COLUMBUS, OHIO—Cognitive impairment at age 12 months predicts a subsequent diagnosis of autism spectrum disorder in children with tuberous sclerosis complex, according to researchers.

The relationship between intellectual disability and social-communication deficits among children with tuberous sclerosis complex, however, requires further investigation, said the investigators.

Shafali S. Jeste, MD, Assistant Professor in Psychiatry and Neurology at the University of California, Los Angeles, and colleagues conducted a longitudinal cohort study of infants with tuberous sclerosis complex to determine early clinical predictors of autism spectrum disorder and characterize the phenotype of autism in young children with tuberous sclerosis complex.

The researchers recruited infants with tuberous sclerosis complex and typically developing infants as young as 3 months and followed them longitudinally until age 36 months. They gathered data including standard cognitive and social-communication measures (ie, Mullen Scales of Early Learning, Autism Observation Scale of Infancy, and the Early Social Communication Scales), comorbidities questionnaires, and a detailed seizure history. Autism spectrum diagnosis was made using the Autism Diagnostic Observation Schedule and confirmed using best clinical estimate at ages 18, 24, and 36 months.

Of a population of 40 infants, 22 received a diagnosis of autism spectrum disorder. Children with autism had significantly greater cognitive delays by age 12 months and a significant decline in nonverbal IQ from ages 12 to 36 months, compared with children without autism. At 24 months, children with autism had significantly greater cognitive impairment, higher anxiety symptoms, more sleep impairment, and a trend toward greater seizure severity. Children not diagnosed with autism had subclinical evidence of social-communication impairment, particularly in language and play.

Do rTMS and Constraint Therapy Reduce Perinatal Stroke Hemiparesis?
Children with hemiparesis resulting from perinatal stroke perceive marked increases in goal-specific function following treatment with repetitive transcranial magnetic stimulation (rTMS) and constraint therapy, investigators reported.

Further study of noninvasive brain stimulation is feasible and may enhance motor learning therapy in such patients, according to the researchers.

Researchers previously had studied rTMS and constraint therapy in adults with stroke, but the treatments had not been examined in perinatal stroke. Adam Kirton, MD, Associate Professor of Pediatrics and Clinical Neurosciences at the University of Calgary in Canada, and colleagues conducted a blinded factorial trial of rTMS and constraint therapy in 45 children with perinatal stroke hemiparesis. Eligible participants were between ages 6 and 18, and the sample’s mean age was 11.

The children were randomized to daily inhibitory rTMS (ie, 1,200 stimulations at 1 Hz) over contralesional M1, constraint therapy, both treatments, or neither treatment. All interventions were administered for two weeks as part of a goal-directed, peer-supported motor learning camp.

The study’s primary outcome measure was the Canadian Occupational Performance Measure (COPM) at one, eight, and 24 weeks. Secondary outcomes included Assisting Hand Assessment (AHA), Melbourne Assessment (MA), safety, and tolerability. The researchers assessed change across treatment groups from baseline to six months and across all time points.

For all participants, COPM performance and satisfaction scores increased, and maximal gains were observed at six months. Linear mixed effects model analysis demonstrated effects of combined rTMS and constraint therapy on AHA gains at all time points. Constraint therapy alone increased AHA at two months, rTMS alone increased AHA at one week, and neither treatment decreased normal hand function. Affected hand function did not decrease with rTMS in children with ipsilateral corticospinal tract arrangements. The procedures were well tolerated.

Arbaclofen May Not Reduce Social Avoidance in Fragile X Syndrome
Arbaclofen may not reduce social avoidance among patients with fragile X syndrome, according to clinical trial results presented. The drug may modify the disease’s trajectory, however, and deserves further testing, said Elizabeth Berry-Kravis, MD, PhD.

Arbaclofen is a specific GABA-B agonist that has been approved to treat spasticity in multiple sclerosis. The drug improved several abnormal phenotypes in animal models of fragile X syndrome and showed promise in a phase II clinical trial. Dr. Berry-Kravis, Associate Professor of Biochemistry, Neurological Sciences, and Pediatrics at Rush Medical College in Chicago, and colleagues conducted two phase III placebo-controlled trials to determine the drug’s safety and efficacy for social avoidance in fragile X syndrome.

The investigators randomized 125 patients to arbaclofen or placebo in a flexible-dose trial. Eligible patients were between ages 12 and 50. In a separate fixed-dose trial, the researchers randomized 172 participants to 5 mg of arbaclofen twice per day, 10 mg of arbaclofen twice per day, 10 mg of arbaclofen three times per day, or placebo. Eligible subjects in this trial were between ages 5 and 11.

The primary end point for both trials was the Fragile X Syndrome Social Avoidance subscale of the Aberrant Behavior Checklist (ABC). Secondary outcomes included other ABC subscale scores, Clinical Global Impression–Improvement score, Clinical Global Impression-Severity score, and Vineland Socialization domain score.

The investigators observed no serious adverse events during the trial. The most common adverse events included headache, vomiting, nausea, irritability, anxiety, hyperactivity, decreased appetite, and infections. In all, 12 patients discontinued participation in the trial because of neurobehavioral adverse events.

The flexible-dose trial did not indicate a benefit for arbaclofen over placebo for any outcome. The highest dose group in the fixed-dose trial had significantly better outcome than those who received placebo on the ABC Fragile X Irritability subscale. The same group demonstrated a trend toward benefit on the ABC Fragile X Social Avoidance and Hyperactivity subscales.

“Data from secondary measures and the long-term treatment extension (improved Vineland Socialization [domain score]) suggest that some patients derive benefit, but these studies illustrate the challenges of translating targeted treatments from animal models to humans in fragile X syndrome,” said Dr. Berry-Kravis.

Everolimus Reduces SEGA Volume in Tuberous Sclerosis Complex
Everolimus, an mTOR inhibitor, significantly reduces the volume of subependymal giant cell astrocytoma (SEGA) in children with tuberous sclerosis complex, according to an extension analysis presented. In a phase III trial, the researchers did not find any new safety concerns to be associated with the drug.

David N. Franz, MD, Pediatric Neurologist at Cincinnati Children’s Hospital Medical Center, and colleagues enrolled 117 patients in a randomized, double-blind trial of everolimus. All patients had SEGA associated with tuberous sclerosis complex of at least 1 cm in diameter. Participants received either 4.5 mg/m2/day of oral everolimus or placebo. The primary end point was SEGA response rate, which the investigators defined as the proportion of patients with 50% or greater reduction in SEGA volume, compared with baseline.

Patients’ mean age was approximately 11, and mean SEGA volume was 2.6 cm³. Participants received treatment for a median of 41 months.

At the original cutoff of the trial, SEGA response rate was 34.6% for everolimus and 0.0% for placebo. At that point, patients on placebo were offered open-label everolimus in the extension phase of the trial. As of January 11, 2013, 111 patients had received at least one dose of everolimus and were included in the extension analysis. The overall SEGA response rate was 48.6%, and the SEGA response rate for everolimus increased steadily until week 96. The duration of SEGA response ranged from 2.1 to 31.1 months.

Adverse events were common, but their incidence decreased with time. Approximately 40% of patients had serious adverse events, and 19% were suspected to be associated with everolimus. The most frequent serious adverse events occurring in more than 3% of patients were pneumonia, pyrexia, gastroenteritis, and convulsion.

—Erik Greb

COLUMBUS, OHIO—Cognitive impairment at age 12 months predicts a subsequent diagnosis of autism spectrum disorder in children with tuberous sclerosis complex, according to researchers.

The relationship between intellectual disability and social-communication deficits among children with tuberous sclerosis complex, however, requires further investigation, said the investigators.

Shafali S. Jeste, MD, Assistant Professor in Psychiatry and Neurology at the University of California, Los Angeles, and colleagues conducted a longitudinal cohort study of infants with tuberous sclerosis complex to determine early clinical predictors of autism spectrum disorder and characterize the phenotype of autism in young children with tuberous sclerosis complex.

The researchers recruited infants with tuberous sclerosis complex and typically developing infants as young as 3 months and followed them longitudinally until age 36 months. They gathered data including standard cognitive and social-communication measures (ie, Mullen Scales of Early Learning, Autism Observation Scale of Infancy, and the Early Social Communication Scales), comorbidities questionnaires, and a detailed seizure history. Autism spectrum diagnosis was made using the Autism Diagnostic Observation Schedule and confirmed using best clinical estimate at ages 18, 24, and 36 months.

Of a population of 40 infants, 22 received a diagnosis of autism spectrum disorder. Children with autism had significantly greater cognitive delays by age 12 months and a significant decline in nonverbal IQ from ages 12 to 36 months, compared with children without autism. At 24 months, children with autism had significantly greater cognitive impairment, higher anxiety symptoms, more sleep impairment, and a trend toward greater seizure severity. Children not diagnosed with autism had subclinical evidence of social-communication impairment, particularly in language and play.

Do rTMS and Constraint Therapy Reduce Perinatal Stroke Hemiparesis?
Children with hemiparesis resulting from perinatal stroke perceive marked increases in goal-specific function following treatment with repetitive transcranial magnetic stimulation (rTMS) and constraint therapy, investigators reported.

Further study of noninvasive brain stimulation is feasible and may enhance motor learning therapy in such patients, according to the researchers.

Researchers previously had studied rTMS and constraint therapy in adults with stroke, but the treatments had not been examined in perinatal stroke. Adam Kirton, MD, Associate Professor of Pediatrics and Clinical Neurosciences at the University of Calgary in Canada, and colleagues conducted a blinded factorial trial of rTMS and constraint therapy in 45 children with perinatal stroke hemiparesis. Eligible participants were between ages 6 and 18, and the sample’s mean age was 11.

The children were randomized to daily inhibitory rTMS (ie, 1,200 stimulations at 1 Hz) over contralesional M1, constraint therapy, both treatments, or neither treatment. All interventions were administered for two weeks as part of a goal-directed, peer-supported motor learning camp.

The study’s primary outcome measure was the Canadian Occupational Performance Measure (COPM) at one, eight, and 24 weeks. Secondary outcomes included Assisting Hand Assessment (AHA), Melbourne Assessment (MA), safety, and tolerability. The researchers assessed change across treatment groups from baseline to six months and across all time points.

For all participants, COPM performance and satisfaction scores increased, and maximal gains were observed at six months. Linear mixed effects model analysis demonstrated effects of combined rTMS and constraint therapy on AHA gains at all time points. Constraint therapy alone increased AHA at two months, rTMS alone increased AHA at one week, and neither treatment decreased normal hand function. Affected hand function did not decrease with rTMS in children with ipsilateral corticospinal tract arrangements. The procedures were well tolerated.

Arbaclofen May Not Reduce Social Avoidance in Fragile X Syndrome
Arbaclofen may not reduce social avoidance among patients with fragile X syndrome, according to clinical trial results presented. The drug may modify the disease’s trajectory, however, and deserves further testing, said Elizabeth Berry-Kravis, MD, PhD.

Arbaclofen is a specific GABA-B agonist that has been approved to treat spasticity in multiple sclerosis. The drug improved several abnormal phenotypes in animal models of fragile X syndrome and showed promise in a phase II clinical trial. Dr. Berry-Kravis, Associate Professor of Biochemistry, Neurological Sciences, and Pediatrics at Rush Medical College in Chicago, and colleagues conducted two phase III placebo-controlled trials to determine the drug’s safety and efficacy for social avoidance in fragile X syndrome.

The investigators randomized 125 patients to arbaclofen or placebo in a flexible-dose trial. Eligible patients were between ages 12 and 50. In a separate fixed-dose trial, the researchers randomized 172 participants to 5 mg of arbaclofen twice per day, 10 mg of arbaclofen twice per day, 10 mg of arbaclofen three times per day, or placebo. Eligible subjects in this trial were between ages 5 and 11.

The primary end point for both trials was the Fragile X Syndrome Social Avoidance subscale of the Aberrant Behavior Checklist (ABC). Secondary outcomes included other ABC subscale scores, Clinical Global Impression–Improvement score, Clinical Global Impression-Severity score, and Vineland Socialization domain score.

The investigators observed no serious adverse events during the trial. The most common adverse events included headache, vomiting, nausea, irritability, anxiety, hyperactivity, decreased appetite, and infections. In all, 12 patients discontinued participation in the trial because of neurobehavioral adverse events.

The flexible-dose trial did not indicate a benefit for arbaclofen over placebo for any outcome. The highest dose group in the fixed-dose trial had significantly better outcome than those who received placebo on the ABC Fragile X Irritability subscale. The same group demonstrated a trend toward benefit on the ABC Fragile X Social Avoidance and Hyperactivity subscales.

“Data from secondary measures and the long-term treatment extension (improved Vineland Socialization [domain score]) suggest that some patients derive benefit, but these studies illustrate the challenges of translating targeted treatments from animal models to humans in fragile X syndrome,” said Dr. Berry-Kravis.

Everolimus Reduces SEGA Volume in Tuberous Sclerosis Complex
Everolimus, an mTOR inhibitor, significantly reduces the volume of subependymal giant cell astrocytoma (SEGA) in children with tuberous sclerosis complex, according to an extension analysis presented. In a phase III trial, the researchers did not find any new safety concerns to be associated with the drug.

David N. Franz, MD, Pediatric Neurologist at Cincinnati Children’s Hospital Medical Center, and colleagues enrolled 117 patients in a randomized, double-blind trial of everolimus. All patients had SEGA associated with tuberous sclerosis complex of at least 1 cm in diameter. Participants received either 4.5 mg/m2/day of oral everolimus or placebo. The primary end point was SEGA response rate, which the investigators defined as the proportion of patients with 50% or greater reduction in SEGA volume, compared with baseline.

Patients’ mean age was approximately 11, and mean SEGA volume was 2.6 cm³. Participants received treatment for a median of 41 months.

At the original cutoff of the trial, SEGA response rate was 34.6% for everolimus and 0.0% for placebo. At that point, patients on placebo were offered open-label everolimus in the extension phase of the trial. As of January 11, 2013, 111 patients had received at least one dose of everolimus and were included in the extension analysis. The overall SEGA response rate was 48.6%, and the SEGA response rate for everolimus increased steadily until week 96. The duration of SEGA response ranged from 2.1 to 31.1 months.

Adverse events were common, but their incidence decreased with time. Approximately 40% of patients had serious adverse events, and 19% were suspected to be associated with everolimus. The most frequent serious adverse events occurring in more than 3% of patients were pneumonia, pyrexia, gastroenteritis, and convulsion.

—Erik Greb

COLUMBUS, OHIO—Cognitive impairment at age 12 months predicts a subsequent diagnosis of autism spectrum disorder in children with tuberous sclerosis complex, according to researchers.

The relationship between intellectual disability and social-communication deficits among children with tuberous sclerosis complex, however, requires further investigation, said the investigators.

Shafali S. Jeste, MD, Assistant Professor in Psychiatry and Neurology at the University of California, Los Angeles, and colleagues conducted a longitudinal cohort study of infants with tuberous sclerosis complex to determine early clinical predictors of autism spectrum disorder and characterize the phenotype of autism in young children with tuberous sclerosis complex.

The researchers recruited infants with tuberous sclerosis complex and typically developing infants as young as 3 months and followed them longitudinally until age 36 months. They gathered data including standard cognitive and social-communication measures (ie, Mullen Scales of Early Learning, Autism Observation Scale of Infancy, and the Early Social Communication Scales), comorbidities questionnaires, and a detailed seizure history. Autism spectrum diagnosis was made using the Autism Diagnostic Observation Schedule and confirmed using best clinical estimate at ages 18, 24, and 36 months.

Of a population of 40 infants, 22 received a diagnosis of autism spectrum disorder. Children with autism had significantly greater cognitive delays by age 12 months and a significant decline in nonverbal IQ from ages 12 to 36 months, compared with children without autism. At 24 months, children with autism had significantly greater cognitive impairment, higher anxiety symptoms, more sleep impairment, and a trend toward greater seizure severity. Children not diagnosed with autism had subclinical evidence of social-communication impairment, particularly in language and play.

Do rTMS and Constraint Therapy Reduce Perinatal Stroke Hemiparesis?
Children with hemiparesis resulting from perinatal stroke perceive marked increases in goal-specific function following treatment with repetitive transcranial magnetic stimulation (rTMS) and constraint therapy, investigators reported.

Further study of noninvasive brain stimulation is feasible and may enhance motor learning therapy in such patients, according to the researchers.

Researchers previously had studied rTMS and constraint therapy in adults with stroke, but the treatments had not been examined in perinatal stroke. Adam Kirton, MD, Associate Professor of Pediatrics and Clinical Neurosciences at the University of Calgary in Canada, and colleagues conducted a blinded factorial trial of rTMS and constraint therapy in 45 children with perinatal stroke hemiparesis. Eligible participants were between ages 6 and 18, and the sample’s mean age was 11.

The children were randomized to daily inhibitory rTMS (ie, 1,200 stimulations at 1 Hz) over contralesional M1, constraint therapy, both treatments, or neither treatment. All interventions were administered for two weeks as part of a goal-directed, peer-supported motor learning camp.

The study’s primary outcome measure was the Canadian Occupational Performance Measure (COPM) at one, eight, and 24 weeks. Secondary outcomes included Assisting Hand Assessment (AHA), Melbourne Assessment (MA), safety, and tolerability. The researchers assessed change across treatment groups from baseline to six months and across all time points.

For all participants, COPM performance and satisfaction scores increased, and maximal gains were observed at six months. Linear mixed effects model analysis demonstrated effects of combined rTMS and constraint therapy on AHA gains at all time points. Constraint therapy alone increased AHA at two months, rTMS alone increased AHA at one week, and neither treatment decreased normal hand function. Affected hand function did not decrease with rTMS in children with ipsilateral corticospinal tract arrangements. The procedures were well tolerated.

Arbaclofen May Not Reduce Social Avoidance in Fragile X Syndrome
Arbaclofen may not reduce social avoidance among patients with fragile X syndrome, according to clinical trial results presented. The drug may modify the disease’s trajectory, however, and deserves further testing, said Elizabeth Berry-Kravis, MD, PhD.

Arbaclofen is a specific GABA-B agonist that has been approved to treat spasticity in multiple sclerosis. The drug improved several abnormal phenotypes in animal models of fragile X syndrome and showed promise in a phase II clinical trial. Dr. Berry-Kravis, Associate Professor of Biochemistry, Neurological Sciences, and Pediatrics at Rush Medical College in Chicago, and colleagues conducted two phase III placebo-controlled trials to determine the drug’s safety and efficacy for social avoidance in fragile X syndrome.

The investigators randomized 125 patients to arbaclofen or placebo in a flexible-dose trial. Eligible patients were between ages 12 and 50. In a separate fixed-dose trial, the researchers randomized 172 participants to 5 mg of arbaclofen twice per day, 10 mg of arbaclofen twice per day, 10 mg of arbaclofen three times per day, or placebo. Eligible subjects in this trial were between ages 5 and 11.

The primary end point for both trials was the Fragile X Syndrome Social Avoidance subscale of the Aberrant Behavior Checklist (ABC). Secondary outcomes included other ABC subscale scores, Clinical Global Impression–Improvement score, Clinical Global Impression-Severity score, and Vineland Socialization domain score.

The investigators observed no serious adverse events during the trial. The most common adverse events included headache, vomiting, nausea, irritability, anxiety, hyperactivity, decreased appetite, and infections. In all, 12 patients discontinued participation in the trial because of neurobehavioral adverse events.

The flexible-dose trial did not indicate a benefit for arbaclofen over placebo for any outcome. The highest dose group in the fixed-dose trial had significantly better outcome than those who received placebo on the ABC Fragile X Irritability subscale. The same group demonstrated a trend toward benefit on the ABC Fragile X Social Avoidance and Hyperactivity subscales.

“Data from secondary measures and the long-term treatment extension (improved Vineland Socialization [domain score]) suggest that some patients derive benefit, but these studies illustrate the challenges of translating targeted treatments from animal models to humans in fragile X syndrome,” said Dr. Berry-Kravis.

Everolimus Reduces SEGA Volume in Tuberous Sclerosis Complex
Everolimus, an mTOR inhibitor, significantly reduces the volume of subependymal giant cell astrocytoma (SEGA) in children with tuberous sclerosis complex, according to an extension analysis presented. In a phase III trial, the researchers did not find any new safety concerns to be associated with the drug.

David N. Franz, MD, Pediatric Neurologist at Cincinnati Children’s Hospital Medical Center, and colleagues enrolled 117 patients in a randomized, double-blind trial of everolimus. All patients had SEGA associated with tuberous sclerosis complex of at least 1 cm in diameter. Participants received either 4.5 mg/m2/day of oral everolimus or placebo. The primary end point was SEGA response rate, which the investigators defined as the proportion of patients with 50% or greater reduction in SEGA volume, compared with baseline.

Patients’ mean age was approximately 11, and mean SEGA volume was 2.6 cm³. Participants received treatment for a median of 41 months.

At the original cutoff of the trial, SEGA response rate was 34.6% for everolimus and 0.0% for placebo. At that point, patients on placebo were offered open-label everolimus in the extension phase of the trial. As of January 11, 2013, 111 patients had received at least one dose of everolimus and were included in the extension analysis. The overall SEGA response rate was 48.6%, and the SEGA response rate for everolimus increased steadily until week 96. The duration of SEGA response ranged from 2.1 to 31.1 months.

Adverse events were common, but their incidence decreased with time. Approximately 40% of patients had serious adverse events, and 19% were suspected to be associated with everolimus. The most frequent serious adverse events occurring in more than 3% of patients were pneumonia, pyrexia, gastroenteritis, and convulsion.

—Erik Greb

SAN DIEGO – Only 1% of families that filled out psychosocial screening questionnaires during medical appointments later sought free mental health consultations, the same rate as for families that were not screened, investigators reported.

“Unless large controlled trials are able to show a process and an outcome benefit, it may be preferable to invest in providing mental health treatment” instead of screening, concluded lead investigator Brianna J. Lewis of the Mount Sinai School of Medicine, New York, and her associates. The researchers presented the findings at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The study was a post-hoc analysis of data on 3,143 patient encounters at a pediatric allergy clinic in New York City between March and September 2013. Two to five days a week, the investigators had asked children aged 8 years and older and their parents to fill out one-page questionnaires about problems such as distress, anxiety, bullying, and quality-of-life issues. They did not screen patients on the other days, “creating a naturalistic opportunity to compare between screened and nonscreened cohorts,” they added. Because screening was part of regular care, participants did not need to provide informed consent, which eliminated the possibility of selection bias, the researchers said.

In all, 6.1% of families who underwent screening were referred to a mental health consultation, but only 1% followed up, even though consults were offered for free and without third-party billing, the researchers said. The follow-up rate also was 1% for the 1,972 families that were not screened. Among the families who pursued a follow-up consult, 56% of the screened group and 67% of the unscreened group received a psychiatric diagnosis (P = 0.26), Ms. Lewis and her associates reported.

Past studies by the investigators showed that screening children and adults during medical care appointments is “hard to justify,” they noted.

The Jaffe Family Foundation, Pine/Segal Family, and Vanech Family Foundation supported the research. The investigators declared no conflicts of interest.

SAN DIEGO – Only 1% of families that filled out psychosocial screening questionnaires during medical appointments later sought free mental health consultations, the same rate as for families that were not screened, investigators reported.

“Unless large controlled trials are able to show a process and an outcome benefit, it may be preferable to invest in providing mental health treatment” instead of screening, concluded lead investigator Brianna J. Lewis of the Mount Sinai School of Medicine, New York, and her associates. The researchers presented the findings at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The study was a post-hoc analysis of data on 3,143 patient encounters at a pediatric allergy clinic in New York City between March and September 2013. Two to five days a week, the investigators had asked children aged 8 years and older and their parents to fill out one-page questionnaires about problems such as distress, anxiety, bullying, and quality-of-life issues. They did not screen patients on the other days, “creating a naturalistic opportunity to compare between screened and nonscreened cohorts,” they added. Because screening was part of regular care, participants did not need to provide informed consent, which eliminated the possibility of selection bias, the researchers said.

In all, 6.1% of families who underwent screening were referred to a mental health consultation, but only 1% followed up, even though consults were offered for free and without third-party billing, the researchers said. The follow-up rate also was 1% for the 1,972 families that were not screened. Among the families who pursued a follow-up consult, 56% of the screened group and 67% of the unscreened group received a psychiatric diagnosis (P = 0.26), Ms. Lewis and her associates reported.

Past studies by the investigators showed that screening children and adults during medical care appointments is “hard to justify,” they noted.

The Jaffe Family Foundation, Pine/Segal Family, and Vanech Family Foundation supported the research. The investigators declared no conflicts of interest.

SAN DIEGO – Only 1% of families that filled out psychosocial screening questionnaires during medical appointments later sought free mental health consultations, the same rate as for families that were not screened, investigators reported.

“Unless large controlled trials are able to show a process and an outcome benefit, it may be preferable to invest in providing mental health treatment” instead of screening, concluded lead investigator Brianna J. Lewis of the Mount Sinai School of Medicine, New York, and her associates. The researchers presented the findings at the annual meeting of the American Academy of Child and Adolescent Psychiatry.

The study was a post-hoc analysis of data on 3,143 patient encounters at a pediatric allergy clinic in New York City between March and September 2013. Two to five days a week, the investigators had asked children aged 8 years and older and their parents to fill out one-page questionnaires about problems such as distress, anxiety, bullying, and quality-of-life issues. They did not screen patients on the other days, “creating a naturalistic opportunity to compare between screened and nonscreened cohorts,” they added. Because screening was part of regular care, participants did not need to provide informed consent, which eliminated the possibility of selection bias, the researchers said.

In all, 6.1% of families who underwent screening were referred to a mental health consultation, but only 1% followed up, even though consults were offered for free and without third-party billing, the researchers said. The follow-up rate also was 1% for the 1,972 families that were not screened. Among the families who pursued a follow-up consult, 56% of the screened group and 67% of the unscreened group received a psychiatric diagnosis (P = 0.26), Ms. Lewis and her associates reported.

Past studies by the investigators showed that screening children and adults during medical care appointments is “hard to justify,” they noted.

The Jaffe Family Foundation, Pine/Segal Family, and Vanech Family Foundation supported the research. The investigators declared no conflicts of interest.

Paul G. Richardson, MD

NEW YORK—Calling the synergy with the proteasome inhibitor “profound,” Paul G. Richardson, MD, presented results on the combination of the pan deacetylase inhibitor panobinostat with bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM).

The phase 3 PANORAMA 1 study confirmed data from the phase 1 and 2 trials, in which the triple combination demonstrated durable responses, even in bortezomib-refractory disease.

Dr Richardson, of the Dana-Farber Cancer Institute in Boston, presented updated data from the PANORAMA 1 trial, which received an award for the most clinically relevant myeloma abstract at the Lymphoma & Myeloma 2014 congress, held October 23–25.

Investigators randomized 768 patients with relapsed or relapsed and refractory MM to receive either panobinostat (n=387) or placebo (n=381) with bortezomib and dexamethasone. Bortezomib-refractory patients were excluded.

The study was conducted in 2 treatment phases, and patients with clinical benefit at the end of the first 24-week phase could proceed to the second treatment phase, consisting of four 42-day cycles.

The primary endpoint was progression-free survival (PFS) according to modified European Society for Blood and Marrow Transplantation criteria.

The key secondary endpoint was overall survival, and additional secondary endpoints included overall response rate, complete response/near complete response, duration of response, time to response, time to progression, quality of life, and safety.

Dr Richardson pointed out that in the first treatment phase, bortezomib was administered twice a week at 1.3 mg/m² intravenously, and, in the second phase, it was given once a week. The panobinostat dose was 20 mg orally 3 times a week, and oral dexamethasone was given at 20 mg on the same day and the day after bortezomib administration.

Patients were a median age of 63 years, and nearly half (48.4%) had received 2 or more prior therapies, including bortezomib, at 43.7% in the panobinostat arm and 42.3% in the placebo arm. Half the patients had prior exposure to thalidomide, and 1 in 4 patients had received bortezomib and an immunomodulator.

Approximately two-thirds of the patients had relapsed MM, and one-third had relapsed and refractory disease.

Twenty-six percent of patients in either arm completed treatment. Forty-four percent of patients in the panobinostat arm and 50% in the placebo arm entered treatment phase 2.

The dose intensity of panobinostat decreased to 78.2% at cycle 3 and remained stable through the rest of the trial. By cycle 3, the majority of patients were receiving 15 mg of panobinostat.

Results

The 3-drug combination met its primary endpoint, with a clinically relevant increase in median PFS of 3.9 months (P<0.0001).

The benefit with panobinostat was maintained regardless of prior treatment history or baseline characteristics.

“There was benefit across all subgroups,” Dr Richardson said, “but especially in the poor-risk group.”

He noted that the overall survival curve was holding between the 2 arms at about a 3-month difference.

And the complete response/near complete response rate in the panobinostat arm was nearly double that of the control arm, at 27.6% and 15.7%, respectively (P=0.00006).

While not significant, there were clinically meaningful improvements in overall response rate, duration of response, and time to progression. The overall response rate with panobinostat was 34.5%, the clinical benefit rate 52.7%, and the median PFS 5.4 months.

Safety

“Overall, side effects were relatively low,” Dr Richardson said, the major ones consisting of hematologic laboratory abnormalities.

Almost 98% of the patients receiving panobinostat and 83.5% of those in the placebo arm had thrombocytopenia of any grade. And 1.6% of patients on panobinostat discontinued due to thrombocytopenia, compared with 0.5% in the control arm.

Dr Richardson said the thrombocytopenia was reversible and not cumulative. Platelet levels rebounded to baseline by day 1 of each cycle.

Lymphopenia, neutropenia, and anemia were also more frequent in the panobinostat arm.

Nonhematologic adverse events, particularly diarrhea and fatigue, were, for the most part, increased over control, with 4.5% of patients on the panobinostat arm discontinuing due to diarrhea and 2.9% discontinuing due to fatigue.

The incidence of adverse events was lower in the second treatment phase, when bortezomib was administered once a week.

And deaths related to study drug were very low, Dr Richardson said, with 11 in the panobinostat arm and 7 in the control arm.

The triple drug combination is “a very important concept going forward,” Dr Richardson said.

Other combinations and additional histone deacetylase inhibitors are being evaluated for MM.

Paul G. Richardson, MD

NEW YORK—Calling the synergy with the proteasome inhibitor “profound,” Paul G. Richardson, MD, presented results on the combination of the pan deacetylase inhibitor panobinostat with bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM).

The phase 3 PANORAMA 1 study confirmed data from the phase 1 and 2 trials, in which the triple combination demonstrated durable responses, even in bortezomib-refractory disease.

Dr Richardson, of the Dana-Farber Cancer Institute in Boston, presented updated data from the PANORAMA 1 trial, which received an award for the most clinically relevant myeloma abstract at the Lymphoma & Myeloma 2014 congress, held October 23–25.

Investigators randomized 768 patients with relapsed or relapsed and refractory MM to receive either panobinostat (n=387) or placebo (n=381) with bortezomib and dexamethasone. Bortezomib-refractory patients were excluded.

The study was conducted in 2 treatment phases, and patients with clinical benefit at the end of the first 24-week phase could proceed to the second treatment phase, consisting of four 42-day cycles.

The primary endpoint was progression-free survival (PFS) according to modified European Society for Blood and Marrow Transplantation criteria.

The key secondary endpoint was overall survival, and additional secondary endpoints included overall response rate, complete response/near complete response, duration of response, time to response, time to progression, quality of life, and safety.

Dr Richardson pointed out that in the first treatment phase, bortezomib was administered twice a week at 1.3 mg/m² intravenously, and, in the second phase, it was given once a week. The panobinostat dose was 20 mg orally 3 times a week, and oral dexamethasone was given at 20 mg on the same day and the day after bortezomib administration.

Patients were a median age of 63 years, and nearly half (48.4%) had received 2 or more prior therapies, including bortezomib, at 43.7% in the panobinostat arm and 42.3% in the placebo arm. Half the patients had prior exposure to thalidomide, and 1 in 4 patients had received bortezomib and an immunomodulator.

Approximately two-thirds of the patients had relapsed MM, and one-third had relapsed and refractory disease.

Twenty-six percent of patients in either arm completed treatment. Forty-four percent of patients in the panobinostat arm and 50% in the placebo arm entered treatment phase 2.

The dose intensity of panobinostat decreased to 78.2% at cycle 3 and remained stable through the rest of the trial. By cycle 3, the majority of patients were receiving 15 mg of panobinostat.

Results

The 3-drug combination met its primary endpoint, with a clinically relevant increase in median PFS of 3.9 months (P<0.0001).

The benefit with panobinostat was maintained regardless of prior treatment history or baseline characteristics.

“There was benefit across all subgroups,” Dr Richardson said, “but especially in the poor-risk group.”

He noted that the overall survival curve was holding between the 2 arms at about a 3-month difference.

And the complete response/near complete response rate in the panobinostat arm was nearly double that of the control arm, at 27.6% and 15.7%, respectively (P=0.00006).

While not significant, there were clinically meaningful improvements in overall response rate, duration of response, and time to progression. The overall response rate with panobinostat was 34.5%, the clinical benefit rate 52.7%, and the median PFS 5.4 months.

Safety

“Overall, side effects were relatively low,” Dr Richardson said, the major ones consisting of hematologic laboratory abnormalities.

Almost 98% of the patients receiving panobinostat and 83.5% of those in the placebo arm had thrombocytopenia of any grade. And 1.6% of patients on panobinostat discontinued due to thrombocytopenia, compared with 0.5% in the control arm.

Dr Richardson said the thrombocytopenia was reversible and not cumulative. Platelet levels rebounded to baseline by day 1 of each cycle.

Lymphopenia, neutropenia, and anemia were also more frequent in the panobinostat arm.

Nonhematologic adverse events, particularly diarrhea and fatigue, were, for the most part, increased over control, with 4.5% of patients on the panobinostat arm discontinuing due to diarrhea and 2.9% discontinuing due to fatigue.

The incidence of adverse events was lower in the second treatment phase, when bortezomib was administered once a week.

And deaths related to study drug were very low, Dr Richardson said, with 11 in the panobinostat arm and 7 in the control arm.

The triple drug combination is “a very important concept going forward,” Dr Richardson said.

Other combinations and additional histone deacetylase inhibitors are being evaluated for MM.

Paul G. Richardson, MD

NEW YORK—Calling the synergy with the proteasome inhibitor “profound,” Paul G. Richardson, MD, presented results on the combination of the pan deacetylase inhibitor panobinostat with bortezomib and dexamethasone in relapsed/refractory multiple myeloma (MM).

The phase 3 PANORAMA 1 study confirmed data from the phase 1 and 2 trials, in which the triple combination demonstrated durable responses, even in bortezomib-refractory disease.

Dr Richardson, of the Dana-Farber Cancer Institute in Boston, presented updated data from the PANORAMA 1 trial, which received an award for the most clinically relevant myeloma abstract at the Lymphoma & Myeloma 2014 congress, held October 23–25.

Investigators randomized 768 patients with relapsed or relapsed and refractory MM to receive either panobinostat (n=387) or placebo (n=381) with bortezomib and dexamethasone. Bortezomib-refractory patients were excluded.

The study was conducted in 2 treatment phases, and patients with clinical benefit at the end of the first 24-week phase could proceed to the second treatment phase, consisting of four 42-day cycles.

The primary endpoint was progression-free survival (PFS) according to modified European Society for Blood and Marrow Transplantation criteria.

The key secondary endpoint was overall survival, and additional secondary endpoints included overall response rate, complete response/near complete response, duration of response, time to response, time to progression, quality of life, and safety.

Dr Richardson pointed out that in the first treatment phase, bortezomib was administered twice a week at 1.3 mg/m² intravenously, and, in the second phase, it was given once a week. The panobinostat dose was 20 mg orally 3 times a week, and oral dexamethasone was given at 20 mg on the same day and the day after bortezomib administration.

Patients were a median age of 63 years, and nearly half (48.4%) had received 2 or more prior therapies, including bortezomib, at 43.7% in the panobinostat arm and 42.3% in the placebo arm. Half the patients had prior exposure to thalidomide, and 1 in 4 patients had received bortezomib and an immunomodulator.

Approximately two-thirds of the patients had relapsed MM, and one-third had relapsed and refractory disease.

Twenty-six percent of patients in either arm completed treatment. Forty-four percent of patients in the panobinostat arm and 50% in the placebo arm entered treatment phase 2.

The dose intensity of panobinostat decreased to 78.2% at cycle 3 and remained stable through the rest of the trial. By cycle 3, the majority of patients were receiving 15 mg of panobinostat.

Results

The 3-drug combination met its primary endpoint, with a clinically relevant increase in median PFS of 3.9 months (P<0.0001).

The benefit with panobinostat was maintained regardless of prior treatment history or baseline characteristics.

“There was benefit across all subgroups,” Dr Richardson said, “but especially in the poor-risk group.”

He noted that the overall survival curve was holding between the 2 arms at about a 3-month difference.

And the complete response/near complete response rate in the panobinostat arm was nearly double that of the control arm, at 27.6% and 15.7%, respectively (P=0.00006).

While not significant, there were clinically meaningful improvements in overall response rate, duration of response, and time to progression. The overall response rate with panobinostat was 34.5%, the clinical benefit rate 52.7%, and the median PFS 5.4 months.

Safety

“Overall, side effects were relatively low,” Dr Richardson said, the major ones consisting of hematologic laboratory abnormalities.

Almost 98% of the patients receiving panobinostat and 83.5% of those in the placebo arm had thrombocytopenia of any grade. And 1.6% of patients on panobinostat discontinued due to thrombocytopenia, compared with 0.5% in the control arm.

Dr Richardson said the thrombocytopenia was reversible and not cumulative. Platelet levels rebounded to baseline by day 1 of each cycle.

Lymphopenia, neutropenia, and anemia were also more frequent in the panobinostat arm.

Nonhematologic adverse events, particularly diarrhea and fatigue, were, for the most part, increased over control, with 4.5% of patients on the panobinostat arm discontinuing due to diarrhea and 2.9% discontinuing due to fatigue.

The incidence of adverse events was lower in the second treatment phase, when bortezomib was administered once a week.

And deaths related to study drug were very low, Dr Richardson said, with 11 in the panobinostat arm and 7 in the control arm.

The triple drug combination is “a very important concept going forward,” Dr Richardson said.

Other combinations and additional histone deacetylase inhibitors are being evaluated for MM.

Cord blood donation

Credit: NHS

Single and double cord blood transplants produce similar outcomes, according to a study of young patients with hematologic disorders.

Researchers found that rates of overall and disease-free survival were not significantly different in patients who received a single unit of cord blood and those who received two units.

Other outcome measures, such as neutrophil recovery, relapse, and transplant-related death, were similar between the two groups as well.

However, patients who received a single cord blood unit showed improved platelet recovery, a lower incidence of grade 3-4 acute graft-vs-host disease (GVHD), and a lower rate of extensive chronic GVHD.

John Wagner, Jr, MD, of the University of Minnesota in Minneapolis, and his colleagues reported these results in NEJM. Dr Wagner previously presented results from this study at ASH 2012.

“Based on promising early studies using two cord blood units in adults for whom one unit is often not sufficient, we designed this study in order to determine if the higher number of blood-forming stem cells in two cord blood units might improve survival,” Dr Wagner said. “What we found, however, was that both treatment arms performed very well, with similar rates of white blood cell recovery and survival.”

The researchers enrolled 224 patients, ages 1 to 21 years, with hematologic disorders, including acute and chronic leukemias as well as myelodysplastic syndromes.

Patients were randomized to receive double-unit (n=111) or single-unit (n=113) cord blood transplants after a uniform myeloablative conditioning regimen and immunoprophylaxis for GVHD.

The researchers matched the treatment arms for age, sex, self-reported race, performance status, degree of donor-recipient HLA matching, disease type, and disease status at transplant.

Survival and relapse

The study’s primary endpoint was 1-year survival, which was 65% in the double-unit arm and 73% in the single-unit arm (P=0.17). In a multivariate analysis, the risk of death did not differ significantly between the arms (hazard ratio=1.34, P=0.20).

Similarly, there was no significant difference in 1-year disease-free survival between the double- and single-unit arms—64% and 70%, respectively (P=0.11). In a multivariate analysis, the risk of relapse or death did not differ significantly between arms (hazard ratio=1.48, P=0.08).

It therefore follows that rates of relapse and transplant-related death were similar at 1 year as well. The incidence of relapse was 14% in the double-unit arm and 12% in the single-unit arm (P=0.12). And rates of transplant-related death were 22% and 19%, respectively (P=0.43).

Recovery and GVHD

The incidence of neutrophil recovery was similar between treatment arms—88% in the double-unit arm and 89% in the single-unit arm (P=0.29) at a median of 23 days (range, 11 to 133) and 21 days (range, 11 to 62) after transplant, respectively.

However, the rate of platelet recovery was significantly higher in the single-unit arm—76% vs 65% (P=0.04). Furthermore, the median time to platelet recovery was 58 days (range, 28 to 295) in the single-unit arm and 84 days (range, 22 to 716) in the double-unit arm.

The rate of grade 2-4 acute GVHD was similar between the treatment arms (P=0.78), but patients in the double-unit arm had a higher incidence of grade 3-4 acute GVHD—23% vs 13% (P=0.02).

There was no difference in the incidence of any chronic GVHD at 1 year after transplant—32% in the double-unit arm and 30% in the single-unit arm (P=0.51). But there was a higher incidence of extensive chronic GVHD after double-unit transplant—15% vs 9% (P=0.05).

“This is helpful news for physicians considering the best treatment options for their patients,” said Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina.

“We found children who have a cord blood unit with an adequate number of cells do not benefit from receiving two units. This reduces the cost of a cord blood transplant for the majority of pediatric patients needing the procedure. However, for larger children without an adequately dosed single cord blood unit, using two units will provide access to a potentially life-saving transplant.”

Cord blood donation

Credit: NHS

Single and double cord blood transplants produce similar outcomes, according to a study of young patients with hematologic disorders.

Researchers found that rates of overall and disease-free survival were not significantly different in patients who received a single unit of cord blood and those who received two units.

Other outcome measures, such as neutrophil recovery, relapse, and transplant-related death, were similar between the two groups as well.

However, patients who received a single cord blood unit showed improved platelet recovery, a lower incidence of grade 3-4 acute graft-vs-host disease (GVHD), and a lower rate of extensive chronic GVHD.

John Wagner, Jr, MD, of the University of Minnesota in Minneapolis, and his colleagues reported these results in NEJM. Dr Wagner previously presented results from this study at ASH 2012.

“Based on promising early studies using two cord blood units in adults for whom one unit is often not sufficient, we designed this study in order to determine if the higher number of blood-forming stem cells in two cord blood units might improve survival,” Dr Wagner said. “What we found, however, was that both treatment arms performed very well, with similar rates of white blood cell recovery and survival.”

The researchers enrolled 224 patients, ages 1 to 21 years, with hematologic disorders, including acute and chronic leukemias as well as myelodysplastic syndromes.

Patients were randomized to receive double-unit (n=111) or single-unit (n=113) cord blood transplants after a uniform myeloablative conditioning regimen and immunoprophylaxis for GVHD.

The researchers matched the treatment arms for age, sex, self-reported race, performance status, degree of donor-recipient HLA matching, disease type, and disease status at transplant.

Survival and relapse

The study’s primary endpoint was 1-year survival, which was 65% in the double-unit arm and 73% in the single-unit arm (P=0.17). In a multivariate analysis, the risk of death did not differ significantly between the arms (hazard ratio=1.34, P=0.20).

Similarly, there was no significant difference in 1-year disease-free survival between the double- and single-unit arms—64% and 70%, respectively (P=0.11). In a multivariate analysis, the risk of relapse or death did not differ significantly between arms (hazard ratio=1.48, P=0.08).

It therefore follows that rates of relapse and transplant-related death were similar at 1 year as well. The incidence of relapse was 14% in the double-unit arm and 12% in the single-unit arm (P=0.12). And rates of transplant-related death were 22% and 19%, respectively (P=0.43).

Recovery and GVHD

The incidence of neutrophil recovery was similar between treatment arms—88% in the double-unit arm and 89% in the single-unit arm (P=0.29) at a median of 23 days (range, 11 to 133) and 21 days (range, 11 to 62) after transplant, respectively.

However, the rate of platelet recovery was significantly higher in the single-unit arm—76% vs 65% (P=0.04). Furthermore, the median time to platelet recovery was 58 days (range, 28 to 295) in the single-unit arm and 84 days (range, 22 to 716) in the double-unit arm.

The rate of grade 2-4 acute GVHD was similar between the treatment arms (P=0.78), but patients in the double-unit arm had a higher incidence of grade 3-4 acute GVHD—23% vs 13% (P=0.02).

There was no difference in the incidence of any chronic GVHD at 1 year after transplant—32% in the double-unit arm and 30% in the single-unit arm (P=0.51). But there was a higher incidence of extensive chronic GVHD after double-unit transplant—15% vs 9% (P=0.05).

“This is helpful news for physicians considering the best treatment options for their patients,” said Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina.

“We found children who have a cord blood unit with an adequate number of cells do not benefit from receiving two units. This reduces the cost of a cord blood transplant for the majority of pediatric patients needing the procedure. However, for larger children without an adequately dosed single cord blood unit, using two units will provide access to a potentially life-saving transplant.”

Cord blood donation

Credit: NHS

Single and double cord blood transplants produce similar outcomes, according to a study of young patients with hematologic disorders.

Researchers found that rates of overall and disease-free survival were not significantly different in patients who received a single unit of cord blood and those who received two units.

Other outcome measures, such as neutrophil recovery, relapse, and transplant-related death, were similar between the two groups as well.

However, patients who received a single cord blood unit showed improved platelet recovery, a lower incidence of grade 3-4 acute graft-vs-host disease (GVHD), and a lower rate of extensive chronic GVHD.

John Wagner, Jr, MD, of the University of Minnesota in Minneapolis, and his colleagues reported these results in NEJM. Dr Wagner previously presented results from this study at ASH 2012.

“Based on promising early studies using two cord blood units in adults for whom one unit is often not sufficient, we designed this study in order to determine if the higher number of blood-forming stem cells in two cord blood units might improve survival,” Dr Wagner said. “What we found, however, was that both treatment arms performed very well, with similar rates of white blood cell recovery and survival.”

The researchers enrolled 224 patients, ages 1 to 21 years, with hematologic disorders, including acute and chronic leukemias as well as myelodysplastic syndromes.

Patients were randomized to receive double-unit (n=111) or single-unit (n=113) cord blood transplants after a uniform myeloablative conditioning regimen and immunoprophylaxis for GVHD.

The researchers matched the treatment arms for age, sex, self-reported race, performance status, degree of donor-recipient HLA matching, disease type, and disease status at transplant.

Survival and relapse

The study’s primary endpoint was 1-year survival, which was 65% in the double-unit arm and 73% in the single-unit arm (P=0.17). In a multivariate analysis, the risk of death did not differ significantly between the arms (hazard ratio=1.34, P=0.20).

Similarly, there was no significant difference in 1-year disease-free survival between the double- and single-unit arms—64% and 70%, respectively (P=0.11). In a multivariate analysis, the risk of relapse or death did not differ significantly between arms (hazard ratio=1.48, P=0.08).

It therefore follows that rates of relapse and transplant-related death were similar at 1 year as well. The incidence of relapse was 14% in the double-unit arm and 12% in the single-unit arm (P=0.12). And rates of transplant-related death were 22% and 19%, respectively (P=0.43).

Recovery and GVHD

The incidence of neutrophil recovery was similar between treatment arms—88% in the double-unit arm and 89% in the single-unit arm (P=0.29) at a median of 23 days (range, 11 to 133) and 21 days (range, 11 to 62) after transplant, respectively.

However, the rate of platelet recovery was significantly higher in the single-unit arm—76% vs 65% (P=0.04). Furthermore, the median time to platelet recovery was 58 days (range, 28 to 295) in the single-unit arm and 84 days (range, 22 to 716) in the double-unit arm.

The rate of grade 2-4 acute GVHD was similar between the treatment arms (P=0.78), but patients in the double-unit arm had a higher incidence of grade 3-4 acute GVHD—23% vs 13% (P=0.02).

There was no difference in the incidence of any chronic GVHD at 1 year after transplant—32% in the double-unit arm and 30% in the single-unit arm (P=0.51). But there was a higher incidence of extensive chronic GVHD after double-unit transplant—15% vs 9% (P=0.05).

“This is helpful news for physicians considering the best treatment options for their patients,” said Joanne Kurtzberg, MD, of Duke University Medical Center in Durham, North Carolina.

“We found children who have a cord blood unit with an adequate number of cells do not benefit from receiving two units. This reduces the cost of a cord blood transplant for the majority of pediatric patients needing the procedure. However, for larger children without an adequately dosed single cord blood unit, using two units will provide access to a potentially life-saving transplant.”

Vials of drug

Credit: Bill Branson

The US Food and Drug Administration (FDA) has granted orphan designation for a human alpha-1 antitrypsin (AAT) product known as Glassia to treat graft-vs-host disease (GVHD).

Orphan drug designation carries multiple benefits, including the availability of grant money, certain tax credits, and 7 years of market exclusivity, as well as the possibility of an expedited regulatory process.

Glassia is the first available ready-to-infuse liquid alpha1-proteinase inhibitor.

The product is already approved by the FDA to treat adults with clinically evident emphysema due to severe congenital AAT deficiency. Glassia is given intravenously once a week to augment the levels of AAT, a protein derived from human plasma, in the blood.

In recent years, researchers have discovered that AAT has anti-inflammatory, tissue protective, immunomodulatory, and anti-apoptotic properties in direct or indirect consequence of its underlying antiprotease capabilities.

These properties may attenuate inflammation by lowering levels of proinflammatory mediators such as cytokines, chemokines, and proteases that are associated with GVHD.

Preliminary human and animal studies indicate that Glassia may be able to treat and reduce the severity of GVHD occurring after allogeneic stem cell transplant.

Researchers are now evaluating Glassia in a phase 1/2 study of 24 GVHD patients with inadequate responses to steroid treatment following allogeneic stem cell transplant. The patients are enrolled in 4 dose cohorts, in which they receive up to 8 doses of Glassia. Interim data from this study is expected by the end of this year.

“Results from this phase 1/2 study in GVHD may support global clinical development activities and may serve as a platform to apply for an expansion of the AAT indications to include general organ transplantation, based on a similar mechanism of action,“ said David Tsur, Co-founder and Chief Executive Officer of Kamada, makers of Glassia.

“GVHD is a disease of significant unmet medical need, and both the disease and current therapy options carry considerable side effects. Given the favorable safety profile of Glassia, there is a strong rationale to support the development of this new indication and an increased likelihood of it becoming an effective therapy for this potentially life-threatening disease.”

“We will pursue discussion with the US and European regulators with regard to our development pathway and with an aim to move forward with a more advanced study of Glassia to treat GVHD.”

For more information on Glassia, see the full prescribing information.

Vials of drug

Credit: Bill Branson

The US Food and Drug Administration (FDA) has granted orphan designation for a human alpha-1 antitrypsin (AAT) product known as Glassia to treat graft-vs-host disease (GVHD).

Orphan drug designation carries multiple benefits, including the availability of grant money, certain tax credits, and 7 years of market exclusivity, as well as the possibility of an expedited regulatory process.

Glassia is the first available ready-to-infuse liquid alpha1-proteinase inhibitor.

The product is already approved by the FDA to treat adults with clinically evident emphysema due to severe congenital AAT deficiency. Glassia is given intravenously once a week to augment the levels of AAT, a protein derived from human plasma, in the blood.

In recent years, researchers have discovered that AAT has anti-inflammatory, tissue protective, immunomodulatory, and anti-apoptotic properties in direct or indirect consequence of its underlying antiprotease capabilities.

These properties may attenuate inflammation by lowering levels of proinflammatory mediators such as cytokines, chemokines, and proteases that are associated with GVHD.

Preliminary human and animal studies indicate that Glassia may be able to treat and reduce the severity of GVHD occurring after allogeneic stem cell transplant.

Researchers are now evaluating Glassia in a phase 1/2 study of 24 GVHD patients with inadequate responses to steroid treatment following allogeneic stem cell transplant. The patients are enrolled in 4 dose cohorts, in which they receive up to 8 doses of Glassia. Interim data from this study is expected by the end of this year.

“Results from this phase 1/2 study in GVHD may support global clinical development activities and may serve as a platform to apply for an expansion of the AAT indications to include general organ transplantation, based on a similar mechanism of action,“ said David Tsur, Co-founder and Chief Executive Officer of Kamada, makers of Glassia.

“GVHD is a disease of significant unmet medical need, and both the disease and current therapy options carry considerable side effects. Given the favorable safety profile of Glassia, there is a strong rationale to support the development of this new indication and an increased likelihood of it becoming an effective therapy for this potentially life-threatening disease.”

“We will pursue discussion with the US and European regulators with regard to our development pathway and with an aim to move forward with a more advanced study of Glassia to treat GVHD.”

For more information on Glassia, see the full prescribing information.

Vials of drug

Credit: Bill Branson

The US Food and Drug Administration (FDA) has granted orphan designation for a human alpha-1 antitrypsin (AAT) product known as Glassia to treat graft-vs-host disease (GVHD).

Orphan drug designation carries multiple benefits, including the availability of grant money, certain tax credits, and 7 years of market exclusivity, as well as the possibility of an expedited regulatory process.

Glassia is the first available ready-to-infuse liquid alpha1-proteinase inhibitor.

The product is already approved by the FDA to treat adults with clinically evident emphysema due to severe congenital AAT deficiency. Glassia is given intravenously once a week to augment the levels of AAT, a protein derived from human plasma, in the blood.

In recent years, researchers have discovered that AAT has anti-inflammatory, tissue protective, immunomodulatory, and anti-apoptotic properties in direct or indirect consequence of its underlying antiprotease capabilities.

These properties may attenuate inflammation by lowering levels of proinflammatory mediators such as cytokines, chemokines, and proteases that are associated with GVHD.

Preliminary human and animal studies indicate that Glassia may be able to treat and reduce the severity of GVHD occurring after allogeneic stem cell transplant.

Researchers are now evaluating Glassia in a phase 1/2 study of 24 GVHD patients with inadequate responses to steroid treatment following allogeneic stem cell transplant. The patients are enrolled in 4 dose cohorts, in which they receive up to 8 doses of Glassia. Interim data from this study is expected by the end of this year.

“Results from this phase 1/2 study in GVHD may support global clinical development activities and may serve as a platform to apply for an expansion of the AAT indications to include general organ transplantation, based on a similar mechanism of action,“ said David Tsur, Co-founder and Chief Executive Officer of Kamada, makers of Glassia.

“GVHD is a disease of significant unmet medical need, and both the disease and current therapy options carry considerable side effects. Given the favorable safety profile of Glassia, there is a strong rationale to support the development of this new indication and an increased likelihood of it becoming an effective therapy for this potentially life-threatening disease.”

“We will pursue discussion with the US and European regulators with regard to our development pathway and with an aim to move forward with a more advanced study of Glassia to treat GVHD.”

For more information on Glassia, see the full prescribing information.

The Centers for Disease Control and Prevention has released “Essentials for Parenting Toddlers and Preschoolers,” an online guide for parents of children 2-4 years of age. The free online resource provides parents with information and recommendations for how to address various concerns that may arise in parenting young children.

The first section in the series, “Communicating with Your Child,” offers resources for parents to develop positive, open communication with toddlers and foster a stronger relationship with children. These skills will come in handy when the child is older and parents may wish to discuss difficult topics such as drugs and alcohol, the CDC said.

© BananaStock/Thinkstock

According to the agency, praise and active listening are two essential skills parents can use when communicating with young children. They offer the following tips:

1. When a child does something right, praise the child. Praise can include actions such as positive verbal reinforcement, hugs, or high fives. This increases the likelihood that he or she will repeat the desired behavior. Likewise, to lessen negative behavior, you may choose to use negative attention such as yelling, correcting, or ignoring the behavior.

2. When a child is talking to you, give him or her your full attention. This will reassure the child that you care about what he or she has to say.

3. Designate time every day to talk and play with your child. This lets children know they are important and helps create a stronger bond.

To read more about effective communication skills with toddlers and preschoolers, visit the CDC website. To view examples of good communication, watch the video, “How to Use Positive Communication.”

[email protected]

The Centers for Disease Control and Prevention has released “Essentials for Parenting Toddlers and Preschoolers,” an online guide for parents of children 2-4 years of age. The free online resource provides parents with information and recommendations for how to address various concerns that may arise in parenting young children.

The first section in the series, “Communicating with Your Child,” offers resources for parents to develop positive, open communication with toddlers and foster a stronger relationship with children. These skills will come in handy when the child is older and parents may wish to discuss difficult topics such as drugs and alcohol, the CDC said.

© BananaStock/Thinkstock

According to the agency, praise and active listening are two essential skills parents can use when communicating with young children. They offer the following tips:

1. When a child does something right, praise the child. Praise can include actions such as positive verbal reinforcement, hugs, or high fives. This increases the likelihood that he or she will repeat the desired behavior. Likewise, to lessen negative behavior, you may choose to use negative attention such as yelling, correcting, or ignoring the behavior.

2. When a child is talking to you, give him or her your full attention. This will reassure the child that you care about what he or she has to say.

3. Designate time every day to talk and play with your child. This lets children know they are important and helps create a stronger bond.

To read more about effective communication skills with toddlers and preschoolers, visit the CDC website. To view examples of good communication, watch the video, “How to Use Positive Communication.”

[email protected]

The Centers for Disease Control and Prevention has released “Essentials for Parenting Toddlers and Preschoolers,” an online guide for parents of children 2-4 years of age. The free online resource provides parents with information and recommendations for how to address various concerns that may arise in parenting young children.

The first section in the series, “Communicating with Your Child,” offers resources for parents to develop positive, open communication with toddlers and foster a stronger relationship with children. These skills will come in handy when the child is older and parents may wish to discuss difficult topics such as drugs and alcohol, the CDC said.

© BananaStock/Thinkstock

According to the agency, praise and active listening are two essential skills parents can use when communicating with young children. They offer the following tips:

1. When a child does something right, praise the child. Praise can include actions such as positive verbal reinforcement, hugs, or high fives. This increases the likelihood that he or she will repeat the desired behavior. Likewise, to lessen negative behavior, you may choose to use negative attention such as yelling, correcting, or ignoring the behavior.

2. When a child is talking to you, give him or her your full attention. This will reassure the child that you care about what he or she has to say.

3. Designate time every day to talk and play with your child. This lets children know they are important and helps create a stronger bond.

To read more about effective communication skills with toddlers and preschoolers, visit the CDC website. To view examples of good communication, watch the video, “How to Use Positive Communication.”

[email protected]

Introduction

Autism spectrum disorder is a neurodevelopmental condition characterized by a heterogeneous grouping of social-communication impairments and behavioral phenomena that are observed in early development and often accompanied by an array of co-occurring issues. The prevalence of autism spectrum disorder (ASD) has risen markedly in the last several years (1 in 68 per a 2014 CDC estimate), and the evidence base for early intervention and other treatment strategies supports the idea that a timely and appropriate diagnosis is critical for promoting positive outcomes for children and their families.

With ASD, there can be wide variety in a young child’s presenting symptoms. Although some youth clearly manifest the hallmark features of ASD, ever-changing development, complicated cognitive profiles, family difficulties, co-occurring mental health problems, and evolving nosology (such as DSM changes) can contribute to the difficulty providers encounter in fully interpreting and identifying ASD symptoms in the course of a typical primary care visit. This case example outlines assessment and diagnostic strategies that may help pediatricians to better understand the complexities of diagnosis, assessment, and treatment for children suspected of having ASD. Ideally, a diagnostic evaluation would quickly follow a standardized screening tool that is positive for concern for ASD (such as the Modified Checklist for Autism in Toddlers – Revised) between the ages of 18 and 24 months.

Case summary

Everett is a 4-year-old boy who presents to an autism diagnostic clinic after his parents expressed concerns about his behavior. Everett is described to be a rigid, stubborn, strong-willed, and easily frustrated boy who began to exhibit aggressive behaviors at 18 months of age. He continues to have almost daily temper tantrums. Notably, Everett did not begin to use single words with communicative intent until he was 24 months old. He will often repeat words nonfunctionally and utter nonsensical verbalizations while spinning in circles and rocking back and forth. Everett enjoys being around peers but has difficulties engaging appropriately with other children, exhibiting poor physical boundaries. Everett’s hearing and vision were previously tested to be without deficit, and there is no history of seizure activity or indication of an underlying metabolic disorder.

Discussion

Everett presents with some signs and symptoms to suggest ASD (namely his communication and language impairments accompanied by some atypical social relatedness and repetitive behaviors). His presentation, however, has many characteristics that while common to ASD are not entirely specific to the diagnosis in a preschooler, and could occur with other disorders. For example, Everett’s social difficulties could be the result of an emerging behavioral disorder (an oppositional defiant disorder) or a primary expressive language disorder, which may manifest with frustration intolerance due to communication difficulties.

With children like Everett, a comprehensive autism diagnostic assessment should be obtained and preferably be comprised of a minimum of two components – a caregiver interview and an observational assessment ideally conducted by an experienced clinical interdisciplinary team. Additionally, evaluations of adaptive skills, cognitive profile, family functioning, social-emotional/behavioral functioning, and sensory issues can be useful to inform treatment planning and diagnosis. Ultimately, the diagnosis of ASD is made after clinicians integrate available information and fully consider the range of differential diagnoses. Clinicians who may participate in the diagnostic process include developmental pediatricians, child psychiatrists, clinical psychologists, speech-language pathologists, and other allied health professionals.

Clinical guidelines suggest that gathering a thorough developmental history, assessing for the characteristic impairments that support an ASD diagnosis, and establishing current levels of functioning can be performed using the semistructured Autism Diagnostic Interview – Revised (ADI-R) with primary caregivers. Information about a child’s social interactions also can be obtained with the use of the Social Responsiveness Scale (SRS), which can yield multi-informant data that helps to capture a youth’s functioning and peer interactions in different settings, including home and school.

The observational assessment ideally utilizes the Autism Diagnostic Observation Schedule (ADOS), a standardized instrument that can evaluate domains of reciprocal social interaction, communication, restricted interests, and repetitive behaviors in a developmentally informed manner. Clinicians should be mindful that certain behaviors may not be displayed during the diagnostic evaluation, and as such, scoring on the ADOS should be integrated with other sources of information and interpreted within a developmental framework; no single result on one instrument is sufficient to make or break an autism diagnosis.

The above-mentioned tools were used in Everett’s assessment. Appraising the collected data, his scoring on the ADOS suggested an autism diagnosis, but information from the ADI-R and SRS were not conclusive. To further evaluate Everett, we incorporated a broad developmental evaluation tool, the Mullen Scales of Early Learning, which provided us with a lens through which to interpret his profile of impairments and strengths. Everett scored with average to above-average skills across all domains, which helped us conceptualize that his social, language, and behavioral struggles were not the result of a global developmental delay or intellectual disability.

Additionally, Everett’s family completed the Vineland Adaptive Behavior Scales (his adaptive socialization skills were a relative weakness, and motor skills were a strength) and Child Behavior Checklists, which revealed the endorsement of emotionally reactive and aggressive behavior symptoms from both parents. Everett’s parents’ mental wellness was assessed with Adult Behavior Checklists in order to provide informed family-based treatment recommendations.

In Everett’s evaluation, enduring challenges in the core symptom domains characterizing ASD were noted. His atypical social affect, limited social awareness, and repetitive patterns of behavior provided evidence that Everett met diagnostic criteria for ASD. Also noted were protective factors that promoted his well-being (he’s verbal, has the capacity to play imaginatively, presents with a supportive family, and demonstrates no significant cognitive deficiencies), which were incorporated into our treatment recommendations. Recommendations included enrollment in structured educational and behavioral interventions, and corresponding parent training treatments to help his caregivers manage his disruptive behaviors while reducing the risk for the development of further emotional/behavioral problems in the future.

Everett’s ASD diagnosis also warranted a referral for genetic testing and/or counseling to help the family to obtain information about the etiology of the disorder, screen for other conditions, and help guide appropriate medical management. There were no other indications to pursue additional medical, imaging, or neurological consultations.

Clinical pearl

For some children, the diagnosis of ASD is unclear. Problems arise in making an accurate diagnosis for a variety of reasons, and fully appreciating a child’s (or adolescent’s) developmental challenges can be difficult, especially given the considerable symptom overlap ASD has with other learning, medical, cognitive, or mental health diagnoses. These children require a diagnostic evaluation using a family-focused and culturally sensitive multidisciplinary approach that incorporates standardized tools. As a primary care provider, it can often be difficult to tease out symptoms and have the time to do a thorough assessment; primary providers should be aware of their local assessment expert resources and referral options.

Jeremiah Dickerson, M.D., a child and adolescent psychiatrist, is an assistant professor of psychiatry at the University of Vermont. Dr. Dickerson is the director of the university’s autism diagnostic clinic. Contact Dr. Dickerson at [email protected].

Introduction

Autism spectrum disorder is a neurodevelopmental condition characterized by a heterogeneous grouping of social-communication impairments and behavioral phenomena that are observed in early development and often accompanied by an array of co-occurring issues. The prevalence of autism spectrum disorder (ASD) has risen markedly in the last several years (1 in 68 per a 2014 CDC estimate), and the evidence base for early intervention and other treatment strategies supports the idea that a timely and appropriate diagnosis is critical for promoting positive outcomes for children and their families.

With ASD, there can be wide variety in a young child’s presenting symptoms. Although some youth clearly manifest the hallmark features of ASD, ever-changing development, complicated cognitive profiles, family difficulties, co-occurring mental health problems, and evolving nosology (such as DSM changes) can contribute to the difficulty providers encounter in fully interpreting and identifying ASD symptoms in the course of a typical primary care visit. This case example outlines assessment and diagnostic strategies that may help pediatricians to better understand the complexities of diagnosis, assessment, and treatment for children suspected of having ASD. Ideally, a diagnostic evaluation would quickly follow a standardized screening tool that is positive for concern for ASD (such as the Modified Checklist for Autism in Toddlers – Revised) between the ages of 18 and 24 months.

Case summary

Everett is a 4-year-old boy who presents to an autism diagnostic clinic after his parents expressed concerns about his behavior. Everett is described to be a rigid, stubborn, strong-willed, and easily frustrated boy who began to exhibit aggressive behaviors at 18 months of age. He continues to have almost daily temper tantrums. Notably, Everett did not begin to use single words with communicative intent until he was 24 months old. He will often repeat words nonfunctionally and utter nonsensical verbalizations while spinning in circles and rocking back and forth. Everett enjoys being around peers but has difficulties engaging appropriately with other children, exhibiting poor physical boundaries. Everett’s hearing and vision were previously tested to be without deficit, and there is no history of seizure activity or indication of an underlying metabolic disorder.

Discussion

Everett presents with some signs and symptoms to suggest ASD (namely his communication and language impairments accompanied by some atypical social relatedness and repetitive behaviors). His presentation, however, has many characteristics that while common to ASD are not entirely specific to the diagnosis in a preschooler, and could occur with other disorders. For example, Everett’s social difficulties could be the result of an emerging behavioral disorder (an oppositional defiant disorder) or a primary expressive language disorder, which may manifest with frustration intolerance due to communication difficulties.

With children like Everett, a comprehensive autism diagnostic assessment should be obtained and preferably be comprised of a minimum of two components – a caregiver interview and an observational assessment ideally conducted by an experienced clinical interdisciplinary team. Additionally, evaluations of adaptive skills, cognitive profile, family functioning, social-emotional/behavioral functioning, and sensory issues can be useful to inform treatment planning and diagnosis. Ultimately, the diagnosis of ASD is made after clinicians integrate available information and fully consider the range of differential diagnoses. Clinicians who may participate in the diagnostic process include developmental pediatricians, child psychiatrists, clinical psychologists, speech-language pathologists, and other allied health professionals.

Clinical guidelines suggest that gathering a thorough developmental history, assessing for the characteristic impairments that support an ASD diagnosis, and establishing current levels of functioning can be performed using the semistructured Autism Diagnostic Interview – Revised (ADI-R) with primary caregivers. Information about a child’s social interactions also can be obtained with the use of the Social Responsiveness Scale (SRS), which can yield multi-informant data that helps to capture a youth’s functioning and peer interactions in different settings, including home and school.

The observational assessment ideally utilizes the Autism Diagnostic Observation Schedule (ADOS), a standardized instrument that can evaluate domains of reciprocal social interaction, communication, restricted interests, and repetitive behaviors in a developmentally informed manner. Clinicians should be mindful that certain behaviors may not be displayed during the diagnostic evaluation, and as such, scoring on the ADOS should be integrated with other sources of information and interpreted within a developmental framework; no single result on one instrument is sufficient to make or break an autism diagnosis.

The above-mentioned tools were used in Everett’s assessment. Appraising the collected data, his scoring on the ADOS suggested an autism diagnosis, but information from the ADI-R and SRS were not conclusive. To further evaluate Everett, we incorporated a broad developmental evaluation tool, the Mullen Scales of Early Learning, which provided us with a lens through which to interpret his profile of impairments and strengths. Everett scored with average to above-average skills across all domains, which helped us conceptualize that his social, language, and behavioral struggles were not the result of a global developmental delay or intellectual disability.

Additionally, Everett’s family completed the Vineland Adaptive Behavior Scales (his adaptive socialization skills were a relative weakness, and motor skills were a strength) and Child Behavior Checklists, which revealed the endorsement of emotionally reactive and aggressive behavior symptoms from both parents. Everett’s parents’ mental wellness was assessed with Adult Behavior Checklists in order to provide informed family-based treatment recommendations.

In Everett’s evaluation, enduring challenges in the core symptom domains characterizing ASD were noted. His atypical social affect, limited social awareness, and repetitive patterns of behavior provided evidence that Everett met diagnostic criteria for ASD. Also noted were protective factors that promoted his well-being (he’s verbal, has the capacity to play imaginatively, presents with a supportive family, and demonstrates no significant cognitive deficiencies), which were incorporated into our treatment recommendations. Recommendations included enrollment in structured educational and behavioral interventions, and corresponding parent training treatments to help his caregivers manage his disruptive behaviors while reducing the risk for the development of further emotional/behavioral problems in the future.

Everett’s ASD diagnosis also warranted a referral for genetic testing and/or counseling to help the family to obtain information about the etiology of the disorder, screen for other conditions, and help guide appropriate medical management. There were no other indications to pursue additional medical, imaging, or neurological consultations.

Clinical pearl

For some children, the diagnosis of ASD is unclear. Problems arise in making an accurate diagnosis for a variety of reasons, and fully appreciating a child’s (or adolescent’s) developmental challenges can be difficult, especially given the considerable symptom overlap ASD has with other learning, medical, cognitive, or mental health diagnoses. These children require a diagnostic evaluation using a family-focused and culturally sensitive multidisciplinary approach that incorporates standardized tools. As a primary care provider, it can often be difficult to tease out symptoms and have the time to do a thorough assessment; primary providers should be aware of their local assessment expert resources and referral options.

Jeremiah Dickerson, M.D., a child and adolescent psychiatrist, is an assistant professor of psychiatry at the University of Vermont. Dr. Dickerson is the director of the university’s autism diagnostic clinic. Contact Dr. Dickerson at [email protected].

Introduction

Autism spectrum disorder is a neurodevelopmental condition characterized by a heterogeneous grouping of social-communication impairments and behavioral phenomena that are observed in early development and often accompanied by an array of co-occurring issues. The prevalence of autism spectrum disorder (ASD) has risen markedly in the last several years (1 in 68 per a 2014 CDC estimate), and the evidence base for early intervention and other treatment strategies supports the idea that a timely and appropriate diagnosis is critical for promoting positive outcomes for children and their families.

With ASD, there can be wide variety in a young child’s presenting symptoms. Although some youth clearly manifest the hallmark features of ASD, ever-changing development, complicated cognitive profiles, family difficulties, co-occurring mental health problems, and evolving nosology (such as DSM changes) can contribute to the difficulty providers encounter in fully interpreting and identifying ASD symptoms in the course of a typical primary care visit. This case example outlines assessment and diagnostic strategies that may help pediatricians to better understand the complexities of diagnosis, assessment, and treatment for children suspected of having ASD. Ideally, a diagnostic evaluation would quickly follow a standardized screening tool that is positive for concern for ASD (such as the Modified Checklist for Autism in Toddlers – Revised) between the ages of 18 and 24 months.

Case summary

Everett is a 4-year-old boy who presents to an autism diagnostic clinic after his parents expressed concerns about his behavior. Everett is described to be a rigid, stubborn, strong-willed, and easily frustrated boy who began to exhibit aggressive behaviors at 18 months of age. He continues to have almost daily temper tantrums. Notably, Everett did not begin to use single words with communicative intent until he was 24 months old. He will often repeat words nonfunctionally and utter nonsensical verbalizations while spinning in circles and rocking back and forth. Everett enjoys being around peers but has difficulties engaging appropriately with other children, exhibiting poor physical boundaries. Everett’s hearing and vision were previously tested to be without deficit, and there is no history of seizure activity or indication of an underlying metabolic disorder.

Discussion

Everett presents with some signs and symptoms to suggest ASD (namely his communication and language impairments accompanied by some atypical social relatedness and repetitive behaviors). His presentation, however, has many characteristics that while common to ASD are not entirely specific to the diagnosis in a preschooler, and could occur with other disorders. For example, Everett’s social difficulties could be the result of an emerging behavioral disorder (an oppositional defiant disorder) or a primary expressive language disorder, which may manifest with frustration intolerance due to communication difficulties.

With children like Everett, a comprehensive autism diagnostic assessment should be obtained and preferably be comprised of a minimum of two components – a caregiver interview and an observational assessment ideally conducted by an experienced clinical interdisciplinary team. Additionally, evaluations of adaptive skills, cognitive profile, family functioning, social-emotional/behavioral functioning, and sensory issues can be useful to inform treatment planning and diagnosis. Ultimately, the diagnosis of ASD is made after clinicians integrate available information and fully consider the range of differential diagnoses. Clinicians who may participate in the diagnostic process include developmental pediatricians, child psychiatrists, clinical psychologists, speech-language pathologists, and other allied health professionals.

Clinical guidelines suggest that gathering a thorough developmental history, assessing for the characteristic impairments that support an ASD diagnosis, and establishing current levels of functioning can be performed using the semistructured Autism Diagnostic Interview – Revised (ADI-R) with primary caregivers. Information about a child’s social interactions also can be obtained with the use of the Social Responsiveness Scale (SRS), which can yield multi-informant data that helps to capture a youth’s functioning and peer interactions in different settings, including home and school.

The observational assessment ideally utilizes the Autism Diagnostic Observation Schedule (ADOS), a standardized instrument that can evaluate domains of reciprocal social interaction, communication, restricted interests, and repetitive behaviors in a developmentally informed manner. Clinicians should be mindful that certain behaviors may not be displayed during the diagnostic evaluation, and as such, scoring on the ADOS should be integrated with other sources of information and interpreted within a developmental framework; no single result on one instrument is sufficient to make or break an autism diagnosis.

The above-mentioned tools were used in Everett’s assessment. Appraising the collected data, his scoring on the ADOS suggested an autism diagnosis, but information from the ADI-R and SRS were not conclusive. To further evaluate Everett, we incorporated a broad developmental evaluation tool, the Mullen Scales of Early Learning, which provided us with a lens through which to interpret his profile of impairments and strengths. Everett scored with average to above-average skills across all domains, which helped us conceptualize that his social, language, and behavioral struggles were not the result of a global developmental delay or intellectual disability.

Additionally, Everett’s family completed the Vineland Adaptive Behavior Scales (his adaptive socialization skills were a relative weakness, and motor skills were a strength) and Child Behavior Checklists, which revealed the endorsement of emotionally reactive and aggressive behavior symptoms from both parents. Everett’s parents’ mental wellness was assessed with Adult Behavior Checklists in order to provide informed family-based treatment recommendations.

In Everett’s evaluation, enduring challenges in the core symptom domains characterizing ASD were noted. His atypical social affect, limited social awareness, and repetitive patterns of behavior provided evidence that Everett met diagnostic criteria for ASD. Also noted were protective factors that promoted his well-being (he’s verbal, has the capacity to play imaginatively, presents with a supportive family, and demonstrates no significant cognitive deficiencies), which were incorporated into our treatment recommendations. Recommendations included enrollment in structured educational and behavioral interventions, and corresponding parent training treatments to help his caregivers manage his disruptive behaviors while reducing the risk for the development of further emotional/behavioral problems in the future.

Everett’s ASD diagnosis also warranted a referral for genetic testing and/or counseling to help the family to obtain information about the etiology of the disorder, screen for other conditions, and help guide appropriate medical management. There were no other indications to pursue additional medical, imaging, or neurological consultations.

Clinical pearl

For some children, the diagnosis of ASD is unclear. Problems arise in making an accurate diagnosis for a variety of reasons, and fully appreciating a child’s (or adolescent’s) developmental challenges can be difficult, especially given the considerable symptom overlap ASD has with other learning, medical, cognitive, or mental health diagnoses. These children require a diagnostic evaluation using a family-focused and culturally sensitive multidisciplinary approach that incorporates standardized tools. As a primary care provider, it can often be difficult to tease out symptoms and have the time to do a thorough assessment; primary providers should be aware of their local assessment expert resources and referral options.

Jeremiah Dickerson, M.D., a child and adolescent psychiatrist, is an assistant professor of psychiatry at the University of Vermont. Dr. Dickerson is the director of the university’s autism diagnostic clinic. Contact Dr. Dickerson at [email protected].

BALTIMORE –Aggressive decompression dramatically improved survival in patients who had trapped ventricle syndrome as a result of tumor or intracerebral hemorrhage in a retrospective study.

Overall mortality in the cohort was 70% among those who had no decompression, Dr. Gabriel L. Pagani-Estevez said at the annual meeting of the American Neurological Association. But it dropped to 19% among those who underwent some form of decompression therapy. Even after controlling for confounding factors like age, etiology, and hemorrhage volume, decompression remained a significant independent predictor of survival, said Dr. Pagani-Estevez, a neurology resident at the Mayo Clinic, Rochester, Minn.

Despite all the methodological issues inherent in a retrospective study, the findings “provide at least a suggestion that neurosurgical intervention can markedly reduce mortality in trapped ventricle syndrome,” he said. “Now, research needs to clarify the ideal intervention, the effect of decompression on functional outcome, and which patients might derive the most benefit from treatment.”

The cohort comprised 392 patients who developed ventricular trapping and were treated during 2002-2010. They were a mean of 58 years old. Most (223) were not on anticoagulation therapy. A total of 80 patients were taking aspirin, and the remainder were taking other anticoagulants. The median midline shift was about 10 mm.

Trapping was caused by a tumor in 177 patients. Other etiologies included intracerebral hemorrhage (80), subdural hematoma (55), trauma (26), and stroke (18). Unspecified causes made up the remainder.

The left lateral ventricle was most often involved (176). The right lateral ventricle was trapped in 159 patients and both were involved in 32. Thirteen patients had a trapped fourth ventricle, and 12 had unspecified trapping.

Some kind of decompression procedure was performed on 221 patients. These included craniotomy (126), craniectomy (26), external ventricular drain (30), ventricular-peritoneal shunt (23), and endoscopic septum pellucidum fenestration (16).

Comparisons showed significantly decreased mortality for intervention vs. nonintervention in groups with various causes of ventricular trapping: intracerebral hemorrhage (48% vs. 95%), tumor (12% vs. 47%), and subdural hematoma (20% vs. 90%).

There were nonsignificant declines in mortality among patients who underwent intervention for ventricular trapping caused by trauma or ischemic stroke, but the number of patients in those subgroups were small, which probably confounded the results, Dr. Pagani-Estevez said.

He then conducted a multivariate analysis to determine patient characteristics that might have contributed to survival. Patients who had a decompression procedure were 87% less likely to die than were those who had not – a highly significant finding (P = .0001). A midline shift conferred a slight increase in the risk of death, while having intracerebral hemorrhage as the trapping etiology increased the risk fourfold.

Trapped ventricle carries a notoriously poor prognosis, said Dr. Alejandro A. Rabinstein, a coauthor on the study. “By the time you develop it, it’s a very bad situation, so whatever way you can achieve decompression may improve the situation,” said Dr. Rabinstein, a critical care neurologist who is also at the Mayo Clinic in Rochester. “If you don’t think the patient has enough left to merit the intervention, then you just don’t do it. But despite that limitation, if you think the patient can recover some function, it’s appropriate. An intervention will make patients survive way more often than no intervention. Without something, though, the prospect of survival is bleak.”

Neither Dr. Pagani-Estevez nor Dr. Rabinstein had any financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE –Aggressive decompression dramatically improved survival in patients who had trapped ventricle syndrome as a result of tumor or intracerebral hemorrhage in a retrospective study.

Overall mortality in the cohort was 70% among those who had no decompression, Dr. Gabriel L. Pagani-Estevez said at the annual meeting of the American Neurological Association. But it dropped to 19% among those who underwent some form of decompression therapy. Even after controlling for confounding factors like age, etiology, and hemorrhage volume, decompression remained a significant independent predictor of survival, said Dr. Pagani-Estevez, a neurology resident at the Mayo Clinic, Rochester, Minn.

Despite all the methodological issues inherent in a retrospective study, the findings “provide at least a suggestion that neurosurgical intervention can markedly reduce mortality in trapped ventricle syndrome,” he said. “Now, research needs to clarify the ideal intervention, the effect of decompression on functional outcome, and which patients might derive the most benefit from treatment.”

The cohort comprised 392 patients who developed ventricular trapping and were treated during 2002-2010. They were a mean of 58 years old. Most (223) were not on anticoagulation therapy. A total of 80 patients were taking aspirin, and the remainder were taking other anticoagulants. The median midline shift was about 10 mm.

Trapping was caused by a tumor in 177 patients. Other etiologies included intracerebral hemorrhage (80), subdural hematoma (55), trauma (26), and stroke (18). Unspecified causes made up the remainder.

The left lateral ventricle was most often involved (176). The right lateral ventricle was trapped in 159 patients and both were involved in 32. Thirteen patients had a trapped fourth ventricle, and 12 had unspecified trapping.

Some kind of decompression procedure was performed on 221 patients. These included craniotomy (126), craniectomy (26), external ventricular drain (30), ventricular-peritoneal shunt (23), and endoscopic septum pellucidum fenestration (16).

Comparisons showed significantly decreased mortality for intervention vs. nonintervention in groups with various causes of ventricular trapping: intracerebral hemorrhage (48% vs. 95%), tumor (12% vs. 47%), and subdural hematoma (20% vs. 90%).

There were nonsignificant declines in mortality among patients who underwent intervention for ventricular trapping caused by trauma or ischemic stroke, but the number of patients in those subgroups were small, which probably confounded the results, Dr. Pagani-Estevez said.

He then conducted a multivariate analysis to determine patient characteristics that might have contributed to survival. Patients who had a decompression procedure were 87% less likely to die than were those who had not – a highly significant finding (P = .0001). A midline shift conferred a slight increase in the risk of death, while having intracerebral hemorrhage as the trapping etiology increased the risk fourfold.

Trapped ventricle carries a notoriously poor prognosis, said Dr. Alejandro A. Rabinstein, a coauthor on the study. “By the time you develop it, it’s a very bad situation, so whatever way you can achieve decompression may improve the situation,” said Dr. Rabinstein, a critical care neurologist who is also at the Mayo Clinic in Rochester. “If you don’t think the patient has enough left to merit the intervention, then you just don’t do it. But despite that limitation, if you think the patient can recover some function, it’s appropriate. An intervention will make patients survive way more often than no intervention. Without something, though, the prospect of survival is bleak.”

Neither Dr. Pagani-Estevez nor Dr. Rabinstein had any financial disclosures.

[email protected]

On Twitter @alz_gal

BALTIMORE –Aggressive decompression dramatically improved survival in patients who had trapped ventricle syndrome as a result of tumor or intracerebral hemorrhage in a retrospective study.

Overall mortality in the cohort was 70% among those who had no decompression, Dr. Gabriel L. Pagani-Estevez said at the annual meeting of the American Neurological Association. But it dropped to 19% among those who underwent some form of decompression therapy. Even after controlling for confounding factors like age, etiology, and hemorrhage volume, decompression remained a significant independent predictor of survival, said Dr. Pagani-Estevez, a neurology resident at the Mayo Clinic, Rochester, Minn.

Despite all the methodological issues inherent in a retrospective study, the findings “provide at least a suggestion that neurosurgical intervention can markedly reduce mortality in trapped ventricle syndrome,” he said. “Now, research needs to clarify the ideal intervention, the effect of decompression on functional outcome, and which patients might derive the most benefit from treatment.”

The cohort comprised 392 patients who developed ventricular trapping and were treated during 2002-2010. They were a mean of 58 years old. Most (223) were not on anticoagulation therapy. A total of 80 patients were taking aspirin, and the remainder were taking other anticoagulants. The median midline shift was about 10 mm.

Trapping was caused by a tumor in 177 patients. Other etiologies included intracerebral hemorrhage (80), subdural hematoma (55), trauma (26), and stroke (18). Unspecified causes made up the remainder.

The left lateral ventricle was most often involved (176). The right lateral ventricle was trapped in 159 patients and both were involved in 32. Thirteen patients had a trapped fourth ventricle, and 12 had unspecified trapping.

Some kind of decompression procedure was performed on 221 patients. These included craniotomy (126), craniectomy (26), external ventricular drain (30), ventricular-peritoneal shunt (23), and endoscopic septum pellucidum fenestration (16).

Comparisons showed significantly decreased mortality for intervention vs. nonintervention in groups with various causes of ventricular trapping: intracerebral hemorrhage (48% vs. 95%), tumor (12% vs. 47%), and subdural hematoma (20% vs. 90%).

There were nonsignificant declines in mortality among patients who underwent intervention for ventricular trapping caused by trauma or ischemic stroke, but the number of patients in those subgroups were small, which probably confounded the results, Dr. Pagani-Estevez said.

He then conducted a multivariate analysis to determine patient characteristics that might have contributed to survival. Patients who had a decompression procedure were 87% less likely to die than were those who had not – a highly significant finding (P = .0001). A midline shift conferred a slight increase in the risk of death, while having intracerebral hemorrhage as the trapping etiology increased the risk fourfold.

Trapped ventricle carries a notoriously poor prognosis, said Dr. Alejandro A. Rabinstein, a coauthor on the study. “By the time you develop it, it’s a very bad situation, so whatever way you can achieve decompression may improve the situation,” said Dr. Rabinstein, a critical care neurologist who is also at the Mayo Clinic in Rochester. “If you don’t think the patient has enough left to merit the intervention, then you just don’t do it. But despite that limitation, if you think the patient can recover some function, it’s appropriate. An intervention will make patients survive way more often than no intervention. Without something, though, the prospect of survival is bleak.”

Neither Dr. Pagani-Estevez nor Dr. Rabinstein had any financial disclosures.

[email protected]

On Twitter @alz_gal

PHILADELPHIA—Internal medicine residents are obtaining transfusion consent from patients despite having poor knowledge of transfusion medicine, according to a study of nearly 500 residents in 9 countries.

On an exam assessing transfusion knowledge, the residents’ mean score was 45.7%.

And in a survey, an overwhelming majority of residents said they had “beginner” or “intermediate” transfusion knowledge.

Still, 89% said they had obtained patient consent for a transfusion.

Richard Haspel, MD, PhD, of Beth Israel Deacon Medical Center and Harvard Medical School in Boston, presented these data at the AABB Annual Meeting 2014 (abstract S45-030G).

“We all know there’s a problem with clinicians not knowing how to transfuse blood,” Dr Haspel began. “I would argue, though, that there are a lot of questions we don’t know the answer to. How prevalent is this problem? Are there some places that do it better than others? What areas need improvement?”

With these questions in mind, Dr Haspel and his colleagues used a 23-question survey and a 20-question exam (validated by the BEST Collaborative) to assess 474 internal medicine residents from 23 sites in 9 countries: Australia, Canada, England, Ireland, Italy, Germany, The Netherlands, Spain, and the US.

The mean score of correct responses in the exam was 45.7%. The mean score was significantly lower for first-year residents (43.9%) than for third- (47.1%; P=0.02) and fourth-year residents (50.6%, P=0.002).

However, as 50.6% was the highest mean score, exam scores were poor regardless of a resident’s time served, Dr Haspel noted. Scores were poor across the different study sites as well, ranging from about 32% to 55%.

The exam included questions on red cells, platelets, plasma, allergic reactions, transfusion-related acute lung injury (TRALI), and transfusion-associated circulatory overload (TACO), among other topics.

As an example, Dr Haspel pointed out that, for the 3 questions on TRALI, the percentage of correct responses did not exceed 15%. This was the topic about which residents seemed the least informed.

Dr Haspel noted that, in general, residents with more medical school hours spent learning about transfusion medicine and those with better perceived quality of their training tended to score higher on the exam. Still, there wasn’t much of a difference in exam scores between residents who said they had beginner, intermediate, or advanced knowledge of transfusion medicine.

Twelve percent of residents said they did not receive any transfusion medicine training in medical school, and 28% said they didn’t receive any training during their residency. About 35% said they received more than 2 hours of training in medical school, and 18% said they received more than 2 hours of training during their residency.

“In terms of the quality of the training, most rated it ‘slightly’ or ‘moderately’ effective,” Dr Haspel said. “In terms of attitudes and perceptions, most of them considered themselves a beginner [48%] or intermediate [48%] in regard to transfusion medicine knowledge.”

Ninety-seven percent of residents said they know how to contact the blood bank, and 72% said they know how to contact a transfusion medicine doctor. But 14% percent of residents did not know if their hospital had transfusion guidelines, and 1% wrongly said their hospital did not have guidelines.

Yet 89% of residents said they had obtained consent for a transfusion from a patient.

On the other hand, most residents (77%) said knowledge of transfusion medicine is “very” or “extremely” important in providing appropriate patient care. And 65% said they would find additional training “very” or “extremely” helpful.

PHILADELPHIA—Internal medicine residents are obtaining transfusion consent from patients despite having poor knowledge of transfusion medicine, according to a study of nearly 500 residents in 9 countries.

On an exam assessing transfusion knowledge, the residents’ mean score was 45.7%.

And in a survey, an overwhelming majority of residents said they had “beginner” or “intermediate” transfusion knowledge.

Still, 89% said they had obtained patient consent for a transfusion.

Richard Haspel, MD, PhD, of Beth Israel Deacon Medical Center and Harvard Medical School in Boston, presented these data at the AABB Annual Meeting 2014 (abstract S45-030G).

“We all know there’s a problem with clinicians not knowing how to transfuse blood,” Dr Haspel began. “I would argue, though, that there are a lot of questions we don’t know the answer to. How prevalent is this problem? Are there some places that do it better than others? What areas need improvement?”

With these questions in mind, Dr Haspel and his colleagues used a 23-question survey and a 20-question exam (validated by the BEST Collaborative) to assess 474 internal medicine residents from 23 sites in 9 countries: Australia, Canada, England, Ireland, Italy, Germany, The Netherlands, Spain, and the US.

The mean score of correct responses in the exam was 45.7%. The mean score was significantly lower for first-year residents (43.9%) than for third- (47.1%; P=0.02) and fourth-year residents (50.6%, P=0.002).

However, as 50.6% was the highest mean score, exam scores were poor regardless of a resident’s time served, Dr Haspel noted. Scores were poor across the different study sites as well, ranging from about 32% to 55%.

The exam included questions on red cells, platelets, plasma, allergic reactions, transfusion-related acute lung injury (TRALI), and transfusion-associated circulatory overload (TACO), among other topics.

As an example, Dr Haspel pointed out that, for the 3 questions on TRALI, the percentage of correct responses did not exceed 15%. This was the topic about which residents seemed the least informed.

Dr Haspel noted that, in general, residents with more medical school hours spent learning about transfusion medicine and those with better perceived quality of their training tended to score higher on the exam. Still, there wasn’t much of a difference in exam scores between residents who said they had beginner, intermediate, or advanced knowledge of transfusion medicine.

Twelve percent of residents said they did not receive any transfusion medicine training in medical school, and 28% said they didn’t receive any training during their residency. About 35% said they received more than 2 hours of training in medical school, and 18% said they received more than 2 hours of training during their residency.

“In terms of the quality of the training, most rated it ‘slightly’ or ‘moderately’ effective,” Dr Haspel said. “In terms of attitudes and perceptions, most of them considered themselves a beginner [48%] or intermediate [48%] in regard to transfusion medicine knowledge.”

Ninety-seven percent of residents said they know how to contact the blood bank, and 72% said they know how to contact a transfusion medicine doctor. But 14% percent of residents did not know if their hospital had transfusion guidelines, and 1% wrongly said their hospital did not have guidelines.

Yet 89% of residents said they had obtained consent for a transfusion from a patient.

On the other hand, most residents (77%) said knowledge of transfusion medicine is “very” or “extremely” important in providing appropriate patient care. And 65% said they would find additional training “very” or “extremely” helpful.

PHILADELPHIA—Internal medicine residents are obtaining transfusion consent from patients despite having poor knowledge of transfusion medicine, according to a study of nearly 500 residents in 9 countries.

On an exam assessing transfusion knowledge, the residents’ mean score was 45.7%.

And in a survey, an overwhelming majority of residents said they had “beginner” or “intermediate” transfusion knowledge.

Still, 89% said they had obtained patient consent for a transfusion.

Richard Haspel, MD, PhD, of Beth Israel Deacon Medical Center and Harvard Medical School in Boston, presented these data at the AABB Annual Meeting 2014 (abstract S45-030G).

“We all know there’s a problem with clinicians not knowing how to transfuse blood,” Dr Haspel began. “I would argue, though, that there are a lot of questions we don’t know the answer to. How prevalent is this problem? Are there some places that do it better than others? What areas need improvement?”

With these questions in mind, Dr Haspel and his colleagues used a 23-question survey and a 20-question exam (validated by the BEST Collaborative) to assess 474 internal medicine residents from 23 sites in 9 countries: Australia, Canada, England, Ireland, Italy, Germany, The Netherlands, Spain, and the US.

The mean score of correct responses in the exam was 45.7%. The mean score was significantly lower for first-year residents (43.9%) than for third- (47.1%; P=0.02) and fourth-year residents (50.6%, P=0.002).

However, as 50.6% was the highest mean score, exam scores were poor regardless of a resident’s time served, Dr Haspel noted. Scores were poor across the different study sites as well, ranging from about 32% to 55%.

The exam included questions on red cells, platelets, plasma, allergic reactions, transfusion-related acute lung injury (TRALI), and transfusion-associated circulatory overload (TACO), among other topics.

As an example, Dr Haspel pointed out that, for the 3 questions on TRALI, the percentage of correct responses did not exceed 15%. This was the topic about which residents seemed the least informed.

Dr Haspel noted that, in general, residents with more medical school hours spent learning about transfusion medicine and those with better perceived quality of their training tended to score higher on the exam. Still, there wasn’t much of a difference in exam scores between residents who said they had beginner, intermediate, or advanced knowledge of transfusion medicine.

Twelve percent of residents said they did not receive any transfusion medicine training in medical school, and 28% said they didn’t receive any training during their residency. About 35% said they received more than 2 hours of training in medical school, and 18% said they received more than 2 hours of training during their residency.

“In terms of the quality of the training, most rated it ‘slightly’ or ‘moderately’ effective,” Dr Haspel said. “In terms of attitudes and perceptions, most of them considered themselves a beginner [48%] or intermediate [48%] in regard to transfusion medicine knowledge.”

Ninety-seven percent of residents said they know how to contact the blood bank, and 72% said they know how to contact a transfusion medicine doctor. But 14% percent of residents did not know if their hospital had transfusion guidelines, and 1% wrongly said their hospital did not have guidelines.

Yet 89% of residents said they had obtained consent for a transfusion from a patient.

On the other hand, most residents (77%) said knowledge of transfusion medicine is “very” or “extremely” important in providing appropriate patient care. And 65% said they would find additional training “very” or “extremely” helpful.

Lab mice

Credit: Aaron Logan

A new method of genome editing can cure hemophilia B in mice, researchers have reported in Nature.

This new technique doesn’t require the co-delivery of an endonuclease to clip the recipient’s DNA at specific locations, and it doesn’t rely on the co-insertion of genetic promoters to activate the new gene’s expression.

These differences may make the new approach both safer and longer-lasting than other genome editing methods, according to researchers.

“It appears that we may be able to achieve lifelong expression of the inserted gene, which is particularly important when treating genetic diseases like hemophilia and severe combined immunodeficiency,” said study author Mark Kay, MD, PhD, of the Stanford University School of Medicine in California.

“We’re able to do this without using promoters or nucleases, which significantly reduces the chances of cancers that can result if the new gene inserts itself at random places in the genome.”

Using their new technique, Dr Kay and his colleagues were able to insert a working copy of the human coagulation factor IX gene into the DNA of mice with hemophilia B. Although the insertion was accomplished in only about 1% of liver cells, those cells made enough factor IX to ameliorate the disorder.

Instead of using nucleases to cut the DNA or a promoter to drive expression of the factor IX gene, the researchers hitched the expression of the new gene to that of albumin.

They used a modified version of adeno-associated virus and relied on homologous recombination to insert the factor IX gene near the albumin gene.

Using a special DNA linker between the genes, the researchers were able to ensure that the clotting factor protein was made hand-in-hand with the highly expressed albumin protein.

During homologous recombination, the cell takes advantage of the fact that it has two copies of every chromosome. By lining up the damaged and undamaged chromosomes, the cell can “crib” off the intact copy to repair the damage without losing vital genetic information.

The researchers used this natural process to copy sequences from the viral vector into the genome at places they chose—in this case, after the albumin gene.

When they tested their approach in newborn lab mice with hemophilia, the team found the animals began to express levels of factor IX that were between 7% and 20% of normal. That amount of clotting factor has been shown in previous studies to be therapeutic in mice.

The researchers further showed that the technique worked as well in adult animals, even though the gene was successfully inserted in fewer than 1 in every 100 liver cells.

“We expected this approach to work best in newborn animals because the liver is still growing,” Dr Kay said. “However, because homologous recombination has been thought to occur mostly in proliferating cells, we didn’t expect it to work as well as it did in adult animals.”

The researchers are now planning to test the technique in mice with livers composed of human and mouse cells, a model that may be a good surrogate to further predict what will happen in humans.

Lab mice

Credit: Aaron Logan

A new method of genome editing can cure hemophilia B in mice, researchers have reported in Nature.

This new technique doesn’t require the co-delivery of an endonuclease to clip the recipient’s DNA at specific locations, and it doesn’t rely on the co-insertion of genetic promoters to activate the new gene’s expression.

These differences may make the new approach both safer and longer-lasting than other genome editing methods, according to researchers.

“It appears that we may be able to achieve lifelong expression of the inserted gene, which is particularly important when treating genetic diseases like hemophilia and severe combined immunodeficiency,” said study author Mark Kay, MD, PhD, of the Stanford University School of Medicine in California.

“We’re able to do this without using promoters or nucleases, which significantly reduces the chances of cancers that can result if the new gene inserts itself at random places in the genome.”

Using their new technique, Dr Kay and his colleagues were able to insert a working copy of the human coagulation factor IX gene into the DNA of mice with hemophilia B. Although the insertion was accomplished in only about 1% of liver cells, those cells made enough factor IX to ameliorate the disorder.

Instead of using nucleases to cut the DNA or a promoter to drive expression of the factor IX gene, the researchers hitched the expression of the new gene to that of albumin.

They used a modified version of adeno-associated virus and relied on homologous recombination to insert the factor IX gene near the albumin gene.

Using a special DNA linker between the genes, the researchers were able to ensure that the clotting factor protein was made hand-in-hand with the highly expressed albumin protein.

During homologous recombination, the cell takes advantage of the fact that it has two copies of every chromosome. By lining up the damaged and undamaged chromosomes, the cell can “crib” off the intact copy to repair the damage without losing vital genetic information.

The researchers used this natural process to copy sequences from the viral vector into the genome at places they chose—in this case, after the albumin gene.

When they tested their approach in newborn lab mice with hemophilia, the team found the animals began to express levels of factor IX that were between 7% and 20% of normal. That amount of clotting factor has been shown in previous studies to be therapeutic in mice.

The researchers further showed that the technique worked as well in adult animals, even though the gene was successfully inserted in fewer than 1 in every 100 liver cells.

“We expected this approach to work best in newborn animals because the liver is still growing,” Dr Kay said. “However, because homologous recombination has been thought to occur mostly in proliferating cells, we didn’t expect it to work as well as it did in adult animals.”

The researchers are now planning to test the technique in mice with livers composed of human and mouse cells, a model that may be a good surrogate to further predict what will happen in humans.

Lab mice

Credit: Aaron Logan

A new method of genome editing can cure hemophilia B in mice, researchers have reported in Nature.

This new technique doesn’t require the co-delivery of an endonuclease to clip the recipient’s DNA at specific locations, and it doesn’t rely on the co-insertion of genetic promoters to activate the new gene’s expression.

These differences may make the new approach both safer and longer-lasting than other genome editing methods, according to researchers.

“It appears that we may be able to achieve lifelong expression of the inserted gene, which is particularly important when treating genetic diseases like hemophilia and severe combined immunodeficiency,” said study author Mark Kay, MD, PhD, of the Stanford University School of Medicine in California.

“We’re able to do this without using promoters or nucleases, which significantly reduces the chances of cancers that can result if the new gene inserts itself at random places in the genome.”

Using their new technique, Dr Kay and his colleagues were able to insert a working copy of the human coagulation factor IX gene into the DNA of mice with hemophilia B. Although the insertion was accomplished in only about 1% of liver cells, those cells made enough factor IX to ameliorate the disorder.

Instead of using nucleases to cut the DNA or a promoter to drive expression of the factor IX gene, the researchers hitched the expression of the new gene to that of albumin.

They used a modified version of adeno-associated virus and relied on homologous recombination to insert the factor IX gene near the albumin gene.

Using a special DNA linker between the genes, the researchers were able to ensure that the clotting factor protein was made hand-in-hand with the highly expressed albumin protein.

During homologous recombination, the cell takes advantage of the fact that it has two copies of every chromosome. By lining up the damaged and undamaged chromosomes, the cell can “crib” off the intact copy to repair the damage without losing vital genetic information.

The researchers used this natural process to copy sequences from the viral vector into the genome at places they chose—in this case, after the albumin gene.

When they tested their approach in newborn lab mice with hemophilia, the team found the animals began to express levels of factor IX that were between 7% and 20% of normal. That amount of clotting factor has been shown in previous studies to be therapeutic in mice.

The researchers further showed that the technique worked as well in adult animals, even though the gene was successfully inserted in fewer than 1 in every 100 liver cells.

“We expected this approach to work best in newborn animals because the liver is still growing,” Dr Kay said. “However, because homologous recombination has been thought to occur mostly in proliferating cells, we didn’t expect it to work as well as it did in adult animals.”

The researchers are now planning to test the technique in mice with livers composed of human and mouse cells, a model that may be a good surrogate to further predict what will happen in humans.