LOS ANGELES—Eating fish at least once per week or eating fish one to three times per month, in addition to taking daily fish oil supplements, may be associated with a reduced risk of multiple sclerosis (MS), according to a preliminary study presented at the American Academy of Neurology’s 70th Annual Meeting. These findings suggest that the omega-3 fatty acids found in fish may be associated with lowering the risk of developing MS.

“Consuming fish that contain omega-3 fatty acids has been shown to have a variety of health benefits, so we wanted to see if this simple lifestyle modification, regularly eating fish and taking fish oil supplements, could reduce the risk of MS,” said lead study author Annette Langer-Gould, MD, PhD, Regional Lead for Clinical and Translational Neuroscience for the Southern California Permanente Medical Group in Pasadena, and Clinical Assistant Professor at the Keck School of Medicine of the University of Southern California in Los Angeles.

For this study, researchers examined the diets of 1,153 people (average age 36) from the MS Sunshine Study, a multi-ethnic matched case-control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California.

Researchers queried participants about how much fish they consumed regularly. Investigators also examined 13 single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2, which regulate fatty acid biosynthesis.

High fish intake was defined as either eating one serving of fish per week or eating one to three servings per month in addition to taking daily fish oil supplements. Low intake was defined as less than one serving of fish per month and no fish oil supplements.

High fish intake was associated with a 45% reduced risk of MS or CIS, when compared with those who ate fish less than once a month and did not take fish oil supplements. A total of 180 of participants with MS had high fish intake compared with 251 of the healthy controls.

In addition, two SNPs, rs174611 and rs174618, in FADS2 were independently associated with a lower risk of MS, even after accounting for high fish intake. This suggests that some people may have a genetic advantage when it comes to regulating fatty acid levels, the researchers noted.

While the study suggests that omega-3 fatty acids, and how they are processed by the body, may play an important role in reducing MS risk. Dr. Langer-Gould and colleagues emphasized that their findings show an association, and not cause and effect. More research is needed to confirm the findings and to examine how omega-3 fatty acids may affect inflammation, metabolism, and nerve function.

The study was supported by the National Institute of Neurological Disorders and Stroke.

LOS ANGELES—Eating fish at least once per week or eating fish one to three times per month, in addition to taking daily fish oil supplements, may be associated with a reduced risk of multiple sclerosis (MS), according to a preliminary study presented at the American Academy of Neurology’s 70th Annual Meeting. These findings suggest that the omega-3 fatty acids found in fish may be associated with lowering the risk of developing MS.

“Consuming fish that contain omega-3 fatty acids has been shown to have a variety of health benefits, so we wanted to see if this simple lifestyle modification, regularly eating fish and taking fish oil supplements, could reduce the risk of MS,” said lead study author Annette Langer-Gould, MD, PhD, Regional Lead for Clinical and Translational Neuroscience for the Southern California Permanente Medical Group in Pasadena, and Clinical Assistant Professor at the Keck School of Medicine of the University of Southern California in Los Angeles.

For this study, researchers examined the diets of 1,153 people (average age 36) from the MS Sunshine Study, a multi-ethnic matched case-control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California.

Researchers queried participants about how much fish they consumed regularly. Investigators also examined 13 single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2, which regulate fatty acid biosynthesis.

High fish intake was defined as either eating one serving of fish per week or eating one to three servings per month in addition to taking daily fish oil supplements. Low intake was defined as less than one serving of fish per month and no fish oil supplements.

High fish intake was associated with a 45% reduced risk of MS or CIS, when compared with those who ate fish less than once a month and did not take fish oil supplements. A total of 180 of participants with MS had high fish intake compared with 251 of the healthy controls.

In addition, two SNPs, rs174611 and rs174618, in FADS2 were independently associated with a lower risk of MS, even after accounting for high fish intake. This suggests that some people may have a genetic advantage when it comes to regulating fatty acid levels, the researchers noted.

While the study suggests that omega-3 fatty acids, and how they are processed by the body, may play an important role in reducing MS risk. Dr. Langer-Gould and colleagues emphasized that their findings show an association, and not cause and effect. More research is needed to confirm the findings and to examine how omega-3 fatty acids may affect inflammation, metabolism, and nerve function.

The study was supported by the National Institute of Neurological Disorders and Stroke.

LOS ANGELES—Eating fish at least once per week or eating fish one to three times per month, in addition to taking daily fish oil supplements, may be associated with a reduced risk of multiple sclerosis (MS), according to a preliminary study presented at the American Academy of Neurology’s 70th Annual Meeting. These findings suggest that the omega-3 fatty acids found in fish may be associated with lowering the risk of developing MS.

“Consuming fish that contain omega-3 fatty acids has been shown to have a variety of health benefits, so we wanted to see if this simple lifestyle modification, regularly eating fish and taking fish oil supplements, could reduce the risk of MS,” said lead study author Annette Langer-Gould, MD, PhD, Regional Lead for Clinical and Translational Neuroscience for the Southern California Permanente Medical Group in Pasadena, and Clinical Assistant Professor at the Keck School of Medicine of the University of Southern California in Los Angeles.

For this study, researchers examined the diets of 1,153 people (average age 36) from the MS Sunshine Study, a multi-ethnic matched case-control study of incident MS or clinically isolated syndrome (CIS), recruited from Kaiser Permanente Southern California.

Researchers queried participants about how much fish they consumed regularly. Investigators also examined 13 single nucleotide polymorphisms (SNPs) in FADS1, FADS2, and ELOV2, which regulate fatty acid biosynthesis.

High fish intake was defined as either eating one serving of fish per week or eating one to three servings per month in addition to taking daily fish oil supplements. Low intake was defined as less than one serving of fish per month and no fish oil supplements.

High fish intake was associated with a 45% reduced risk of MS or CIS, when compared with those who ate fish less than once a month and did not take fish oil supplements. A total of 180 of participants with MS had high fish intake compared with 251 of the healthy controls.

In addition, two SNPs, rs174611 and rs174618, in FADS2 were independently associated with a lower risk of MS, even after accounting for high fish intake. This suggests that some people may have a genetic advantage when it comes to regulating fatty acid levels, the researchers noted.

While the study suggests that omega-3 fatty acids, and how they are processed by the body, may play an important role in reducing MS risk. Dr. Langer-Gould and colleagues emphasized that their findings show an association, and not cause and effect. More research is needed to confirm the findings and to examine how omega-3 fatty acids may affect inflammation, metabolism, and nerve function.

The study was supported by the National Institute of Neurological Disorders and Stroke.

Endocrine-disrupting chemicals (EDCs) are structurally similar to endogenous hormones and are therefore capable of mimicking these natural hormones, interfering with their biosynthesis, transport, binding action, and/or elimination. In animal studies and human clinical observational and epidemiologic studies of various EDCs, these chemicals have consistently been associated with diabetes mellitus, obesity, hormone-sensitive cancers, neurodevelopmental disorders in children exposed prenatally, and reproductive health.

In 2009, the Endocrine Society published a scientific statement in which it called EDCs a significant concern to human health (Endocr Rev. 2009;30[4]:293-342). Several years later, the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine issued a Committee Opinion on Exposure to Toxic Environmental Agents, warning that patient exposure to EDCs and other toxic environmental agents can have a “profound and lasting effect” on reproductive health outcomes across the life course and calling the reduction of exposure a “critical area of intervention” for ob.gyns. and other reproductive health care professionals (Obstet Gynecol. 2013;122[4]:931-5).

University of Cincinnati

Low-dose effects

EDCs are used in the manufacture of pesticides, industrial chemicals, plastics and plasticizers, hand sanitizers, medical equipment, dental sealants, a variety of personal care products, cosmetics, and other common consumer and household products. They’re found, for example, in sunscreens, canned foods and beverages, food-packaging materials, baby bottles, flame-retardant furniture, stain-resistant carpet, and shoes. We are all ingesting and breathing them in to some degree.

Bisphenol A (BPA), one of the most extensively studied EDCs, is found in the thermal receipt paper routinely used by gas stations, supermarkets, and other stores. In a small study we conducted at Harvard, we found that urinary BPA concentrations increased after continual handling of receipts for 2 hours without gloves but did not increase significantly when gloves were used (JAMA. 2014 Feb 26;311[8]:859-60).

Through its National Health and Nutrition Examination Survey, the Centers for Disease Control and Prevention has reported detection rates of between 75% and 99% for different EDCs in urine samples collected from a representative sample of the U.S. population. In other human research, several EDCs have been shown to cross the placenta and have been measured in maternal blood and urine and in cord blood and amniotic fluid, as well as in placental tissue at birth.

It is interesting to note that BPA’s structure is similar to that of diethylstilbestrol (DES). BPA was first shown to have estrogenic activity in 1936 and was originally considered for use in pharmaceuticals to prevent miscarriages, spontaneous abortions, and premature labor but was put aside in favor of DES. (DES was eventually found to be carcinogenic and was taken off the market.) In the 1950s, the use of BPA was resuscitated though not in pharmaceuticals.

A potential risk factor for GDM

Quite a lot of research has been done on EDCs and the risk of type 2 diabetes. A recent meta-analysis that included 41 cross-sectional and 8 prospective studies found that serum concentrations of dioxins, polychlorinated biphenyls, and chlorinated pesticides – and urine concentrations of BPA and phthalates – were significantly associated with type 2 diabetes risk. Comparing the highest and lowest concentration categories, the pooled relative risk was 1.45 for BPA and phthalates. EDC concentrations also were associated with indicators of impaired fasting glucose and insulin resistance (J Diabetes. 2016 Jul;8[4]:516-32).

Cincinnati Children's Hospital Medical Center

Such an exosome-mediated signaling pathway provides us with the opportunity to isolate exosomes, sequence the miRNAs, and look at whether women who are exposed to higher levels of EDCs (as indicated in urine concentration) have a particular miRNA signature that correlates with GDM. In other words, we’re working to determine whether particular EDCs and exposure levels affect the miRNA placental profiles, and if these profiles are predictive of GDM.

Thus far, in a pilot prospective cohort study of pregnant women, we are seeing hints of altered miRNA expression in relation to GDM. We have selected study participants who are at high risk of developing GDM (for example, prepregnancy body mass index greater than 30, past pregnancy with GDM, or macrosomia) because we suspect that, in many women, EDCs are a tipping point for the development of GDM rather than a sole causative factor. In addition to understanding the impact of EDCs on GDM, it is our hope that miRNAs in maternal circulation will serve as a noninvasive biomarker for early detection of GDM development or susceptibility.

Dr. Ehrlich is an assistant professor of pediatrics and environmental health at Cincinnati Children’s Hospital Medical Center.

Endocrine-disrupting chemicals (EDCs) are structurally similar to endogenous hormones and are therefore capable of mimicking these natural hormones, interfering with their biosynthesis, transport, binding action, and/or elimination. In animal studies and human clinical observational and epidemiologic studies of various EDCs, these chemicals have consistently been associated with diabetes mellitus, obesity, hormone-sensitive cancers, neurodevelopmental disorders in children exposed prenatally, and reproductive health.

In 2009, the Endocrine Society published a scientific statement in which it called EDCs a significant concern to human health (Endocr Rev. 2009;30[4]:293-342). Several years later, the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine issued a Committee Opinion on Exposure to Toxic Environmental Agents, warning that patient exposure to EDCs and other toxic environmental agents can have a “profound and lasting effect” on reproductive health outcomes across the life course and calling the reduction of exposure a “critical area of intervention” for ob.gyns. and other reproductive health care professionals (Obstet Gynecol. 2013;122[4]:931-5).

University of Cincinnati

Low-dose effects

EDCs are used in the manufacture of pesticides, industrial chemicals, plastics and plasticizers, hand sanitizers, medical equipment, dental sealants, a variety of personal care products, cosmetics, and other common consumer and household products. They’re found, for example, in sunscreens, canned foods and beverages, food-packaging materials, baby bottles, flame-retardant furniture, stain-resistant carpet, and shoes. We are all ingesting and breathing them in to some degree.

Bisphenol A (BPA), one of the most extensively studied EDCs, is found in the thermal receipt paper routinely used by gas stations, supermarkets, and other stores. In a small study we conducted at Harvard, we found that urinary BPA concentrations increased after continual handling of receipts for 2 hours without gloves but did not increase significantly when gloves were used (JAMA. 2014 Feb 26;311[8]:859-60).

Through its National Health and Nutrition Examination Survey, the Centers for Disease Control and Prevention has reported detection rates of between 75% and 99% for different EDCs in urine samples collected from a representative sample of the U.S. population. In other human research, several EDCs have been shown to cross the placenta and have been measured in maternal blood and urine and in cord blood and amniotic fluid, as well as in placental tissue at birth.

It is interesting to note that BPA’s structure is similar to that of diethylstilbestrol (DES). BPA was first shown to have estrogenic activity in 1936 and was originally considered for use in pharmaceuticals to prevent miscarriages, spontaneous abortions, and premature labor but was put aside in favor of DES. (DES was eventually found to be carcinogenic and was taken off the market.) In the 1950s, the use of BPA was resuscitated though not in pharmaceuticals.

A potential risk factor for GDM

Quite a lot of research has been done on EDCs and the risk of type 2 diabetes. A recent meta-analysis that included 41 cross-sectional and 8 prospective studies found that serum concentrations of dioxins, polychlorinated biphenyls, and chlorinated pesticides – and urine concentrations of BPA and phthalates – were significantly associated with type 2 diabetes risk. Comparing the highest and lowest concentration categories, the pooled relative risk was 1.45 for BPA and phthalates. EDC concentrations also were associated with indicators of impaired fasting glucose and insulin resistance (J Diabetes. 2016 Jul;8[4]:516-32).

Cincinnati Children's Hospital Medical Center

Such an exosome-mediated signaling pathway provides us with the opportunity to isolate exosomes, sequence the miRNAs, and look at whether women who are exposed to higher levels of EDCs (as indicated in urine concentration) have a particular miRNA signature that correlates with GDM. In other words, we’re working to determine whether particular EDCs and exposure levels affect the miRNA placental profiles, and if these profiles are predictive of GDM.

Thus far, in a pilot prospective cohort study of pregnant women, we are seeing hints of altered miRNA expression in relation to GDM. We have selected study participants who are at high risk of developing GDM (for example, prepregnancy body mass index greater than 30, past pregnancy with GDM, or macrosomia) because we suspect that, in many women, EDCs are a tipping point for the development of GDM rather than a sole causative factor. In addition to understanding the impact of EDCs on GDM, it is our hope that miRNAs in maternal circulation will serve as a noninvasive biomarker for early detection of GDM development or susceptibility.

Dr. Ehrlich is an assistant professor of pediatrics and environmental health at Cincinnati Children’s Hospital Medical Center.

Endocrine-disrupting chemicals (EDCs) are structurally similar to endogenous hormones and are therefore capable of mimicking these natural hormones, interfering with their biosynthesis, transport, binding action, and/or elimination. In animal studies and human clinical observational and epidemiologic studies of various EDCs, these chemicals have consistently been associated with diabetes mellitus, obesity, hormone-sensitive cancers, neurodevelopmental disorders in children exposed prenatally, and reproductive health.

In 2009, the Endocrine Society published a scientific statement in which it called EDCs a significant concern to human health (Endocr Rev. 2009;30[4]:293-342). Several years later, the American College of Obstetricians and Gynecologists and the American Society for Reproductive Medicine issued a Committee Opinion on Exposure to Toxic Environmental Agents, warning that patient exposure to EDCs and other toxic environmental agents can have a “profound and lasting effect” on reproductive health outcomes across the life course and calling the reduction of exposure a “critical area of intervention” for ob.gyns. and other reproductive health care professionals (Obstet Gynecol. 2013;122[4]:931-5).

University of Cincinnati

Low-dose effects

EDCs are used in the manufacture of pesticides, industrial chemicals, plastics and plasticizers, hand sanitizers, medical equipment, dental sealants, a variety of personal care products, cosmetics, and other common consumer and household products. They’re found, for example, in sunscreens, canned foods and beverages, food-packaging materials, baby bottles, flame-retardant furniture, stain-resistant carpet, and shoes. We are all ingesting and breathing them in to some degree.

Bisphenol A (BPA), one of the most extensively studied EDCs, is found in the thermal receipt paper routinely used by gas stations, supermarkets, and other stores. In a small study we conducted at Harvard, we found that urinary BPA concentrations increased after continual handling of receipts for 2 hours without gloves but did not increase significantly when gloves were used (JAMA. 2014 Feb 26;311[8]:859-60).

Through its National Health and Nutrition Examination Survey, the Centers for Disease Control and Prevention has reported detection rates of between 75% and 99% for different EDCs in urine samples collected from a representative sample of the U.S. population. In other human research, several EDCs have been shown to cross the placenta and have been measured in maternal blood and urine and in cord blood and amniotic fluid, as well as in placental tissue at birth.

It is interesting to note that BPA’s structure is similar to that of diethylstilbestrol (DES). BPA was first shown to have estrogenic activity in 1936 and was originally considered for use in pharmaceuticals to prevent miscarriages, spontaneous abortions, and premature labor but was put aside in favor of DES. (DES was eventually found to be carcinogenic and was taken off the market.) In the 1950s, the use of BPA was resuscitated though not in pharmaceuticals.

A potential risk factor for GDM

Quite a lot of research has been done on EDCs and the risk of type 2 diabetes. A recent meta-analysis that included 41 cross-sectional and 8 prospective studies found that serum concentrations of dioxins, polychlorinated biphenyls, and chlorinated pesticides – and urine concentrations of BPA and phthalates – were significantly associated with type 2 diabetes risk. Comparing the highest and lowest concentration categories, the pooled relative risk was 1.45 for BPA and phthalates. EDC concentrations also were associated with indicators of impaired fasting glucose and insulin resistance (J Diabetes. 2016 Jul;8[4]:516-32).

Cincinnati Children's Hospital Medical Center

Such an exosome-mediated signaling pathway provides us with the opportunity to isolate exosomes, sequence the miRNAs, and look at whether women who are exposed to higher levels of EDCs (as indicated in urine concentration) have a particular miRNA signature that correlates with GDM. In other words, we’re working to determine whether particular EDCs and exposure levels affect the miRNA placental profiles, and if these profiles are predictive of GDM.

Thus far, in a pilot prospective cohort study of pregnant women, we are seeing hints of altered miRNA expression in relation to GDM. We have selected study participants who are at high risk of developing GDM (for example, prepregnancy body mass index greater than 30, past pregnancy with GDM, or macrosomia) because we suspect that, in many women, EDCs are a tipping point for the development of GDM rather than a sole causative factor. In addition to understanding the impact of EDCs on GDM, it is our hope that miRNAs in maternal circulation will serve as a noninvasive biomarker for early detection of GDM development or susceptibility.

Dr. Ehrlich is an assistant professor of pediatrics and environmental health at Cincinnati Children’s Hospital Medical Center.

Pregnancy presents a unique opportunity for ob.gyns. to counsel their patients on the benefits of adopting healthy lifestyle habits. Women routinely seek care from a practitioner on a regular basis. Expectant mothers are highly motivated to take care of themselves for the sake of their developing babies. Patients can be much more receptive to recommendations from their health care teams during pregnancy than they might be outside of pregnancy. Frequent biometric analyses allow ob.gyns. to monitor patients’ progress and let them know, in a supportive manner, where they might be “falling short” of their health goals.

Several years ago, our guest author, Dr. Shelley Ehrlich of the University of Cincinnati, spoke at a diabetes in pregnancy meeting about her research on BPA and its potential association with the development of gestational diabetes mellitus (GDM). As a perinatologist who worked for many years with patients who had diabetes in pregnancy, I was particularly struck by her preliminary findings which indicated that BPA might be altering gene expression, thereby leading to pregnancy-related disorders. At the time, Dr. Ehrlich’s research was still in the very early stages. However, her results were a new way of answering the age-old question of why some women, including those without other overt risk factors, might develop GDM.

Therefore, I’m delighted that Dr. Ehrlich agreed to author this month’s class to provide an overview of where her last few years of research has taken her.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Pregnancy presents a unique opportunity for ob.gyns. to counsel their patients on the benefits of adopting healthy lifestyle habits. Women routinely seek care from a practitioner on a regular basis. Expectant mothers are highly motivated to take care of themselves for the sake of their developing babies. Patients can be much more receptive to recommendations from their health care teams during pregnancy than they might be outside of pregnancy. Frequent biometric analyses allow ob.gyns. to monitor patients’ progress and let them know, in a supportive manner, where they might be “falling short” of their health goals.

Several years ago, our guest author, Dr. Shelley Ehrlich of the University of Cincinnati, spoke at a diabetes in pregnancy meeting about her research on BPA and its potential association with the development of gestational diabetes mellitus (GDM). As a perinatologist who worked for many years with patients who had diabetes in pregnancy, I was particularly struck by her preliminary findings which indicated that BPA might be altering gene expression, thereby leading to pregnancy-related disorders. At the time, Dr. Ehrlich’s research was still in the very early stages. However, her results were a new way of answering the age-old question of why some women, including those without other overt risk factors, might develop GDM.

Therefore, I’m delighted that Dr. Ehrlich agreed to author this month’s class to provide an overview of where her last few years of research has taken her.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Pregnancy presents a unique opportunity for ob.gyns. to counsel their patients on the benefits of adopting healthy lifestyle habits. Women routinely seek care from a practitioner on a regular basis. Expectant mothers are highly motivated to take care of themselves for the sake of their developing babies. Patients can be much more receptive to recommendations from their health care teams during pregnancy than they might be outside of pregnancy. Frequent biometric analyses allow ob.gyns. to monitor patients’ progress and let them know, in a supportive manner, where they might be “falling short” of their health goals.

Several years ago, our guest author, Dr. Shelley Ehrlich of the University of Cincinnati, spoke at a diabetes in pregnancy meeting about her research on BPA and its potential association with the development of gestational diabetes mellitus (GDM). As a perinatologist who worked for many years with patients who had diabetes in pregnancy, I was particularly struck by her preliminary findings which indicated that BPA might be altering gene expression, thereby leading to pregnancy-related disorders. At the time, Dr. Ehrlich’s research was still in the very early stages. However, her results were a new way of answering the age-old question of why some women, including those without other overt risk factors, might develop GDM.

Therefore, I’m delighted that Dr. Ehrlich agreed to author this month’s class to provide an overview of where her last few years of research has taken her.

Dr. Reece, who specializes in maternal-fetal medicine, is vice president for medical affairs at the University of Maryland, Baltimore, as well as the John Z. and Akiko K. Bowers Distinguished Professor and dean of the school of medicine. Dr. Reece said he had no relevant financial disclosures. He is the medical editor of this column. Contact him at [email protected].

Many individuals with metabolically healthy obesity (MHO) will progress to metabolic syndrome over time, putting them at increased risk of cardiovascular disease (CVD), analysis of population-based longitudinal cohort study suggests.

Nearly half of the individuals with MHO developed metabolic syndrome over time, according to the analysis of 6,809 participants followed since the year 2000 in the Multi-Ethnic Study of Atherosclerosis.

Those who developed metabolic syndrome had an increased risk of CVD, compared with those who did not, according to results published in the Journal of the American College of Cardiology.

The results provide new evidence that MHO alone is not a stable or reliable characterization of lower CVD risk, according to Morgana Mongraw-Chaffin, PhD, of the department of epidemiology and prevention at Wake Forest University, Winston-Salem, N.C., and her coauthors.

“Instead, MHO signals an opportunity for weight reduction, and prevention and management of existing metabolic syndrome components should be prioritized,” Dr. Mongraw-Chaffin and her colleagues wrote.

Individuals with MHO, defined in this study as a body mass index of 30 kg/m² or greater without metabolic syndrome, have a relatively favorable metabolic profile. However, their precise level of CVD risk remains contentious, the investigators noted.

“Although the accumulating evidence is leaning toward the consensus that MHO is not a low-risk state compared with metabolically healthy normal weight, many questions remain about the risk stratification for this group and what causes the heterogeneity seen in the literature,” they wrote.

SOURCE: Mongraw-Chaffin M et al. J Am Coll Cardiol 2018 May 1;71(17):1857-65.

Many individuals with metabolically healthy obesity (MHO) will progress to metabolic syndrome over time, putting them at increased risk of cardiovascular disease (CVD), analysis of population-based longitudinal cohort study suggests.

Nearly half of the individuals with MHO developed metabolic syndrome over time, according to the analysis of 6,809 participants followed since the year 2000 in the Multi-Ethnic Study of Atherosclerosis.

Those who developed metabolic syndrome had an increased risk of CVD, compared with those who did not, according to results published in the Journal of the American College of Cardiology.

The results provide new evidence that MHO alone is not a stable or reliable characterization of lower CVD risk, according to Morgana Mongraw-Chaffin, PhD, of the department of epidemiology and prevention at Wake Forest University, Winston-Salem, N.C., and her coauthors.

“Instead, MHO signals an opportunity for weight reduction, and prevention and management of existing metabolic syndrome components should be prioritized,” Dr. Mongraw-Chaffin and her colleagues wrote.

Individuals with MHO, defined in this study as a body mass index of 30 kg/m² or greater without metabolic syndrome, have a relatively favorable metabolic profile. However, their precise level of CVD risk remains contentious, the investigators noted.

“Although the accumulating evidence is leaning toward the consensus that MHO is not a low-risk state compared with metabolically healthy normal weight, many questions remain about the risk stratification for this group and what causes the heterogeneity seen in the literature,” they wrote.

SOURCE: Mongraw-Chaffin M et al. J Am Coll Cardiol 2018 May 1;71(17):1857-65.

Many individuals with metabolically healthy obesity (MHO) will progress to metabolic syndrome over time, putting them at increased risk of cardiovascular disease (CVD), analysis of population-based longitudinal cohort study suggests.

Nearly half of the individuals with MHO developed metabolic syndrome over time, according to the analysis of 6,809 participants followed since the year 2000 in the Multi-Ethnic Study of Atherosclerosis.

Those who developed metabolic syndrome had an increased risk of CVD, compared with those who did not, according to results published in the Journal of the American College of Cardiology.

The results provide new evidence that MHO alone is not a stable or reliable characterization of lower CVD risk, according to Morgana Mongraw-Chaffin, PhD, of the department of epidemiology and prevention at Wake Forest University, Winston-Salem, N.C., and her coauthors.

“Instead, MHO signals an opportunity for weight reduction, and prevention and management of existing metabolic syndrome components should be prioritized,” Dr. Mongraw-Chaffin and her colleagues wrote.

Individuals with MHO, defined in this study as a body mass index of 30 kg/m² or greater without metabolic syndrome, have a relatively favorable metabolic profile. However, their precise level of CVD risk remains contentious, the investigators noted.

“Although the accumulating evidence is leaning toward the consensus that MHO is not a low-risk state compared with metabolically healthy normal weight, many questions remain about the risk stratification for this group and what causes the heterogeneity seen in the literature,” they wrote.

SOURCE: Mongraw-Chaffin M et al. J Am Coll Cardiol 2018 May 1;71(17):1857-65.

MADRID – Five days of nitrofurantoin was significantly more effective than was a single large dose of fosfomycin in effecting both clinical and microbiological cure among women with uncomplicated lower urinary tract infections (UTIs), a randomized study has determined.

By 28 days, clinical resolution had occurred in 70% of those who took nitrofurantoin and 58% of those who took fosfomycin – a statistically significant 12% difference, Angela Huttner, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

But the benefit was even more pronounced in women whose infections were caused by Escherichia coli, with a 28% spread in clinical resolution, (78% vs. 50%) and a 14-point spread in microbiological cure (72% vs. 58%), said Dr. Huttner of Geneva University, Switzerland.

The results were simultaneously published online in JAMA (2018 Apr 22. doi: 10.1001/jama.2018.3627).

Michele G. Sullivan/MDedge News

SOURCE: Huttner A et al. ECCMID 2018. Abstract O0479.

MADRID – Five days of nitrofurantoin was significantly more effective than was a single large dose of fosfomycin in effecting both clinical and microbiological cure among women with uncomplicated lower urinary tract infections (UTIs), a randomized study has determined.

By 28 days, clinical resolution had occurred in 70% of those who took nitrofurantoin and 58% of those who took fosfomycin – a statistically significant 12% difference, Angela Huttner, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

But the benefit was even more pronounced in women whose infections were caused by Escherichia coli, with a 28% spread in clinical resolution, (78% vs. 50%) and a 14-point spread in microbiological cure (72% vs. 58%), said Dr. Huttner of Geneva University, Switzerland.

The results were simultaneously published online in JAMA (2018 Apr 22. doi: 10.1001/jama.2018.3627).

Michele G. Sullivan/MDedge News

SOURCE: Huttner A et al. ECCMID 2018. Abstract O0479.

MADRID – Five days of nitrofurantoin was significantly more effective than was a single large dose of fosfomycin in effecting both clinical and microbiological cure among women with uncomplicated lower urinary tract infections (UTIs), a randomized study has determined.

By 28 days, clinical resolution had occurred in 70% of those who took nitrofurantoin and 58% of those who took fosfomycin – a statistically significant 12% difference, Angela Huttner, MD, said at the European Society of Clinical Microbiology and Infectious Diseases annual congress.

But the benefit was even more pronounced in women whose infections were caused by Escherichia coli, with a 28% spread in clinical resolution, (78% vs. 50%) and a 14-point spread in microbiological cure (72% vs. 58%), said Dr. Huttner of Geneva University, Switzerland.

The results were simultaneously published online in JAMA (2018 Apr 22. doi: 10.1001/jama.2018.3627).

Michele G. Sullivan/MDedge News

SOURCE: Huttner A et al. ECCMID 2018. Abstract O0479.

The last two decades have seen an ever-growing number of reports on risks of fetal exposure to medicines used to treat depression during pregnancy. These reports have described issues ranging from estimated risk of congenital malformations following fetal exposure to various psychotropics such as SSRIs or atypical antipsychotics to adverse neonatal effects such as poor neonatal adaptation syndrome. More recent reports, derived primarily from large administrative databases, have focused on concerns regarding both risk for later childhood psychopathology such as autism or ADHD or neurobehavioral sequelae such as motor or speech delay following fetal exposure to antidepressants.

When considering the potential risks of fetal exposure to antidepressants on the spectrum of relevant outcomes, it is important to keep in mind the risks of not receiving antidepressant treatment. Data on known risks of antidepressant use during pregnancy are well described, but the literature supporting adverse effects of untreated depression during pregnancy has also grown substantially. For example, accumulated data over the last several years supports heightened risk for obstetrical and neonatal complications among women who suffer from untreated depression and recent data is inconclusive regarding the effects of untreated maternal depression on gene expression in the CNS during gestation and the effects of depression during pregnancy on development of actual brain structures in areas of the brain that modulate emotion and behavior.

monkeybusinessimages/Thinkstock

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

The last two decades have seen an ever-growing number of reports on risks of fetal exposure to medicines used to treat depression during pregnancy. These reports have described issues ranging from estimated risk of congenital malformations following fetal exposure to various psychotropics such as SSRIs or atypical antipsychotics to adverse neonatal effects such as poor neonatal adaptation syndrome. More recent reports, derived primarily from large administrative databases, have focused on concerns regarding both risk for later childhood psychopathology such as autism or ADHD or neurobehavioral sequelae such as motor or speech delay following fetal exposure to antidepressants.

When considering the potential risks of fetal exposure to antidepressants on the spectrum of relevant outcomes, it is important to keep in mind the risks of not receiving antidepressant treatment. Data on known risks of antidepressant use during pregnancy are well described, but the literature supporting adverse effects of untreated depression during pregnancy has also grown substantially. For example, accumulated data over the last several years supports heightened risk for obstetrical and neonatal complications among women who suffer from untreated depression and recent data is inconclusive regarding the effects of untreated maternal depression on gene expression in the CNS during gestation and the effects of depression during pregnancy on development of actual brain structures in areas of the brain that modulate emotion and behavior.

monkeybusinessimages/Thinkstock

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

The last two decades have seen an ever-growing number of reports on risks of fetal exposure to medicines used to treat depression during pregnancy. These reports have described issues ranging from estimated risk of congenital malformations following fetal exposure to various psychotropics such as SSRIs or atypical antipsychotics to adverse neonatal effects such as poor neonatal adaptation syndrome. More recent reports, derived primarily from large administrative databases, have focused on concerns regarding both risk for later childhood psychopathology such as autism or ADHD or neurobehavioral sequelae such as motor or speech delay following fetal exposure to antidepressants.

When considering the potential risks of fetal exposure to antidepressants on the spectrum of relevant outcomes, it is important to keep in mind the risks of not receiving antidepressant treatment. Data on known risks of antidepressant use during pregnancy are well described, but the literature supporting adverse effects of untreated depression during pregnancy has also grown substantially. For example, accumulated data over the last several years supports heightened risk for obstetrical and neonatal complications among women who suffer from untreated depression and recent data is inconclusive regarding the effects of untreated maternal depression on gene expression in the CNS during gestation and the effects of depression during pregnancy on development of actual brain structures in areas of the brain that modulate emotion and behavior.

monkeybusinessimages/Thinkstock

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.

Many adolescents and young adults with inflammatory bowel disease (IBD) use marijuana and perceive little to no harm from regular use, according to study findings.

In a cross-sectional study of 99 patients with IBD aged 13-22 years, 32% of participants reported ever having used marijuana or endorsing use in the past 6 months. Additionally, 42% of patients perceived little to no risk of harm with regular use, reported Edward J. Hoffenberg, MD, of the departments of pediatrics and psychiatry at the University of Colorado, Aurora, and his associates.

Stockphoto4u/iStockphoto

SOURCE: Hoffenberg EJ et al. 2018. doi: 10.1016/j.jpeds.2018.03.041.

Many adolescents and young adults with inflammatory bowel disease (IBD) use marijuana and perceive little to no harm from regular use, according to study findings.

In a cross-sectional study of 99 patients with IBD aged 13-22 years, 32% of participants reported ever having used marijuana or endorsing use in the past 6 months. Additionally, 42% of patients perceived little to no risk of harm with regular use, reported Edward J. Hoffenberg, MD, of the departments of pediatrics and psychiatry at the University of Colorado, Aurora, and his associates.

Stockphoto4u/iStockphoto

SOURCE: Hoffenberg EJ et al. 2018. doi: 10.1016/j.jpeds.2018.03.041.

Many adolescents and young adults with inflammatory bowel disease (IBD) use marijuana and perceive little to no harm from regular use, according to study findings.

In a cross-sectional study of 99 patients with IBD aged 13-22 years, 32% of participants reported ever having used marijuana or endorsing use in the past 6 months. Additionally, 42% of patients perceived little to no risk of harm with regular use, reported Edward J. Hoffenberg, MD, of the departments of pediatrics and psychiatry at the University of Colorado, Aurora, and his associates.

Stockphoto4u/iStockphoto

SOURCE: Hoffenberg EJ et al. 2018. doi: 10.1016/j.jpeds.2018.03.041.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

CHICAGO – The intratumoral Toll-Like Receptor 9 (TLR-9) agonist, CMP-001, in combination with pembrolizumab in advanced melanoma patients, was well tolerated with a durable systemic clinical response, according to early results from an ongoing phase 1 trial.

Objective response rates on weekly (n = 56) and every 3 weeks schedules (n = 13) were 23% (13%-36%) and 15% (2%-45%) respectively, reported Mohammed M. Milhem, MBBS, of the University of Iowa, Iowa City.

For those dosed weekly at low dose (less than 5 mL) and high dose (5 mL or more), the ORR was 19% (n = 43, 95% confidence interval, 8%-33%) and 27% (n = 26, 95% CI, 12%-48%), respectively. Activity was demonstrated in subjects regardless of tumor burden, Dr. Milhem said at the annual meeting of the American Association for Cancer Research.

In this phase 1b study with a 3+3 design of dose escalation and expansion, the researchers enrolled patients with advanced melanoma who did not respond or had progressed resistant on prior anti-PD-1 monotherapy or in combination. CMP-001 was injected intratumorally in combination with pembrolizumab as per label intravenously.

The study drug CMP-001 has two components, a 30-mer CpG-A DNA oligonucleotide and a nonvirulent virus-like particle (VLP). The CpG-A DNA is packaged within the VLP that protects it from degradation and also allows TLR9 receptor uptake. CpG-A DNA acts as a TLR9 agonist by binding to it, thereby activating plasmacytoid dendritic cells (pDCs) within the tumor microenvironment. The activation results in secretion of large amounts of type 1 interferon and Th1 chemokines, changing the microenvironment from a “cold/desert-like” immune suppressed state to a “hot” antitumor inflamed state, Dr. Milhem said.

“The T cells thus generated can mediate tumor rejection both in the injected and noninjected tumor,” he said. Two CMP-001 schedules were evaluated, weekly for 7 weeks or weekly for 2 weeks, followed thereafter by every 3 weeks until discontinuation (due to progression, toxicity, investigator decision, or withdrawal of consent). Scans were done every 12 weeks and tumor response was assessed by RECIST v1.1.

The CMP-001 dose escalation scheme ranged from 1 mg to 10 mg. The maximum tolerated dose was not reached and the dose of 5 mg/weekly plus pembrolizumab was used for the dose expansion phase. It was up to the investigator to increase the dose to 10 mg since maximum tolerated dose was not reached. The key inclusion criteria were metastatic or unresectable melanoma; in the dose escalation phase prior best response to anti-PD1-based therapy was disease progression or stable disease. In the dose expansion phase, patients who had progressed on anti-PD1 based therapy were allowed regardless of best response. There was no restriction on the number of prior lines of therapy.

A total of 69 subjects were treated, 44 subjects from dose escalation and 25 in the expansion phase (ongoing). Two subjects discontinued because of treatment-related adverse events. The rest of the patients had a manageable toxicity profile consisting predominantly of fever, nausea/vomiting, hypotension and rigors. Severe grade 3/4 treatment-related adverse events were reported in more than 1 subject, with hypotension (n = 9, 13%) being the most prominent AE, followed by anemia (n = 2, 3%), chills (n = 2, 3%), and hypertension (n = 2, 3%). Hypotension was manageable by responsive fluid resuscitation and in some patients required stress dose steroids. Most of these side effects occurred 1-4 hours after the CMP-001 injection.

Of the 18 responders, 1 progressed, 2 withdrew consent, and 13 remain on study with 2 subjects maintaining their response though week 72. The median duration of response was not reached. Regression of noninjected tumors occurred in cutaneous, nodal, hepatic, and splenic metastases.

“CMP-001 plus pembrolizumab induced systemic antitumor activity, and not just local efficacy since both injected and noninjected target lesions changed from baseline per RECIST,” Dr. Milhem said. Not only did the responders show a rapid reduction in target lesions from baseline, but also a durable tumor regression as usually seen with other immunotherapeutics.

Immunohistochemical analysis of tumor biopsies demonstrated increase in CD8 (greater than fivefold) and PD-L1 expression, 5 weeks after therapy in a subset of patients with pre- and posttreatment biopsies. Transcriptional analysis by RNA-seq revealed induction of T cell inflamed gene signature, notably significant upregulation of TLR, and IFN-responsive genes.

It would be interesting to further investigate how this combination therapy compares with other strategies in a similar clinical scenario, such as oncolytic virus, other TLR ligands or means of APC activation, discussant Jedd Wolchok, MD, PhD, pointed out. Understanding resistance mechanisms at an individual patient level and optimal patient selection for this combination therapy remains a challenge, he said.

Dr. Milhem had no financial relationships to disclose.

SOURCE: Milhem MD et al. AACR Annual Meeting Abstract CT144.

Asthma patients who struggle with poor control despite using inhaled corticosteroids can benefit from additional treatment with long-acting muscarinic antagonists (LAMAs) or single maintenance and reliever therapy, suggest data from a pair of systematic reviews and meta-analyses.

Asthma control remains a problem for many patients despite the daily use of inhaled corticosteroids. The current preferred adjunct therapy for patients aged 12 years and older is long-acting beta-agonists (LABAs), wrote Diana M. Sobieraj, PharmD, of the University of Connecticut School of Pharmacy, Storrs, and her colleagues in a study published in JAMA. The researchers examined the efficacy of other adjunct therapies and therapeutic regimes, including the use of a LAMA, in two studies of patients with persistent asthma.

MattZ90/thinkstockphotos

“Triple therapy was not significantly associated with improvements in rescue medication use vs. combined inhaled corticosteroids and LABA therapy,” the researchers added.

The review of LAMAs used as add-on therapy was limited by several factors, including a primary focus on tiotropium, a lack of analysis of harms or the costs of the various therapies, the lack of data for children, and an inability to perform a subgroup analysis, the researchers said. Although LAMA use was associated with a lower risk of asthma exacerbation, compared with placebo use, the review could not adequately compare LAMA with controllers other than LABA, they added.

In the second analysis, which also was published in JAMA, the researchers evaluated the use of inhaled corticosteroids and LABAs as both a controller and quick-relief treatment, a strategy known as SMART, or Single Maintenance and Reliever Therapy. The SMART protocol, which is not approved in the United States, involved taking a combination of the corticosteroid budesonide and the LABA formoterol in a dry-powder inhaler in most of the studies reviewed.

Overall, in the analysis of 22,524 patients aged 12 years and older, an absolute risk difference of –2.8% for asthma exacerbations was seen in those who used the SMART protocol versus those who used a higher dose of inhaled corticosteroids and inhaled LABA as controller therapy.

In addition, data from 341 children aged 4-11 years showed a –12% absolute difference in risk of asthma exacerbation with the SMART therapy.

In trials that compared patients using the SMART protocol with those taking only the dose of inhaled corticosteroids called for by SMART, the protocol was associated with an improvement in forced expiratory volume in 1 second (FEV₁) and a reduction in the need for rescue medication.

The SMART protocol also demonstrated advantages over taking the same dose of inhaled corticosteroid called for by SMART plus a LABA controller therapy or a higher dose of inhaled corticosteroids with a LABA controller therapy. Specifically, SMART patients experienced a –6.4% risk of asthma exacerbations, versus the first comparator group; and a –2.7% risk of asthma, compared with the group who took a higher dose of inhaled corticosteroids with LABA controller therapy.

No significant associations appeared in any of the studies between the SMART protocol and outcomes that included all-cause mortality or changes in FEV₁, forced vital capacity, or the percentage of predicted FEV₁, when compared with those for patients who used a LABA controller therapy plus inhaled corticosteroids at either dose.

The SMART protocol review was limited by factors that included a lack of data on adverse events, a lack of subgroup analysis, and the potential for bias, because of the open label nature of some of the studies, the researchers noted.

However, despite the limitations in both reviews, the results support the SMART strategy and LAMAs as alternatives for patients with persistent asthma, and highlight the need for further research, they noted.

The reviews were supported by the Agency for Healthcare Research and Quality. Dr. Sobieraj had no financial conflicts to disclose.

SOURCE: Sobieraj D et al. JAMA. 2018;319(14):1473-84. Sobieraj D et al. JAMA. 2018;319(14):1485-96.

Asthma patients who struggle with poor control despite using inhaled corticosteroids can benefit from additional treatment with long-acting muscarinic antagonists (LAMAs) or single maintenance and reliever therapy, suggest data from a pair of systematic reviews and meta-analyses.

Asthma control remains a problem for many patients despite the daily use of inhaled corticosteroids. The current preferred adjunct therapy for patients aged 12 years and older is long-acting beta-agonists (LABAs), wrote Diana M. Sobieraj, PharmD, of the University of Connecticut School of Pharmacy, Storrs, and her colleagues in a study published in JAMA. The researchers examined the efficacy of other adjunct therapies and therapeutic regimes, including the use of a LAMA, in two studies of patients with persistent asthma.

MattZ90/thinkstockphotos

“Triple therapy was not significantly associated with improvements in rescue medication use vs. combined inhaled corticosteroids and LABA therapy,” the researchers added.

The review of LAMAs used as add-on therapy was limited by several factors, including a primary focus on tiotropium, a lack of analysis of harms or the costs of the various therapies, the lack of data for children, and an inability to perform a subgroup analysis, the researchers said. Although LAMA use was associated with a lower risk of asthma exacerbation, compared with placebo use, the review could not adequately compare LAMA with controllers other than LABA, they added.

In the second analysis, which also was published in JAMA, the researchers evaluated the use of inhaled corticosteroids and LABAs as both a controller and quick-relief treatment, a strategy known as SMART, or Single Maintenance and Reliever Therapy. The SMART protocol, which is not approved in the United States, involved taking a combination of the corticosteroid budesonide and the LABA formoterol in a dry-powder inhaler in most of the studies reviewed.

Overall, in the analysis of 22,524 patients aged 12 years and older, an absolute risk difference of –2.8% for asthma exacerbations was seen in those who used the SMART protocol versus those who used a higher dose of inhaled corticosteroids and inhaled LABA as controller therapy.

In addition, data from 341 children aged 4-11 years showed a –12% absolute difference in risk of asthma exacerbation with the SMART therapy.

In trials that compared patients using the SMART protocol with those taking only the dose of inhaled corticosteroids called for by SMART, the protocol was associated with an improvement in forced expiratory volume in 1 second (FEV₁) and a reduction in the need for rescue medication.

The SMART protocol also demonstrated advantages over taking the same dose of inhaled corticosteroid called for by SMART plus a LABA controller therapy or a higher dose of inhaled corticosteroids with a LABA controller therapy. Specifically, SMART patients experienced a –6.4% risk of asthma exacerbations, versus the first comparator group; and a –2.7% risk of asthma, compared with the group who took a higher dose of inhaled corticosteroids with LABA controller therapy.

No significant associations appeared in any of the studies between the SMART protocol and outcomes that included all-cause mortality or changes in FEV₁, forced vital capacity, or the percentage of predicted FEV₁, when compared with those for patients who used a LABA controller therapy plus inhaled corticosteroids at either dose.

The SMART protocol review was limited by factors that included a lack of data on adverse events, a lack of subgroup analysis, and the potential for bias, because of the open label nature of some of the studies, the researchers noted.

However, despite the limitations in both reviews, the results support the SMART strategy and LAMAs as alternatives for patients with persistent asthma, and highlight the need for further research, they noted.

The reviews were supported by the Agency for Healthcare Research and Quality. Dr. Sobieraj had no financial conflicts to disclose.

SOURCE: Sobieraj D et al. JAMA. 2018;319(14):1473-84. Sobieraj D et al. JAMA. 2018;319(14):1485-96.

Asthma patients who struggle with poor control despite using inhaled corticosteroids can benefit from additional treatment with long-acting muscarinic antagonists (LAMAs) or single maintenance and reliever therapy, suggest data from a pair of systematic reviews and meta-analyses.

Asthma control remains a problem for many patients despite the daily use of inhaled corticosteroids. The current preferred adjunct therapy for patients aged 12 years and older is long-acting beta-agonists (LABAs), wrote Diana M. Sobieraj, PharmD, of the University of Connecticut School of Pharmacy, Storrs, and her colleagues in a study published in JAMA. The researchers examined the efficacy of other adjunct therapies and therapeutic regimes, including the use of a LAMA, in two studies of patients with persistent asthma.

MattZ90/thinkstockphotos

“Triple therapy was not significantly associated with improvements in rescue medication use vs. combined inhaled corticosteroids and LABA therapy,” the researchers added.

The review of LAMAs used as add-on therapy was limited by several factors, including a primary focus on tiotropium, a lack of analysis of harms or the costs of the various therapies, the lack of data for children, and an inability to perform a subgroup analysis, the researchers said. Although LAMA use was associated with a lower risk of asthma exacerbation, compared with placebo use, the review could not adequately compare LAMA with controllers other than LABA, they added.

In the second analysis, which also was published in JAMA, the researchers evaluated the use of inhaled corticosteroids and LABAs as both a controller and quick-relief treatment, a strategy known as SMART, or Single Maintenance and Reliever Therapy. The SMART protocol, which is not approved in the United States, involved taking a combination of the corticosteroid budesonide and the LABA formoterol in a dry-powder inhaler in most of the studies reviewed.

Overall, in the analysis of 22,524 patients aged 12 years and older, an absolute risk difference of –2.8% for asthma exacerbations was seen in those who used the SMART protocol versus those who used a higher dose of inhaled corticosteroids and inhaled LABA as controller therapy.

In addition, data from 341 children aged 4-11 years showed a –12% absolute difference in risk of asthma exacerbation with the SMART therapy.

In trials that compared patients using the SMART protocol with those taking only the dose of inhaled corticosteroids called for by SMART, the protocol was associated with an improvement in forced expiratory volume in 1 second (FEV₁) and a reduction in the need for rescue medication.

The SMART protocol also demonstrated advantages over taking the same dose of inhaled corticosteroid called for by SMART plus a LABA controller therapy or a higher dose of inhaled corticosteroids with a LABA controller therapy. Specifically, SMART patients experienced a –6.4% risk of asthma exacerbations, versus the first comparator group; and a –2.7% risk of asthma, compared with the group who took a higher dose of inhaled corticosteroids with LABA controller therapy.

No significant associations appeared in any of the studies between the SMART protocol and outcomes that included all-cause mortality or changes in FEV₁, forced vital capacity, or the percentage of predicted FEV₁, when compared with those for patients who used a LABA controller therapy plus inhaled corticosteroids at either dose.

The SMART protocol review was limited by factors that included a lack of data on adverse events, a lack of subgroup analysis, and the potential for bias, because of the open label nature of some of the studies, the researchers noted.

However, despite the limitations in both reviews, the results support the SMART strategy and LAMAs as alternatives for patients with persistent asthma, and highlight the need for further research, they noted.

The reviews were supported by the Agency for Healthcare Research and Quality. Dr. Sobieraj had no financial conflicts to disclose.

SOURCE: Sobieraj D et al. JAMA. 2018;319(14):1473-84. Sobieraj D et al. JAMA. 2018;319(14):1485-96.

Patients with inflammatory bowel disease had about a 28% higher risk of Parkinson’s disease (PD) than that of matched controls in a large retrospective analysis of administrative health care claims.

But tumor necrosis factor (TNF) inhibitor therapy appeared to attenuate this risk, wrote Inga Peter, PhD, of Icahn School of Medicine at Mount Sinai, New York, and her associates. Patients with inflammatory bowel disease (IBD) who received TNF inhibitors were 78% less likely to develop PD than were those who did not (P = .03). “Reducing systemic inflammation in at-risk individuals may decrease the incidence of PD [Parkinson disease],” the researchers wrote. The study was published online April 23 in JAMA Neurology.

The researchers queried the Truven Health MarketScan database and the Medicare Supplemental Database for patients with IBD from 2000 through 2016. The databases included more than 170 million patients, of whom 144,018 had at least two IBD-related claims, at least 6 months of follow-up, and no baseline PD diagnosis. These patients were matched by age, sex, and treatment year with 720,090 individuals without IBD from the same databases.

A total of 1,796 patients had at least two recorded PD diagnoses and had filled at least one associated prescription, said the researchers. Based on this PD definition, patients with IBD developed PD at a 28% higher rate than that of matched controls (adjusted IRR, 1.28; 95% CI, 1.14 to 1.44; P less than .001).

Among the IBD patients, those receiving anti-TNF therapy developed about 0.08 cases of PD for every 1,000 person-years, versus 0.76 PD cases per 1,000 person-years in the group not receiving anti-TNF therapy. After adjustment for age, sex, and time at risk, anti-TNF therapy was associated with a 78% reduction in the incidence of PD among IBD patients (adjusted incidence rate ratio, 0.22; 95% confidence interval, 0.05-0.88; P = .03).

“In summary, we showed a potential clinical link between IBD and PD, supporting shared mechanisms involved in the pathogenesis of these diseases,” the researchers wrote. “Moreover, our data suggest that early exposure to anti-TNF therapy may reduce the risk of PD among patients with IBD, potentially owing to a reduction in systemic inflammation. These findings should be further assessed and confirmed by other studies.”

Dr. Peter received support from the Leona M. and Harry B. Helmsley Charitable Trust. AbbVie employed three coinvestigators. Two coinvestigators had other ties to Abbvie and Amgen.

SOURCE: Peter I et al. JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0605.

Patients with inflammatory bowel disease had about a 28% higher risk of Parkinson’s disease (PD) than that of matched controls in a large retrospective analysis of administrative health care claims.

But tumor necrosis factor (TNF) inhibitor therapy appeared to attenuate this risk, wrote Inga Peter, PhD, of Icahn School of Medicine at Mount Sinai, New York, and her associates. Patients with inflammatory bowel disease (IBD) who received TNF inhibitors were 78% less likely to develop PD than were those who did not (P = .03). “Reducing systemic inflammation in at-risk individuals may decrease the incidence of PD [Parkinson disease],” the researchers wrote. The study was published online April 23 in JAMA Neurology.

The researchers queried the Truven Health MarketScan database and the Medicare Supplemental Database for patients with IBD from 2000 through 2016. The databases included more than 170 million patients, of whom 144,018 had at least two IBD-related claims, at least 6 months of follow-up, and no baseline PD diagnosis. These patients were matched by age, sex, and treatment year with 720,090 individuals without IBD from the same databases.

A total of 1,796 patients had at least two recorded PD diagnoses and had filled at least one associated prescription, said the researchers. Based on this PD definition, patients with IBD developed PD at a 28% higher rate than that of matched controls (adjusted IRR, 1.28; 95% CI, 1.14 to 1.44; P less than .001).

Among the IBD patients, those receiving anti-TNF therapy developed about 0.08 cases of PD for every 1,000 person-years, versus 0.76 PD cases per 1,000 person-years in the group not receiving anti-TNF therapy. After adjustment for age, sex, and time at risk, anti-TNF therapy was associated with a 78% reduction in the incidence of PD among IBD patients (adjusted incidence rate ratio, 0.22; 95% confidence interval, 0.05-0.88; P = .03).

“In summary, we showed a potential clinical link between IBD and PD, supporting shared mechanisms involved in the pathogenesis of these diseases,” the researchers wrote. “Moreover, our data suggest that early exposure to anti-TNF therapy may reduce the risk of PD among patients with IBD, potentially owing to a reduction in systemic inflammation. These findings should be further assessed and confirmed by other studies.”

Dr. Peter received support from the Leona M. and Harry B. Helmsley Charitable Trust. AbbVie employed three coinvestigators. Two coinvestigators had other ties to Abbvie and Amgen.

SOURCE: Peter I et al. JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0605.

Patients with inflammatory bowel disease had about a 28% higher risk of Parkinson’s disease (PD) than that of matched controls in a large retrospective analysis of administrative health care claims.

But tumor necrosis factor (TNF) inhibitor therapy appeared to attenuate this risk, wrote Inga Peter, PhD, of Icahn School of Medicine at Mount Sinai, New York, and her associates. Patients with inflammatory bowel disease (IBD) who received TNF inhibitors were 78% less likely to develop PD than were those who did not (P = .03). “Reducing systemic inflammation in at-risk individuals may decrease the incidence of PD [Parkinson disease],” the researchers wrote. The study was published online April 23 in JAMA Neurology.

The researchers queried the Truven Health MarketScan database and the Medicare Supplemental Database for patients with IBD from 2000 through 2016. The databases included more than 170 million patients, of whom 144,018 had at least two IBD-related claims, at least 6 months of follow-up, and no baseline PD diagnosis. These patients were matched by age, sex, and treatment year with 720,090 individuals without IBD from the same databases.

A total of 1,796 patients had at least two recorded PD diagnoses and had filled at least one associated prescription, said the researchers. Based on this PD definition, patients with IBD developed PD at a 28% higher rate than that of matched controls (adjusted IRR, 1.28; 95% CI, 1.14 to 1.44; P less than .001).

Among the IBD patients, those receiving anti-TNF therapy developed about 0.08 cases of PD for every 1,000 person-years, versus 0.76 PD cases per 1,000 person-years in the group not receiving anti-TNF therapy. After adjustment for age, sex, and time at risk, anti-TNF therapy was associated with a 78% reduction in the incidence of PD among IBD patients (adjusted incidence rate ratio, 0.22; 95% confidence interval, 0.05-0.88; P = .03).

“In summary, we showed a potential clinical link between IBD and PD, supporting shared mechanisms involved in the pathogenesis of these diseases,” the researchers wrote. “Moreover, our data suggest that early exposure to anti-TNF therapy may reduce the risk of PD among patients with IBD, potentially owing to a reduction in systemic inflammation. These findings should be further assessed and confirmed by other studies.”

Dr. Peter received support from the Leona M. and Harry B. Helmsley Charitable Trust. AbbVie employed three coinvestigators. Two coinvestigators had other ties to Abbvie and Amgen.

SOURCE: Peter I et al. JAMA Neurol. 2018 Apr 23. doi: 10.1001/jamaneurol.2018.0605.