PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.

Will Pass/MDedge News

“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.

Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.

“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”

A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.


Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”

When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.

Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).

In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.

“This has stepped up the game hugely,” Dr. Pasi said.

The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.

Gene modification is also not coming anytime soon.

“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”

Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.

“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”

Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.

Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.

“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”

The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.

Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”

Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.

“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”

PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.

Will Pass/MDedge News

“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.

Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.

“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”

A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.


Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”

When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.

Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).

In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.

“This has stepped up the game hugely,” Dr. Pasi said.

The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.

Gene modification is also not coming anytime soon.

“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”

Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.

“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”

Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.

Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.

“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”

The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.

Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”

Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.

“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”

PRAGUE – Adeno-associated virus (AAV)–based gene therapy is probably not the “endgame” in gene therapy for hemophilia, according to John Pasi, MD, PhD, director of the Haemophilia Centre at the Royal London Hospital.

Will Pass/MDedge News

“Gene therapy today is essentially gene therapy version 1.0,” Dr. Pasi said, kicking off the third day at the annual congress of the European Association for Haemophilia and Allied Disorders.

Interwoven with a summary of recent research and upcoming trends, Dr. Pasi reflected upon the medical community’s expectations for gene therapy, both past and present.

“For years,” Dr. Pasi said, “gene therapy has been regarded, essentially, as the Holy Grail of treatment for hemophilia.” This sentiment has been supported by the fact that hemophilia “is a single-gene disorder with a cause and effect relationship that is extremely clear and straightforward for us to recognize.”

A small increase in clotting factor can significantly reduce bleeding while providing a measurable efficacy outcome, making it a strong research candidate.


Looking back, however, when gene therapy research began in the early 1990s, it “really did go through a peak of inflated expectations,” Dr. Pasi said. “We thought for years it was just around the corner. But there were abject failures; there were learning curves we had to go through to understand many of the issues that gene therapy threw up, which we didn’t understand at the beginning.”

When this early excitement was met with tough realities, a period of disillusionment began and persisted through the early 2000s. Dr. Pasi suggested that this period of disillusionment may be reaching an end because of a “huge amount of steady work” that has ushered in a new period of productivity.

Dr. Pasi cited two 2017 studies published in the New England Journal of Medicine by Savita Rangarajan, MBBS, and colleagues and Lindsey A. George, MD, and colleagues for hemophilia A and B, respectively (N Engl J Med. 2017; 377:2519-30; N Engl J Med. 2017; 377:2215-27).

In contrast with previous studies showing factor levels in the single digits, recent studies have achieved normal-range values. Seeing such improvements in hemophilia A, is a particular source of optimism; historically, gene therapy for hemophilia A has lagged behind hemophilia B because of a larger gene that is more difficult to work with.

“This has stepped up the game hugely,” Dr. Pasi said.

The elements of gene therapy for hemophilia may change over time. For instance, lentiviruses could be used instead of AAV-based methods, and ex vivo techniques could make a comeback, potentially using different tissue sources. These changes are likely on the distant horizon, however.

Gene modification is also not coming anytime soon.

“Gene replacement, gene editing, and gene repair are something that we hear a lot about in the general field of gene therapy,” Dr. Pasi said, “But in practical terms for our patients, we probably are a significant way off from this at the moment, and this is because we know and we all recognize that there are a wide range of mutations causing hemophilia, and many of these are highly specific; we will need specific gene therapies to address specific mutations.”

Dr. Pasi likened the current state of gene therapy to that of the self-driving car, suggesting that “we still have strides to make, and there are still things we can improve on beyond what we have today.

“The biggest question for gene therapy today is durability,” Dr. Pasi said. “How long are these things going to last?”

Patients from earlier studies are now crossing the half-decade mark, albeit with relatively low factor levels, compared with recent techniques. One such study, presented at the 2018 annual meeting of the American Society of Hematology by Amit C. Nathwani, MD, PhD, and colleagues, is “very critical to our understanding,” Dr. Pasi said, referring to patients who are now 6-8 years post treatment. “What we see is … continued, stable expression of factor IX,” he said.

Alongside questions of durability, safety remains paramount in the quest for better methods of gene therapy.

“We are seeing liver function abnormalities,” Dr. Pasi said, noting that these tend to be transient elevations of ALT. “We know that many patients now have to receive steroid treatment, which very effectively reduces the immune response, but it is something that we are increasingly having to bear in mind.”

The latest techniques are using liver-specific promoters in novel synthetic capsids, and more capsids are under development.

Dr. Pasi also emphasized safety and caution. “We must never forget that gene therapy is a completely new approach to treatment, and we’ve got to think about safety. It is the number one priority when we are investigating new treatments.”

Safety remains untested in several key patient subpopulations, including children and those with comorbidities or inhibitors.

“For gene therapy in 2019,” he said, “we’ve made massive strides, but we’re not quite there yet.”

DALLAS – A number of sociodemographic factors may influence health and disability insurance access by individuals with multiple sclerosis, including employment, age, gender, disease duration, marital status, and ethnicity, results from a large survey suggest.

“The last similar work was conducted over 10 years ago and so much has happened in the meantime, including the Great Recession and the introduction of the Affordable Care Act, that offers protection for health care but not for other important types of insurance (short- and long-term disability, long-term care, and life),” lead study author Sarah Planchon, PhD, said in an interview in advance of the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “MS is one of the most costly chronic diseases today. That is not only because of the cost of disease-modifying therapies but also because of lost employment and income. We wanted to better understand the insurance landscape so that we could in turn educate patients and professionals about the protection these insurances offer and advise them on how to obtain these policies.”

In an effort to evaluate factors that affect insurance access in MS, Dr. Planchon, a project scientist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio, and her colleagues used the North American Research Committee on MS (NARCOMS), iConquerMS, and the National Multiple Sclerosis Society to survey 2,507 individuals with the disease regarding insurance, demographic, health, disability, and employment status. They used covariate-adjusted nominal logistic regression to estimate odds ratios for the likelihood of having or not having a type of insurance. The majority of respondents (83%) were female, their mean age was 54 years, 91% were white, 65% were currently married, and their mean disease duration at the time of the survey was 16 years. In addition, 43% were employed full/part-time, and 29% were not employed or retired because of disability. Nearly all respondents (96%) reported having health insurance, while 59% had life insurance, 29% had private long-term disability insurance, 18% had short-term disability insurance, and 10% had long-term care insurance.

The researchers found that employment status had the greatest impact on insurance coverage. Of those with health insurance, 33% were employed full-time, compared with 89% of those with short-term disability insurance, 42% of those with private long-term disability insurance, 44% of those with long-term care insurance, and 41% of those with life insurance. Logistic regression analyses indicated that respondents employed part time were significantly more likely to have short-term disability insurance if they were currently married (odds ratio, 4.4). Short-term disability insurance was significantly more likely among fully employed patients with disease duration of 5-10 years vs. more than 20 years (OR, 2.0). Private long-term disability insurance was significantly associated with female gender (OR, 1.6), age 50-59 years vs. younger than 40 (OR, 1.6), full-time vs. part-time employment (OR, 2.3), and shorter disease duration (ORs, 1.4-1.6 for 6-10, 11-15, and 16-20 years’ duration). Long-term care insurance was associated with older age (ORs, 2.5 and 4.3 for those aged 50-59 and 60-65 vs. younger than 40), and having excellent or good general health status vs. fair or poor (OR, 1.8). Life insurance was associated with non-Hispanic ethnicity (OR, 1.6), full-time vs. part-time employment (OR, 2.4), older age (ORs, 1.6-1.7 for ages 40-49 and 50-59 vs. younger than 40), and marital status (currently/previously married, ORs, 1.6-2.6). Considering the high rate of survey respondents with health insurance, covariate-adjusted modeling was not applicable.

“The number of people with MS who do not have long-term care insurance was surprisingly high,” Dr. Planchon said. “Although the improved treatment climate recently may decrease the long-term disability levels, we do not yet know this with certainty. A large number of people with MS are likely to need long-term care in the future, which often is a significant financial burden to families.” The findings suggest that clinical care teams “need to initiate early discussions of possible long-term needs with their patients,” she continued. “Incorporation of social work teams, who are familiar with the needs of people with MS and insurance options available to them, within MS specialty practices will bolster the comprehensive care of patients and their families.”

She acknowledged certain limitations of the study, including the low proportion of respondents who were Hispanic/Latino and African American (about 4% each). “The insurance landscape may differ in these groups compared to the majority Caucasian population who responded to this survey,” Dr. Planchon said.

The National Multiple Sclerosis Society funded the study. Dr. Planchon reported having no relevant financial disclosures.

dbrunk@mdedge.com

SOURCE: Planchon S et al. ACTRIMS Forum 2019, Abstract P295.

DALLAS – A number of sociodemographic factors may influence health and disability insurance access by individuals with multiple sclerosis, including employment, age, gender, disease duration, marital status, and ethnicity, results from a large survey suggest.

“The last similar work was conducted over 10 years ago and so much has happened in the meantime, including the Great Recession and the introduction of the Affordable Care Act, that offers protection for health care but not for other important types of insurance (short- and long-term disability, long-term care, and life),” lead study author Sarah Planchon, PhD, said in an interview in advance of the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “MS is one of the most costly chronic diseases today. That is not only because of the cost of disease-modifying therapies but also because of lost employment and income. We wanted to better understand the insurance landscape so that we could in turn educate patients and professionals about the protection these insurances offer and advise them on how to obtain these policies.”

In an effort to evaluate factors that affect insurance access in MS, Dr. Planchon, a project scientist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio, and her colleagues used the North American Research Committee on MS (NARCOMS), iConquerMS, and the National Multiple Sclerosis Society to survey 2,507 individuals with the disease regarding insurance, demographic, health, disability, and employment status. They used covariate-adjusted nominal logistic regression to estimate odds ratios for the likelihood of having or not having a type of insurance. The majority of respondents (83%) were female, their mean age was 54 years, 91% were white, 65% were currently married, and their mean disease duration at the time of the survey was 16 years. In addition, 43% were employed full/part-time, and 29% were not employed or retired because of disability. Nearly all respondents (96%) reported having health insurance, while 59% had life insurance, 29% had private long-term disability insurance, 18% had short-term disability insurance, and 10% had long-term care insurance.

The researchers found that employment status had the greatest impact on insurance coverage. Of those with health insurance, 33% were employed full-time, compared with 89% of those with short-term disability insurance, 42% of those with private long-term disability insurance, 44% of those with long-term care insurance, and 41% of those with life insurance. Logistic regression analyses indicated that respondents employed part time were significantly more likely to have short-term disability insurance if they were currently married (odds ratio, 4.4). Short-term disability insurance was significantly more likely among fully employed patients with disease duration of 5-10 years vs. more than 20 years (OR, 2.0). Private long-term disability insurance was significantly associated with female gender (OR, 1.6), age 50-59 years vs. younger than 40 (OR, 1.6), full-time vs. part-time employment (OR, 2.3), and shorter disease duration (ORs, 1.4-1.6 for 6-10, 11-15, and 16-20 years’ duration). Long-term care insurance was associated with older age (ORs, 2.5 and 4.3 for those aged 50-59 and 60-65 vs. younger than 40), and having excellent or good general health status vs. fair or poor (OR, 1.8). Life insurance was associated with non-Hispanic ethnicity (OR, 1.6), full-time vs. part-time employment (OR, 2.4), older age (ORs, 1.6-1.7 for ages 40-49 and 50-59 vs. younger than 40), and marital status (currently/previously married, ORs, 1.6-2.6). Considering the high rate of survey respondents with health insurance, covariate-adjusted modeling was not applicable.

“The number of people with MS who do not have long-term care insurance was surprisingly high,” Dr. Planchon said. “Although the improved treatment climate recently may decrease the long-term disability levels, we do not yet know this with certainty. A large number of people with MS are likely to need long-term care in the future, which often is a significant financial burden to families.” The findings suggest that clinical care teams “need to initiate early discussions of possible long-term needs with their patients,” she continued. “Incorporation of social work teams, who are familiar with the needs of people with MS and insurance options available to them, within MS specialty practices will bolster the comprehensive care of patients and their families.”

She acknowledged certain limitations of the study, including the low proportion of respondents who were Hispanic/Latino and African American (about 4% each). “The insurance landscape may differ in these groups compared to the majority Caucasian population who responded to this survey,” Dr. Planchon said.

The National Multiple Sclerosis Society funded the study. Dr. Planchon reported having no relevant financial disclosures.

dbrunk@mdedge.com

SOURCE: Planchon S et al. ACTRIMS Forum 2019, Abstract P295.

DALLAS – A number of sociodemographic factors may influence health and disability insurance access by individuals with multiple sclerosis, including employment, age, gender, disease duration, marital status, and ethnicity, results from a large survey suggest.

“The last similar work was conducted over 10 years ago and so much has happened in the meantime, including the Great Recession and the introduction of the Affordable Care Act, that offers protection for health care but not for other important types of insurance (short- and long-term disability, long-term care, and life),” lead study author Sarah Planchon, PhD, said in an interview in advance of the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “MS is one of the most costly chronic diseases today. That is not only because of the cost of disease-modifying therapies but also because of lost employment and income. We wanted to better understand the insurance landscape so that we could in turn educate patients and professionals about the protection these insurances offer and advise them on how to obtain these policies.”

In an effort to evaluate factors that affect insurance access in MS, Dr. Planchon, a project scientist at the Mellen Center for Multiple Sclerosis at the Cleveland Clinic in Ohio, and her colleagues used the North American Research Committee on MS (NARCOMS), iConquerMS, and the National Multiple Sclerosis Society to survey 2,507 individuals with the disease regarding insurance, demographic, health, disability, and employment status. They used covariate-adjusted nominal logistic regression to estimate odds ratios for the likelihood of having or not having a type of insurance. The majority of respondents (83%) were female, their mean age was 54 years, 91% were white, 65% were currently married, and their mean disease duration at the time of the survey was 16 years. In addition, 43% were employed full/part-time, and 29% were not employed or retired because of disability. Nearly all respondents (96%) reported having health insurance, while 59% had life insurance, 29% had private long-term disability insurance, 18% had short-term disability insurance, and 10% had long-term care insurance.

The researchers found that employment status had the greatest impact on insurance coverage. Of those with health insurance, 33% were employed full-time, compared with 89% of those with short-term disability insurance, 42% of those with private long-term disability insurance, 44% of those with long-term care insurance, and 41% of those with life insurance. Logistic regression analyses indicated that respondents employed part time were significantly more likely to have short-term disability insurance if they were currently married (odds ratio, 4.4). Short-term disability insurance was significantly more likely among fully employed patients with disease duration of 5-10 years vs. more than 20 years (OR, 2.0). Private long-term disability insurance was significantly associated with female gender (OR, 1.6), age 50-59 years vs. younger than 40 (OR, 1.6), full-time vs. part-time employment (OR, 2.3), and shorter disease duration (ORs, 1.4-1.6 for 6-10, 11-15, and 16-20 years’ duration). Long-term care insurance was associated with older age (ORs, 2.5 and 4.3 for those aged 50-59 and 60-65 vs. younger than 40), and having excellent or good general health status vs. fair or poor (OR, 1.8). Life insurance was associated with non-Hispanic ethnicity (OR, 1.6), full-time vs. part-time employment (OR, 2.4), older age (ORs, 1.6-1.7 for ages 40-49 and 50-59 vs. younger than 40), and marital status (currently/previously married, ORs, 1.6-2.6). Considering the high rate of survey respondents with health insurance, covariate-adjusted modeling was not applicable.

“The number of people with MS who do not have long-term care insurance was surprisingly high,” Dr. Planchon said. “Although the improved treatment climate recently may decrease the long-term disability levels, we do not yet know this with certainty. A large number of people with MS are likely to need long-term care in the future, which often is a significant financial burden to families.” The findings suggest that clinical care teams “need to initiate early discussions of possible long-term needs with their patients,” she continued. “Incorporation of social work teams, who are familiar with the needs of people with MS and insurance options available to them, within MS specialty practices will bolster the comprehensive care of patients and their families.”

She acknowledged certain limitations of the study, including the low proportion of respondents who were Hispanic/Latino and African American (about 4% each). “The insurance landscape may differ in these groups compared to the majority Caucasian population who responded to this survey,” Dr. Planchon said.

The National Multiple Sclerosis Society funded the study. Dr. Planchon reported having no relevant financial disclosures.

dbrunk@mdedge.com

SOURCE: Planchon S et al. ACTRIMS Forum 2019, Abstract P295.

DALLAS – A battery of smartphone-based tests has been developed to help detect visual pathway disturbances in MS patients and to follow them over time.

“One of the ideas is, can you design something that’s so easy to use and quick that it’s not a burden on the patient?” Randy H. Kardon, MD, PhD, said in an interview at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “The other was to test a couple of different modalities. By that I mean we test visual acuity, contrast sensitivity, and critical flicker fusion, which is a way of measuring the speed of conduction of nerves in the visual system.”

Dr. Kardon, professor of neuro-ophthalmology at the University of Iowa, Iowa City, worked with colleagues from Aalborg University, Denmark, to study these tests and a novel measure known as the vanishing optotype on 117 patients with MS and 103 age-matched controls. They found that the tests “very nicely discriminated between normal eyes from patients that had MS,” said Dr. Kardon, director of the Iowa City VA Center for Prevention and Treatment of Visual Loss. “Furthermore, we could determine which eyes from the MS patients had previous optic neuritis and which eyes hadn’t. We’re now looking for partners to go forward with larger studies to validate it further and refine these tests even more.”

Dr. Kardon disclosed that he has received funding from the National Eye Institute, the Department of Defense, and from VA Rehabilitation Research and Development. He was also a member of the Novartis steering committee for the OCTiMS study and is a cofounder of MedFace and FaceX.

dbrunk@mdedge.com

DALLAS – A battery of smartphone-based tests has been developed to help detect visual pathway disturbances in MS patients and to follow them over time.

“One of the ideas is, can you design something that’s so easy to use and quick that it’s not a burden on the patient?” Randy H. Kardon, MD, PhD, said in an interview at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “The other was to test a couple of different modalities. By that I mean we test visual acuity, contrast sensitivity, and critical flicker fusion, which is a way of measuring the speed of conduction of nerves in the visual system.”

Dr. Kardon, professor of neuro-ophthalmology at the University of Iowa, Iowa City, worked with colleagues from Aalborg University, Denmark, to study these tests and a novel measure known as the vanishing optotype on 117 patients with MS and 103 age-matched controls. They found that the tests “very nicely discriminated between normal eyes from patients that had MS,” said Dr. Kardon, director of the Iowa City VA Center for Prevention and Treatment of Visual Loss. “Furthermore, we could determine which eyes from the MS patients had previous optic neuritis and which eyes hadn’t. We’re now looking for partners to go forward with larger studies to validate it further and refine these tests even more.”

Dr. Kardon disclosed that he has received funding from the National Eye Institute, the Department of Defense, and from VA Rehabilitation Research and Development. He was also a member of the Novartis steering committee for the OCTiMS study and is a cofounder of MedFace and FaceX.

dbrunk@mdedge.com

DALLAS – A battery of smartphone-based tests has been developed to help detect visual pathway disturbances in MS patients and to follow them over time.

“One of the ideas is, can you design something that’s so easy to use and quick that it’s not a burden on the patient?” Randy H. Kardon, MD, PhD, said in an interview at the meeting held by the Americas Committee for Treatment and Research in Multiple Sclerosis. “The other was to test a couple of different modalities. By that I mean we test visual acuity, contrast sensitivity, and critical flicker fusion, which is a way of measuring the speed of conduction of nerves in the visual system.”

Dr. Kardon, professor of neuro-ophthalmology at the University of Iowa, Iowa City, worked with colleagues from Aalborg University, Denmark, to study these tests and a novel measure known as the vanishing optotype on 117 patients with MS and 103 age-matched controls. They found that the tests “very nicely discriminated between normal eyes from patients that had MS,” said Dr. Kardon, director of the Iowa City VA Center for Prevention and Treatment of Visual Loss. “Furthermore, we could determine which eyes from the MS patients had previous optic neuritis and which eyes hadn’t. We’re now looking for partners to go forward with larger studies to validate it further and refine these tests even more.”

Dr. Kardon disclosed that he has received funding from the National Eye Institute, the Department of Defense, and from VA Rehabilitation Research and Development. He was also a member of the Novartis steering committee for the OCTiMS study and is a cofounder of MedFace and FaceX.

dbrunk@mdedge.com

WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.

Neil Osterweil/MDedge News

In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.

In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.

The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.

The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.

The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.

The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).

In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.

“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
 

IMiDs and thromboembolism

In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.

“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.

There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.

Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.

“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.

He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.

WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.

Neil Osterweil/MDedge News

In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.

In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.

The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.

The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.

The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.

The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).

In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.

“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
 

IMiDs and thromboembolism

In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.

“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.

There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.

Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.

“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.

He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.

WASHINGTON – Proteasome inhibitors are essential components of therapeutic regimens for multiple myeloma, but at least one member of this class of life-extending agents, carfilzomib (Kyprolis), is also associated with a significant increase in risk of heart failure, cautioned a specialist in plasma cell disorders.

Neil Osterweil/MDedge News

In addition, immunomodulating agents such as lenalidomide (Revlimid) and pomalidomide (Pomalyst) are associated with increased risk for thromboembolic events, said R. Frank Cornell, MD, clinical director of plasma cell disorders at Vanderbilt University Medical Center in Nashville, Tenn.

In an ongoing, prospective study comparing rates of cardiac adverse events in patients receiving carfilzomib or another proteasome inhibitor, bortezomib (Velcade), Dr. Cornell and his colleagues found that while there were no significant differences in progression-free survival (PFS) or overall survival (OS) between the treatments, “patients who experienced a cardiovascular event had significantly worse progression-free and overall survival compared to those that did not have a cardiovascular event,” he said at the American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient meeting.

The Prospective Observation of Cardiac Safety With Proteasome Inhibition (PROTECT) trial, scheduled for completion in August 2019, enrolled 95 patients with relapsed multiple myeloma and randomly assigned them on a 2:1 basis to receive carfilzomib or bortezomib.

The investigators found that cardiovascular adverse events occurred in 33 of the 65 patients (51%) randomized to carfilzomib, compared with 5 of 30 patients (17%) assigned to bortezomib.

The events included grade 1 or 2 heart failure (HF) in 12 patients on carfilzomib vs. 2 on bortezomib, and grade 3 or 4 HF in 11 vs. 1, respectively. Hypertension was significantly more frequent among patients on carfilzomib, and one patient on carfilzomib died from the acute coronary syndrome 24 hours after receiving carfilzomib in the second week of treatment.

The investigators found that both B-type natriuretic peptide (BNP) and N-terminal pro b-type natriuretic peptide (NT-proBNP) were highly predictive of cardiovascular adverse events. Patients on carfilzomib who had levels of the markers above normal at baseline had an odds ratio (OR) for cardiovascular events of 7.39 (P less than .0001), and those with BNP or NT-proBNP increases at week 2 or 3 during cycle 1 had an OR for a cardiovascular adverse event of 63.5 (P less than .001).

In multivariate analysis, the risk for cardiovascular events for patients treated with carfilzomib was significantly lower for patients with one or no traditional cardiovascular risk factors, compared with patients with two or more.

“Prospective monitoring with natriuretic peptides should be considered, particularly early in treatment,” Dr. Cornell said.
 

IMiDs and thromboembolism

In early clinical trials of immunomodulators (IMiDs) for multiple myeloma, investigators saw that the incidence of thromboembolic events was lower among patients who received thromboprophylaxis than among those who did not, Dr. Cornell noted.

“From this, certain guidelines have been developed such that all patients considered to be at risk should at least receive an aspirin, 81-325 mg, and patients at higher risk for thromboembolism should receive low-molecular-weight heparin or therapeutic-dose warfarin,” he said.

There is little guidance, however, about the use of direct oral anticoagulants in this population, he added, a fact that prompted him and his colleagues in oncology and cardiology to perform a pilot study of apixaban (Eliquis) for primary prevention of venous thromboembolism (VTE) in patients with multiple myeloma who were receiving immunodulatory drugs.

Results of the pilot study, reported in a poster session at the 2018 annual meeting of the American Society of Hematology, showed that among 50 patients who received apixaban 2.5 mg twice daily for 6 months during IMiD therapy, there were no VTEs, stroke, or myocardial infarction, and no episodes of major bleeding. There were just three nonmajor bleeding events, and one early withdrawal from apixaban due to an allergic reaction manifesting as generalized edema.

“Further study is needed to validate this as a potential primary prophylaxis in patients receiving IMiDs for multiple myeloma,” Dr. Cornell said.

He reported having no financial disclosures. Millennium Pharmaceuticals is a sponsor of the PROTECT trial.

PRAGUE – Clinicians should prioritize treatment duration with factors or bypassing agents – not dose level – when managing breakthrough bleeds in patients with hemophilia who are on non–factor replacement therapy, according to a leading expert.

Will Pass/MDedge News

Duration of treatment is more strongly associated with thromboembolism than dose magnitude, said Andreas Tiede, MD, PhD, head of hemostaseology at Hannover (Germany) Medical School in Germany, noting that recommendations vary by non–factor replacement agent.

These remarks were part of a presentation about novel agents for treatment of hemophilia with inhibitors delivered at the annual congress of the European Association for Haemophilia and Allied Disorders.

“Concomitant use of factor products, both factor VIII and IX, and the bypassing agents, have usually preceded thromboembolic events in clinical trials [for non–factor replacement therapies] so this [topic] is crucial,” Dr. Tiede said.

Other experts recommend lower doses and shorter treatment durations. “I think that’s reasonable, but with some question mark behind the low doses,” he said. “I think it depends a little bit on the interaction between the non–factor replacement therapy and the bypassing agent in your patient.”

With a busy pipeline of non–factor replacement agents for hemophilia, such interactions are becoming increasingly relevant for clinicians and their patients.

Emicizumab, for instance, which is now approved for hemophilia with or without inhibitors, has synergistic activity with activated prothrombin complex concentrates (APCC). This was demonstrated by an emicizumab prophylaxis trial in which five out of eight patients with breakthrough bleeding who were treated with APPC at a dose higher than 100 IU/kg per day for more than 24 hours developed thrombotic microangiopathy. (N Engl J Med. 2017;377:809-18).

Other patients who received multiple infusions of APCC developed skin necrosis, cavernous vein thrombosis, and thrombophlebitis. Consequently, it is now recommended that APCC be avoided in patients taking emicizumab, and if unavoidable, given at the lowest dose possible. However, Dr. Tiede advised that this recommendation for APCC should not be extrapolated to encompass all factors and bypassing agents, based on existing data.

“Regarding higher or lower doses for initial treatment, I would be a little bit more careful,” he said. “That obviously depends on [whether] there is a synergistic effect with the non–factor replacement therapy and the bypassing agent. Synergistic effects have clearly been shown for the interaction of emicizumab and APCC, but when it comes to the interaction between emicizumab and VIIa, I’m not so sure. I don’t think that we have enough evidence to recommend lower doses of VIIa.”

Dr. Tiede also suggested that lower doses of factor VIII are probably unnecessary. “At high doses or high concentrations of factor VIII, emicizumab’s low affinity to the targets will not result in any significant action anymore,” he said. “So I think we have to wait for more data from basic research and also more clinical data.”

Regarding concern for duration of therapy, Dr. Tiede explained that, when treating breakthrough bleeding in a patient on non–factor replacement therapy, “the patient’s hemostatic protection level will never fall to zero, as it would have done in a patient treated previously, on demand with bypassing agents only.” Since hemostatic protection levels never return to zero, it is easier to enter the thromboembolic danger zone.

This risk was recently demonstrated by an emerging non-factor replacement therapy. In a phase 3 trial for fitusiran – a small interfering RNA therapy that targets antithrombin – a patient with hemophilia A developed a breakthrough bleed and 31-46 IU/kg of factor VIII was given, resulting in fatal cerebral sinus thrombosis. After a temporary hold, the study restarted with new limits on factor and bypassing agent doses.

Dr. Tiede reported financial relationships with Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, and other companies.

PRAGUE – Clinicians should prioritize treatment duration with factors or bypassing agents – not dose level – when managing breakthrough bleeds in patients with hemophilia who are on non–factor replacement therapy, according to a leading expert.

Will Pass/MDedge News

Duration of treatment is more strongly associated with thromboembolism than dose magnitude, said Andreas Tiede, MD, PhD, head of hemostaseology at Hannover (Germany) Medical School in Germany, noting that recommendations vary by non–factor replacement agent.

These remarks were part of a presentation about novel agents for treatment of hemophilia with inhibitors delivered at the annual congress of the European Association for Haemophilia and Allied Disorders.

“Concomitant use of factor products, both factor VIII and IX, and the bypassing agents, have usually preceded thromboembolic events in clinical trials [for non–factor replacement therapies] so this [topic] is crucial,” Dr. Tiede said.

Other experts recommend lower doses and shorter treatment durations. “I think that’s reasonable, but with some question mark behind the low doses,” he said. “I think it depends a little bit on the interaction between the non–factor replacement therapy and the bypassing agent in your patient.”

With a busy pipeline of non–factor replacement agents for hemophilia, such interactions are becoming increasingly relevant for clinicians and their patients.

Emicizumab, for instance, which is now approved for hemophilia with or without inhibitors, has synergistic activity with activated prothrombin complex concentrates (APCC). This was demonstrated by an emicizumab prophylaxis trial in which five out of eight patients with breakthrough bleeding who were treated with APPC at a dose higher than 100 IU/kg per day for more than 24 hours developed thrombotic microangiopathy. (N Engl J Med. 2017;377:809-18).

Other patients who received multiple infusions of APCC developed skin necrosis, cavernous vein thrombosis, and thrombophlebitis. Consequently, it is now recommended that APCC be avoided in patients taking emicizumab, and if unavoidable, given at the lowest dose possible. However, Dr. Tiede advised that this recommendation for APCC should not be extrapolated to encompass all factors and bypassing agents, based on existing data.

“Regarding higher or lower doses for initial treatment, I would be a little bit more careful,” he said. “That obviously depends on [whether] there is a synergistic effect with the non–factor replacement therapy and the bypassing agent. Synergistic effects have clearly been shown for the interaction of emicizumab and APCC, but when it comes to the interaction between emicizumab and VIIa, I’m not so sure. I don’t think that we have enough evidence to recommend lower doses of VIIa.”

Dr. Tiede also suggested that lower doses of factor VIII are probably unnecessary. “At high doses or high concentrations of factor VIII, emicizumab’s low affinity to the targets will not result in any significant action anymore,” he said. “So I think we have to wait for more data from basic research and also more clinical data.”

Regarding concern for duration of therapy, Dr. Tiede explained that, when treating breakthrough bleeding in a patient on non–factor replacement therapy, “the patient’s hemostatic protection level will never fall to zero, as it would have done in a patient treated previously, on demand with bypassing agents only.” Since hemostatic protection levels never return to zero, it is easier to enter the thromboembolic danger zone.

This risk was recently demonstrated by an emerging non-factor replacement therapy. In a phase 3 trial for fitusiran – a small interfering RNA therapy that targets antithrombin – a patient with hemophilia A developed a breakthrough bleed and 31-46 IU/kg of factor VIII was given, resulting in fatal cerebral sinus thrombosis. After a temporary hold, the study restarted with new limits on factor and bypassing agent doses.

Dr. Tiede reported financial relationships with Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, and other companies.

PRAGUE – Clinicians should prioritize treatment duration with factors or bypassing agents – not dose level – when managing breakthrough bleeds in patients with hemophilia who are on non–factor replacement therapy, according to a leading expert.

Will Pass/MDedge News

Duration of treatment is more strongly associated with thromboembolism than dose magnitude, said Andreas Tiede, MD, PhD, head of hemostaseology at Hannover (Germany) Medical School in Germany, noting that recommendations vary by non–factor replacement agent.

These remarks were part of a presentation about novel agents for treatment of hemophilia with inhibitors delivered at the annual congress of the European Association for Haemophilia and Allied Disorders.

“Concomitant use of factor products, both factor VIII and IX, and the bypassing agents, have usually preceded thromboembolic events in clinical trials [for non–factor replacement therapies] so this [topic] is crucial,” Dr. Tiede said.

Other experts recommend lower doses and shorter treatment durations. “I think that’s reasonable, but with some question mark behind the low doses,” he said. “I think it depends a little bit on the interaction between the non–factor replacement therapy and the bypassing agent in your patient.”

With a busy pipeline of non–factor replacement agents for hemophilia, such interactions are becoming increasingly relevant for clinicians and their patients.

Emicizumab, for instance, which is now approved for hemophilia with or without inhibitors, has synergistic activity with activated prothrombin complex concentrates (APCC). This was demonstrated by an emicizumab prophylaxis trial in which five out of eight patients with breakthrough bleeding who were treated with APPC at a dose higher than 100 IU/kg per day for more than 24 hours developed thrombotic microangiopathy. (N Engl J Med. 2017;377:809-18).

Other patients who received multiple infusions of APCC developed skin necrosis, cavernous vein thrombosis, and thrombophlebitis. Consequently, it is now recommended that APCC be avoided in patients taking emicizumab, and if unavoidable, given at the lowest dose possible. However, Dr. Tiede advised that this recommendation for APCC should not be extrapolated to encompass all factors and bypassing agents, based on existing data.

“Regarding higher or lower doses for initial treatment, I would be a little bit more careful,” he said. “That obviously depends on [whether] there is a synergistic effect with the non–factor replacement therapy and the bypassing agent. Synergistic effects have clearly been shown for the interaction of emicizumab and APCC, but when it comes to the interaction between emicizumab and VIIa, I’m not so sure. I don’t think that we have enough evidence to recommend lower doses of VIIa.”

Dr. Tiede also suggested that lower doses of factor VIII are probably unnecessary. “At high doses or high concentrations of factor VIII, emicizumab’s low affinity to the targets will not result in any significant action anymore,” he said. “So I think we have to wait for more data from basic research and also more clinical data.”

Regarding concern for duration of therapy, Dr. Tiede explained that, when treating breakthrough bleeding in a patient on non–factor replacement therapy, “the patient’s hemostatic protection level will never fall to zero, as it would have done in a patient treated previously, on demand with bypassing agents only.” Since hemostatic protection levels never return to zero, it is easier to enter the thromboembolic danger zone.

This risk was recently demonstrated by an emerging non-factor replacement therapy. In a phase 3 trial for fitusiran – a small interfering RNA therapy that targets antithrombin – a patient with hemophilia A developed a breakthrough bleed and 31-46 IU/kg of factor VIII was given, resulting in fatal cerebral sinus thrombosis. After a temporary hold, the study restarted with new limits on factor and bypassing agent doses.

Dr. Tiede reported financial relationships with Bayer, Biotest, CSL Behring, Novo Nordisk, Pfizer, and other companies.

Prostate cancer patients with cardiovascular disease (CVD) who are treated with abiraterone acetate (Zytiga) have an increased risk of death within 6 months of starting therapy, compared with those without preexisting CVD, according to an analysis of Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data.

Of 2,845 patients diagnosed with prostate cancer between 1991 and 2013 and treated with abiraterone acetate (AA) between 2011 and 2014, 1,924 (67.6%) had at least one serious preexisting CVD condition. Mortality within 6 months of treatment initiation in those with preexisting CVD ranged from 21.4% to 25.6%, depending on the type of condition, compared with 15.8% among those with no preexisting CVD, Grace Lu-Yao, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research annual meeting in Atlanta.

An additional analysis of health care utilization showed that AA treatment was associated with risks for all patients, regardless of CVD; among patients without chemotherapy and without CVD, the hospitalization rate increased by 53%, and in those with preexisting CVD the rate increased from 34% to 55%, depending on the cardiovascular condition, said Dr. Lu-Yao, associate director for population science at the Sidney Kimmel Cancer Center at Jefferson, Philadelphia.


Since patients with preexisting CVD are frequently excluded from clinical trials of AA, its effects in this population are uncertain. However, these data – though limited by the retrospective nature of the study – provide evidence that a significant proportion of patients treated in the real world differ from those in clinical trials, and therefore that the trial findings may not apply to patients who are excluded, said Dr. Lu-Yao, professor and vice chair in the department of medical Oncology at the Sidney Kimmel Medical College.

AA, which was initially approved in 2011 for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel, received additional approval in 2018 for use in combination with prednisone for metastatic high-risk castration-sensitive prostate cancer.

The potential for expanded use of AA further underscores the need for improved understanding of its effects in the real-world setting, she noted.

This study was funded by a Pennsylvania CURE Program award and the National Cancer Institute. Dr. Lu-Yao has no direct conflicts to declare except that her spouse, who has no involvement with this study, is an officer of Sun Pharmaceutical Industries Inc.

SOURCE: Lu-Yao G et al. AACR 2019, Abstract preview.

Prostate cancer patients with cardiovascular disease (CVD) who are treated with abiraterone acetate (Zytiga) have an increased risk of death within 6 months of starting therapy, compared with those without preexisting CVD, according to an analysis of Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data.

Of 2,845 patients diagnosed with prostate cancer between 1991 and 2013 and treated with abiraterone acetate (AA) between 2011 and 2014, 1,924 (67.6%) had at least one serious preexisting CVD condition. Mortality within 6 months of treatment initiation in those with preexisting CVD ranged from 21.4% to 25.6%, depending on the type of condition, compared with 15.8% among those with no preexisting CVD, Grace Lu-Yao, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research annual meeting in Atlanta.

An additional analysis of health care utilization showed that AA treatment was associated with risks for all patients, regardless of CVD; among patients without chemotherapy and without CVD, the hospitalization rate increased by 53%, and in those with preexisting CVD the rate increased from 34% to 55%, depending on the cardiovascular condition, said Dr. Lu-Yao, associate director for population science at the Sidney Kimmel Cancer Center at Jefferson, Philadelphia.


Since patients with preexisting CVD are frequently excluded from clinical trials of AA, its effects in this population are uncertain. However, these data – though limited by the retrospective nature of the study – provide evidence that a significant proportion of patients treated in the real world differ from those in clinical trials, and therefore that the trial findings may not apply to patients who are excluded, said Dr. Lu-Yao, professor and vice chair in the department of medical Oncology at the Sidney Kimmel Medical College.

AA, which was initially approved in 2011 for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel, received additional approval in 2018 for use in combination with prednisone for metastatic high-risk castration-sensitive prostate cancer.

The potential for expanded use of AA further underscores the need for improved understanding of its effects in the real-world setting, she noted.

This study was funded by a Pennsylvania CURE Program award and the National Cancer Institute. Dr. Lu-Yao has no direct conflicts to declare except that her spouse, who has no involvement with this study, is an officer of Sun Pharmaceutical Industries Inc.

SOURCE: Lu-Yao G et al. AACR 2019, Abstract preview.

Prostate cancer patients with cardiovascular disease (CVD) who are treated with abiraterone acetate (Zytiga) have an increased risk of death within 6 months of starting therapy, compared with those without preexisting CVD, according to an analysis of Surveillance, Epidemiology, and End Results (SEER)–Medicare linked data.

Of 2,845 patients diagnosed with prostate cancer between 1991 and 2013 and treated with abiraterone acetate (AA) between 2011 and 2014, 1,924 (67.6%) had at least one serious preexisting CVD condition. Mortality within 6 months of treatment initiation in those with preexisting CVD ranged from 21.4% to 25.6%, depending on the type of condition, compared with 15.8% among those with no preexisting CVD, Grace Lu-Yao, PhD, reported during a press conference highlighting data to be presented at the upcoming American Association for Cancer Research annual meeting in Atlanta.

An additional analysis of health care utilization showed that AA treatment was associated with risks for all patients, regardless of CVD; among patients without chemotherapy and without CVD, the hospitalization rate increased by 53%, and in those with preexisting CVD the rate increased from 34% to 55%, depending on the cardiovascular condition, said Dr. Lu-Yao, associate director for population science at the Sidney Kimmel Cancer Center at Jefferson, Philadelphia.


Since patients with preexisting CVD are frequently excluded from clinical trials of AA, its effects in this population are uncertain. However, these data – though limited by the retrospective nature of the study – provide evidence that a significant proportion of patients treated in the real world differ from those in clinical trials, and therefore that the trial findings may not apply to patients who are excluded, said Dr. Lu-Yao, professor and vice chair in the department of medical Oncology at the Sidney Kimmel Medical College.

AA, which was initially approved in 2011 for use in combination with prednisone in patients with metastatic castration-resistant prostate cancer who were previously treated with docetaxel, received additional approval in 2018 for use in combination with prednisone for metastatic high-risk castration-sensitive prostate cancer.

The potential for expanded use of AA further underscores the need for improved understanding of its effects in the real-world setting, she noted.

This study was funded by a Pennsylvania CURE Program award and the National Cancer Institute. Dr. Lu-Yao has no direct conflicts to declare except that her spouse, who has no involvement with this study, is an officer of Sun Pharmaceutical Industries Inc.

SOURCE: Lu-Yao G et al. AACR 2019, Abstract preview.

For the many people who expect you to lead, your role – among others – is to create coherence. That coherence characterizes the logic and consistency of what you do in your organization. It assembles the individual work of many different people into a whole that functions well. Coherence in your workplace helps people make sense of what they are doing and why it matters.

Our very rational brain craves coherence. We assemble facts, emotions, ambitions and our life stories into narratives that define who we are, what we are doing, and why it is important. An effective organizational “metaleader” encourages that process for followers. It helps people make sense of the work side of their life.

When coherence is absent, the workplace is riddled with contradictions, unpredictability, and dissonance. People are expected to accomplish tasks for which the time, tools, and talent are missing. There is a perplexed swirl of high activity and low productivity. Expectations for high quality of care and patient satisfaction are contradicted by an overbearing workload, reams of paper work, and the low morale that leaves the work force lethargic. “What we are doing here and how we are doing it doesn’t make sense,” exemplifies the exasperation of working amid incoherence. The department does not drive together toward success-oriented performance. Instead, different people, priorities, and opportunities will be positioned in conflict with one another. For people in your group and those surrounding it, morale and motivation suffer. There is the risk that people will descend into malaise.

Creating coherence is a complex metaleadership process. A large health care center is a cacophony of priorities, of which advancing quality of care is but one. There are other objectives, some contradictory, that also absorb time and attention: achievement of financial benchmarks, promotion of professional careers, and the individual hopes and desires of patients. Systematically aligning those many priorities and objectives is a process of both design and leadership.

The metaleadership model is a strategy for building coherence amid the complexity of health care operations. For those unfamiliar with metaleadership: The prefix “meta-” refers to a wider perspective on what is happening, the people involved, and the overall combination of objectives. The three dimensions of practice are: 1) the Person of the metaleader – your own priorities, values and emotional intelligence; 2) the Situation – what is happening and what ought to be done about it; and 3) Connectivity of Effort, which leads down to subordinates, up to bosses, across to other internal departments, and beyond to external organizations and professionals.

In building connectivity of effort, the metaleader links the many sides of the work being accomplished. The intent is to balance – purposefully – different organizational objectives into a combined whole that gets the jobs done. Furthermore, that coherence links and adapts what people are doing to the situation at hand. And in essence, the person of the leader cannot lead broader coherence if not coherent in her or his own thinking, attitudes, and behaviors, so achievement of personal and professional clarity of purpose is important.

The question for you: How do you as a hospitalist leader create coherence in what you are leading given the changing priorities, actions, and turbulence of current health policy and the market?

The answers lie in the communication you foster and clarify. That communication demands clarity and diplomacy. It is multidirectional such that messages and information in your leading down, up, across, and beyond complement and inform one another.

An illustration of one pathway: You learn from senior management about cuts in the budget. You reflect with them on the choices implicit in those cuts. Perhaps there are better ways to reduce expenditures and increase revenues that offer an alternative pathway to a balanced budget? When communicating with your subordinates, you open conversation on ways to enhance efficiencies and assure quality. You explore avenues to partner with other departments within your institution on how you can link and leverage services and capabilities. And you consider your marketplace and the actions you can take to reinforce your department and assure the volume necessary to achieve budget and quality objectives. And through it all, you monitor the situation. What are the effects of the budget adjustments, and what can be done to sustain the coherence of the work and output of the department? It is a leadership process of constant situational awareness, personal commitment, and connectivity of effort.

An illustration of another pathway: Resist the change and argue forcefully for holding onto the current budget and workforce. Though you do not possess the authority to control larger budgetary decisions, you employ influence well beyond your authority. You recruit allies to your cause, advocates who believe in the purpose you are promoting. You build an alternative coherence, mindful of fostering friendship and minimizing alienation. You are recognized for the passion of your professional commitment and your capacity to uphold quality care and organizational balance.

Two very different pathways to crafting coherence. Leaders of each perceive their actions to advance priority coherence objectives. Apply this question to your own complex problem solving.

Metaleaders forge coherence through the narratives they build and the consistency with those themes and priorities. When everyone on your staff, from physicians to housekeeping personnel, can say “I am here to help save lives,” you know that your followers are on board with a shared mission. They recognize that their efforts contribute to that overall mission. Each person has a role to play, and her or his work fits with the efforts of others, and the bottom line accomplishments of the department.

The coherence you forge assists your followers to make sense of what they are doing and how it fits what others are doing. Work is fulfilling. Beyond that, in a turbulent health care system, you anticipate both problems and opportunities with strategies to meet them. You stay ahead of the game to ensure that people within and outside the department are aligned to maximize opportunities for success.

This is particularly important for the hospitalist. Your job is to fashion coherence on many levels. First, coherent patient care for the patient. Second, coherent interactions among professionals. Finally, organizational coherence, so one piece of the puzzle fits with others. And, when there is a need to recalculate, you adapt and develop solutions that fit the people and situation at hand.

Dr. Marcus is coauthor of Renegotiating Health Care: Resolving Conflict to Build Collaboration, Second Edition (San Francisco: Jossey-Bass Publishers, 2011) and is Director of the Program for Health Care Negotiation and Conflict Resolution, Harvard T.H. Chan School of Public Health, Boston. Dr. Marcus teaches regularly in the SHM Leadership Academy. He can be reached at ljmarcus@hsph.harvard.edu.

For the many people who expect you to lead, your role – among others – is to create coherence. That coherence characterizes the logic and consistency of what you do in your organization. It assembles the individual work of many different people into a whole that functions well. Coherence in your workplace helps people make sense of what they are doing and why it matters.

Our very rational brain craves coherence. We assemble facts, emotions, ambitions and our life stories into narratives that define who we are, what we are doing, and why it is important. An effective organizational “metaleader” encourages that process for followers. It helps people make sense of the work side of their life.

When coherence is absent, the workplace is riddled with contradictions, unpredictability, and dissonance. People are expected to accomplish tasks for which the time, tools, and talent are missing. There is a perplexed swirl of high activity and low productivity. Expectations for high quality of care and patient satisfaction are contradicted by an overbearing workload, reams of paper work, and the low morale that leaves the work force lethargic. “What we are doing here and how we are doing it doesn’t make sense,” exemplifies the exasperation of working amid incoherence. The department does not drive together toward success-oriented performance. Instead, different people, priorities, and opportunities will be positioned in conflict with one another. For people in your group and those surrounding it, morale and motivation suffer. There is the risk that people will descend into malaise.

Creating coherence is a complex metaleadership process. A large health care center is a cacophony of priorities, of which advancing quality of care is but one. There are other objectives, some contradictory, that also absorb time and attention: achievement of financial benchmarks, promotion of professional careers, and the individual hopes and desires of patients. Systematically aligning those many priorities and objectives is a process of both design and leadership.

The metaleadership model is a strategy for building coherence amid the complexity of health care operations. For those unfamiliar with metaleadership: The prefix “meta-” refers to a wider perspective on what is happening, the people involved, and the overall combination of objectives. The three dimensions of practice are: 1) the Person of the metaleader – your own priorities, values and emotional intelligence; 2) the Situation – what is happening and what ought to be done about it; and 3) Connectivity of Effort, which leads down to subordinates, up to bosses, across to other internal departments, and beyond to external organizations and professionals.

In building connectivity of effort, the metaleader links the many sides of the work being accomplished. The intent is to balance – purposefully – different organizational objectives into a combined whole that gets the jobs done. Furthermore, that coherence links and adapts what people are doing to the situation at hand. And in essence, the person of the leader cannot lead broader coherence if not coherent in her or his own thinking, attitudes, and behaviors, so achievement of personal and professional clarity of purpose is important.

The question for you: How do you as a hospitalist leader create coherence in what you are leading given the changing priorities, actions, and turbulence of current health policy and the market?

The answers lie in the communication you foster and clarify. That communication demands clarity and diplomacy. It is multidirectional such that messages and information in your leading down, up, across, and beyond complement and inform one another.

An illustration of one pathway: You learn from senior management about cuts in the budget. You reflect with them on the choices implicit in those cuts. Perhaps there are better ways to reduce expenditures and increase revenues that offer an alternative pathway to a balanced budget? When communicating with your subordinates, you open conversation on ways to enhance efficiencies and assure quality. You explore avenues to partner with other departments within your institution on how you can link and leverage services and capabilities. And you consider your marketplace and the actions you can take to reinforce your department and assure the volume necessary to achieve budget and quality objectives. And through it all, you monitor the situation. What are the effects of the budget adjustments, and what can be done to sustain the coherence of the work and output of the department? It is a leadership process of constant situational awareness, personal commitment, and connectivity of effort.

An illustration of another pathway: Resist the change and argue forcefully for holding onto the current budget and workforce. Though you do not possess the authority to control larger budgetary decisions, you employ influence well beyond your authority. You recruit allies to your cause, advocates who believe in the purpose you are promoting. You build an alternative coherence, mindful of fostering friendship and minimizing alienation. You are recognized for the passion of your professional commitment and your capacity to uphold quality care and organizational balance.

Two very different pathways to crafting coherence. Leaders of each perceive their actions to advance priority coherence objectives. Apply this question to your own complex problem solving.

Metaleaders forge coherence through the narratives they build and the consistency with those themes and priorities. When everyone on your staff, from physicians to housekeeping personnel, can say “I am here to help save lives,” you know that your followers are on board with a shared mission. They recognize that their efforts contribute to that overall mission. Each person has a role to play, and her or his work fits with the efforts of others, and the bottom line accomplishments of the department.

The coherence you forge assists your followers to make sense of what they are doing and how it fits what others are doing. Work is fulfilling. Beyond that, in a turbulent health care system, you anticipate both problems and opportunities with strategies to meet them. You stay ahead of the game to ensure that people within and outside the department are aligned to maximize opportunities for success.

This is particularly important for the hospitalist. Your job is to fashion coherence on many levels. First, coherent patient care for the patient. Second, coherent interactions among professionals. Finally, organizational coherence, so one piece of the puzzle fits with others. And, when there is a need to recalculate, you adapt and develop solutions that fit the people and situation at hand.

Dr. Marcus is coauthor of Renegotiating Health Care: Resolving Conflict to Build Collaboration, Second Edition (San Francisco: Jossey-Bass Publishers, 2011) and is Director of the Program for Health Care Negotiation and Conflict Resolution, Harvard T.H. Chan School of Public Health, Boston. Dr. Marcus teaches regularly in the SHM Leadership Academy. He can be reached at ljmarcus@hsph.harvard.edu.

For the many people who expect you to lead, your role – among others – is to create coherence. That coherence characterizes the logic and consistency of what you do in your organization. It assembles the individual work of many different people into a whole that functions well. Coherence in your workplace helps people make sense of what they are doing and why it matters.

Our very rational brain craves coherence. We assemble facts, emotions, ambitions and our life stories into narratives that define who we are, what we are doing, and why it is important. An effective organizational “metaleader” encourages that process for followers. It helps people make sense of the work side of their life.

When coherence is absent, the workplace is riddled with contradictions, unpredictability, and dissonance. People are expected to accomplish tasks for which the time, tools, and talent are missing. There is a perplexed swirl of high activity and low productivity. Expectations for high quality of care and patient satisfaction are contradicted by an overbearing workload, reams of paper work, and the low morale that leaves the work force lethargic. “What we are doing here and how we are doing it doesn’t make sense,” exemplifies the exasperation of working amid incoherence. The department does not drive together toward success-oriented performance. Instead, different people, priorities, and opportunities will be positioned in conflict with one another. For people in your group and those surrounding it, morale and motivation suffer. There is the risk that people will descend into malaise.

Creating coherence is a complex metaleadership process. A large health care center is a cacophony of priorities, of which advancing quality of care is but one. There are other objectives, some contradictory, that also absorb time and attention: achievement of financial benchmarks, promotion of professional careers, and the individual hopes and desires of patients. Systematically aligning those many priorities and objectives is a process of both design and leadership.

The metaleadership model is a strategy for building coherence amid the complexity of health care operations. For those unfamiliar with metaleadership: The prefix “meta-” refers to a wider perspective on what is happening, the people involved, and the overall combination of objectives. The three dimensions of practice are: 1) the Person of the metaleader – your own priorities, values and emotional intelligence; 2) the Situation – what is happening and what ought to be done about it; and 3) Connectivity of Effort, which leads down to subordinates, up to bosses, across to other internal departments, and beyond to external organizations and professionals.

In building connectivity of effort, the metaleader links the many sides of the work being accomplished. The intent is to balance – purposefully – different organizational objectives into a combined whole that gets the jobs done. Furthermore, that coherence links and adapts what people are doing to the situation at hand. And in essence, the person of the leader cannot lead broader coherence if not coherent in her or his own thinking, attitudes, and behaviors, so achievement of personal and professional clarity of purpose is important.

The question for you: How do you as a hospitalist leader create coherence in what you are leading given the changing priorities, actions, and turbulence of current health policy and the market?

The answers lie in the communication you foster and clarify. That communication demands clarity and diplomacy. It is multidirectional such that messages and information in your leading down, up, across, and beyond complement and inform one another.

An illustration of one pathway: You learn from senior management about cuts in the budget. You reflect with them on the choices implicit in those cuts. Perhaps there are better ways to reduce expenditures and increase revenues that offer an alternative pathway to a balanced budget? When communicating with your subordinates, you open conversation on ways to enhance efficiencies and assure quality. You explore avenues to partner with other departments within your institution on how you can link and leverage services and capabilities. And you consider your marketplace and the actions you can take to reinforce your department and assure the volume necessary to achieve budget and quality objectives. And through it all, you monitor the situation. What are the effects of the budget adjustments, and what can be done to sustain the coherence of the work and output of the department? It is a leadership process of constant situational awareness, personal commitment, and connectivity of effort.

An illustration of another pathway: Resist the change and argue forcefully for holding onto the current budget and workforce. Though you do not possess the authority to control larger budgetary decisions, you employ influence well beyond your authority. You recruit allies to your cause, advocates who believe in the purpose you are promoting. You build an alternative coherence, mindful of fostering friendship and minimizing alienation. You are recognized for the passion of your professional commitment and your capacity to uphold quality care and organizational balance.

Two very different pathways to crafting coherence. Leaders of each perceive their actions to advance priority coherence objectives. Apply this question to your own complex problem solving.

Metaleaders forge coherence through the narratives they build and the consistency with those themes and priorities. When everyone on your staff, from physicians to housekeeping personnel, can say “I am here to help save lives,” you know that your followers are on board with a shared mission. They recognize that their efforts contribute to that overall mission. Each person has a role to play, and her or his work fits with the efforts of others, and the bottom line accomplishments of the department.

The coherence you forge assists your followers to make sense of what they are doing and how it fits what others are doing. Work is fulfilling. Beyond that, in a turbulent health care system, you anticipate both problems and opportunities with strategies to meet them. You stay ahead of the game to ensure that people within and outside the department are aligned to maximize opportunities for success.

This is particularly important for the hospitalist. Your job is to fashion coherence on many levels. First, coherent patient care for the patient. Second, coherent interactions among professionals. Finally, organizational coherence, so one piece of the puzzle fits with others. And, when there is a need to recalculate, you adapt and develop solutions that fit the people and situation at hand.

Dr. Marcus is coauthor of Renegotiating Health Care: Resolving Conflict to Build Collaboration, Second Edition (San Francisco: Jossey-Bass Publishers, 2011) and is Director of the Program for Health Care Negotiation and Conflict Resolution, Harvard T.H. Chan School of Public Health, Boston. Dr. Marcus teaches regularly in the SHM Leadership Academy. He can be reached at ljmarcus@hsph.harvard.edu.

Migraine is associated with aberrant connections from the somatosensory cortex to the frontal lobe, according to a recent study. The frequency-specific increases in connectivity in terms of strength, path length, and clustering coefficients support the notion that migraineurs have elevated cortical networks. Twenty-two migraineurs in the interictal phase and 22 sex- and age-matched healthy volunteers were studied using a whole-head magnetoencephalography (MEG) system. Researchers found:

• The brain network patterns revealed that the patients with migraine exhibited remarkably increased functional connectivity in the high-frequency (250–1000 Hz) band between the sensory cortex and the frontal lobe.
• The results of quantitative analysis of graph theory showed that the patients had:

1. an increased degree of connectivity in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands;
2. an increased connectivity strength in the beta (13–30 Hz) and gamma (30–80 Hz) bands;
3. an increased path length in the beta (13–30 Hz), gamma (30–80 Hz) and ripple (80–250 Hz) bands; and
4. an increased clustering coefficient in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands.

Ren J, Xiang J, Chen Y, li F, Wu T, Shi J. Abnormal functional connectivity under somatosensory stimulation in migraine: A multi-frequency magnetoencephalography study. J Headache Pain. 2019;20(1):3. doi:10.1186/s10194-019-0958-3.

Migraine is associated with aberrant connections from the somatosensory cortex to the frontal lobe, according to a recent study. The frequency-specific increases in connectivity in terms of strength, path length, and clustering coefficients support the notion that migraineurs have elevated cortical networks. Twenty-two migraineurs in the interictal phase and 22 sex- and age-matched healthy volunteers were studied using a whole-head magnetoencephalography (MEG) system. Researchers found:

• The brain network patterns revealed that the patients with migraine exhibited remarkably increased functional connectivity in the high-frequency (250–1000 Hz) band between the sensory cortex and the frontal lobe.
• The results of quantitative analysis of graph theory showed that the patients had:

1. an increased degree of connectivity in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands;
2. an increased connectivity strength in the beta (13–30 Hz) and gamma (30–80 Hz) bands;
3. an increased path length in the beta (13–30 Hz), gamma (30–80 Hz) and ripple (80–250 Hz) bands; and
4. an increased clustering coefficient in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands.

Ren J, Xiang J, Chen Y, li F, Wu T, Shi J. Abnormal functional connectivity under somatosensory stimulation in migraine: A multi-frequency magnetoencephalography study. J Headache Pain. 2019;20(1):3. doi:10.1186/s10194-019-0958-3.

Migraine is associated with aberrant connections from the somatosensory cortex to the frontal lobe, according to a recent study. The frequency-specific increases in connectivity in terms of strength, path length, and clustering coefficients support the notion that migraineurs have elevated cortical networks. Twenty-two migraineurs in the interictal phase and 22 sex- and age-matched healthy volunteers were studied using a whole-head magnetoencephalography (MEG) system. Researchers found:

• The brain network patterns revealed that the patients with migraine exhibited remarkably increased functional connectivity in the high-frequency (250–1000 Hz) band between the sensory cortex and the frontal lobe.
• The results of quantitative analysis of graph theory showed that the patients had:

1. an increased degree of connectivity in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands;
2. an increased connectivity strength in the beta (13–30 Hz) and gamma (30–80 Hz) bands;
3. an increased path length in the beta (13–30 Hz), gamma (30–80 Hz) and ripple (80–250 Hz) bands; and
4. an increased clustering coefficient in the theta (4–8 Hz), beta (13–30 Hz) and gamma (30–80 Hz) bands.

Ren J, Xiang J, Chen Y, li F, Wu T, Shi J. Abnormal functional connectivity under somatosensory stimulation in migraine: A multi-frequency magnetoencephalography study. J Headache Pain. 2019;20(1):3. doi:10.1186/s10194-019-0958-3.

Migraine is more frequent in patients with subclinical hypothyroidism in respect to controls, according to a recent study. Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. Researchers found:

• The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs 13%; OR 5.80).
• Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls.
• Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine.
• Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine.

Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39(1):15–20. doi:10.1177/0333102418769917.

Migraine is more frequent in patients with subclinical hypothyroidism in respect to controls, according to a recent study. Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. Researchers found:

• The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs 13%; OR 5.80).
• Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls.
• Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine.
• Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine.

Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39(1):15–20. doi:10.1177/0333102418769917.

Migraine is more frequent in patients with subclinical hypothyroidism in respect to controls, according to a recent study. Using a case-control strategy, 151 consecutive subclinical hypothyroidism patients (mean age 48.36 ± 15.86 years) and 150 controls (mean age 50.86 ± 9.19 years) were recruited. In all subjects, migraine characteristics were collected through a direct interview. Clinical and biochemical parameters (thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and anti-thyroid antibodies) were compared between subclinical hypothyroidism patients in comorbidity with migraine and subclinical hypothyroidism patients without migraine. Researchers found:

• The prevalence of lifetime migraine was significantly higher in subclinical hypothyroidism patients in comparison with controls (46% vs 13%; OR 5.80).
• Both migraine without and with aura were significantly higher in subclinical hypothyroidism patients than controls.
• Thyroid hormones and concentrations of antibodies did not differ between subclinical hypothyroidism patients with and without migraine.
• Interestingly, a comorbidity for autoimmune diseases was observed in subclinical hypothyroidism patients with migraine in respect to those without migraine.

Rubino E, Rainero I, Garino F, et al. Subclinical hypothyroidism is associated with migraine: A case-control study. Cephalalgia. 2019;39(1):15–20. doi:10.1177/0333102418769917.

Demographics and migraine diagnosis in the pediatric population are associated with evidence-based medicine and opioid/barbiturates. This according to a recent study that aimed to evaluate providers’ use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children’s initial presentation of acute migraine or primary headache. Primary care, therefore, provides an opportunity to target provider interventions to enhance effective pediatric headache treatment. This retrospective, observational study utilized patient (children aged 6–17) and provider/encounter characteristics extracted from the patient’s electronic health record from 2008 to 2014 during an initial encounter for migraine or primary headache. Researchers found:

• In all, 38,926 patients (56.7% female, mean age=12.1) and 1617 providers were evaluated.
• Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine.
• Older children (OR=1.07), females (OR=1.14), and those diagnosed with migraine (OR=4.71) were more likely to receive evidence-based medicine.
• Among prescriptions, 15.8% were for opioids/barbiturates.
• Older children (OR=1.14) and those cared for in the emergency department/urgent care (OR=2.02) were at increased risk.

Seng EK, Gelfand AA, Nicholson RA. Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data. [Published online ahead of print February 20, 2019]. Cephalalgia. doi:10.1177%2F0333102419833080.

Demographics and migraine diagnosis in the pediatric population are associated with evidence-based medicine and opioid/barbiturates. This according to a recent study that aimed to evaluate providers’ use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children’s initial presentation of acute migraine or primary headache. Primary care, therefore, provides an opportunity to target provider interventions to enhance effective pediatric headache treatment. This retrospective, observational study utilized patient (children aged 6–17) and provider/encounter characteristics extracted from the patient’s electronic health record from 2008 to 2014 during an initial encounter for migraine or primary headache. Researchers found:

• In all, 38,926 patients (56.7% female, mean age=12.1) and 1617 providers were evaluated.
• Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine.
• Older children (OR=1.07), females (OR=1.14), and those diagnosed with migraine (OR=4.71) were more likely to receive evidence-based medicine.
• Among prescriptions, 15.8% were for opioids/barbiturates.
• Older children (OR=1.14) and those cared for in the emergency department/urgent care (OR=2.02) were at increased risk.

Seng EK, Gelfand AA, Nicholson RA. Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data. [Published online ahead of print February 20, 2019]. Cephalalgia. doi:10.1177%2F0333102419833080.

Demographics and migraine diagnosis in the pediatric population are associated with evidence-based medicine and opioid/barbiturates. This according to a recent study that aimed to evaluate providers’ use and predictors of evidence-based medicine or opioid/barbiturate as first-line acute treatment for children’s initial presentation of acute migraine or primary headache. Primary care, therefore, provides an opportunity to target provider interventions to enhance effective pediatric headache treatment. This retrospective, observational study utilized patient (children aged 6–17) and provider/encounter characteristics extracted from the patient’s electronic health record from 2008 to 2014 during an initial encounter for migraine or primary headache. Researchers found:

• In all, 38,926 patients (56.7% female, mean age=12.1) and 1617 providers were evaluated.
• Only 17.7% of patients were diagnosed with migraine; 16.1% received evidence-based medicine.
• Older children (OR=1.07), females (OR=1.14), and those diagnosed with migraine (OR=4.71) were more likely to receive evidence-based medicine.
• Among prescriptions, 15.8% were for opioids/barbiturates.
• Older children (OR=1.14) and those cared for in the emergency department/urgent care (OR=2.02) were at increased risk.

Seng EK, Gelfand AA, Nicholson RA. Assessing evidence-based medicine and opioid/barbiturate as first-line acute treatment of pediatric migraine and primary headache: A retrospective observational study of health systems data. [Published online ahead of print February 20, 2019]. Cephalalgia. doi:10.1177%2F0333102419833080.