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Launch of adalimumab biosimilar Amjevita postponed
Amgen, maker of the adalimumab biosimilar Amjevita (adalimumab-atto) has reached an agreement with AbbVie, manufacturer of the originator adalimumab Humira, that halts marketing of Amjevita in the United States until 2023 and in Europe until 2018, according to a company statement.
The deal between the two manufacturers settles a patent infringement lawsuit that AbbVie brought against Amgen after it received Food and Drug Administration approval in September 2016 for seven of Humira’s nine indications: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, and polyarticular juvenile idiopathic arthritis. Amjevita is not approved for two of Humira’s indications, hidradenitis suppurativa and uveitis.
Amgen said in its statement that AbbVie will grant patent licenses for the use and sale of Amjevita worldwide, on a country-by-country basis, with current expectations that marketing will begin in Europe on Oct. 16, 2018, and in the United States on Jan. 31, 2023. Amjevita is named Amgevita in Europe.
Amgen, maker of the adalimumab biosimilar Amjevita (adalimumab-atto) has reached an agreement with AbbVie, manufacturer of the originator adalimumab Humira, that halts marketing of Amjevita in the United States until 2023 and in Europe until 2018, according to a company statement.
The deal between the two manufacturers settles a patent infringement lawsuit that AbbVie brought against Amgen after it received Food and Drug Administration approval in September 2016 for seven of Humira’s nine indications: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, and polyarticular juvenile idiopathic arthritis. Amjevita is not approved for two of Humira’s indications, hidradenitis suppurativa and uveitis.
Amgen said in its statement that AbbVie will grant patent licenses for the use and sale of Amjevita worldwide, on a country-by-country basis, with current expectations that marketing will begin in Europe on Oct. 16, 2018, and in the United States on Jan. 31, 2023. Amjevita is named Amgevita in Europe.
Amgen, maker of the adalimumab biosimilar Amjevita (adalimumab-atto) has reached an agreement with AbbVie, manufacturer of the originator adalimumab Humira, that halts marketing of Amjevita in the United States until 2023 and in Europe until 2018, according to a company statement.
The deal between the two manufacturers settles a patent infringement lawsuit that AbbVie brought against Amgen after it received Food and Drug Administration approval in September 2016 for seven of Humira’s nine indications: rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, plaque psoriasis, and polyarticular juvenile idiopathic arthritis. Amjevita is not approved for two of Humira’s indications, hidradenitis suppurativa and uveitis.
Amgen said in its statement that AbbVie will grant patent licenses for the use and sale of Amjevita worldwide, on a country-by-country basis, with current expectations that marketing will begin in Europe on Oct. 16, 2018, and in the United States on Jan. 31, 2023. Amjevita is named Amgevita in Europe.
Under our noses
If you graduated from medical school after 1990, you may be surprised to learn that there was a time when the typical general pediatrician could go through an entire day of seeing patients and not write a single prescription for a stimulant medication. In fact, he or she could go for several months without writing for any controlled substance.
ADHD is a modern phenomenon. There always have been children with “ants in their pants” who couldn’t sit still. And there always were “daydreamers” who didn’t pay attention in school. But in the 1970s, the number of children who might now be labeled as having ADHD was nowhere near the 11% often quoted for the prevalence in the current pediatric population.
Could there be some genetic selection process that is favoring the birth and survival of hyperactive and distractible children? In the last decade or two, biologists have discovered evolutionary changes in some animals occurring at pace far faster than had been previously imagined. However, a Darwinian explanation seems unlikely in the case of the emergence of ADHD.
Could it be a diet laced with high fructose sugars or artificial dyes and food coloring? While there continues to be a significant number of parents whose anecdotal observations point to a relationship between diet and behavior, to date controlled studies have not supported a dietary cause for the ADHD phenomenon.
Within a few years of beginning my dual careers as parent and pediatrician, I began to notice that children who were sleep deprived often were distractible and inattentive. Some also were hyperactive, an observation that initially seemed counterintuitive. Over the ensuing four decades, I have become more convinced that a substantial driver of the emergence of the ADHD phenomenon is the fact that the North American lifestyle places sleep so far down on its priority list that a significant percentage of both the pediatric and adult populations are sleep deprived.
I freely admit that my initial anecdotal observations have evolved to the point of an obsession. Of course, I look at the data that show that children are getting less sleep than they did a century ago and suspect that this decline must somehow be reflected in their behavior (“Never enough sleep: A brief history of sleep recommendations for children” by Matricciani et al. Pediatrics. 2012 Mar;129[3]:548-56). And, of course, I wonder whether the success and popularity of stimulant medication to treat ADHD is just chance or whether it simply could be waking up a bunch of children who aren’t getting enough sleep.
At times, it has been a lonely several decades, trying to convince parents and other pediatricians that sleep may be the answer. I can’t point to my own research because I have been too busy doing general pediatrics. I can only point to the observations of others that fit into my construct.
You can imagine the warm glow that swept over me when I came across an article in the Washington Post titled “Could some ADHD be a type of sleep disorder? That would fundamentally change how we treat it” (A.E. Cha, Sep. 20, 2017). The studies referred to in the article are not terribly earth shaking. But it was nice to read some quotes in a national newspaper from scientists who share my suspicions about sleep deprivation as a major contributor to the ADHD phenomenon. I instantly felt less lonely.
Unfortunately, it is still a long way from this token recognition in the Washington Post to convincing parents and pediatricians to do the heavy lifting that will be required to undo decades of our society’s sleep-unfriendly norms. It’s so much easier to pull out a prescription pad and write for a stimulant.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”
Email him at pdnews@frontlinemedcom.com.
If you graduated from medical school after 1990, you may be surprised to learn that there was a time when the typical general pediatrician could go through an entire day of seeing patients and not write a single prescription for a stimulant medication. In fact, he or she could go for several months without writing for any controlled substance.
ADHD is a modern phenomenon. There always have been children with “ants in their pants” who couldn’t sit still. And there always were “daydreamers” who didn’t pay attention in school. But in the 1970s, the number of children who might now be labeled as having ADHD was nowhere near the 11% often quoted for the prevalence in the current pediatric population.
Could there be some genetic selection process that is favoring the birth and survival of hyperactive and distractible children? In the last decade or two, biologists have discovered evolutionary changes in some animals occurring at pace far faster than had been previously imagined. However, a Darwinian explanation seems unlikely in the case of the emergence of ADHD.
Could it be a diet laced with high fructose sugars or artificial dyes and food coloring? While there continues to be a significant number of parents whose anecdotal observations point to a relationship between diet and behavior, to date controlled studies have not supported a dietary cause for the ADHD phenomenon.
Within a few years of beginning my dual careers as parent and pediatrician, I began to notice that children who were sleep deprived often were distractible and inattentive. Some also were hyperactive, an observation that initially seemed counterintuitive. Over the ensuing four decades, I have become more convinced that a substantial driver of the emergence of the ADHD phenomenon is the fact that the North American lifestyle places sleep so far down on its priority list that a significant percentage of both the pediatric and adult populations are sleep deprived.
I freely admit that my initial anecdotal observations have evolved to the point of an obsession. Of course, I look at the data that show that children are getting less sleep than they did a century ago and suspect that this decline must somehow be reflected in their behavior (“Never enough sleep: A brief history of sleep recommendations for children” by Matricciani et al. Pediatrics. 2012 Mar;129[3]:548-56). And, of course, I wonder whether the success and popularity of stimulant medication to treat ADHD is just chance or whether it simply could be waking up a bunch of children who aren’t getting enough sleep.
At times, it has been a lonely several decades, trying to convince parents and other pediatricians that sleep may be the answer. I can’t point to my own research because I have been too busy doing general pediatrics. I can only point to the observations of others that fit into my construct.
You can imagine the warm glow that swept over me when I came across an article in the Washington Post titled “Could some ADHD be a type of sleep disorder? That would fundamentally change how we treat it” (A.E. Cha, Sep. 20, 2017). The studies referred to in the article are not terribly earth shaking. But it was nice to read some quotes in a national newspaper from scientists who share my suspicions about sleep deprivation as a major contributor to the ADHD phenomenon. I instantly felt less lonely.
Unfortunately, it is still a long way from this token recognition in the Washington Post to convincing parents and pediatricians to do the heavy lifting that will be required to undo decades of our society’s sleep-unfriendly norms. It’s so much easier to pull out a prescription pad and write for a stimulant.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”
Email him at pdnews@frontlinemedcom.com.
If you graduated from medical school after 1990, you may be surprised to learn that there was a time when the typical general pediatrician could go through an entire day of seeing patients and not write a single prescription for a stimulant medication. In fact, he or she could go for several months without writing for any controlled substance.
ADHD is a modern phenomenon. There always have been children with “ants in their pants” who couldn’t sit still. And there always were “daydreamers” who didn’t pay attention in school. But in the 1970s, the number of children who might now be labeled as having ADHD was nowhere near the 11% often quoted for the prevalence in the current pediatric population.
Could there be some genetic selection process that is favoring the birth and survival of hyperactive and distractible children? In the last decade or two, biologists have discovered evolutionary changes in some animals occurring at pace far faster than had been previously imagined. However, a Darwinian explanation seems unlikely in the case of the emergence of ADHD.
Could it be a diet laced with high fructose sugars or artificial dyes and food coloring? While there continues to be a significant number of parents whose anecdotal observations point to a relationship between diet and behavior, to date controlled studies have not supported a dietary cause for the ADHD phenomenon.
Within a few years of beginning my dual careers as parent and pediatrician, I began to notice that children who were sleep deprived often were distractible and inattentive. Some also were hyperactive, an observation that initially seemed counterintuitive. Over the ensuing four decades, I have become more convinced that a substantial driver of the emergence of the ADHD phenomenon is the fact that the North American lifestyle places sleep so far down on its priority list that a significant percentage of both the pediatric and adult populations are sleep deprived.
I freely admit that my initial anecdotal observations have evolved to the point of an obsession. Of course, I look at the data that show that children are getting less sleep than they did a century ago and suspect that this decline must somehow be reflected in their behavior (“Never enough sleep: A brief history of sleep recommendations for children” by Matricciani et al. Pediatrics. 2012 Mar;129[3]:548-56). And, of course, I wonder whether the success and popularity of stimulant medication to treat ADHD is just chance or whether it simply could be waking up a bunch of children who aren’t getting enough sleep.
At times, it has been a lonely several decades, trying to convince parents and other pediatricians that sleep may be the answer. I can’t point to my own research because I have been too busy doing general pediatrics. I can only point to the observations of others that fit into my construct.
You can imagine the warm glow that swept over me when I came across an article in the Washington Post titled “Could some ADHD be a type of sleep disorder? That would fundamentally change how we treat it” (A.E. Cha, Sep. 20, 2017). The studies referred to in the article are not terribly earth shaking. But it was nice to read some quotes in a national newspaper from scientists who share my suspicions about sleep deprivation as a major contributor to the ADHD phenomenon. I instantly felt less lonely.
Unfortunately, it is still a long way from this token recognition in the Washington Post to convincing parents and pediatricians to do the heavy lifting that will be required to undo decades of our society’s sleep-unfriendly norms. It’s so much easier to pull out a prescription pad and write for a stimulant.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”
Email him at pdnews@frontlinemedcom.com.
Transoral robotic surgery assessed for oral lesions
A single-arm study is being conducted at the Ohio State University Comprehensive Cancer Center, Columbus, to assess transoral robotic surgery (TORS) for oral and laryngopharyngeal benign and malignant lesions using the da Vinci Robotic Surgical System.
The study started in 2007, and the estimated completion date is December 2020. Investigators hope to enroll 360 adults.
Patients are scheduled for regular postop visits to assess quality of life and other matters. Those unable to return to Ohio State University are contacted by phone or provided with the questionnaire by mail.
A single-arm study is being conducted at the Ohio State University Comprehensive Cancer Center, Columbus, to assess transoral robotic surgery (TORS) for oral and laryngopharyngeal benign and malignant lesions using the da Vinci Robotic Surgical System.
The study started in 2007, and the estimated completion date is December 2020. Investigators hope to enroll 360 adults.
Patients are scheduled for regular postop visits to assess quality of life and other matters. Those unable to return to Ohio State University are contacted by phone or provided with the questionnaire by mail.
A single-arm study is being conducted at the Ohio State University Comprehensive Cancer Center, Columbus, to assess transoral robotic surgery (TORS) for oral and laryngopharyngeal benign and malignant lesions using the da Vinci Robotic Surgical System.
The study started in 2007, and the estimated completion date is December 2020. Investigators hope to enroll 360 adults.
Patients are scheduled for regular postop visits to assess quality of life and other matters. Those unable to return to Ohio State University are contacted by phone or provided with the questionnaire by mail.
‘Without clinical prodrome’
For the most part pediatricians are insulated from death. Our little patients are surprisingly resilient. Once past that anxiety-provoking transition from placental dependence to air breathing, children will thrive in an environment that includes immunizations, potable water, and adequate nutrition. But pediatric deaths do occur infrequently in North America, and they are particularly unsettling to us because we are so unaccustomed to processing the emotions that swirl around the end of life. Did I miss something at the last health maintenance visit? Should I have taken more seriously that call last week about what sounded like a simple viral prodrome? Should I have asked that mother to make an appointment?
Their approach, which has been labeled the Robert’s Program, is particularly appealing because it is careful to address the families’ concerns about their surviving and future children. I found the inclusion of the dead child’s pediatrician and the office of the chief medical examiner in the summation of the investigation especially appealing.
However, I have trouble envisioning how this novel approach, funded by several philanthropic organizations, could be rolled out on a larger scale. Here in Maine and in many other smaller cash-strapped communities, the medical examiner’s office is overburdened with opioid overdoses and traumatic deaths. The police and sheriffs’ departments may lack sufficient training and experience to do careful scene investigations.
In reviewing the summary of the 17 deaths included in the article, I was struck by the inclusion of 3 cases in which the final cause of death was meningitis or encephalitis “without clinical prodrome.”
While a thorough investigation did eventually unearth the cause of death in these three cases, it is in that devilish prodrome that the seeds of guilt can continue to germinate. Parents and physicians will continue to wonder whether someone else with more sensitive antennae might have picked up those early signs of impending disaster. The answer is that there probably wasn’t anyone with better antennae, but there may have been someone with better luck.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”
For the most part pediatricians are insulated from death. Our little patients are surprisingly resilient. Once past that anxiety-provoking transition from placental dependence to air breathing, children will thrive in an environment that includes immunizations, potable water, and adequate nutrition. But pediatric deaths do occur infrequently in North America, and they are particularly unsettling to us because we are so unaccustomed to processing the emotions that swirl around the end of life. Did I miss something at the last health maintenance visit? Should I have taken more seriously that call last week about what sounded like a simple viral prodrome? Should I have asked that mother to make an appointment?
Their approach, which has been labeled the Robert’s Program, is particularly appealing because it is careful to address the families’ concerns about their surviving and future children. I found the inclusion of the dead child’s pediatrician and the office of the chief medical examiner in the summation of the investigation especially appealing.
However, I have trouble envisioning how this novel approach, funded by several philanthropic organizations, could be rolled out on a larger scale. Here in Maine and in many other smaller cash-strapped communities, the medical examiner’s office is overburdened with opioid overdoses and traumatic deaths. The police and sheriffs’ departments may lack sufficient training and experience to do careful scene investigations.
In reviewing the summary of the 17 deaths included in the article, I was struck by the inclusion of 3 cases in which the final cause of death was meningitis or encephalitis “without clinical prodrome.”
While a thorough investigation did eventually unearth the cause of death in these three cases, it is in that devilish prodrome that the seeds of guilt can continue to germinate. Parents and physicians will continue to wonder whether someone else with more sensitive antennae might have picked up those early signs of impending disaster. The answer is that there probably wasn’t anyone with better antennae, but there may have been someone with better luck.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”
For the most part pediatricians are insulated from death. Our little patients are surprisingly resilient. Once past that anxiety-provoking transition from placental dependence to air breathing, children will thrive in an environment that includes immunizations, potable water, and adequate nutrition. But pediatric deaths do occur infrequently in North America, and they are particularly unsettling to us because we are so unaccustomed to processing the emotions that swirl around the end of life. Did I miss something at the last health maintenance visit? Should I have taken more seriously that call last week about what sounded like a simple viral prodrome? Should I have asked that mother to make an appointment?
Their approach, which has been labeled the Robert’s Program, is particularly appealing because it is careful to address the families’ concerns about their surviving and future children. I found the inclusion of the dead child’s pediatrician and the office of the chief medical examiner in the summation of the investigation especially appealing.
However, I have trouble envisioning how this novel approach, funded by several philanthropic organizations, could be rolled out on a larger scale. Here in Maine and in many other smaller cash-strapped communities, the medical examiner’s office is overburdened with opioid overdoses and traumatic deaths. The police and sheriffs’ departments may lack sufficient training and experience to do careful scene investigations.
In reviewing the summary of the 17 deaths included in the article, I was struck by the inclusion of 3 cases in which the final cause of death was meningitis or encephalitis “without clinical prodrome.”
While a thorough investigation did eventually unearth the cause of death in these three cases, it is in that devilish prodrome that the seeds of guilt can continue to germinate. Parents and physicians will continue to wonder whether someone else with more sensitive antennae might have picked up those early signs of impending disaster. The answer is that there probably wasn’t anyone with better antennae, but there may have been someone with better luck.
Dr. Wilkoff practiced primary care pediatrics in Brunswick, Maine, for nearly 40 years. He has authored several books on behavioral pediatrics, including “How to Say No to Your Toddler.”
Robotic surgery technologies have unique learning curves for trainees
Training surgeons to use robotic technology involves learning curves, and a study has found that robotic technologies have unique learning curve profiles that have implications for the time and number of procedures needed to achieve competence.
Giorgio Mazzon, MD, of the Institute of Urology at University College Hospital, London, and his colleagues reviewed the literature on training surgeons in the use of a variety of technologies for urological procedures. They analyzed learning curves for virtual reality robotic simulators, robot-assisted laparoscopic radical prostatectomy (RALP), robot-assisted radical cystectomy (RARC), and robot-assisted partial nephrectomy (RAPN) (Curr Urol Rep. 2017 Sep 23;18:89).
RARC learning curves are more rapid than RALP, but this may be due to the fact that most surgeons practice RALP before learning RARC. It is estimated that it takes 21 procedures for operating time to plateau and 30 patients for proper lymph node yield and positive surgical margins of less than 5% to occur (Eur Urol. 2010 Aug;58[2]:197-202).Safety and competence in RAPN is usually defined by operating times, warm ischemic time, positive surgical margin, and complication rates. It has been reported that RAPN can be safely performed with completion of 25-30 cases (Eur Urol. 2010 Jul;58[1]:127-32).The results of the review “should inform trainers and trainees on what outcomes are expected at a given stage of training,” according to the investigators.
They reported no relevant financial disclosures.
Training surgeons to use robotic technology involves learning curves, and a study has found that robotic technologies have unique learning curve profiles that have implications for the time and number of procedures needed to achieve competence.
Giorgio Mazzon, MD, of the Institute of Urology at University College Hospital, London, and his colleagues reviewed the literature on training surgeons in the use of a variety of technologies for urological procedures. They analyzed learning curves for virtual reality robotic simulators, robot-assisted laparoscopic radical prostatectomy (RALP), robot-assisted radical cystectomy (RARC), and robot-assisted partial nephrectomy (RAPN) (Curr Urol Rep. 2017 Sep 23;18:89).
RARC learning curves are more rapid than RALP, but this may be due to the fact that most surgeons practice RALP before learning RARC. It is estimated that it takes 21 procedures for operating time to plateau and 30 patients for proper lymph node yield and positive surgical margins of less than 5% to occur (Eur Urol. 2010 Aug;58[2]:197-202).Safety and competence in RAPN is usually defined by operating times, warm ischemic time, positive surgical margin, and complication rates. It has been reported that RAPN can be safely performed with completion of 25-30 cases (Eur Urol. 2010 Jul;58[1]:127-32).The results of the review “should inform trainers and trainees on what outcomes are expected at a given stage of training,” according to the investigators.
They reported no relevant financial disclosures.
Training surgeons to use robotic technology involves learning curves, and a study has found that robotic technologies have unique learning curve profiles that have implications for the time and number of procedures needed to achieve competence.
Giorgio Mazzon, MD, of the Institute of Urology at University College Hospital, London, and his colleagues reviewed the literature on training surgeons in the use of a variety of technologies for urological procedures. They analyzed learning curves for virtual reality robotic simulators, robot-assisted laparoscopic radical prostatectomy (RALP), robot-assisted radical cystectomy (RARC), and robot-assisted partial nephrectomy (RAPN) (Curr Urol Rep. 2017 Sep 23;18:89).
RARC learning curves are more rapid than RALP, but this may be due to the fact that most surgeons practice RALP before learning RARC. It is estimated that it takes 21 procedures for operating time to plateau and 30 patients for proper lymph node yield and positive surgical margins of less than 5% to occur (Eur Urol. 2010 Aug;58[2]:197-202).Safety and competence in RAPN is usually defined by operating times, warm ischemic time, positive surgical margin, and complication rates. It has been reported that RAPN can be safely performed with completion of 25-30 cases (Eur Urol. 2010 Jul;58[1]:127-32).The results of the review “should inform trainers and trainees on what outcomes are expected at a given stage of training,” according to the investigators.
They reported no relevant financial disclosures.
FROM CURRENT UROLOGY REPORTS
Key clinical point:
Major finding: For virtual reality training programs, recommendations for achieving safety and competence is between 4 and 12 hours of training in a simulator.
Data source: Review of studies of learning curves in robotic urological surgery.
Disclosures: The researchers reported no financial disclosures.
Biophysical properties of HCV evolve over course of infection
Hepatitis C virus (HCV) particles are of lowest density and most infectious early in the course of infection, based on findings from a study of chimeric mice.
Over time, however, viral density became more heterogeneous and infectivity fell, reported Ursula Andreo, PhD, of Rockefeller University, New York, with her coinvestigators. A diet of 10% sucrose, which in rats induces hepatic secretion of very-low-density lipoprotein (VLDL), caused HCV particles to become slightly lower density and more infectious in the mice, the researchers reported. Although the shift was “minor,” it “correlated with a trend toward enhanced triglyceride and cholesterol levels in the same fractions,” they wrote. They recommended studying high-fat diets to determine whether altering the VLDL secretion pathway affects the biophysical properties of HCV. “A high-fat diet might have a more significant impact on the lipoprotein profile in this humanized mouse model,” they wrote in Cellular and Molecular Gastroenterology and Hepatology (2017 Jul;4[3]:405-17).
Because HCV tends to associate with lipoproteins, it shows a range of buoyant densities in the blood of infected patients. The “entry, replication, and assembly [of the virion] are linked closely to host lipid and lipoprotein metabolism,” wrote Dr. Andreo and her colleagues.
They created an in vivo model to study the buoyant density and infectivity of HCV particles, as well as their interaction with lipoproteins, by grafting human hepatocytes into the livers of immunodeficient mice that were homozygous recessive for fumarylacetoacetate hydrolase. Next, they infected 13 of these chimeric mice with J6-JFH1, an HCV strain that can establish long-term infections in mice that have human liver grafts (Proc Natl Acad Sci USA. 2006;103[10]:3805-9). The human liver xenograft reconstituted the FAH gene, restoring triglycerides to normal levels in the chimeric mice and creating a suitable “humanlike” model of lipoprotein metabolism, the investigators wrote.
Density fractionation of infectious mouse serum revealed higher infectivity in the low-density fractions soon after infection, which also has been observed in a human liver chimeric mouse model of severe combined immunodeficiency disease, they added. In the HCV model, the human liver grafts were conserved 5 weeks after infection, and the mice had a lower proportion of lighter, infectious HCV particles.
The researchers lacked sufficient material to directly study the composition of virions or detect viral proteins in the various density fractions. However, they determined that apolipoprotein C1 was the lightest fraction and that apolipoprotein E was mainly found in the five lightest fractions. Both these apolipoproteins are “essential factors of HCV infectivity,” and neither redistributed over time, they said. They suggested using immunoelectron microscopy or mass spectrometry to study the nature and infectivity of viral particles further.
In humans, ingesting a high-fat milkshake increases detectable HCV RNA in the VLDL fraction, the researchers noted. In rodents, a sucrose diet also has been found to increase VLDL lipidation and secretion, so they gave five of the infected chimeric mice drinking water containing 10% sucrose. After 5 weeks, these mice had increased infectivity and higher levels of triglycerides and cholesterol, but the effect was small and disappeared after the sucrose was withdrawn.
HCV “circulates as a population of particles of light, as well as dense, buoyant densities, and both are infectious,” the researchers concluded. “Changes in diet, as well as conditions such as fasting and feeding, affect the distribution of HCV buoyant density gradients.”
Funders included the National Institutes of Health and the American Association for the Study of Liver Diseases. The investigators disclosed no conflicts.
A hallmark of HCV infection is the association of virus particles with lipoproteins. The HCV virion (lipo-viro particle, LVP) is composed of nucleocapsid and envelope glycoproteins associated with very-low- and low-density lipoproteins, cholesterol, and apolipoproteins. The lipid components determine the size, density, hepatotropism, and infectivity of LVPs and play a role in cell entry, morphogenesis, release, and viral escape mechanisms. LVPs undergo dynamic changes during infection, and dietary triglycerides induce alterations in their biophysical properties and infectivity.
Dr. Andreo and colleagues used humanized Fah–/– mice to analyze the evolution of HCV particles during infection. As previously reported, two viral populations of different densities were detected in mice sera, with higher infectivity observed for the low-density population. The proportions and infectivity of these populations varied during infection, reflecting changes in biochemical features of the virus. Sucrose diet influenced the properties of virus particles; these properties’ changes correlated with a redistribution of triglycerides and cholesterol among lipoproteins.
Changes in biochemical features of the virus during infection represent a fascinating aspect of the structural heterogeneity, which influences HCV infectivity and evolution of the disease. Further studies in experimental models that reproduce the lipoprotein-dependent morphogenesis and release of virus particles, maturation, and intravascular remodeling of HCV-associated lipoproteins would help to develop novel lipid-targeting inhibitors to improve existing therapies.
Agata Budkowska, PhD, is scientific advisor for the department of international affairs at the Institut Pasteur, Paris. She has no conflicts of interest.
A hallmark of HCV infection is the association of virus particles with lipoproteins. The HCV virion (lipo-viro particle, LVP) is composed of nucleocapsid and envelope glycoproteins associated with very-low- and low-density lipoproteins, cholesterol, and apolipoproteins. The lipid components determine the size, density, hepatotropism, and infectivity of LVPs and play a role in cell entry, morphogenesis, release, and viral escape mechanisms. LVPs undergo dynamic changes during infection, and dietary triglycerides induce alterations in their biophysical properties and infectivity.
Dr. Andreo and colleagues used humanized Fah–/– mice to analyze the evolution of HCV particles during infection. As previously reported, two viral populations of different densities were detected in mice sera, with higher infectivity observed for the low-density population. The proportions and infectivity of these populations varied during infection, reflecting changes in biochemical features of the virus. Sucrose diet influenced the properties of virus particles; these properties’ changes correlated with a redistribution of triglycerides and cholesterol among lipoproteins.
Changes in biochemical features of the virus during infection represent a fascinating aspect of the structural heterogeneity, which influences HCV infectivity and evolution of the disease. Further studies in experimental models that reproduce the lipoprotein-dependent morphogenesis and release of virus particles, maturation, and intravascular remodeling of HCV-associated lipoproteins would help to develop novel lipid-targeting inhibitors to improve existing therapies.
Agata Budkowska, PhD, is scientific advisor for the department of international affairs at the Institut Pasteur, Paris. She has no conflicts of interest.
A hallmark of HCV infection is the association of virus particles with lipoproteins. The HCV virion (lipo-viro particle, LVP) is composed of nucleocapsid and envelope glycoproteins associated with very-low- and low-density lipoproteins, cholesterol, and apolipoproteins. The lipid components determine the size, density, hepatotropism, and infectivity of LVPs and play a role in cell entry, morphogenesis, release, and viral escape mechanisms. LVPs undergo dynamic changes during infection, and dietary triglycerides induce alterations in their biophysical properties and infectivity.
Dr. Andreo and colleagues used humanized Fah–/– mice to analyze the evolution of HCV particles during infection. As previously reported, two viral populations of different densities were detected in mice sera, with higher infectivity observed for the low-density population. The proportions and infectivity of these populations varied during infection, reflecting changes in biochemical features of the virus. Sucrose diet influenced the properties of virus particles; these properties’ changes correlated with a redistribution of triglycerides and cholesterol among lipoproteins.
Changes in biochemical features of the virus during infection represent a fascinating aspect of the structural heterogeneity, which influences HCV infectivity and evolution of the disease. Further studies in experimental models that reproduce the lipoprotein-dependent morphogenesis and release of virus particles, maturation, and intravascular remodeling of HCV-associated lipoproteins would help to develop novel lipid-targeting inhibitors to improve existing therapies.
Agata Budkowska, PhD, is scientific advisor for the department of international affairs at the Institut Pasteur, Paris. She has no conflicts of interest.
Hepatitis C virus (HCV) particles are of lowest density and most infectious early in the course of infection, based on findings from a study of chimeric mice.
Over time, however, viral density became more heterogeneous and infectivity fell, reported Ursula Andreo, PhD, of Rockefeller University, New York, with her coinvestigators. A diet of 10% sucrose, which in rats induces hepatic secretion of very-low-density lipoprotein (VLDL), caused HCV particles to become slightly lower density and more infectious in the mice, the researchers reported. Although the shift was “minor,” it “correlated with a trend toward enhanced triglyceride and cholesterol levels in the same fractions,” they wrote. They recommended studying high-fat diets to determine whether altering the VLDL secretion pathway affects the biophysical properties of HCV. “A high-fat diet might have a more significant impact on the lipoprotein profile in this humanized mouse model,” they wrote in Cellular and Molecular Gastroenterology and Hepatology (2017 Jul;4[3]:405-17).
Because HCV tends to associate with lipoproteins, it shows a range of buoyant densities in the blood of infected patients. The “entry, replication, and assembly [of the virion] are linked closely to host lipid and lipoprotein metabolism,” wrote Dr. Andreo and her colleagues.
They created an in vivo model to study the buoyant density and infectivity of HCV particles, as well as their interaction with lipoproteins, by grafting human hepatocytes into the livers of immunodeficient mice that were homozygous recessive for fumarylacetoacetate hydrolase. Next, they infected 13 of these chimeric mice with J6-JFH1, an HCV strain that can establish long-term infections in mice that have human liver grafts (Proc Natl Acad Sci USA. 2006;103[10]:3805-9). The human liver xenograft reconstituted the FAH gene, restoring triglycerides to normal levels in the chimeric mice and creating a suitable “humanlike” model of lipoprotein metabolism, the investigators wrote.
Density fractionation of infectious mouse serum revealed higher infectivity in the low-density fractions soon after infection, which also has been observed in a human liver chimeric mouse model of severe combined immunodeficiency disease, they added. In the HCV model, the human liver grafts were conserved 5 weeks after infection, and the mice had a lower proportion of lighter, infectious HCV particles.
The researchers lacked sufficient material to directly study the composition of virions or detect viral proteins in the various density fractions. However, they determined that apolipoprotein C1 was the lightest fraction and that apolipoprotein E was mainly found in the five lightest fractions. Both these apolipoproteins are “essential factors of HCV infectivity,” and neither redistributed over time, they said. They suggested using immunoelectron microscopy or mass spectrometry to study the nature and infectivity of viral particles further.
In humans, ingesting a high-fat milkshake increases detectable HCV RNA in the VLDL fraction, the researchers noted. In rodents, a sucrose diet also has been found to increase VLDL lipidation and secretion, so they gave five of the infected chimeric mice drinking water containing 10% sucrose. After 5 weeks, these mice had increased infectivity and higher levels of triglycerides and cholesterol, but the effect was small and disappeared after the sucrose was withdrawn.
HCV “circulates as a population of particles of light, as well as dense, buoyant densities, and both are infectious,” the researchers concluded. “Changes in diet, as well as conditions such as fasting and feeding, affect the distribution of HCV buoyant density gradients.”
Funders included the National Institutes of Health and the American Association for the Study of Liver Diseases. The investigators disclosed no conflicts.
Hepatitis C virus (HCV) particles are of lowest density and most infectious early in the course of infection, based on findings from a study of chimeric mice.
Over time, however, viral density became more heterogeneous and infectivity fell, reported Ursula Andreo, PhD, of Rockefeller University, New York, with her coinvestigators. A diet of 10% sucrose, which in rats induces hepatic secretion of very-low-density lipoprotein (VLDL), caused HCV particles to become slightly lower density and more infectious in the mice, the researchers reported. Although the shift was “minor,” it “correlated with a trend toward enhanced triglyceride and cholesterol levels in the same fractions,” they wrote. They recommended studying high-fat diets to determine whether altering the VLDL secretion pathway affects the biophysical properties of HCV. “A high-fat diet might have a more significant impact on the lipoprotein profile in this humanized mouse model,” they wrote in Cellular and Molecular Gastroenterology and Hepatology (2017 Jul;4[3]:405-17).
Because HCV tends to associate with lipoproteins, it shows a range of buoyant densities in the blood of infected patients. The “entry, replication, and assembly [of the virion] are linked closely to host lipid and lipoprotein metabolism,” wrote Dr. Andreo and her colleagues.
They created an in vivo model to study the buoyant density and infectivity of HCV particles, as well as their interaction with lipoproteins, by grafting human hepatocytes into the livers of immunodeficient mice that were homozygous recessive for fumarylacetoacetate hydrolase. Next, they infected 13 of these chimeric mice with J6-JFH1, an HCV strain that can establish long-term infections in mice that have human liver grafts (Proc Natl Acad Sci USA. 2006;103[10]:3805-9). The human liver xenograft reconstituted the FAH gene, restoring triglycerides to normal levels in the chimeric mice and creating a suitable “humanlike” model of lipoprotein metabolism, the investigators wrote.
Density fractionation of infectious mouse serum revealed higher infectivity in the low-density fractions soon after infection, which also has been observed in a human liver chimeric mouse model of severe combined immunodeficiency disease, they added. In the HCV model, the human liver grafts were conserved 5 weeks after infection, and the mice had a lower proportion of lighter, infectious HCV particles.
The researchers lacked sufficient material to directly study the composition of virions or detect viral proteins in the various density fractions. However, they determined that apolipoprotein C1 was the lightest fraction and that apolipoprotein E was mainly found in the five lightest fractions. Both these apolipoproteins are “essential factors of HCV infectivity,” and neither redistributed over time, they said. They suggested using immunoelectron microscopy or mass spectrometry to study the nature and infectivity of viral particles further.
In humans, ingesting a high-fat milkshake increases detectable HCV RNA in the VLDL fraction, the researchers noted. In rodents, a sucrose diet also has been found to increase VLDL lipidation and secretion, so they gave five of the infected chimeric mice drinking water containing 10% sucrose. After 5 weeks, these mice had increased infectivity and higher levels of triglycerides and cholesterol, but the effect was small and disappeared after the sucrose was withdrawn.
HCV “circulates as a population of particles of light, as well as dense, buoyant densities, and both are infectious,” the researchers concluded. “Changes in diet, as well as conditions such as fasting and feeding, affect the distribution of HCV buoyant density gradients.”
Funders included the National Institutes of Health and the American Association for the Study of Liver Diseases. The investigators disclosed no conflicts.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Key clinical point: The biophysical properties of the hepatitis C virus evolve during the course of infection and shift with dietary changes.
Major finding: Density fractionation of infectious mouse serum showed higher infectivity in the low-density fractions soon after infection, but heterogeneity subsequently increased while infectivity decreased. A 5-week diet of 10% sucrose produced a minor shift toward infectivity that correlated with redistribution of triglycerides and cholesterol.
Data source: A study of 13 human liver chimeric mice.
Disclosures: Funders included the National Institutes of Health and the American Association for the Study of Liver Diseases. The investigators disclosed no conflicts.
Personality changes may not occur before Alzheimer’s onset
Personality changes do not presage dementia, at least when examined through the lens of self-report, a large retrospective study has determined.
Dementia patients do show personality characteristics that are different from those of their cognitively normal peers, wrote Antonio Terracciano, PhD (JAMA Psychiatry. 2017 Sep 20. doi: 10.1001/jamapsychiatry.2017.2816). Notably, they tend to be more neurotic and less conscientious, he noted. But among more than 2,000 older adults with up to 36 years of data, no temporal associations were found between these traits and the onset of cognitive difficulty, even within a few years of the onset of dementia symptoms.
“From a clinical perspective, these findings suggest that tracking change in self-rated personality as an early indicator of dementia is unlikely to be fruitful, while a single assessment provides reliable information on the personality traits that increase resilience [e.g., conscientiousness] or vulnerability [e.g., neuroticism] to clinical dementia,” wrote Dr. Terracciano of Florida State University, Tallahassee, and his coauthors.
However, the authors noted, it’s possible that self-reported personality may not be as good a marker of dementia-related personality change as informant report.
“Self-rated personality provides participants’ perspectives of themselves. … Individuals with AD could be anosognosic to change in their psychological trains and functioning. Self-reported personality might remain stable and reflect premorbid functioning more than current traits,” the researchers wrote.
The study tracked 2,046 community-living older adults who were part of the Baltimore Longitudinal Study of Aging, which began in 1958. Healthy individuals of different ages are continuously enrolled in the study and assessed with regular follow-up visits. These visits include cognitive and neuropsychiatric assessments, from which data for this study were extracted. The mean follow-up time was about 12 years, but some subjects had up to 36 years. From 1980 to 2016, the group completed more than 8,000 assessments and accumulated 24,569 person/years of follow-up.
Dr. Terracciano examined the cohort’s Revised NEO Personality Inventory results, a 240-item questionnaire that assesses 30 facets of personality in the dimensions of neuroticism, extraversion, openness, agreeableness, and conscientiousness. Cognitive decline was assessed by results on the Clinical Dementia Rating Scale and the older Dementia Questionnaire.
At the end of the follow-up period, 104 subjects (5%) had developed mild cognitive impairment, and 255 (12.5%) all-cause dementia; of those, 194 (9.5%) were later diagnosed with Alzheimer’s disease. In an unadjusted analysis, the authors found that the group that eventually developed AD scored higher on neuroticism, and lower on extraversion, openness, and conscientiousness than did the nonaffected subjects.
Over time, the authors found some changes in the reference group, including small declines in neuroticism and extraversion, and small increases in agreeableness and conscientiousness. However, when they looked at the trajectory of change, they found no significant differences in the rate of any change, compared with the AD group – although that group continued to display changes in its baseline difference of neuroticism and conscientiousness.
“Although the trajectories were similar, there were significant ... differences on the intercept,” they wrote. “The AD cohort scored higher on neuroticism and lower on conscientiousness and extraversion than the nonimpaired group.”
The team ran several temporal analyses on the data, and none found any significant temporal association with accelerated personality change in the AD group, the MCI group, or the all-cause dementia groups compared with the reference group, with one exception: Subjects with MCI showed a steeper decline in openness than did nonaffected subjects.
Those results were consistent even when they examined the two assessments performed just before the onset of cognitive symptoms (a mean of 6 and 3 years). “Consistent with the results and the broader literature, the AD group scored higher on neuroticism and lower on conscientiousness. Contrary to expectations, the AD group did not increase in neuroticism and decline in conscientiousness.”
The findings may shed some light on the chicken-or-egg question of personality change and dementia, they suggested.
“This research has relevance to the question of reverse causality for the association between personality and risk of incident AD. That is, if personality changed in response to increasing neuropathology in the brain in the preclinical phase, the association between personality and AD could have been due to the disease process rather than personality as an independent risk factor. We did not, however, find any evidence that neuroticism and conscientiousness changed significantly as the onset of disease approached. Thus, rather than an effect of AD neuropathology, these traits appear to confer risk for the development of the disease.”
The Baltimore Longitudinal Study of Aging is supported by the National Institutes of Health. Neither Dr. Terracciano nor his colleagues had financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
Personality changes do not presage dementia, at least when examined through the lens of self-report, a large retrospective study has determined.
Dementia patients do show personality characteristics that are different from those of their cognitively normal peers, wrote Antonio Terracciano, PhD (JAMA Psychiatry. 2017 Sep 20. doi: 10.1001/jamapsychiatry.2017.2816). Notably, they tend to be more neurotic and less conscientious, he noted. But among more than 2,000 older adults with up to 36 years of data, no temporal associations were found between these traits and the onset of cognitive difficulty, even within a few years of the onset of dementia symptoms.
“From a clinical perspective, these findings suggest that tracking change in self-rated personality as an early indicator of dementia is unlikely to be fruitful, while a single assessment provides reliable information on the personality traits that increase resilience [e.g., conscientiousness] or vulnerability [e.g., neuroticism] to clinical dementia,” wrote Dr. Terracciano of Florida State University, Tallahassee, and his coauthors.
However, the authors noted, it’s possible that self-reported personality may not be as good a marker of dementia-related personality change as informant report.
“Self-rated personality provides participants’ perspectives of themselves. … Individuals with AD could be anosognosic to change in their psychological trains and functioning. Self-reported personality might remain stable and reflect premorbid functioning more than current traits,” the researchers wrote.
The study tracked 2,046 community-living older adults who were part of the Baltimore Longitudinal Study of Aging, which began in 1958. Healthy individuals of different ages are continuously enrolled in the study and assessed with regular follow-up visits. These visits include cognitive and neuropsychiatric assessments, from which data for this study were extracted. The mean follow-up time was about 12 years, but some subjects had up to 36 years. From 1980 to 2016, the group completed more than 8,000 assessments and accumulated 24,569 person/years of follow-up.
Dr. Terracciano examined the cohort’s Revised NEO Personality Inventory results, a 240-item questionnaire that assesses 30 facets of personality in the dimensions of neuroticism, extraversion, openness, agreeableness, and conscientiousness. Cognitive decline was assessed by results on the Clinical Dementia Rating Scale and the older Dementia Questionnaire.
At the end of the follow-up period, 104 subjects (5%) had developed mild cognitive impairment, and 255 (12.5%) all-cause dementia; of those, 194 (9.5%) were later diagnosed with Alzheimer’s disease. In an unadjusted analysis, the authors found that the group that eventually developed AD scored higher on neuroticism, and lower on extraversion, openness, and conscientiousness than did the nonaffected subjects.
Over time, the authors found some changes in the reference group, including small declines in neuroticism and extraversion, and small increases in agreeableness and conscientiousness. However, when they looked at the trajectory of change, they found no significant differences in the rate of any change, compared with the AD group – although that group continued to display changes in its baseline difference of neuroticism and conscientiousness.
“Although the trajectories were similar, there were significant ... differences on the intercept,” they wrote. “The AD cohort scored higher on neuroticism and lower on conscientiousness and extraversion than the nonimpaired group.”
The team ran several temporal analyses on the data, and none found any significant temporal association with accelerated personality change in the AD group, the MCI group, or the all-cause dementia groups compared with the reference group, with one exception: Subjects with MCI showed a steeper decline in openness than did nonaffected subjects.
Those results were consistent even when they examined the two assessments performed just before the onset of cognitive symptoms (a mean of 6 and 3 years). “Consistent with the results and the broader literature, the AD group scored higher on neuroticism and lower on conscientiousness. Contrary to expectations, the AD group did not increase in neuroticism and decline in conscientiousness.”
The findings may shed some light on the chicken-or-egg question of personality change and dementia, they suggested.
“This research has relevance to the question of reverse causality for the association between personality and risk of incident AD. That is, if personality changed in response to increasing neuropathology in the brain in the preclinical phase, the association between personality and AD could have been due to the disease process rather than personality as an independent risk factor. We did not, however, find any evidence that neuroticism and conscientiousness changed significantly as the onset of disease approached. Thus, rather than an effect of AD neuropathology, these traits appear to confer risk for the development of the disease.”
The Baltimore Longitudinal Study of Aging is supported by the National Institutes of Health. Neither Dr. Terracciano nor his colleagues had financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
Personality changes do not presage dementia, at least when examined through the lens of self-report, a large retrospective study has determined.
Dementia patients do show personality characteristics that are different from those of their cognitively normal peers, wrote Antonio Terracciano, PhD (JAMA Psychiatry. 2017 Sep 20. doi: 10.1001/jamapsychiatry.2017.2816). Notably, they tend to be more neurotic and less conscientious, he noted. But among more than 2,000 older adults with up to 36 years of data, no temporal associations were found between these traits and the onset of cognitive difficulty, even within a few years of the onset of dementia symptoms.
“From a clinical perspective, these findings suggest that tracking change in self-rated personality as an early indicator of dementia is unlikely to be fruitful, while a single assessment provides reliable information on the personality traits that increase resilience [e.g., conscientiousness] or vulnerability [e.g., neuroticism] to clinical dementia,” wrote Dr. Terracciano of Florida State University, Tallahassee, and his coauthors.
However, the authors noted, it’s possible that self-reported personality may not be as good a marker of dementia-related personality change as informant report.
“Self-rated personality provides participants’ perspectives of themselves. … Individuals with AD could be anosognosic to change in their psychological trains and functioning. Self-reported personality might remain stable and reflect premorbid functioning more than current traits,” the researchers wrote.
The study tracked 2,046 community-living older adults who were part of the Baltimore Longitudinal Study of Aging, which began in 1958. Healthy individuals of different ages are continuously enrolled in the study and assessed with regular follow-up visits. These visits include cognitive and neuropsychiatric assessments, from which data for this study were extracted. The mean follow-up time was about 12 years, but some subjects had up to 36 years. From 1980 to 2016, the group completed more than 8,000 assessments and accumulated 24,569 person/years of follow-up.
Dr. Terracciano examined the cohort’s Revised NEO Personality Inventory results, a 240-item questionnaire that assesses 30 facets of personality in the dimensions of neuroticism, extraversion, openness, agreeableness, and conscientiousness. Cognitive decline was assessed by results on the Clinical Dementia Rating Scale and the older Dementia Questionnaire.
At the end of the follow-up period, 104 subjects (5%) had developed mild cognitive impairment, and 255 (12.5%) all-cause dementia; of those, 194 (9.5%) were later diagnosed with Alzheimer’s disease. In an unadjusted analysis, the authors found that the group that eventually developed AD scored higher on neuroticism, and lower on extraversion, openness, and conscientiousness than did the nonaffected subjects.
Over time, the authors found some changes in the reference group, including small declines in neuroticism and extraversion, and small increases in agreeableness and conscientiousness. However, when they looked at the trajectory of change, they found no significant differences in the rate of any change, compared with the AD group – although that group continued to display changes in its baseline difference of neuroticism and conscientiousness.
“Although the trajectories were similar, there were significant ... differences on the intercept,” they wrote. “The AD cohort scored higher on neuroticism and lower on conscientiousness and extraversion than the nonimpaired group.”
The team ran several temporal analyses on the data, and none found any significant temporal association with accelerated personality change in the AD group, the MCI group, or the all-cause dementia groups compared with the reference group, with one exception: Subjects with MCI showed a steeper decline in openness than did nonaffected subjects.
Those results were consistent even when they examined the two assessments performed just before the onset of cognitive symptoms (a mean of 6 and 3 years). “Consistent with the results and the broader literature, the AD group scored higher on neuroticism and lower on conscientiousness. Contrary to expectations, the AD group did not increase in neuroticism and decline in conscientiousness.”
The findings may shed some light on the chicken-or-egg question of personality change and dementia, they suggested.
“This research has relevance to the question of reverse causality for the association between personality and risk of incident AD. That is, if personality changed in response to increasing neuropathology in the brain in the preclinical phase, the association between personality and AD could have been due to the disease process rather than personality as an independent risk factor. We did not, however, find any evidence that neuroticism and conscientiousness changed significantly as the onset of disease approached. Thus, rather than an effect of AD neuropathology, these traits appear to confer risk for the development of the disease.”
The Baltimore Longitudinal Study of Aging is supported by the National Institutes of Health. Neither Dr. Terracciano nor his colleagues had financial disclosures.
msullivan@frontlinemedcom.com
On Twitter @alz_gal
FROM JAMA PSYCHIATRY
Key clinical point:
Major finding: Although patients with AD scored higher on neuroticism and lower on conscientiousness, those traits did not change any faster than personality traits in the nonaffected subjects.
Data source: The study comprised 2,046 subjects with up to 36 years’ follow-up.
Disclosures: The Baltimore Longitudinal Study on Aging is funded by the National Institutes of Health. Neither Dr. Terracciano nor his coauthors had financial disclosures.
Insist on flu vaccination for all, say experts
sponsored by the National Foundation for Infectious Diseases.
Some good news about the flu – vaccination rates increased slightly last year, compared with the previous year among all individuals aged 6 months and older without contraindications, according to data from the Centers for Disease Control and Prevention.
Experts continue to recommend annual influenza vaccination for all persons aged 6 months and older, but they emphasize the need to identify those at risk of not getting vaccinated and develop strategies to increase vaccination coverage.
“Vaccines are among the greatest public health achievements of modern times, but they are only as useful as we as a society take advantage of them,” Secretary of Health & Human Services Thomas E. Price, MD, said at the briefing.
Overall flu vaccination in the United States was 47% for the 2016-2017 season, compared with 46% during the 2015-2016 season, according to data from the Centers for Disease Control and Prevention.
Dr. Price emphasized that vaccination is only part of a successful flu prevention strategy. Stay home when you are sick to help avoid spreading germs to others and take antiviral drugs if a doctor prescribes them to help reduce and avoid complications from flu, he said.
Children aged 6-23 months were the only population subgroup to meet the 70% Healthy People 2020 goal last year, with a rate of 73%, said Patricia A. Stinchfield, RN, CPNP, senior director of infection prevention and control at Children’s Hospital Minnesota, Minneapolis.
“Our goal is to increase coverage for children of all ages,” she said. But it’s not just about the kids themselves, she emphasized.
“If your child gets the flu, they expose babies, grandparents, pregnant women. We need to vaccinate children to protect the public at large,” she said. In addition, health care professionals must be clear about recommending vaccination. The research shows that a specific recommendation often makes the difference for vaccinating families.
Pregnant women are among those who can and should safely be vaccinated, Ms. Stinchfield emphasized. Flu vaccination among pregnant women was 54% in 2016-2017, similar to the past three flu seasons, and approximately two-thirds (67%) of pregnant women in 2016-2017 reported that a health care provider recommended and offered flu vaccination, according to CDC data.
Older adults also are important targets for flu vaccination, noted Kathleen M. Neuzil, MD, director of the Center for Vaccine Development at the University of Maryland, Baltimore. Last year, approximately 65% of U.S. adults aged 65 years and older were vaccinated, which was the largest subgroup of adults aged 18 years and older, she said. Older adults may be caring for frail spouses or infant grandchildren, so protecting others should be a motivating factor in continuing to encourage vaccination in this age group, she noted.
The flu vaccine supply is plentiful going into the start of the 2016-2017 flu season, with an estimated 166 million doses available in several formulations, said Daniel B. Jernigan, MD, director of the CDC’s Influenza Division.
Options for vaccination include the standard vaccine, a cell-based vaccine, and a recombinant vaccine. In addition, an adjuvanted vaccine and a high-dose vaccine are available specifically for adults aged 65 years and older; these vaccines are designed to provoke a stronger immune response, Dr. Jernigan said.
However, the briefing participants agreed that the best strategy is to get vaccinated as soon as possible, rather than postponing vaccination in order to secure a particular vaccine type.
Clinicians should not underestimate the power of leading by example when it comes to flu vaccination, Dr. Schaffner noted. Support from the highest levels of administration is important to help overcome barriers to vaccination coverage for health care workers by making vaccination easy and accessible, he said.
The overall influenza vaccination coverage estimate among health care providers was 79% for the 2016-2017 season, similar to the 2014-2015 and 2015-2016 seasons, but representing a 15% increase since 2010-2011. Vaccination coverage was highest among health care personnel whose workplaces required it.
Complete data on 2016-2017 vaccination coverage in health care workers and in pregnant women were published in the CDC’s Morbidity and Mortality Weekly Report on Sept. 29.
The CDC’s complete flu vaccination recommendations are available online.
The briefing participants had no relevant financial conflicts to disclose.
sponsored by the National Foundation for Infectious Diseases.
Some good news about the flu – vaccination rates increased slightly last year, compared with the previous year among all individuals aged 6 months and older without contraindications, according to data from the Centers for Disease Control and Prevention.
Experts continue to recommend annual influenza vaccination for all persons aged 6 months and older, but they emphasize the need to identify those at risk of not getting vaccinated and develop strategies to increase vaccination coverage.
“Vaccines are among the greatest public health achievements of modern times, but they are only as useful as we as a society take advantage of them,” Secretary of Health & Human Services Thomas E. Price, MD, said at the briefing.
Overall flu vaccination in the United States was 47% for the 2016-2017 season, compared with 46% during the 2015-2016 season, according to data from the Centers for Disease Control and Prevention.
Dr. Price emphasized that vaccination is only part of a successful flu prevention strategy. Stay home when you are sick to help avoid spreading germs to others and take antiviral drugs if a doctor prescribes them to help reduce and avoid complications from flu, he said.
Children aged 6-23 months were the only population subgroup to meet the 70% Healthy People 2020 goal last year, with a rate of 73%, said Patricia A. Stinchfield, RN, CPNP, senior director of infection prevention and control at Children’s Hospital Minnesota, Minneapolis.
“Our goal is to increase coverage for children of all ages,” she said. But it’s not just about the kids themselves, she emphasized.
“If your child gets the flu, they expose babies, grandparents, pregnant women. We need to vaccinate children to protect the public at large,” she said. In addition, health care professionals must be clear about recommending vaccination. The research shows that a specific recommendation often makes the difference for vaccinating families.
Pregnant women are among those who can and should safely be vaccinated, Ms. Stinchfield emphasized. Flu vaccination among pregnant women was 54% in 2016-2017, similar to the past three flu seasons, and approximately two-thirds (67%) of pregnant women in 2016-2017 reported that a health care provider recommended and offered flu vaccination, according to CDC data.
Older adults also are important targets for flu vaccination, noted Kathleen M. Neuzil, MD, director of the Center for Vaccine Development at the University of Maryland, Baltimore. Last year, approximately 65% of U.S. adults aged 65 years and older were vaccinated, which was the largest subgroup of adults aged 18 years and older, she said. Older adults may be caring for frail spouses or infant grandchildren, so protecting others should be a motivating factor in continuing to encourage vaccination in this age group, she noted.
The flu vaccine supply is plentiful going into the start of the 2016-2017 flu season, with an estimated 166 million doses available in several formulations, said Daniel B. Jernigan, MD, director of the CDC’s Influenza Division.
Options for vaccination include the standard vaccine, a cell-based vaccine, and a recombinant vaccine. In addition, an adjuvanted vaccine and a high-dose vaccine are available specifically for adults aged 65 years and older; these vaccines are designed to provoke a stronger immune response, Dr. Jernigan said.
However, the briefing participants agreed that the best strategy is to get vaccinated as soon as possible, rather than postponing vaccination in order to secure a particular vaccine type.
Clinicians should not underestimate the power of leading by example when it comes to flu vaccination, Dr. Schaffner noted. Support from the highest levels of administration is important to help overcome barriers to vaccination coverage for health care workers by making vaccination easy and accessible, he said.
The overall influenza vaccination coverage estimate among health care providers was 79% for the 2016-2017 season, similar to the 2014-2015 and 2015-2016 seasons, but representing a 15% increase since 2010-2011. Vaccination coverage was highest among health care personnel whose workplaces required it.
Complete data on 2016-2017 vaccination coverage in health care workers and in pregnant women were published in the CDC’s Morbidity and Mortality Weekly Report on Sept. 29.
The CDC’s complete flu vaccination recommendations are available online.
The briefing participants had no relevant financial conflicts to disclose.
sponsored by the National Foundation for Infectious Diseases.
Some good news about the flu – vaccination rates increased slightly last year, compared with the previous year among all individuals aged 6 months and older without contraindications, according to data from the Centers for Disease Control and Prevention.
Experts continue to recommend annual influenza vaccination for all persons aged 6 months and older, but they emphasize the need to identify those at risk of not getting vaccinated and develop strategies to increase vaccination coverage.
“Vaccines are among the greatest public health achievements of modern times, but they are only as useful as we as a society take advantage of them,” Secretary of Health & Human Services Thomas E. Price, MD, said at the briefing.
Overall flu vaccination in the United States was 47% for the 2016-2017 season, compared with 46% during the 2015-2016 season, according to data from the Centers for Disease Control and Prevention.
Dr. Price emphasized that vaccination is only part of a successful flu prevention strategy. Stay home when you are sick to help avoid spreading germs to others and take antiviral drugs if a doctor prescribes them to help reduce and avoid complications from flu, he said.
Children aged 6-23 months were the only population subgroup to meet the 70% Healthy People 2020 goal last year, with a rate of 73%, said Patricia A. Stinchfield, RN, CPNP, senior director of infection prevention and control at Children’s Hospital Minnesota, Minneapolis.
“Our goal is to increase coverage for children of all ages,” she said. But it’s not just about the kids themselves, she emphasized.
“If your child gets the flu, they expose babies, grandparents, pregnant women. We need to vaccinate children to protect the public at large,” she said. In addition, health care professionals must be clear about recommending vaccination. The research shows that a specific recommendation often makes the difference for vaccinating families.
Pregnant women are among those who can and should safely be vaccinated, Ms. Stinchfield emphasized. Flu vaccination among pregnant women was 54% in 2016-2017, similar to the past three flu seasons, and approximately two-thirds (67%) of pregnant women in 2016-2017 reported that a health care provider recommended and offered flu vaccination, according to CDC data.
Older adults also are important targets for flu vaccination, noted Kathleen M. Neuzil, MD, director of the Center for Vaccine Development at the University of Maryland, Baltimore. Last year, approximately 65% of U.S. adults aged 65 years and older were vaccinated, which was the largest subgroup of adults aged 18 years and older, she said. Older adults may be caring for frail spouses or infant grandchildren, so protecting others should be a motivating factor in continuing to encourage vaccination in this age group, she noted.
The flu vaccine supply is plentiful going into the start of the 2016-2017 flu season, with an estimated 166 million doses available in several formulations, said Daniel B. Jernigan, MD, director of the CDC’s Influenza Division.
Options for vaccination include the standard vaccine, a cell-based vaccine, and a recombinant vaccine. In addition, an adjuvanted vaccine and a high-dose vaccine are available specifically for adults aged 65 years and older; these vaccines are designed to provoke a stronger immune response, Dr. Jernigan said.
However, the briefing participants agreed that the best strategy is to get vaccinated as soon as possible, rather than postponing vaccination in order to secure a particular vaccine type.
Clinicians should not underestimate the power of leading by example when it comes to flu vaccination, Dr. Schaffner noted. Support from the highest levels of administration is important to help overcome barriers to vaccination coverage for health care workers by making vaccination easy and accessible, he said.
The overall influenza vaccination coverage estimate among health care providers was 79% for the 2016-2017 season, similar to the 2014-2015 and 2015-2016 seasons, but representing a 15% increase since 2010-2011. Vaccination coverage was highest among health care personnel whose workplaces required it.
Complete data on 2016-2017 vaccination coverage in health care workers and in pregnant women were published in the CDC’s Morbidity and Mortality Weekly Report on Sept. 29.
The CDC’s complete flu vaccination recommendations are available online.
The briefing participants had no relevant financial conflicts to disclose.
ADHD meds don’t raise seizure risk in epilepsy patients
PARIS – The use of attention-deficit/hyperactivity disorder medications is not associated with increased risk of epileptic seizures in patients with both disorders, according to an analysis of Swedish national registry data.
“Seizure history should not exempt patients from ADHD medication treatment,” Isabell Brikell stated at the annual congress of the European College of Neuropsychopharmacology.
“That’s why it’s such an important question, whether ADHD medications increase the risk of seizures,” observed Ms. Brikell, a PhD candidate in psychiatric genetics and epidemiology at the Karolinska Institute in Stockholm.
Swedish health care registries are famously comprehensive. For example, the Swedish prescription medication registry that Ms. Brikell and her coinvestigators tapped into for their ADHD/epilepsy study contains information on 99% of all prescriptions ordered in the country since 2005.
She reported on 38,247 Swedish patients with epilepsy born during 1976-2008 and followed during 2006-2013. Forty-eight percent were female. They collectively experienced 30,093 acute epileptic seizures of sufficient severity that they presented to a hospital for an unplanned visit. When the investigators compared the rate of seizures while the patients with ADHD were on a collective 4,248 ADHD medication exposure periods to that of epilepsy patients without ADHD, they found that the seizure risk was actually 17% lower in ADHD patients while on medication. This difference fell just shy of statistical significance. The analysis was adjusted for gender, age, and time on ADHD medications.
However, Ms. Brikell and her coworkers also performed a separate analysis for each individual with ADHD in which they compared seizure rates when a given patient was on ADHD medication versus off medication, a design that controls for many of the potential confounding factors that can occur with observational data. The seizure risk proved to be 19% lower while an individual was on ADHD medication – and this difference was indeed statistically significant.
In an interview, Ms. Brikell noted that the Swedish data are confirmed by a much larger National Institute of Mental Health–sponsored American study she was involved with that is now under review for publication. The U.S. study, which used the enormous MarketScan private health insurance database, demonstrated with the power provided by very large patient numbers that the seizure risk was convincingly lower while dual-diagnosis patients were on ADHD medication than when they were off.
“It’s reassuring to see the same effect across two countries with such different health care systems,” she commented.
Epilepsy is known to be inherently associated with a threefold increased prevalence of ADHD.
Ms. Brikell’s study was funded by the Swedish Research Council, the U.S. National Institute of Mental Health, and the Swedish Initiative for Research on Microdata in the Social and Medical Sciences. She reported having no financial conflicts of interest.
PARIS – The use of attention-deficit/hyperactivity disorder medications is not associated with increased risk of epileptic seizures in patients with both disorders, according to an analysis of Swedish national registry data.
“Seizure history should not exempt patients from ADHD medication treatment,” Isabell Brikell stated at the annual congress of the European College of Neuropsychopharmacology.
“That’s why it’s such an important question, whether ADHD medications increase the risk of seizures,” observed Ms. Brikell, a PhD candidate in psychiatric genetics and epidemiology at the Karolinska Institute in Stockholm.
Swedish health care registries are famously comprehensive. For example, the Swedish prescription medication registry that Ms. Brikell and her coinvestigators tapped into for their ADHD/epilepsy study contains information on 99% of all prescriptions ordered in the country since 2005.
She reported on 38,247 Swedish patients with epilepsy born during 1976-2008 and followed during 2006-2013. Forty-eight percent were female. They collectively experienced 30,093 acute epileptic seizures of sufficient severity that they presented to a hospital for an unplanned visit. When the investigators compared the rate of seizures while the patients with ADHD were on a collective 4,248 ADHD medication exposure periods to that of epilepsy patients without ADHD, they found that the seizure risk was actually 17% lower in ADHD patients while on medication. This difference fell just shy of statistical significance. The analysis was adjusted for gender, age, and time on ADHD medications.
However, Ms. Brikell and her coworkers also performed a separate analysis for each individual with ADHD in which they compared seizure rates when a given patient was on ADHD medication versus off medication, a design that controls for many of the potential confounding factors that can occur with observational data. The seizure risk proved to be 19% lower while an individual was on ADHD medication – and this difference was indeed statistically significant.
In an interview, Ms. Brikell noted that the Swedish data are confirmed by a much larger National Institute of Mental Health–sponsored American study she was involved with that is now under review for publication. The U.S. study, which used the enormous MarketScan private health insurance database, demonstrated with the power provided by very large patient numbers that the seizure risk was convincingly lower while dual-diagnosis patients were on ADHD medication than when they were off.
“It’s reassuring to see the same effect across two countries with such different health care systems,” she commented.
Epilepsy is known to be inherently associated with a threefold increased prevalence of ADHD.
Ms. Brikell’s study was funded by the Swedish Research Council, the U.S. National Institute of Mental Health, and the Swedish Initiative for Research on Microdata in the Social and Medical Sciences. She reported having no financial conflicts of interest.
PARIS – The use of attention-deficit/hyperactivity disorder medications is not associated with increased risk of epileptic seizures in patients with both disorders, according to an analysis of Swedish national registry data.
“Seizure history should not exempt patients from ADHD medication treatment,” Isabell Brikell stated at the annual congress of the European College of Neuropsychopharmacology.
“That’s why it’s such an important question, whether ADHD medications increase the risk of seizures,” observed Ms. Brikell, a PhD candidate in psychiatric genetics and epidemiology at the Karolinska Institute in Stockholm.
Swedish health care registries are famously comprehensive. For example, the Swedish prescription medication registry that Ms. Brikell and her coinvestigators tapped into for their ADHD/epilepsy study contains information on 99% of all prescriptions ordered in the country since 2005.
She reported on 38,247 Swedish patients with epilepsy born during 1976-2008 and followed during 2006-2013. Forty-eight percent were female. They collectively experienced 30,093 acute epileptic seizures of sufficient severity that they presented to a hospital for an unplanned visit. When the investigators compared the rate of seizures while the patients with ADHD were on a collective 4,248 ADHD medication exposure periods to that of epilepsy patients without ADHD, they found that the seizure risk was actually 17% lower in ADHD patients while on medication. This difference fell just shy of statistical significance. The analysis was adjusted for gender, age, and time on ADHD medications.
However, Ms. Brikell and her coworkers also performed a separate analysis for each individual with ADHD in which they compared seizure rates when a given patient was on ADHD medication versus off medication, a design that controls for many of the potential confounding factors that can occur with observational data. The seizure risk proved to be 19% lower while an individual was on ADHD medication – and this difference was indeed statistically significant.
In an interview, Ms. Brikell noted that the Swedish data are confirmed by a much larger National Institute of Mental Health–sponsored American study she was involved with that is now under review for publication. The U.S. study, which used the enormous MarketScan private health insurance database, demonstrated with the power provided by very large patient numbers that the seizure risk was convincingly lower while dual-diagnosis patients were on ADHD medication than when they were off.
“It’s reassuring to see the same effect across two countries with such different health care systems,” she commented.
Epilepsy is known to be inherently associated with a threefold increased prevalence of ADHD.
Ms. Brikell’s study was funded by the Swedish Research Council, the U.S. National Institute of Mental Health, and the Swedish Initiative for Research on Microdata in the Social and Medical Sciences. She reported having no financial conflicts of interest.
AT THE ECNP CONGRESS
Key clinical point:
Major finding: Patients with ADHD and a history of epilepsy were at 19% lower risk of experiencing seizures while on ADHD medication than when off it.
Data source: This was an observational study of prospectively collected data on all of the nearly 40,000 Swedish patients with epilepsy born during 1976-2008.
Disclosures: The study was funded by the Swedish Research Council, the U.S. National Institute of Mental Health, and the Swedish Initiative for Research on Microdata in the Social and Medical Sciences. The presenter reported having no financial conflicts of interest.
Atypical Fibroxanthoma Arising Within Erosive Pustular Dermatosis of the Scalp
Atypical fibroxanthoma (AFX) is a low-grade dermal malignancy comprised of atypical spindle cells.1 Classified as a superficial fibrohistiocytic tumor with intermediate malignant potential, AFX has an incidence of approximately 0.24% worldwide.2 The tumor appears mainly on the head and neck in sun-exposed areas but can occur less frequently on the trunk and limbs in non–sun-exposed areas. There is a 70% to 80% predominance in men aged 69 to 77 years, with lesions primarily occurring in sun-exposed areas of the head and neck.3 A median period of 4 months between time of onset and time of diagnosis has been previously established.4
When AFX does occur in non–sun-exposed areas, it tends to be in a younger patient population. Clinically, it presents as a rather nondescript, firm, erythematous papule or nodule less than 2 cm in diameter. Atypical fibroxanthoma most often presents asymptomatically, but the tumor may ulcerate and bleed, though pain and pruritus are uncommon.5 Findings are nonspecific, and the diagnosis must be confirmed with biopsy, as it can resemble other common dermatological lesions. The pathogenesis of AFX has been controversial. Two different studies looked at AFX using electron microscopy and concluded that the tumor most closely resembled a myofibroblast,6,7 which is consistent with current thinking today.
Atypical fibroxanthoma is believed to be associated with p53 mutation and is closely linked with exposure to UV radiation due to its predominance in sun-exposed areas. Other predisposing factors may include prior exposure to UV radiation, history of organ transplantation, immunosuppression, advanced age in men, and xeroderma pigmentosum. The differential diagnosis for AFX encompasses basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, adnexal tumor, and pyogenic granuloma.
Case Report
On physical examination, the lesions appeared erosive with crusting and granulation tissue (Figure 1A). The presentation was consistent with erosive pustular dermatosis of the scalp. Biopsy revealed granulation tissue. The patient underwent PDT and prednisone treatment with improvement. Additional biopsies revealed AKs. His condition improved with 2 PDT sessions but never fully cleared. During the PDT sessions, the patient reported intense unilateral headaches without visual changes. The headaches were intermittent and not apparently related to the treatments. He was referred for a temporal artery biopsy and rebiopsy of the remaining lesion on the scalp. The temporal artery biopsy was negative. The lesion that remained was a large nodule on the vertex scalp, and biopsy revealed AFX.
Immunohistochemical marker studies for S-100 and cytokeratin were negative. Invasion into subcutaneous fat was encountered (Figure 2A). Highly atypical spindle cells and mitoses were present (Figure 2B). Neoplastic cells were noted adjacent to nerve (Figure 2C). Excision of the lesion was curative, and his symptoms of pain and erosive pustular dermatosis resolved weeks thereafter (Figure 1B). The area of erosive pustular dermatosis was not excised, but symptoms resolved weeks following excision of the AFX.
Comment
Our case of AFX is unique due to the patient’s atypical presentation of severe pain. Because AFX usually presents asymptomatically, pain is an uncommon symptom. Based on the histologic findings in our case, we suspected that neural involvement of the tumor most likely explained the intense pain that our patient experienced.
The presence of erosive pustular dermatosis of the scalp also is interesting in our case. This elderly man had an extensive history of actinic damage and had reported pustules, scaling, itching, and scabbing of the scalp. It is possible that erosive pustular dermatosis was superimposed over the tumor and could have been the reason that multiple biopsies were needed to eventually arrive at a diagnosis. The coexistence of the 2 entities suggests that the chronic actinic damage played a role in the etiology of both.
Classification
There is a question regarding nomenclature when discussing AFX. Atypical fibroxanthoma has been referred to as a variant of undifferentiated pleomorphic sarcoma, which is a type of soft tissue sarcoma. Atypical fibroxanthoma can be referred to as undifferentiated pleomorphic sarcoma if it is more than 2 cm in diameter, if it involves the fascia or subcutaneous tissue, or if there is evidence of necrosis.3 Atypical fibroxanthoma generally is confined to the head and neck region and usually is less than 2 cm in diameter. In this patient, the presentation was consistent with AFX, as there was evidence of necrosis and invasion into the subcutaneous fat. The fact that the lesion also appeared on the scalp further supported the diagnosis of AFX.
Pathology
Biopsy of AFX typically reveals a spindle cell proliferation that usually arises in the setting of profound actinic damage. The epidermis may or may not be ulcerated, and in most cases, it is seen in close proximity to the overlying epidermis but not arising from it.8 Classic AFX is composed of highly atypical histiocytelike (epithelioid) cells admixed with pleomorphic spindle cells and giant cells, all showing frequent mitoses including atypical ones.9 Several histologic subtypes of AFX have been described, including clear cell, granular cell, pigmented cell, chondroid, osteoid, osteoclastic, and the most common spindle cell subtype.9 Features that indicate potential aggressive behavior include infiltration into the subcutaneous tissue, vascular invasion, and presence of necrosis. A diagnosis of AFX is made by exclusion of other malignant neoplasms with similar morphology, namely spindle cell squamous cell carcinoma, spindle cell melanoma, and leiomyoscarcoma.9 As such, immunohistochemistry plays a critical role in distinguishing these lesions, as they arise as part of the differential diagnosis. A panel of immunohistochemical stains is helpful for diagnosis and commonly includes but is not limited to S-100, Melan-A, smooth muscle actin, desmin, and cytokeratin.
Sampling error is an inherent flaw in any biopsy specimen. The eventual diagnosis of AFX in our case supports the argument for multiple biopsies of an unknown lesion, seeing as the affected area was interpreted as both granulation tissue and AK prior to the eventual diagnosis. Repeat biopsies, especially if a lesion is nonhealing, often can help clinicians arrive at a definitive diagnosis.
Treatment
Different treatment options have been used to manage AFX. Mohs micrographic surgery is most often used because of its tissue-sparing potential, often giving the most cosmetically appealing result. Wide local excision is another surgical technique utilized, generally with fixed margins of at least 1 cm.10 Radiation at the tumor site is used as a treatment method but most often during cases of reoccurrence. Cryotherapy as well as electrodesiccation and curettage are possible treatment options but are not the standard of care.
- Helwig EB. Atypical fibroxanthoma, in tumor seminar. proceedings of 18th Annual Seminar of San Antonio Society of Pathologists, 1961. Tex State J Med. 1963;59:664-667.
- Anderson HL, Joseph AK. A pilot feasibility study of a rare skin tumor database. Dermatol Surg. 2007;33:693-696.
- Iorizzo LJ 3rd, Brown MD. Atypical fibroxanthoma: a review of the literature. Dermatol Surg. 2011;37:146-157.
- Fretzin DF, Helwig EB. Atypical fibroxanthoma of the skin. a clinicopathologic study of 140 cases. Cancer. 1973;31:1541-1552.
- Vandergriff TW, Reed JA, Orengo IF. An unusual presentation of atypical fibroxanthoma. Dermatol Online J. 2008;14:6.
- Weedon D, Kerr JF. Atypical fibroxanthoma of skin: an electron microscope study. Pathology. 1975;7:173-177.
- Woyke S, Domagala W, Olszewski W, et al. Pseudosarcoma of the skin. an electron microscopic study and comparison with the fine structure of spindle-cell variant of squamous carcinoma. Cancer. 1974;33:970-980.
- Edward S, Yung A. Essential Dermatopathology. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.
- Luzar B, Calonje E. Morphologic and immunohistochemical characteristics of atypical fibroxanthoma with a special emphasis on potential diagnostic pitfalls: a review. J Cutan Pathol. 2010;37:301-309.
- González-García R, Nam-Cha SH, Muñoz-Guerra MF, et al. Atypical fibroxanthoma of the head and neck: report of 5 cases. J Oral Maxillofac Surg. 2007;65:526-531.
Atypical fibroxanthoma (AFX) is a low-grade dermal malignancy comprised of atypical spindle cells.1 Classified as a superficial fibrohistiocytic tumor with intermediate malignant potential, AFX has an incidence of approximately 0.24% worldwide.2 The tumor appears mainly on the head and neck in sun-exposed areas but can occur less frequently on the trunk and limbs in non–sun-exposed areas. There is a 70% to 80% predominance in men aged 69 to 77 years, with lesions primarily occurring in sun-exposed areas of the head and neck.3 A median period of 4 months between time of onset and time of diagnosis has been previously established.4
When AFX does occur in non–sun-exposed areas, it tends to be in a younger patient population. Clinically, it presents as a rather nondescript, firm, erythematous papule or nodule less than 2 cm in diameter. Atypical fibroxanthoma most often presents asymptomatically, but the tumor may ulcerate and bleed, though pain and pruritus are uncommon.5 Findings are nonspecific, and the diagnosis must be confirmed with biopsy, as it can resemble other common dermatological lesions. The pathogenesis of AFX has been controversial. Two different studies looked at AFX using electron microscopy and concluded that the tumor most closely resembled a myofibroblast,6,7 which is consistent with current thinking today.
Atypical fibroxanthoma is believed to be associated with p53 mutation and is closely linked with exposure to UV radiation due to its predominance in sun-exposed areas. Other predisposing factors may include prior exposure to UV radiation, history of organ transplantation, immunosuppression, advanced age in men, and xeroderma pigmentosum. The differential diagnosis for AFX encompasses basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, adnexal tumor, and pyogenic granuloma.
Case Report
On physical examination, the lesions appeared erosive with crusting and granulation tissue (Figure 1A). The presentation was consistent with erosive pustular dermatosis of the scalp. Biopsy revealed granulation tissue. The patient underwent PDT and prednisone treatment with improvement. Additional biopsies revealed AKs. His condition improved with 2 PDT sessions but never fully cleared. During the PDT sessions, the patient reported intense unilateral headaches without visual changes. The headaches were intermittent and not apparently related to the treatments. He was referred for a temporal artery biopsy and rebiopsy of the remaining lesion on the scalp. The temporal artery biopsy was negative. The lesion that remained was a large nodule on the vertex scalp, and biopsy revealed AFX.
Immunohistochemical marker studies for S-100 and cytokeratin were negative. Invasion into subcutaneous fat was encountered (Figure 2A). Highly atypical spindle cells and mitoses were present (Figure 2B). Neoplastic cells were noted adjacent to nerve (Figure 2C). Excision of the lesion was curative, and his symptoms of pain and erosive pustular dermatosis resolved weeks thereafter (Figure 1B). The area of erosive pustular dermatosis was not excised, but symptoms resolved weeks following excision of the AFX.
Comment
Our case of AFX is unique due to the patient’s atypical presentation of severe pain. Because AFX usually presents asymptomatically, pain is an uncommon symptom. Based on the histologic findings in our case, we suspected that neural involvement of the tumor most likely explained the intense pain that our patient experienced.
The presence of erosive pustular dermatosis of the scalp also is interesting in our case. This elderly man had an extensive history of actinic damage and had reported pustules, scaling, itching, and scabbing of the scalp. It is possible that erosive pustular dermatosis was superimposed over the tumor and could have been the reason that multiple biopsies were needed to eventually arrive at a diagnosis. The coexistence of the 2 entities suggests that the chronic actinic damage played a role in the etiology of both.
Classification
There is a question regarding nomenclature when discussing AFX. Atypical fibroxanthoma has been referred to as a variant of undifferentiated pleomorphic sarcoma, which is a type of soft tissue sarcoma. Atypical fibroxanthoma can be referred to as undifferentiated pleomorphic sarcoma if it is more than 2 cm in diameter, if it involves the fascia or subcutaneous tissue, or if there is evidence of necrosis.3 Atypical fibroxanthoma generally is confined to the head and neck region and usually is less than 2 cm in diameter. In this patient, the presentation was consistent with AFX, as there was evidence of necrosis and invasion into the subcutaneous fat. The fact that the lesion also appeared on the scalp further supported the diagnosis of AFX.
Pathology
Biopsy of AFX typically reveals a spindle cell proliferation that usually arises in the setting of profound actinic damage. The epidermis may or may not be ulcerated, and in most cases, it is seen in close proximity to the overlying epidermis but not arising from it.8 Classic AFX is composed of highly atypical histiocytelike (epithelioid) cells admixed with pleomorphic spindle cells and giant cells, all showing frequent mitoses including atypical ones.9 Several histologic subtypes of AFX have been described, including clear cell, granular cell, pigmented cell, chondroid, osteoid, osteoclastic, and the most common spindle cell subtype.9 Features that indicate potential aggressive behavior include infiltration into the subcutaneous tissue, vascular invasion, and presence of necrosis. A diagnosis of AFX is made by exclusion of other malignant neoplasms with similar morphology, namely spindle cell squamous cell carcinoma, spindle cell melanoma, and leiomyoscarcoma.9 As such, immunohistochemistry plays a critical role in distinguishing these lesions, as they arise as part of the differential diagnosis. A panel of immunohistochemical stains is helpful for diagnosis and commonly includes but is not limited to S-100, Melan-A, smooth muscle actin, desmin, and cytokeratin.
Sampling error is an inherent flaw in any biopsy specimen. The eventual diagnosis of AFX in our case supports the argument for multiple biopsies of an unknown lesion, seeing as the affected area was interpreted as both granulation tissue and AK prior to the eventual diagnosis. Repeat biopsies, especially if a lesion is nonhealing, often can help clinicians arrive at a definitive diagnosis.
Treatment
Different treatment options have been used to manage AFX. Mohs micrographic surgery is most often used because of its tissue-sparing potential, often giving the most cosmetically appealing result. Wide local excision is another surgical technique utilized, generally with fixed margins of at least 1 cm.10 Radiation at the tumor site is used as a treatment method but most often during cases of reoccurrence. Cryotherapy as well as electrodesiccation and curettage are possible treatment options but are not the standard of care.
Atypical fibroxanthoma (AFX) is a low-grade dermal malignancy comprised of atypical spindle cells.1 Classified as a superficial fibrohistiocytic tumor with intermediate malignant potential, AFX has an incidence of approximately 0.24% worldwide.2 The tumor appears mainly on the head and neck in sun-exposed areas but can occur less frequently on the trunk and limbs in non–sun-exposed areas. There is a 70% to 80% predominance in men aged 69 to 77 years, with lesions primarily occurring in sun-exposed areas of the head and neck.3 A median period of 4 months between time of onset and time of diagnosis has been previously established.4
When AFX does occur in non–sun-exposed areas, it tends to be in a younger patient population. Clinically, it presents as a rather nondescript, firm, erythematous papule or nodule less than 2 cm in diameter. Atypical fibroxanthoma most often presents asymptomatically, but the tumor may ulcerate and bleed, though pain and pruritus are uncommon.5 Findings are nonspecific, and the diagnosis must be confirmed with biopsy, as it can resemble other common dermatological lesions. The pathogenesis of AFX has been controversial. Two different studies looked at AFX using electron microscopy and concluded that the tumor most closely resembled a myofibroblast,6,7 which is consistent with current thinking today.
Atypical fibroxanthoma is believed to be associated with p53 mutation and is closely linked with exposure to UV radiation due to its predominance in sun-exposed areas. Other predisposing factors may include prior exposure to UV radiation, history of organ transplantation, immunosuppression, advanced age in men, and xeroderma pigmentosum. The differential diagnosis for AFX encompasses basal cell carcinoma, squamous cell carcinoma, Merkel cell carcinoma, adnexal tumor, and pyogenic granuloma.
Case Report
On physical examination, the lesions appeared erosive with crusting and granulation tissue (Figure 1A). The presentation was consistent with erosive pustular dermatosis of the scalp. Biopsy revealed granulation tissue. The patient underwent PDT and prednisone treatment with improvement. Additional biopsies revealed AKs. His condition improved with 2 PDT sessions but never fully cleared. During the PDT sessions, the patient reported intense unilateral headaches without visual changes. The headaches were intermittent and not apparently related to the treatments. He was referred for a temporal artery biopsy and rebiopsy of the remaining lesion on the scalp. The temporal artery biopsy was negative. The lesion that remained was a large nodule on the vertex scalp, and biopsy revealed AFX.
Immunohistochemical marker studies for S-100 and cytokeratin were negative. Invasion into subcutaneous fat was encountered (Figure 2A). Highly atypical spindle cells and mitoses were present (Figure 2B). Neoplastic cells were noted adjacent to nerve (Figure 2C). Excision of the lesion was curative, and his symptoms of pain and erosive pustular dermatosis resolved weeks thereafter (Figure 1B). The area of erosive pustular dermatosis was not excised, but symptoms resolved weeks following excision of the AFX.
Comment
Our case of AFX is unique due to the patient’s atypical presentation of severe pain. Because AFX usually presents asymptomatically, pain is an uncommon symptom. Based on the histologic findings in our case, we suspected that neural involvement of the tumor most likely explained the intense pain that our patient experienced.
The presence of erosive pustular dermatosis of the scalp also is interesting in our case. This elderly man had an extensive history of actinic damage and had reported pustules, scaling, itching, and scabbing of the scalp. It is possible that erosive pustular dermatosis was superimposed over the tumor and could have been the reason that multiple biopsies were needed to eventually arrive at a diagnosis. The coexistence of the 2 entities suggests that the chronic actinic damage played a role in the etiology of both.
Classification
There is a question regarding nomenclature when discussing AFX. Atypical fibroxanthoma has been referred to as a variant of undifferentiated pleomorphic sarcoma, which is a type of soft tissue sarcoma. Atypical fibroxanthoma can be referred to as undifferentiated pleomorphic sarcoma if it is more than 2 cm in diameter, if it involves the fascia or subcutaneous tissue, or if there is evidence of necrosis.3 Atypical fibroxanthoma generally is confined to the head and neck region and usually is less than 2 cm in diameter. In this patient, the presentation was consistent with AFX, as there was evidence of necrosis and invasion into the subcutaneous fat. The fact that the lesion also appeared on the scalp further supported the diagnosis of AFX.
Pathology
Biopsy of AFX typically reveals a spindle cell proliferation that usually arises in the setting of profound actinic damage. The epidermis may or may not be ulcerated, and in most cases, it is seen in close proximity to the overlying epidermis but not arising from it.8 Classic AFX is composed of highly atypical histiocytelike (epithelioid) cells admixed with pleomorphic spindle cells and giant cells, all showing frequent mitoses including atypical ones.9 Several histologic subtypes of AFX have been described, including clear cell, granular cell, pigmented cell, chondroid, osteoid, osteoclastic, and the most common spindle cell subtype.9 Features that indicate potential aggressive behavior include infiltration into the subcutaneous tissue, vascular invasion, and presence of necrosis. A diagnosis of AFX is made by exclusion of other malignant neoplasms with similar morphology, namely spindle cell squamous cell carcinoma, spindle cell melanoma, and leiomyoscarcoma.9 As such, immunohistochemistry plays a critical role in distinguishing these lesions, as they arise as part of the differential diagnosis. A panel of immunohistochemical stains is helpful for diagnosis and commonly includes but is not limited to S-100, Melan-A, smooth muscle actin, desmin, and cytokeratin.
Sampling error is an inherent flaw in any biopsy specimen. The eventual diagnosis of AFX in our case supports the argument for multiple biopsies of an unknown lesion, seeing as the affected area was interpreted as both granulation tissue and AK prior to the eventual diagnosis. Repeat biopsies, especially if a lesion is nonhealing, often can help clinicians arrive at a definitive diagnosis.
Treatment
Different treatment options have been used to manage AFX. Mohs micrographic surgery is most often used because of its tissue-sparing potential, often giving the most cosmetically appealing result. Wide local excision is another surgical technique utilized, generally with fixed margins of at least 1 cm.10 Radiation at the tumor site is used as a treatment method but most often during cases of reoccurrence. Cryotherapy as well as electrodesiccation and curettage are possible treatment options but are not the standard of care.
- Helwig EB. Atypical fibroxanthoma, in tumor seminar. proceedings of 18th Annual Seminar of San Antonio Society of Pathologists, 1961. Tex State J Med. 1963;59:664-667.
- Anderson HL, Joseph AK. A pilot feasibility study of a rare skin tumor database. Dermatol Surg. 2007;33:693-696.
- Iorizzo LJ 3rd, Brown MD. Atypical fibroxanthoma: a review of the literature. Dermatol Surg. 2011;37:146-157.
- Fretzin DF, Helwig EB. Atypical fibroxanthoma of the skin. a clinicopathologic study of 140 cases. Cancer. 1973;31:1541-1552.
- Vandergriff TW, Reed JA, Orengo IF. An unusual presentation of atypical fibroxanthoma. Dermatol Online J. 2008;14:6.
- Weedon D, Kerr JF. Atypical fibroxanthoma of skin: an electron microscope study. Pathology. 1975;7:173-177.
- Woyke S, Domagala W, Olszewski W, et al. Pseudosarcoma of the skin. an electron microscopic study and comparison with the fine structure of spindle-cell variant of squamous carcinoma. Cancer. 1974;33:970-980.
- Edward S, Yung A. Essential Dermatopathology. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.
- Luzar B, Calonje E. Morphologic and immunohistochemical characteristics of atypical fibroxanthoma with a special emphasis on potential diagnostic pitfalls: a review. J Cutan Pathol. 2010;37:301-309.
- González-García R, Nam-Cha SH, Muñoz-Guerra MF, et al. Atypical fibroxanthoma of the head and neck: report of 5 cases. J Oral Maxillofac Surg. 2007;65:526-531.
- Helwig EB. Atypical fibroxanthoma, in tumor seminar. proceedings of 18th Annual Seminar of San Antonio Society of Pathologists, 1961. Tex State J Med. 1963;59:664-667.
- Anderson HL, Joseph AK. A pilot feasibility study of a rare skin tumor database. Dermatol Surg. 2007;33:693-696.
- Iorizzo LJ 3rd, Brown MD. Atypical fibroxanthoma: a review of the literature. Dermatol Surg. 2011;37:146-157.
- Fretzin DF, Helwig EB. Atypical fibroxanthoma of the skin. a clinicopathologic study of 140 cases. Cancer. 1973;31:1541-1552.
- Vandergriff TW, Reed JA, Orengo IF. An unusual presentation of atypical fibroxanthoma. Dermatol Online J. 2008;14:6.
- Weedon D, Kerr JF. Atypical fibroxanthoma of skin: an electron microscope study. Pathology. 1975;7:173-177.
- Woyke S, Domagala W, Olszewski W, et al. Pseudosarcoma of the skin. an electron microscopic study and comparison with the fine structure of spindle-cell variant of squamous carcinoma. Cancer. 1974;33:970-980.
- Edward S, Yung A. Essential Dermatopathology. Philadelphia, PA: Lippincott Williams & Wilkins; 2012.
- Luzar B, Calonje E. Morphologic and immunohistochemical characteristics of atypical fibroxanthoma with a special emphasis on potential diagnostic pitfalls: a review. J Cutan Pathol. 2010;37:301-309.
- González-García R, Nam-Cha SH, Muñoz-Guerra MF, et al. Atypical fibroxanthoma of the head and neck: report of 5 cases. J Oral Maxillofac Surg. 2007;65:526-531.
Practice Points
- Atypical fibroxanthoma predominantly occurs in older men on the head and neck.
- Erosive pustular dermatosis may be a benign entity, but if it does not resolve, continue to rebiopsy, as rare tumors may mimic this condition.
