregnancy affects sleep patterns, she said.
By crowdsourcing to pregnant women themselves – by asking them to voluntarily offer data and make observations, “we’re researching on a large scale and doing so relatively cost effectively,” said Dr. Signore, an ob.gyn. “Women who are interested in contributing to science can [do so] on their own terms. They can visit PregSource on their own time and enter as much data as they want.”
Hal E. Lawrence III, MD, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists, called the project “groundbreaking” and said that NICHD should have “no problem” meeting its initial target of 100,000 pregnant women. “This is different from the other pregnancy apps,” he said. “This is more of a reporting and an informative [site], which the others aren’t.”
ACOG is one of about a dozen partnering organizations – along with the American Academy of Pediatrics and the American College of Nurse-Midwives – that have worked with NICHD on shaping the project and contributing content for a resource library that PregSource participants will have access to.
The project is currently in a “soft-launch phase,” Dr. Signore said, and will step up its outreach to women and providers in January.
Along with the current series of “trackers” and monthly questionnaires (in addition to questionnaires about prepregnancy health), women who indicate that they have physical disabilities or certain complications or conditions such as diabetes will be asked to participate in additional information-gathering modules. And once the project has amassed enough data, women will be able to compare specific experiences with those of other participants.
“A woman who’s 5 months’ pregnant and completes questions on nausea and vomiting, say, can click a button and see how everyone else who’s been in PregSource at this time has answered that question,” Dr. Signore said. “Or a woman who indicates she’s having a lot of heartburn at 27 weeks can learn about how many other women are having heartburn. We think this will be valuable for women, because [they’re] always wondering, ‘Is my experience unique?’ ”
NICHD officials said they hope women will share with their ob.gyns. or other providers the charts from their PregSource trackers, such as those plotting the individual’s weight gain against Institute of Medicine-recommended weight gain ranges. “We like to think that PregSource will promote conversations and shared decision making. . .and hopefully that it will improve that individual woman’s outcomes,” Dr. Signore said.
Indeed, said Uma M. Reddy, MD, MPH, project scientist for the NICHD’s Maternal-Fetal Medicine Units (MFMU) Network, women who use PregSource’s trackers should be “more in tune with their pregnancies” and with staying healthy. She and other experts touted PregSource at the recent biennial meeting of the Diabetes in Pregnancy Study Group.
The NICHD also plans to gently nudge women toward any relevant clinical studies underway in their locales “by simply notifying the women and making the information available to them,” Dr. Signore said. In addition, the project will invite women to track their experiences for several years after childbirth so more data can be generated on associations between pregnancy and child and maternal health. “Just as with the whole project, we’re trying to take into account the benefit-burden ratio and hope that women will continue to see value,” she said.
The NICHD-sponsored project will not sell or share any personal information to a third party, and participants will not receive any ads or product announcements. Data from the project – all of it de-identified – will be shared with approved researchers for their own analyses.
“We see it being already equipped to answer [existing] questions and to probe relationships” between pregnancy characteristics and complications, for instance, Dr. Signore said. “But it also could be a hypothesis-generating resource.”
A Spanish version will come “once we know we’ve optimized functionality and syntax,” she said. And overall, the NICHD is ready for growth, both in numbers of participants and in content.
ACOG is rooting for its success, Dr. Lawrence said. “We’ll have to wait and see how the results help us, but I’ll tell you one thing, having no data will never help us.”
Research on pregnancy is now being crowdsourced, with pregnant women being asked in a new federal research project to “tell researchers and health care providers what pregnancy is really like.”
The project, PregSource, was launched in November by the National Institute of Child Health and Human Development (NICHD). Women who join PregSource (https://pregsource.nih.gov) are asked to chart changes to their weight, sleep, mood, morning sickness, and physical activity and to answer monthly online surveys about their pregnancy experiences, symptoms, and complications. It is hoped that resulting de-identified data will help inform future studies and improve maternal care, NICHD officials said.
“We had come to the recognition that we – the scientific community – lack a comprehensive database about how pregnancy affects women in the modern world,” said Caroline Signore, MD, MPH, deputy director of NICHD’s division of extramural research and principal investigator of PregSource.
“We spend a lot of time talking about the complications of pregnancy, but we don’t know a whole lot about the baseline experiences. . .the experiential trends of pregnancy” such as how many women experience morning sickness and for how long, and how pregnancy affects sleep patterns, she said.
By crowdsourcing to pregnant women themselves – by asking them to voluntarily offer data and make observations, “we’re researching on a large scale and doing so relatively cost effectively,” said Dr. Signore, an ob.gyn. “Women who are interested in contributing to science can [do so] on their own terms. They can visit PregSource on their own time and enter as much data as they want.”
Hal E. Lawrence III, MD, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists, called the project “groundbreaking” and said that NICHD should have “no problem” meeting its initial target of 100,000 pregnant women. “This is different from the other pregnancy apps,” he said. “This is more of a reporting and an informative [site], which the others aren’t.”
ACOG is one of about a dozen partnering organizations – along with the American Academy of Pediatrics and the American College of Nurse-Midwives – that have worked with NICHD on shaping the project and contributing content for a resource library that PregSource participants will have access to.
The project is currently in a “soft-launch phase,” Dr. Signore said, and will step up its outreach to women and providers in January.
Along with the current series of “trackers” and monthly questionnaires (in addition to questionnaires about prepregnancy health), women who indicate that they have physical disabilities or certain complications or conditions such as diabetes will be asked to participate in additional information-gathering modules. And once the project has amassed enough data, women will be able to compare specific experiences with those of other participants.
“A woman who’s 5 months’ pregnant and completes questions on nausea and vomiting, say, can click a button and see how everyone else who’s been in PregSource at this time has answered that question,” Dr. Signore said. “Or a woman who indicates she’s having a lot of heartburn at 27 weeks can learn about how many other women are having heartburn. We think this will be valuable for women, because [they’re] always wondering, ‘Is my experience unique?’ ”
NICHD officials said they hope women will share with their ob.gyns. or other providers the charts from their PregSource trackers, such as those plotting the individual’s weight gain against Institute of Medicine-recommended weight gain ranges. “We like to think that PregSource will promote conversations and shared decision making. . .and hopefully that it will improve that individual woman’s outcomes,” Dr. Signore said.
Indeed, said Uma M. Reddy, MD, MPH, project scientist for the NICHD’s Maternal-Fetal Medicine Units (MFMU) Network, women who use PregSource’s trackers should be “more in tune with their pregnancies” and with staying healthy. She and other experts touted PregSource at the recent biennial meeting of the Diabetes in Pregnancy Study Group.
The NICHD also plans to gently nudge women toward any relevant clinical studies underway in their locales “by simply notifying the women and making the information available to them,” Dr. Signore said. In addition, the project will invite women to track their experiences for several years after childbirth so more data can be generated on associations between pregnancy and child and maternal health. “Just as with the whole project, we’re trying to take into account the benefit-burden ratio and hope that women will continue to see value,” she said.
The NICHD-sponsored project will not sell or share any personal information to a third party, and participants will not receive any ads or product announcements. Data from the project – all of it de-identified – will be shared with approved researchers for their own analyses.
“We see it being already equipped to answer [existing] questions and to probe relationships” between pregnancy characteristics and complications, for instance, Dr. Signore said. “But it also could be a hypothesis-generating resource.”
A Spanish version will come “once we know we’ve optimized functionality and syntax,” she said. And overall, the NICHD is ready for growth, both in numbers of participants and in content.
ACOG is rooting for its success, Dr. Lawrence said. “We’ll have to wait and see how the results help us, but I’ll tell you one thing, having no data will never help us.”
First-in-class glutaminase inhibitor combats anti-PD-1/PD-L1 resistance
NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.
Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.
Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.
In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).
During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.
Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.
Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.
“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.
In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.
A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.
In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).
“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.
The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.
“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.
Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.
NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.
Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.
Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.
In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).
During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.
Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.
Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.
“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.
In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.
A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.
In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).
“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.
The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.
“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.
Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.
NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.
Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.
CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.
Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.
In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).
During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.
Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.
Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.
“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.
In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.
A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.
In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).
“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.
The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.
“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.
Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.
AT SITC 2017
Key clinical point:
Major finding: The objective response rate in advanced melanoma patients refractory to anti-PD-1/PD-L1 therapy was 19%.
Data source: A phase 1/2 study of 82 patients.
Disclosures: Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel or as a board member for multiple companies.