FROM JAMA PEDIATRICS

Children and adolescents with traumatic brain injury (TBI) might be at increased risk of developing attention-deficit/hyperactivity disorder (ADHD) years after the injury, a prospective cohort study published March 19 shows.

Severe TBI was associated with significantly increased risk of new onset ADHD versus controls in the study, which was based on parent-completed assessments done as late as 6.8 years after the initial injury, according to results presented in JAMA Pediatrics.

Although children with severe TBI were at highest risk, those with less severe TBI had about twice the risk of developing ADHD, compared with control subjects who had no brain injury, the study results suggest.

Taken together, the findings suggest a need for long-term monitoring for attention problems, wrote investigator Megan E. Narad, PhD, of Cincinnati Children’s Hospital Medical Center, and her co-authors.

“Physicians and other clinicians should continue to be vigilant in monitoring attention problems in patients with a history of brain injury, even if it has been a number of years since the injury, the injury was moderate in nature, or the patient experienced a predominantly positive recovery,” Dr. Narad and her colleagues wrote.

The results were based on long-term analysis of 187 children who were hospitalized for TBI or orthopedic injury between the ages of 3 and 7 years. That group included 81 children with TBI and 106 with orthopedic injury.

Parents completed assessments soon after the injury, then again at 6 months, 12 months, 18 months, 3.4 years, and 6.8 years afterward, according to the study.

Over the full follow-up period, 48 children (25.7%) met the investigators’ definition of “secondary ADHD,” or onset of ADHD symptoms after an injury. They found that compared with orthopedic injury, the severe TBI was associated with new ADHD (hazard ratio, 3.62; 95% confidence interval, 1.59-8.26), the investigators reported.
In patients with mild or moderate TBI, associations with new onset ADHD did not meet the statistical significance threshol. However, compared with the orthopedic injury group, the risk for ADHD in TBI severity subgroups were up to 4 times higher.

This is not the first study showing an elevated risk of ADHD in TBI patients, but previous studies have not adequately considered the potential for ADHD to develop many years after the injury, according to investigators.

“Although most children with severe TBI who developed secondary ADHD did so within the first 18 months after injury, a portion of those with complicated mild and moderate TBI demonstrated new onset of secondary ADHD at the final two assessments, highlighting the importance of continued monitoring even years after TBI,” Dr. Narad and her colleagues wrote.

The study was funded by several sources, including the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the state of Ohio’s Emergency Medical Services.

Dr. Narad reported no relevant disclosures. Other study authors reported disclosures related to Akili Interactive Labs, Multi-Health Systems, Optimal Medicine, and IXICO.

[email protected]

SOURCE: Narad ME et al. JAMA Pediatr. 2018 Mar 19. doi: 10.1001/jamapediatrics.2017.5746.


 

FROM JAMA PEDIATRICS

Children and adolescents with traumatic brain injury (TBI) might be at increased risk of developing attention-deficit/hyperactivity disorder (ADHD) years after the injury, a prospective cohort study published March 19 shows.

Severe TBI was associated with significantly increased risk of new onset ADHD versus controls in the study, which was based on parent-completed assessments done as late as 6.8 years after the initial injury, according to results presented in JAMA Pediatrics.

Although children with severe TBI were at highest risk, those with less severe TBI had about twice the risk of developing ADHD, compared with control subjects who had no brain injury, the study results suggest.

Taken together, the findings suggest a need for long-term monitoring for attention problems, wrote investigator Megan E. Narad, PhD, of Cincinnati Children’s Hospital Medical Center, and her co-authors.

“Physicians and other clinicians should continue to be vigilant in monitoring attention problems in patients with a history of brain injury, even if it has been a number of years since the injury, the injury was moderate in nature, or the patient experienced a predominantly positive recovery,” Dr. Narad and her colleagues wrote.

The results were based on long-term analysis of 187 children who were hospitalized for TBI or orthopedic injury between the ages of 3 and 7 years. That group included 81 children with TBI and 106 with orthopedic injury.

Parents completed assessments soon after the injury, then again at 6 months, 12 months, 18 months, 3.4 years, and 6.8 years afterward, according to the study.

Over the full follow-up period, 48 children (25.7%) met the investigators’ definition of “secondary ADHD,” or onset of ADHD symptoms after an injury. They found that compared with orthopedic injury, the severe TBI was associated with new ADHD (hazard ratio, 3.62; 95% confidence interval, 1.59-8.26), the investigators reported.
In patients with mild or moderate TBI, associations with new onset ADHD did not meet the statistical significance threshol. However, compared with the orthopedic injury group, the risk for ADHD in TBI severity subgroups were up to 4 times higher.

This is not the first study showing an elevated risk of ADHD in TBI patients, but previous studies have not adequately considered the potential for ADHD to develop many years after the injury, according to investigators.

“Although most children with severe TBI who developed secondary ADHD did so within the first 18 months after injury, a portion of those with complicated mild and moderate TBI demonstrated new onset of secondary ADHD at the final two assessments, highlighting the importance of continued monitoring even years after TBI,” Dr. Narad and her colleagues wrote.

The study was funded by several sources, including the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the state of Ohio’s Emergency Medical Services.

Dr. Narad reported no relevant disclosures. Other study authors reported disclosures related to Akili Interactive Labs, Multi-Health Systems, Optimal Medicine, and IXICO.

[email protected]

SOURCE: Narad ME et al. JAMA Pediatr. 2018 Mar 19. doi: 10.1001/jamapediatrics.2017.5746.


 

FROM JAMA PEDIATRICS

Children and adolescents with traumatic brain injury (TBI) might be at increased risk of developing attention-deficit/hyperactivity disorder (ADHD) years after the injury, a prospective cohort study published March 19 shows.

Severe TBI was associated with significantly increased risk of new onset ADHD versus controls in the study, which was based on parent-completed assessments done as late as 6.8 years after the initial injury, according to results presented in JAMA Pediatrics.

Although children with severe TBI were at highest risk, those with less severe TBI had about twice the risk of developing ADHD, compared with control subjects who had no brain injury, the study results suggest.

Taken together, the findings suggest a need for long-term monitoring for attention problems, wrote investigator Megan E. Narad, PhD, of Cincinnati Children’s Hospital Medical Center, and her co-authors.

“Physicians and other clinicians should continue to be vigilant in monitoring attention problems in patients with a history of brain injury, even if it has been a number of years since the injury, the injury was moderate in nature, or the patient experienced a predominantly positive recovery,” Dr. Narad and her colleagues wrote.

The results were based on long-term analysis of 187 children who were hospitalized for TBI or orthopedic injury between the ages of 3 and 7 years. That group included 81 children with TBI and 106 with orthopedic injury.

Parents completed assessments soon after the injury, then again at 6 months, 12 months, 18 months, 3.4 years, and 6.8 years afterward, according to the study.

Over the full follow-up period, 48 children (25.7%) met the investigators’ definition of “secondary ADHD,” or onset of ADHD symptoms after an injury. They found that compared with orthopedic injury, the severe TBI was associated with new ADHD (hazard ratio, 3.62; 95% confidence interval, 1.59-8.26), the investigators reported.
In patients with mild or moderate TBI, associations with new onset ADHD did not meet the statistical significance threshol. However, compared with the orthopedic injury group, the risk for ADHD in TBI severity subgroups were up to 4 times higher.

This is not the first study showing an elevated risk of ADHD in TBI patients, but previous studies have not adequately considered the potential for ADHD to develop many years after the injury, according to investigators.

“Although most children with severe TBI who developed secondary ADHD did so within the first 18 months after injury, a portion of those with complicated mild and moderate TBI demonstrated new onset of secondary ADHD at the final two assessments, highlighting the importance of continued monitoring even years after TBI,” Dr. Narad and her colleagues wrote.

The study was funded by several sources, including the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the state of Ohio’s Emergency Medical Services.

Dr. Narad reported no relevant disclosures. Other study authors reported disclosures related to Akili Interactive Labs, Multi-Health Systems, Optimal Medicine, and IXICO.

[email protected]

SOURCE: Narad ME et al. JAMA Pediatr. 2018 Mar 19. doi: 10.1001/jamapediatrics.2017.5746.


 

PHILADELPHIA – When evaluating patients with established non-alcoholic fatty liver disease (NAFLD), using pre-screening criteria may help identify the subset of patients who should be subjected to liver biopsy, according to Vinod K. Rustgi, MD.

The recently described pre-screening criteria include a set of patient and disease characteristics that identify who might be at highest risk for non-alcoholic steatohepatitis (NASH) and fibrosis, said Dr. Rustgi, chief of hepatology at Rutgers Robert Wood Johnson Medical School in New Brunswick, N.J.

“Eighty-five percent of the patients who fall into this category will actually have fibrosis on liver biopsy. So it’s a good way to screen out who you want to actually biopsy,” Dr. Rustgi said at the meeting, jointly provided by Rutgers and Global Academy for Medical Education.

Liver biopsy needs to be considered in patients with NAFLD who are at increased risk of having advanced fibrosis, according to the latest practice guidance on diagnosis and management of NAFLD (Hepatology. 2018 Jan;67[1]:328-57).

PHILADELPHIA – When evaluating patients with established non-alcoholic fatty liver disease (NAFLD), using pre-screening criteria may help identify the subset of patients who should be subjected to liver biopsy, according to Vinod K. Rustgi, MD.

The recently described pre-screening criteria include a set of patient and disease characteristics that identify who might be at highest risk for non-alcoholic steatohepatitis (NASH) and fibrosis, said Dr. Rustgi, chief of hepatology at Rutgers Robert Wood Johnson Medical School in New Brunswick, N.J.

“Eighty-five percent of the patients who fall into this category will actually have fibrosis on liver biopsy. So it’s a good way to screen out who you want to actually biopsy,” Dr. Rustgi said at the meeting, jointly provided by Rutgers and Global Academy for Medical Education.

Liver biopsy needs to be considered in patients with NAFLD who are at increased risk of having advanced fibrosis, according to the latest practice guidance on diagnosis and management of NAFLD (Hepatology. 2018 Jan;67[1]:328-57).

PHILADELPHIA – When evaluating patients with established non-alcoholic fatty liver disease (NAFLD), using pre-screening criteria may help identify the subset of patients who should be subjected to liver biopsy, according to Vinod K. Rustgi, MD.

The recently described pre-screening criteria include a set of patient and disease characteristics that identify who might be at highest risk for non-alcoholic steatohepatitis (NASH) and fibrosis, said Dr. Rustgi, chief of hepatology at Rutgers Robert Wood Johnson Medical School in New Brunswick, N.J.

“Eighty-five percent of the patients who fall into this category will actually have fibrosis on liver biopsy. So it’s a good way to screen out who you want to actually biopsy,” Dr. Rustgi said at the meeting, jointly provided by Rutgers and Global Academy for Medical Education.

Liver biopsy needs to be considered in patients with NAFLD who are at increased risk of having advanced fibrosis, according to the latest practice guidance on diagnosis and management of NAFLD (Hepatology. 2018 Jan;67[1]:328-57).

Three regular meals a day are best for type 2 diabetes, surgery is more successful for adrenal cortical carcinoma, how thyroid-stimulating hormone affects infertility, and new practice guidelines on testosterone therapy make their debut.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

Three regular meals a day are best for type 2 diabetes, surgery is more successful for adrenal cortical carcinoma, how thyroid-stimulating hormone affects infertility, and new practice guidelines on testosterone therapy make their debut.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

Three regular meals a day are best for type 2 diabetes, surgery is more successful for adrenal cortical carcinoma, how thyroid-stimulating hormone affects infertility, and new practice guidelines on testosterone therapy make their debut.

Listen to the MDedge Daily News podcast for all the details on today’s top news.


 

Thrombectomy is currently approved for use up to 6 hours after symptom onset; the researchers from the Endovascular Therapy Following Imaging Evaluation for the Ischemic Stroke (DEFUSE 3) trial discovered that even 16 hours after symptom onset, the procedure could improve outcomes compared with those of standard medical therapy.

Using automated software to analyze perfusion magnetic resonance imaging or computer tomography scans, the researchers identified patients thought to have salvageable tissue. The patients were randomly assigned to receive endovascular thrombectomy plus standard medical therapy or medical therapy alone.

In the thrombectomy group, 45% of patients achieved functional independence compared with 17% of the control group. Thrombectomy also was associated with improved survival: 14% of the treated group died within 90 days of the study compared with 26% of the control group.

The DEFUSE 3 trial is a large study supported by StrokeNet, a network of hospitals providing research infrastructure for multisite clinical trials, in this case, at 38 centers. The study was ended early because of “overwhelming” evidence of benefit from the clot removal procedure.

“These striking results will have an immediate impact and save people from lifelong disability or death,” said Walter Korshetz, MD, director of the National Institute of Neurological Disorders and Stroke. “I really cannot overstate the size of this effect.” He adds that 1 of 3 stroke patients with at-risk brain tissue improves, and some may walk out of the hospital “saved from what would otherwise have been a devastating brain injury.”

Thrombectomy is currently approved for use up to 6 hours after symptom onset; the researchers from the Endovascular Therapy Following Imaging Evaluation for the Ischemic Stroke (DEFUSE 3) trial discovered that even 16 hours after symptom onset, the procedure could improve outcomes compared with those of standard medical therapy.

Using automated software to analyze perfusion magnetic resonance imaging or computer tomography scans, the researchers identified patients thought to have salvageable tissue. The patients were randomly assigned to receive endovascular thrombectomy plus standard medical therapy or medical therapy alone.

In the thrombectomy group, 45% of patients achieved functional independence compared with 17% of the control group. Thrombectomy also was associated with improved survival: 14% of the treated group died within 90 days of the study compared with 26% of the control group.

The DEFUSE 3 trial is a large study supported by StrokeNet, a network of hospitals providing research infrastructure for multisite clinical trials, in this case, at 38 centers. The study was ended early because of “overwhelming” evidence of benefit from the clot removal procedure.

“These striking results will have an immediate impact and save people from lifelong disability or death,” said Walter Korshetz, MD, director of the National Institute of Neurological Disorders and Stroke. “I really cannot overstate the size of this effect.” He adds that 1 of 3 stroke patients with at-risk brain tissue improves, and some may walk out of the hospital “saved from what would otherwise have been a devastating brain injury.”

Thrombectomy is currently approved for use up to 6 hours after symptom onset; the researchers from the Endovascular Therapy Following Imaging Evaluation for the Ischemic Stroke (DEFUSE 3) trial discovered that even 16 hours after symptom onset, the procedure could improve outcomes compared with those of standard medical therapy.

Using automated software to analyze perfusion magnetic resonance imaging or computer tomography scans, the researchers identified patients thought to have salvageable tissue. The patients were randomly assigned to receive endovascular thrombectomy plus standard medical therapy or medical therapy alone.

In the thrombectomy group, 45% of patients achieved functional independence compared with 17% of the control group. Thrombectomy also was associated with improved survival: 14% of the treated group died within 90 days of the study compared with 26% of the control group.

The DEFUSE 3 trial is a large study supported by StrokeNet, a network of hospitals providing research infrastructure for multisite clinical trials, in this case, at 38 centers. The study was ended early because of “overwhelming” evidence of benefit from the clot removal procedure.

“These striking results will have an immediate impact and save people from lifelong disability or death,” said Walter Korshetz, MD, director of the National Institute of Neurological Disorders and Stroke. “I really cannot overstate the size of this effect.” He adds that 1 of 3 stroke patients with at-risk brain tissue improves, and some may walk out of the hospital “saved from what would otherwise have been a devastating brain injury.”

David Barrett, MD, PhD

Researchers analyzed peripheral blood T cells from 157 pediatric cancer patients at diagnosis and after chemotherapy and found the potential to produce effective chimeric antigen receptor (CAR) T cells declined with each cycle of chemotherapy.

This was also true for acute lymphoblastic leukemia (ALL) and Wilms’ tumor, which had high CAR T-cell manufacturing potential in the pre-chemotherapy samples.

Children younger than 3 years particularly showed a significant decline in CAR T-cell potential with cumulative cycles of chemotherapy.

“Everybody knows that chemotherapy is really bad for your T cells, and the more chemo you get, the less likely you are to have healthy T cells,” David M. Barrett, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania, said at a press preview of research to be presented at the AACR Annual Meeting 2018.

“We know a lot about what a highly active, highly successful CAR T cell looks like right before it goes back into the patient after it’s finished manufacturing,” Dr Barrett added.

But he and his colleagues wanted to determine what goes into producing high-quality cells from a patient and the difference between cells that were good starting material and cells that weren’t.

The investigators analyzed blood samples from pediatric patients with ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms’ tumor, Hodgkin lymphoma, chronic myeloid leukemia, and Ewing sarcoma. The team collected samples at diagnosis and after every cycle of chemotherapy.

Using flow cytometry, they quantified the CD3+ cell population and expanded the T cells using CD3 and CD28 stimulatory beads, “the backbone of pretty much every center’s way to make CAR T cells in the lab,” Dr Barrett said.

And the researchers found poor CAR T-cell manufacturing potential in all tumor types at diagnosis except for ALL and Wilms’ tumor. In standard-risk and high-risk ALL, more than 90% of patients had high-quality T cells at diagnosis.

The team report the findings in abstract 1631, which is scheduled to be presented at the AACR Annual Meeting on April 15.

“This may have played into why pediatric ALL is one of the great successes with CAR T-cell therapy,” Dr Barrett explained. “We may have actually been working with uniquely well-suited, good starting material to build a CAR T cell.”

T cells from lymphoma patients—Burkitt lymphoma, diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and Hodgkin lymphoma—were actually quite poor in their potential to become good CAR T cells, Dr Barrett noted.

“This may be reflected clinically in pediatrics at Children’s Hospital of Philadelphia,” he said. “We’ve only been able to successfully treat 3 children with lymphoma, as opposed to more than 200 children with leukemia.”

The only other type of tumor that seemed to have good CAR T potential was Wilms’ tumor.

“I don’t have a CAR T cell for Wilms’ tumor yet,” Dr Barrett said, “but, if I wanted to make one, I would at least have a degree of confidence that the cells gotten from a patient would at least be able to be successfully made into a highly functional T cell that can go back into a patient.”

The investigators also observed that cumulative chemotherapy alters the metabolic profile in T cells, “gradually turning them by cycle 6 into something that doesn’t work anymore,” Dr Barrett said.

The researchers then looked into what differences there were in the quality of collected T cells and found that metabolic changes varied with tumor and treatment.

T cells with poor CAR T-cell potential were biased toward using glycolysis as their energy source instead of using fatty acids.

“Normal, healthy donor T cells cluster together in terms of metabolic pathways that are active or inactive,” Dr Barrett explained.

“[P]atients who had leukemia and the Wilms’ tumor patients could make successful CAR T cells from those samples. On the other hand, solid tumors and a Hodgkin disease patient look like they have a very different metabolic profile. And that is associated with failure to make a good CAR T cell.”

The investigators were able to get the T cells to shift metabolic pathways by “essentially force-feeding T cells things like fatty acids so they don’t use as much glucose,” Dr Barrett said.

“We’ve had some success in force-feeding them essentially neutral amino acids and others like arginine. And so you can actually potentially provide a T cell with an attractive alternative fuel source.”

Dr Barrett noted that the findings have already altered practice for children at his institution.

They now collect T cells early even if the patient is not eligible for a CAR trial, “simply because we know that cumulative chemotherapy is going to progressively deteriorate the likelihood that those cells will make a functional CAR product, and we’ve been recommending that to other centers,” Dr Barrett said.

“We’re trying to understand what goes into making the best starting material so that we can alter our approaches to make sure that we make a highly functional CAR T-cell product not only for kids with leukemia and CART19, but also potentially for solid tumor CARs as we try to develop those in the future.” 

David Barrett, MD, PhD

Researchers analyzed peripheral blood T cells from 157 pediatric cancer patients at diagnosis and after chemotherapy and found the potential to produce effective chimeric antigen receptor (CAR) T cells declined with each cycle of chemotherapy.

This was also true for acute lymphoblastic leukemia (ALL) and Wilms’ tumor, which had high CAR T-cell manufacturing potential in the pre-chemotherapy samples.

Children younger than 3 years particularly showed a significant decline in CAR T-cell potential with cumulative cycles of chemotherapy.

“Everybody knows that chemotherapy is really bad for your T cells, and the more chemo you get, the less likely you are to have healthy T cells,” David M. Barrett, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania, said at a press preview of research to be presented at the AACR Annual Meeting 2018.

“We know a lot about what a highly active, highly successful CAR T cell looks like right before it goes back into the patient after it’s finished manufacturing,” Dr Barrett added.

But he and his colleagues wanted to determine what goes into producing high-quality cells from a patient and the difference between cells that were good starting material and cells that weren’t.

The investigators analyzed blood samples from pediatric patients with ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms’ tumor, Hodgkin lymphoma, chronic myeloid leukemia, and Ewing sarcoma. The team collected samples at diagnosis and after every cycle of chemotherapy.

Using flow cytometry, they quantified the CD3+ cell population and expanded the T cells using CD3 and CD28 stimulatory beads, “the backbone of pretty much every center’s way to make CAR T cells in the lab,” Dr Barrett said.

And the researchers found poor CAR T-cell manufacturing potential in all tumor types at diagnosis except for ALL and Wilms’ tumor. In standard-risk and high-risk ALL, more than 90% of patients had high-quality T cells at diagnosis.

The team report the findings in abstract 1631, which is scheduled to be presented at the AACR Annual Meeting on April 15.

“This may have played into why pediatric ALL is one of the great successes with CAR T-cell therapy,” Dr Barrett explained. “We may have actually been working with uniquely well-suited, good starting material to build a CAR T cell.”

T cells from lymphoma patients—Burkitt lymphoma, diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and Hodgkin lymphoma—were actually quite poor in their potential to become good CAR T cells, Dr Barrett noted.

“This may be reflected clinically in pediatrics at Children’s Hospital of Philadelphia,” he said. “We’ve only been able to successfully treat 3 children with lymphoma, as opposed to more than 200 children with leukemia.”

The only other type of tumor that seemed to have good CAR T potential was Wilms’ tumor.

“I don’t have a CAR T cell for Wilms’ tumor yet,” Dr Barrett said, “but, if I wanted to make one, I would at least have a degree of confidence that the cells gotten from a patient would at least be able to be successfully made into a highly functional T cell that can go back into a patient.”

The investigators also observed that cumulative chemotherapy alters the metabolic profile in T cells, “gradually turning them by cycle 6 into something that doesn’t work anymore,” Dr Barrett said.

The researchers then looked into what differences there were in the quality of collected T cells and found that metabolic changes varied with tumor and treatment.

T cells with poor CAR T-cell potential were biased toward using glycolysis as their energy source instead of using fatty acids.

“Normal, healthy donor T cells cluster together in terms of metabolic pathways that are active or inactive,” Dr Barrett explained.

“[P]atients who had leukemia and the Wilms’ tumor patients could make successful CAR T cells from those samples. On the other hand, solid tumors and a Hodgkin disease patient look like they have a very different metabolic profile. And that is associated with failure to make a good CAR T cell.”

The investigators were able to get the T cells to shift metabolic pathways by “essentially force-feeding T cells things like fatty acids so they don’t use as much glucose,” Dr Barrett said.

“We’ve had some success in force-feeding them essentially neutral amino acids and others like arginine. And so you can actually potentially provide a T cell with an attractive alternative fuel source.”

Dr Barrett noted that the findings have already altered practice for children at his institution.

They now collect T cells early even if the patient is not eligible for a CAR trial, “simply because we know that cumulative chemotherapy is going to progressively deteriorate the likelihood that those cells will make a functional CAR product, and we’ve been recommending that to other centers,” Dr Barrett said.

“We’re trying to understand what goes into making the best starting material so that we can alter our approaches to make sure that we make a highly functional CAR T-cell product not only for kids with leukemia and CART19, but also potentially for solid tumor CARs as we try to develop those in the future.” 

David Barrett, MD, PhD

Researchers analyzed peripheral blood T cells from 157 pediatric cancer patients at diagnosis and after chemotherapy and found the potential to produce effective chimeric antigen receptor (CAR) T cells declined with each cycle of chemotherapy.

This was also true for acute lymphoblastic leukemia (ALL) and Wilms’ tumor, which had high CAR T-cell manufacturing potential in the pre-chemotherapy samples.

Children younger than 3 years particularly showed a significant decline in CAR T-cell potential with cumulative cycles of chemotherapy.

“Everybody knows that chemotherapy is really bad for your T cells, and the more chemo you get, the less likely you are to have healthy T cells,” David M. Barrett, MD, PhD, of Children’s Hospital of Philadelphia in Pennsylvania, said at a press preview of research to be presented at the AACR Annual Meeting 2018.

“We know a lot about what a highly active, highly successful CAR T cell looks like right before it goes back into the patient after it’s finished manufacturing,” Dr Barrett added.

But he and his colleagues wanted to determine what goes into producing high-quality cells from a patient and the difference between cells that were good starting material and cells that weren’t.

The investigators analyzed blood samples from pediatric patients with ALL, non-Hodgkin lymphoma, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms’ tumor, Hodgkin lymphoma, chronic myeloid leukemia, and Ewing sarcoma. The team collected samples at diagnosis and after every cycle of chemotherapy.

Using flow cytometry, they quantified the CD3+ cell population and expanded the T cells using CD3 and CD28 stimulatory beads, “the backbone of pretty much every center’s way to make CAR T cells in the lab,” Dr Barrett said.

And the researchers found poor CAR T-cell manufacturing potential in all tumor types at diagnosis except for ALL and Wilms’ tumor. In standard-risk and high-risk ALL, more than 90% of patients had high-quality T cells at diagnosis.

The team report the findings in abstract 1631, which is scheduled to be presented at the AACR Annual Meeting on April 15.

“This may have played into why pediatric ALL is one of the great successes with CAR T-cell therapy,” Dr Barrett explained. “We may have actually been working with uniquely well-suited, good starting material to build a CAR T cell.”

T cells from lymphoma patients—Burkitt lymphoma, diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and Hodgkin lymphoma—were actually quite poor in their potential to become good CAR T cells, Dr Barrett noted.

“This may be reflected clinically in pediatrics at Children’s Hospital of Philadelphia,” he said. “We’ve only been able to successfully treat 3 children with lymphoma, as opposed to more than 200 children with leukemia.”

The only other type of tumor that seemed to have good CAR T potential was Wilms’ tumor.

“I don’t have a CAR T cell for Wilms’ tumor yet,” Dr Barrett said, “but, if I wanted to make one, I would at least have a degree of confidence that the cells gotten from a patient would at least be able to be successfully made into a highly functional T cell that can go back into a patient.”

The investigators also observed that cumulative chemotherapy alters the metabolic profile in T cells, “gradually turning them by cycle 6 into something that doesn’t work anymore,” Dr Barrett said.

The researchers then looked into what differences there were in the quality of collected T cells and found that metabolic changes varied with tumor and treatment.

T cells with poor CAR T-cell potential were biased toward using glycolysis as their energy source instead of using fatty acids.

“Normal, healthy donor T cells cluster together in terms of metabolic pathways that are active or inactive,” Dr Barrett explained.

“[P]atients who had leukemia and the Wilms’ tumor patients could make successful CAR T cells from those samples. On the other hand, solid tumors and a Hodgkin disease patient look like they have a very different metabolic profile. And that is associated with failure to make a good CAR T cell.”

The investigators were able to get the T cells to shift metabolic pathways by “essentially force-feeding T cells things like fatty acids so they don’t use as much glucose,” Dr Barrett said.

“We’ve had some success in force-feeding them essentially neutral amino acids and others like arginine. And so you can actually potentially provide a T cell with an attractive alternative fuel source.”

Dr Barrett noted that the findings have already altered practice for children at his institution.

They now collect T cells early even if the patient is not eligible for a CAR trial, “simply because we know that cumulative chemotherapy is going to progressively deteriorate the likelihood that those cells will make a functional CAR product, and we’ve been recommending that to other centers,” Dr Barrett said.

“We’re trying to understand what goes into making the best starting material so that we can alter our approaches to make sure that we make a highly functional CAR T-cell product not only for kids with leukemia and CART19, but also potentially for solid tumor CARs as we try to develop those in the future.” 

CHICAGO – An anti-inflammatory treatment targeting interleukin-1 receptors eased symptoms in hypogonadal men with obesity and metabolic syndrome,according to a study presented at the annual meeting of the Endocrine Society.

The treatment helps patients by targeting testosterone deficiency associated with metabolic syndrome as well as inflammation associated with hypogonadism.

“Antagonism of the interleukin inflammatory pathway led to improved endogenous testosterone production,” said presenter Fahim Ebrahimi, MD, of the University Hospital Basel, Switzerland. “Even with a clinical period so short, only 4 weeks, we have seen reduced blood pressure and increased grip strength.”

A total of 70 men with metabolic syndrome and hypergonadism from the University Hospital in Basel and Kantonsspital Aarau, Switzerland, were included in the randomized, double-blind, placebo-controlled study.

[email protected]

SOURCE: Ebrahimi F. et al. ENDO 2018, Abstract OR15-6.

CHICAGO – An anti-inflammatory treatment targeting interleukin-1 receptors eased symptoms in hypogonadal men with obesity and metabolic syndrome,according to a study presented at the annual meeting of the Endocrine Society.

The treatment helps patients by targeting testosterone deficiency associated with metabolic syndrome as well as inflammation associated with hypogonadism.

“Antagonism of the interleukin inflammatory pathway led to improved endogenous testosterone production,” said presenter Fahim Ebrahimi, MD, of the University Hospital Basel, Switzerland. “Even with a clinical period so short, only 4 weeks, we have seen reduced blood pressure and increased grip strength.”

A total of 70 men with metabolic syndrome and hypergonadism from the University Hospital in Basel and Kantonsspital Aarau, Switzerland, were included in the randomized, double-blind, placebo-controlled study.

[email protected]

SOURCE: Ebrahimi F. et al. ENDO 2018, Abstract OR15-6.

CHICAGO – An anti-inflammatory treatment targeting interleukin-1 receptors eased symptoms in hypogonadal men with obesity and metabolic syndrome,according to a study presented at the annual meeting of the Endocrine Society.

The treatment helps patients by targeting testosterone deficiency associated with metabolic syndrome as well as inflammation associated with hypogonadism.

“Antagonism of the interleukin inflammatory pathway led to improved endogenous testosterone production,” said presenter Fahim Ebrahimi, MD, of the University Hospital Basel, Switzerland. “Even with a clinical period so short, only 4 weeks, we have seen reduced blood pressure and increased grip strength.”

A total of 70 men with metabolic syndrome and hypergonadism from the University Hospital in Basel and Kantonsspital Aarau, Switzerland, were included in the randomized, double-blind, placebo-controlled study.

[email protected]

SOURCE: Ebrahimi F. et al. ENDO 2018, Abstract OR15-6.

CHICAGO – There is no “safe” lower glycemic threshold for pregnant women with diabetes below which adverse maternal and fetal/neonatal outcomes aren’t seen. In particular, “several retrospective studies have shown that the risk for congenital malformations is increased with higher hemoglobin A_1c levels,” said Susan Kirk, MD, speaking at a “Meet the Professor” session at the annual meeting of the Endocrine Society.

However, pointed out Dr. Kirk, fact-based counseling about pregnancy risks for women with type 1 or type 2 diabetes can – and should – occur within the framework of a strong and accepting physician-patient relationship.

Most women with diabetes have received pre-conception counseling about the risks of pregnancy with diabetes and the importance of glycemic control. “Despite that, I think many of us are often surprised by the percentage of unplanned pregnancies,” said Dr. Kirk, of the University of Virginia, Charlottesville, in an interview.

“What I have learned is that the desire to become pregnant is so strong, and the contemplation of all the adverse events that can happen … is really scary, not only to the woman but to her partner as well.”

Dr. Kirk continued, “The more compassion you can show, and the more emphasis that you can place on the fact that she’s most likely to have a healthy baby, the chances are she’ll work with you from the beginning to get her control where she needs to be.”

Target numbers for hemoglobin A_1c have become lower over the past several years, with the American Diabetes Association now recommending pre-conception levels below 6.5%. “There’s no randomized controlled trial that defines what that ideal number should be, but with the passage of time and some larger studies, we now know that ‘as close to normal as possible’ should be the goal,” Dr. Kirk said. This means that if women can tolerate the lower blood glucose levels without serious symptoms of hypoglycemia, a level of less than 6% is more preferable still, she said.

In terms of medication management for women with diabetes who become pregnant, physicians need to think about angiotensin converting enzyme inhibitors and statins, both of which are contraindicated for use during pregnancy. If a patient is pregnant or trying for a pregnancy, “I will stop those, and either leave them off all medicine entirely, or transition them to something that’s safe for use during pregnancy,” said Dr. Kirk.

[email protected]

SOURCE: Kirk S. ENDO 2018, Session M-02-3.

CHICAGO – There is no “safe” lower glycemic threshold for pregnant women with diabetes below which adverse maternal and fetal/neonatal outcomes aren’t seen. In particular, “several retrospective studies have shown that the risk for congenital malformations is increased with higher hemoglobin A_1c levels,” said Susan Kirk, MD, speaking at a “Meet the Professor” session at the annual meeting of the Endocrine Society.

However, pointed out Dr. Kirk, fact-based counseling about pregnancy risks for women with type 1 or type 2 diabetes can – and should – occur within the framework of a strong and accepting physician-patient relationship.

Most women with diabetes have received pre-conception counseling about the risks of pregnancy with diabetes and the importance of glycemic control. “Despite that, I think many of us are often surprised by the percentage of unplanned pregnancies,” said Dr. Kirk, of the University of Virginia, Charlottesville, in an interview.

“What I have learned is that the desire to become pregnant is so strong, and the contemplation of all the adverse events that can happen … is really scary, not only to the woman but to her partner as well.”

Dr. Kirk continued, “The more compassion you can show, and the more emphasis that you can place on the fact that she’s most likely to have a healthy baby, the chances are she’ll work with you from the beginning to get her control where she needs to be.”

Target numbers for hemoglobin A_1c have become lower over the past several years, with the American Diabetes Association now recommending pre-conception levels below 6.5%. “There’s no randomized controlled trial that defines what that ideal number should be, but with the passage of time and some larger studies, we now know that ‘as close to normal as possible’ should be the goal,” Dr. Kirk said. This means that if women can tolerate the lower blood glucose levels without serious symptoms of hypoglycemia, a level of less than 6% is more preferable still, she said.

In terms of medication management for women with diabetes who become pregnant, physicians need to think about angiotensin converting enzyme inhibitors and statins, both of which are contraindicated for use during pregnancy. If a patient is pregnant or trying for a pregnancy, “I will stop those, and either leave them off all medicine entirely, or transition them to something that’s safe for use during pregnancy,” said Dr. Kirk.

[email protected]

SOURCE: Kirk S. ENDO 2018, Session M-02-3.

CHICAGO – There is no “safe” lower glycemic threshold for pregnant women with diabetes below which adverse maternal and fetal/neonatal outcomes aren’t seen. In particular, “several retrospective studies have shown that the risk for congenital malformations is increased with higher hemoglobin A_1c levels,” said Susan Kirk, MD, speaking at a “Meet the Professor” session at the annual meeting of the Endocrine Society.

However, pointed out Dr. Kirk, fact-based counseling about pregnancy risks for women with type 1 or type 2 diabetes can – and should – occur within the framework of a strong and accepting physician-patient relationship.

Most women with diabetes have received pre-conception counseling about the risks of pregnancy with diabetes and the importance of glycemic control. “Despite that, I think many of us are often surprised by the percentage of unplanned pregnancies,” said Dr. Kirk, of the University of Virginia, Charlottesville, in an interview.

“What I have learned is that the desire to become pregnant is so strong, and the contemplation of all the adverse events that can happen … is really scary, not only to the woman but to her partner as well.”

Dr. Kirk continued, “The more compassion you can show, and the more emphasis that you can place on the fact that she’s most likely to have a healthy baby, the chances are she’ll work with you from the beginning to get her control where she needs to be.”

Target numbers for hemoglobin A_1c have become lower over the past several years, with the American Diabetes Association now recommending pre-conception levels below 6.5%. “There’s no randomized controlled trial that defines what that ideal number should be, but with the passage of time and some larger studies, we now know that ‘as close to normal as possible’ should be the goal,” Dr. Kirk said. This means that if women can tolerate the lower blood glucose levels without serious symptoms of hypoglycemia, a level of less than 6% is more preferable still, she said.

In terms of medication management for women with diabetes who become pregnant, physicians need to think about angiotensin converting enzyme inhibitors and statins, both of which are contraindicated for use during pregnancy. If a patient is pregnant or trying for a pregnancy, “I will stop those, and either leave them off all medicine entirely, or transition them to something that’s safe for use during pregnancy,” said Dr. Kirk.

[email protected]

SOURCE: Kirk S. ENDO 2018, Session M-02-3.

CHICAGO – Certain serum microRNA profiles hold promise for postsurgery monitoring of patients with papillary thyroid cancer, according to Francesca Rosignolo, PhD, of the University of Rome.

The usual tool for trying to detect recurrence while following patients with papillary thyroid cancer after surgery has been the serum thyroglobulin assay. However, management of papillary thyroid cancer has become more conservative, involving lobectomy and isthmusectomy on the affected side rather than total gland resection. The benefit of the conservative approach is to avoid complications while maintaining an overall survival rate equivalent to the more extensive approach.

The investigators measured 754 miRNAs in serum samples of 11 patients with papillary thyroid cancer both before and 30 days after surgical thyroidectomy. They re-evaluated major candidate miRNAs using absolute quantitative polymerase chain reaction analysis in an independent cohort of 44 other patients with papillary thyroid cancer or benign nodules or 20 healthy controls, Dr. Rosignolo said at the annual meeting of the Endocrine Society.

The 2 miRNAs most significantly associated with thyroid tumors were then assessed in matched serum samples (before and 30 days, and 1 to 2 years after surgery) from the 20 PTC patients with complete follow-up datasets and results correlated with American Thyroid Association (ATA) responses to therapy.

[email protected]

SOURCE: Rosignolo F et al. J Endo Soc. 2017;1(1)3-13. ENDO 2018, Abstract OR17-1.

CHICAGO – Certain serum microRNA profiles hold promise for postsurgery monitoring of patients with papillary thyroid cancer, according to Francesca Rosignolo, PhD, of the University of Rome.

The usual tool for trying to detect recurrence while following patients with papillary thyroid cancer after surgery has been the serum thyroglobulin assay. However, management of papillary thyroid cancer has become more conservative, involving lobectomy and isthmusectomy on the affected side rather than total gland resection. The benefit of the conservative approach is to avoid complications while maintaining an overall survival rate equivalent to the more extensive approach.

The investigators measured 754 miRNAs in serum samples of 11 patients with papillary thyroid cancer both before and 30 days after surgical thyroidectomy. They re-evaluated major candidate miRNAs using absolute quantitative polymerase chain reaction analysis in an independent cohort of 44 other patients with papillary thyroid cancer or benign nodules or 20 healthy controls, Dr. Rosignolo said at the annual meeting of the Endocrine Society.

The 2 miRNAs most significantly associated with thyroid tumors were then assessed in matched serum samples (before and 30 days, and 1 to 2 years after surgery) from the 20 PTC patients with complete follow-up datasets and results correlated with American Thyroid Association (ATA) responses to therapy.

[email protected]

SOURCE: Rosignolo F et al. J Endo Soc. 2017;1(1)3-13. ENDO 2018, Abstract OR17-1.

CHICAGO – Certain serum microRNA profiles hold promise for postsurgery monitoring of patients with papillary thyroid cancer, according to Francesca Rosignolo, PhD, of the University of Rome.

The usual tool for trying to detect recurrence while following patients with papillary thyroid cancer after surgery has been the serum thyroglobulin assay. However, management of papillary thyroid cancer has become more conservative, involving lobectomy and isthmusectomy on the affected side rather than total gland resection. The benefit of the conservative approach is to avoid complications while maintaining an overall survival rate equivalent to the more extensive approach.

The investigators measured 754 miRNAs in serum samples of 11 patients with papillary thyroid cancer both before and 30 days after surgical thyroidectomy. They re-evaluated major candidate miRNAs using absolute quantitative polymerase chain reaction analysis in an independent cohort of 44 other patients with papillary thyroid cancer or benign nodules or 20 healthy controls, Dr. Rosignolo said at the annual meeting of the Endocrine Society.

The 2 miRNAs most significantly associated with thyroid tumors were then assessed in matched serum samples (before and 30 days, and 1 to 2 years after surgery) from the 20 PTC patients with complete follow-up datasets and results correlated with American Thyroid Association (ATA) responses to therapy.

[email protected]

SOURCE: Rosignolo F et al. J Endo Soc. 2017;1(1)3-13. ENDO 2018, Abstract OR17-1.

ORLANDO – Switching to mepolizumab resulted in a clinically significant benefit and a reduction in exacerbations for patients with severe eosinophilic asthma, according to late-breaking research presented at the joint congress of the American Academy of Allergy, Asthma, and Immunology and the World Asthma Organization.

Frank C. Albers, MD, PhD, of GlaxoSmithKline in Chapel Hill, N.C., and his colleagues examined safety and efficacy outcomes for 145 patients aged 12 years or older with severe eosinophilic asthma (SEA) that was not well-controlled with omalizumab.

“You see similar research in oncology where, if a patient doesn’t respond, you want to try a switch,” Dr. Albers said in an interview. “The key is deciphering which patients would benefit from a switch.”

The researchers discontinued omalizumab at baseline and treated patients with 100 mg of mepolizumab every 4 weeks for 28 weeks and observed patients for 4 more weeks following last treatment. They examined Asthma Control Questionnaire-5 and St. George’s Respiratory Questionnaire results. In a secondary analysis, the researchers also compared their results with placebo-arm data from previously published research.

[email protected]

SOURCE: Albers FC et al. AAAAI/WAO Joint Congress, Posters L29 and L30.


http://www.jacionline.org/article/S0091-6749(17)32864-6/abstract
 

ORLANDO – Switching to mepolizumab resulted in a clinically significant benefit and a reduction in exacerbations for patients with severe eosinophilic asthma, according to late-breaking research presented at the joint congress of the American Academy of Allergy, Asthma, and Immunology and the World Asthma Organization.

Frank C. Albers, MD, PhD, of GlaxoSmithKline in Chapel Hill, N.C., and his colleagues examined safety and efficacy outcomes for 145 patients aged 12 years or older with severe eosinophilic asthma (SEA) that was not well-controlled with omalizumab.

“You see similar research in oncology where, if a patient doesn’t respond, you want to try a switch,” Dr. Albers said in an interview. “The key is deciphering which patients would benefit from a switch.”

The researchers discontinued omalizumab at baseline and treated patients with 100 mg of mepolizumab every 4 weeks for 28 weeks and observed patients for 4 more weeks following last treatment. They examined Asthma Control Questionnaire-5 and St. George’s Respiratory Questionnaire results. In a secondary analysis, the researchers also compared their results with placebo-arm data from previously published research.

[email protected]

SOURCE: Albers FC et al. AAAAI/WAO Joint Congress, Posters L29 and L30.


http://www.jacionline.org/article/S0091-6749(17)32864-6/abstract
 

ORLANDO – Switching to mepolizumab resulted in a clinically significant benefit and a reduction in exacerbations for patients with severe eosinophilic asthma, according to late-breaking research presented at the joint congress of the American Academy of Allergy, Asthma, and Immunology and the World Asthma Organization.

Frank C. Albers, MD, PhD, of GlaxoSmithKline in Chapel Hill, N.C., and his colleagues examined safety and efficacy outcomes for 145 patients aged 12 years or older with severe eosinophilic asthma (SEA) that was not well-controlled with omalizumab.

“You see similar research in oncology where, if a patient doesn’t respond, you want to try a switch,” Dr. Albers said in an interview. “The key is deciphering which patients would benefit from a switch.”

The researchers discontinued omalizumab at baseline and treated patients with 100 mg of mepolizumab every 4 weeks for 28 weeks and observed patients for 4 more weeks following last treatment. They examined Asthma Control Questionnaire-5 and St. George’s Respiratory Questionnaire results. In a secondary analysis, the researchers also compared their results with placebo-arm data from previously published research.

[email protected]

SOURCE: Albers FC et al. AAAAI/WAO Joint Congress, Posters L29 and L30.


http://www.jacionline.org/article/S0091-6749(17)32864-6/abstract
 

PHILADELPHIA – When evaluating potential causes of gastroparesis, cannabis use is a “do not miss” diagnosis that is easy to overlook and likely on the rise, according to Anthony J. Lembo, MD.

“This is not an infrequent problem, and I’ve even missed it a couple of times,” said Dr. Lembo, director of the GI Motility Laboratory at Beth Israel Deaconess Medical Center, Boston.

The rate of U.S. emergency department visits for vomiting with cannabis use disorder rose from 2.3 to 13.3 per 100,000 visits from 2006 to 2013, according to an analysis recently published by Dr. Lembo and colleagues (J Clin Gastroenterol. 2017 Oct 31. doi: 10.1097/MCG.0000000000000944).

The study showed that men between 20 and 29 years were the most common group presenting for vomiting with cannabis use disorder.

“It was only after we managed to hospitalize him because he was losing so much weight that he came out and talked to one of the residents that he was an actually a daily pot smoker,” Dr. Lembo said. “Once we stopped it, the symptoms went away.”

PHILADELPHIA – When evaluating potential causes of gastroparesis, cannabis use is a “do not miss” diagnosis that is easy to overlook and likely on the rise, according to Anthony J. Lembo, MD.

“This is not an infrequent problem, and I’ve even missed it a couple of times,” said Dr. Lembo, director of the GI Motility Laboratory at Beth Israel Deaconess Medical Center, Boston.

The rate of U.S. emergency department visits for vomiting with cannabis use disorder rose from 2.3 to 13.3 per 100,000 visits from 2006 to 2013, according to an analysis recently published by Dr. Lembo and colleagues (J Clin Gastroenterol. 2017 Oct 31. doi: 10.1097/MCG.0000000000000944).

The study showed that men between 20 and 29 years were the most common group presenting for vomiting with cannabis use disorder.

“It was only after we managed to hospitalize him because he was losing so much weight that he came out and talked to one of the residents that he was an actually a daily pot smoker,” Dr. Lembo said. “Once we stopped it, the symptoms went away.”

PHILADELPHIA – When evaluating potential causes of gastroparesis, cannabis use is a “do not miss” diagnosis that is easy to overlook and likely on the rise, according to Anthony J. Lembo, MD.

“This is not an infrequent problem, and I’ve even missed it a couple of times,” said Dr. Lembo, director of the GI Motility Laboratory at Beth Israel Deaconess Medical Center, Boston.

The rate of U.S. emergency department visits for vomiting with cannabis use disorder rose from 2.3 to 13.3 per 100,000 visits from 2006 to 2013, according to an analysis recently published by Dr. Lembo and colleagues (J Clin Gastroenterol. 2017 Oct 31. doi: 10.1097/MCG.0000000000000944).

The study showed that men between 20 and 29 years were the most common group presenting for vomiting with cannabis use disorder.

“It was only after we managed to hospitalize him because he was losing so much weight that he came out and talked to one of the residents that he was an actually a daily pot smoker,” Dr. Lembo said. “Once we stopped it, the symptoms went away.”