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Metabolomics of liquid biopsies offer a comprehensive look at NAFLD
BOSTON – Metabolomics of liquid biopsies noninvasively identified nonalcoholic fatty liver disease (NAFLD) with and without steatosis, and assessed the severity of both steatosis and fibrosis, Puneet Puri, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases.
“These data provide proof of concept that liquid biopsy metabolomics can be used to resolve diagnostic questions in NAFLD management,” said Dr. Puri of Virginia Commonwealth University Medical Center in Richmond.
The researchers first developed a model that distinguished NAFLD patients from controls based on body mass index and the relative plasma concentrations of 11 triglycerides. This model correctly classified patients and controls 90% of the time (area under the receiver operating characteristic curve [AUROC], 0.90; standard deviation, 0.02) in the discovery cohort, and 93% of the time in the validation cohort (AUROC, 0.93; SD, 0.03). The sensitivity of the model was 98% in the discovery cohort and 97% in the validation cohort, and its specificity was 78% in the discovery cohort and 82% in the validation cohort.
The investigators then developed a lipodomic signature to assess the severity of steatosis in NAFLD patients, using magnetic resonance (MR) hepatic fat fraction data as the standard. This lipodomic signature correlated with MR with an r value of 0.81 (P less than .0001).
Next, they evaluated metabolomics for diagnosing nonalcoholic steatohepatitis (NASH). A model that accounted for body mass index (BMI) and the relative concentrations of 20 triglycerides distinguished biopsy-confirmed nonalcoholic fatty liver without steatosis from NASH with an AUROC of 0.95, a sensitivity of 0.83, and a specificity of 0.94 in the discovery cohort. In the validation cohort, the AUROC was 0.84, sensitivity was 79%, and specificity was 92%.
Finally, the researchers developed a way to use metabolomics to evaluate the severity of fibrosis. An algorithm that incorporated 16 variables for phospholipids, triacylglycerols, and nonesterified fatty acids distinguished F0 from F1 through F4 fibrosis with an AUROC of 0.92. Its sensitivity was 90%, and its specificity was 77%. A separate algorithm that incorporated five variables for phospholipids, triacylglycerols, acylcarnitines, sphingolipids, and sterols distinguished F1/F2 fibrosis from F3/F4 fibrosis with an AUROC of 0.89. Its sensitivity was only 62%, but its specificity was 93%.
This proof-of-concept study supports the idea that NAFLD and NASH cause metabolic changes, which in turn alter the circulating metabolome and can be noninvasively measured for diagnostic purposes, Dr. Puri concluded.
Dr. Puri did not list funding sources. He reported having no relevant financial conflicts of interest.
BOSTON – Metabolomics of liquid biopsies noninvasively identified nonalcoholic fatty liver disease (NAFLD) with and without steatosis, and assessed the severity of both steatosis and fibrosis, Puneet Puri, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases.
“These data provide proof of concept that liquid biopsy metabolomics can be used to resolve diagnostic questions in NAFLD management,” said Dr. Puri of Virginia Commonwealth University Medical Center in Richmond.
The researchers first developed a model that distinguished NAFLD patients from controls based on body mass index and the relative plasma concentrations of 11 triglycerides. This model correctly classified patients and controls 90% of the time (area under the receiver operating characteristic curve [AUROC], 0.90; standard deviation, 0.02) in the discovery cohort, and 93% of the time in the validation cohort (AUROC, 0.93; SD, 0.03). The sensitivity of the model was 98% in the discovery cohort and 97% in the validation cohort, and its specificity was 78% in the discovery cohort and 82% in the validation cohort.
The investigators then developed a lipodomic signature to assess the severity of steatosis in NAFLD patients, using magnetic resonance (MR) hepatic fat fraction data as the standard. This lipodomic signature correlated with MR with an r value of 0.81 (P less than .0001).
Next, they evaluated metabolomics for diagnosing nonalcoholic steatohepatitis (NASH). A model that accounted for body mass index (BMI) and the relative concentrations of 20 triglycerides distinguished biopsy-confirmed nonalcoholic fatty liver without steatosis from NASH with an AUROC of 0.95, a sensitivity of 0.83, and a specificity of 0.94 in the discovery cohort. In the validation cohort, the AUROC was 0.84, sensitivity was 79%, and specificity was 92%.
Finally, the researchers developed a way to use metabolomics to evaluate the severity of fibrosis. An algorithm that incorporated 16 variables for phospholipids, triacylglycerols, and nonesterified fatty acids distinguished F0 from F1 through F4 fibrosis with an AUROC of 0.92. Its sensitivity was 90%, and its specificity was 77%. A separate algorithm that incorporated five variables for phospholipids, triacylglycerols, acylcarnitines, sphingolipids, and sterols distinguished F1/F2 fibrosis from F3/F4 fibrosis with an AUROC of 0.89. Its sensitivity was only 62%, but its specificity was 93%.
This proof-of-concept study supports the idea that NAFLD and NASH cause metabolic changes, which in turn alter the circulating metabolome and can be noninvasively measured for diagnostic purposes, Dr. Puri concluded.
Dr. Puri did not list funding sources. He reported having no relevant financial conflicts of interest.
BOSTON – Metabolomics of liquid biopsies noninvasively identified nonalcoholic fatty liver disease (NAFLD) with and without steatosis, and assessed the severity of both steatosis and fibrosis, Puneet Puri, MD, reported at the annual meeting of the American Association for the Study of Liver Diseases.
“These data provide proof of concept that liquid biopsy metabolomics can be used to resolve diagnostic questions in NAFLD management,” said Dr. Puri of Virginia Commonwealth University Medical Center in Richmond.
The researchers first developed a model that distinguished NAFLD patients from controls based on body mass index and the relative plasma concentrations of 11 triglycerides. This model correctly classified patients and controls 90% of the time (area under the receiver operating characteristic curve [AUROC], 0.90; standard deviation, 0.02) in the discovery cohort, and 93% of the time in the validation cohort (AUROC, 0.93; SD, 0.03). The sensitivity of the model was 98% in the discovery cohort and 97% in the validation cohort, and its specificity was 78% in the discovery cohort and 82% in the validation cohort.
The investigators then developed a lipodomic signature to assess the severity of steatosis in NAFLD patients, using magnetic resonance (MR) hepatic fat fraction data as the standard. This lipodomic signature correlated with MR with an r value of 0.81 (P less than .0001).
Next, they evaluated metabolomics for diagnosing nonalcoholic steatohepatitis (NASH). A model that accounted for body mass index (BMI) and the relative concentrations of 20 triglycerides distinguished biopsy-confirmed nonalcoholic fatty liver without steatosis from NASH with an AUROC of 0.95, a sensitivity of 0.83, and a specificity of 0.94 in the discovery cohort. In the validation cohort, the AUROC was 0.84, sensitivity was 79%, and specificity was 92%.
Finally, the researchers developed a way to use metabolomics to evaluate the severity of fibrosis. An algorithm that incorporated 16 variables for phospholipids, triacylglycerols, and nonesterified fatty acids distinguished F0 from F1 through F4 fibrosis with an AUROC of 0.92. Its sensitivity was 90%, and its specificity was 77%. A separate algorithm that incorporated five variables for phospholipids, triacylglycerols, acylcarnitines, sphingolipids, and sterols distinguished F1/F2 fibrosis from F3/F4 fibrosis with an AUROC of 0.89. Its sensitivity was only 62%, but its specificity was 93%.
This proof-of-concept study supports the idea that NAFLD and NASH cause metabolic changes, which in turn alter the circulating metabolome and can be noninvasively measured for diagnostic purposes, Dr. Puri concluded.
Dr. Puri did not list funding sources. He reported having no relevant financial conflicts of interest.
AT THE LIVER MEETING 2016
Key clinical point: Metabolomics of liquid biopsies identified and characterized nonalcoholic fatty liver disease in a proof-of-concept study.
Major finding: Four distinct models diagnosed NAFLD, diagnosed NASH, and characterized the severity of steatosis and fibrosis.
Data source: A multicenter study of 817 patients with biopsy-confirmed NAFLD and 130 biopsy-confirmed controls.
Disclosures: Dr. Puri did not list funding sources. He reported having no relevant financial conflicts of interest.
VIDEO: Denosumab trumps risedronate in bone building for glucocorticoid-induced osteoporosis
WASHINGTON – Denosumab built significantly more bone at the hip and lumbar spine than did risedronate when given for 1 year to patients with glucocorticoid-induced osteoporosis in an ongoing 2-year, head-to-head, randomized trial.
Denosumab (Prolia) is currently approved for the treatment of postmenopausal osteoporosis, and it performed so well in the trial that it could be put forward for the indication of glucocorticoid-induced osteoporosis as well, Kenneth Saag, MD, said at the annual meeting of the American College of Rheumatology.
“I would say there is definitely potential for this as a new therapeutic option for these patients,” he said in a video interview about the trial’s primary outcome of denosumab’s noninferiority to risedronate in percentage change in bone mineral density (BMD) at the lumbar spine after 1 year and secondary outcomes of the superiority of denosumab over risedronate in total hip and lumbar spine BMD at 1 year.
Denosumab is a particularly intriguing treatment option for patients with glucocorticoid-induced osteoporosis. They experience a double hit on bone health: increased RANKL, a protein that stimulates osteoclast development, and decreased osteoprotegerin, a protein that inhibits osteoclasts. Denosumab is a RANKL-inhibitor and, as such, tamps down on osteoclastic bone remodeling, said Dr. Saag, vice chair of the department of medicine and director of the Center for Education and Research on Therapeutics at the University of Alabama at Birmingham.
The phase III trial comprised 795 patients who were taking corticosteroids for a variety of rheumatic diseases, including rheumatoid arthritis, polymyalgia rheumatica, and systemic lupus erythematosus, and randomized them to denosumab or risedronate, which is already FDA approved for glucocorticoid-induced bone loss. Patients were randomized to 24 months of subcutaneous denosumab 60 mg given every 6 months or oral risedronate 5-mg daily. The study is still ongoing to test secondary outcomes at 24 months.
The patients were split into those who were continuing glucocorticoid therapy (505) and those who were just initiating it (290). Patients’ mean age ranged from 61 to 67 years, with the glucocorticoid-initiating group (GC-I) being somewhat older. The mean daily prednisone-equivalent dose was 16 mg in that group and 12 mg in the glucocorticoid-continuing group (GC-C). The mean BMD T-scores in the GC-C group were –1.96 at the lumbar spine and –1.56 at the total hip. In the GC-I group, BMD T-scores were –1.06 at the lumbar spine and –0.98 at the total hip.
In the GC-C group, denosumab increased BMD significantly more than risedronate at both spine and hip. At the lumbar spine, denosumab was associated with a mean increase of 4.4% over baseline, compared with a 2.3% increase with risedronate. Total hip BMD increased 2.1% with denosumab and 0.6% with risedronate.
The results were similar in the GC-I group. Denosumab increased lumbar spine BMD by 3.8% over baseline, compared with an increase of 0.8% with risedronate. Total hip BMD increased 1.7% with denosumab and 0.2% with risedronate.
Denosumab was also associated with significantly greater increases in femoral neck BMD in both groups, Dr. Saag noted. There were no significant differences in markers of bone turnover between the treatment groups. Adverse events, including pneumonia, diverticulitis, and bronchitis, were similar.
Amgen, manufacturer of denosumab, is sponsoring the 24-month study. Dr. Saag has been a consultant for Amgen. One coauthor is an employee of Amgen, and others disclosed financial relationships with Amgen and other pharmaceutical companies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @alz_gal
WASHINGTON – Denosumab built significantly more bone at the hip and lumbar spine than did risedronate when given for 1 year to patients with glucocorticoid-induced osteoporosis in an ongoing 2-year, head-to-head, randomized trial.
Denosumab (Prolia) is currently approved for the treatment of postmenopausal osteoporosis, and it performed so well in the trial that it could be put forward for the indication of glucocorticoid-induced osteoporosis as well, Kenneth Saag, MD, said at the annual meeting of the American College of Rheumatology.
“I would say there is definitely potential for this as a new therapeutic option for these patients,” he said in a video interview about the trial’s primary outcome of denosumab’s noninferiority to risedronate in percentage change in bone mineral density (BMD) at the lumbar spine after 1 year and secondary outcomes of the superiority of denosumab over risedronate in total hip and lumbar spine BMD at 1 year.
Denosumab is a particularly intriguing treatment option for patients with glucocorticoid-induced osteoporosis. They experience a double hit on bone health: increased RANKL, a protein that stimulates osteoclast development, and decreased osteoprotegerin, a protein that inhibits osteoclasts. Denosumab is a RANKL-inhibitor and, as such, tamps down on osteoclastic bone remodeling, said Dr. Saag, vice chair of the department of medicine and director of the Center for Education and Research on Therapeutics at the University of Alabama at Birmingham.
The phase III trial comprised 795 patients who were taking corticosteroids for a variety of rheumatic diseases, including rheumatoid arthritis, polymyalgia rheumatica, and systemic lupus erythematosus, and randomized them to denosumab or risedronate, which is already FDA approved for glucocorticoid-induced bone loss. Patients were randomized to 24 months of subcutaneous denosumab 60 mg given every 6 months or oral risedronate 5-mg daily. The study is still ongoing to test secondary outcomes at 24 months.
The patients were split into those who were continuing glucocorticoid therapy (505) and those who were just initiating it (290). Patients’ mean age ranged from 61 to 67 years, with the glucocorticoid-initiating group (GC-I) being somewhat older. The mean daily prednisone-equivalent dose was 16 mg in that group and 12 mg in the glucocorticoid-continuing group (GC-C). The mean BMD T-scores in the GC-C group were –1.96 at the lumbar spine and –1.56 at the total hip. In the GC-I group, BMD T-scores were –1.06 at the lumbar spine and –0.98 at the total hip.
In the GC-C group, denosumab increased BMD significantly more than risedronate at both spine and hip. At the lumbar spine, denosumab was associated with a mean increase of 4.4% over baseline, compared with a 2.3% increase with risedronate. Total hip BMD increased 2.1% with denosumab and 0.6% with risedronate.
The results were similar in the GC-I group. Denosumab increased lumbar spine BMD by 3.8% over baseline, compared with an increase of 0.8% with risedronate. Total hip BMD increased 1.7% with denosumab and 0.2% with risedronate.
Denosumab was also associated with significantly greater increases in femoral neck BMD in both groups, Dr. Saag noted. There were no significant differences in markers of bone turnover between the treatment groups. Adverse events, including pneumonia, diverticulitis, and bronchitis, were similar.
Amgen, manufacturer of denosumab, is sponsoring the 24-month study. Dr. Saag has been a consultant for Amgen. One coauthor is an employee of Amgen, and others disclosed financial relationships with Amgen and other pharmaceutical companies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @alz_gal
WASHINGTON – Denosumab built significantly more bone at the hip and lumbar spine than did risedronate when given for 1 year to patients with glucocorticoid-induced osteoporosis in an ongoing 2-year, head-to-head, randomized trial.
Denosumab (Prolia) is currently approved for the treatment of postmenopausal osteoporosis, and it performed so well in the trial that it could be put forward for the indication of glucocorticoid-induced osteoporosis as well, Kenneth Saag, MD, said at the annual meeting of the American College of Rheumatology.
“I would say there is definitely potential for this as a new therapeutic option for these patients,” he said in a video interview about the trial’s primary outcome of denosumab’s noninferiority to risedronate in percentage change in bone mineral density (BMD) at the lumbar spine after 1 year and secondary outcomes of the superiority of denosumab over risedronate in total hip and lumbar spine BMD at 1 year.
Denosumab is a particularly intriguing treatment option for patients with glucocorticoid-induced osteoporosis. They experience a double hit on bone health: increased RANKL, a protein that stimulates osteoclast development, and decreased osteoprotegerin, a protein that inhibits osteoclasts. Denosumab is a RANKL-inhibitor and, as such, tamps down on osteoclastic bone remodeling, said Dr. Saag, vice chair of the department of medicine and director of the Center for Education and Research on Therapeutics at the University of Alabama at Birmingham.
The phase III trial comprised 795 patients who were taking corticosteroids for a variety of rheumatic diseases, including rheumatoid arthritis, polymyalgia rheumatica, and systemic lupus erythematosus, and randomized them to denosumab or risedronate, which is already FDA approved for glucocorticoid-induced bone loss. Patients were randomized to 24 months of subcutaneous denosumab 60 mg given every 6 months or oral risedronate 5-mg daily. The study is still ongoing to test secondary outcomes at 24 months.
The patients were split into those who were continuing glucocorticoid therapy (505) and those who were just initiating it (290). Patients’ mean age ranged from 61 to 67 years, with the glucocorticoid-initiating group (GC-I) being somewhat older. The mean daily prednisone-equivalent dose was 16 mg in that group and 12 mg in the glucocorticoid-continuing group (GC-C). The mean BMD T-scores in the GC-C group were –1.96 at the lumbar spine and –1.56 at the total hip. In the GC-I group, BMD T-scores were –1.06 at the lumbar spine and –0.98 at the total hip.
In the GC-C group, denosumab increased BMD significantly more than risedronate at both spine and hip. At the lumbar spine, denosumab was associated with a mean increase of 4.4% over baseline, compared with a 2.3% increase with risedronate. Total hip BMD increased 2.1% with denosumab and 0.6% with risedronate.
The results were similar in the GC-I group. Denosumab increased lumbar spine BMD by 3.8% over baseline, compared with an increase of 0.8% with risedronate. Total hip BMD increased 1.7% with denosumab and 0.2% with risedronate.
Denosumab was also associated with significantly greater increases in femoral neck BMD in both groups, Dr. Saag noted. There were no significant differences in markers of bone turnover between the treatment groups. Adverse events, including pneumonia, diverticulitis, and bronchitis, were similar.
Amgen, manufacturer of denosumab, is sponsoring the 24-month study. Dr. Saag has been a consultant for Amgen. One coauthor is an employee of Amgen, and others disclosed financial relationships with Amgen and other pharmaceutical companies.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
[email protected]
On Twitter @alz_gal
AT THE ACR ANNUAL MEETING
Key clinical point:
Major finding: In patients on continuous glucocorticoid therapy, denosumab increased BMD by 4.4% at the lumbar spine and 2.1% at the total hip, compared with increases of 2.3% and 0.6% with risedronate.
Data source: 12-month results of the 24-month, phase III study of 795 patients.
Disclosures: Amgen sponsored the study. Dr. Saag has been a consultant for the company. One coauthor is an employee of Amgen, and others disclosed financial relationships with Amgen and other pharmaceutical companies.
Study shows NJ tube and PEG-J on par for enteral nutrition, but each has complications
CORONADO, CALIF. – Percutaneous gastrostomy with jejunal extension (PEG-J) is an appealing and effective method for delivery of enteral nutrition in necrotizing pancreatitis patients, without the mechanical issues and discomfort associated with nasojejunal (NJ) tube, results from a single-center retrospective study showed.
“The advantages of PEG-J route for enteral nutrition in necrotizing pancreatitis patients must be weighed carefully against the potentially severe complication profile,” study author Alexandra M. Roch, MD, said at the annual meeting of the Western Surgical Association.
Historically, the preferred way to manage patients with necrotizing pancreatitis was via parenteral nutrition with a lack of pancreatic stimulation, said Dr. Roch, of the department of surgery at Indiana University, Indianapolis. However, parenteral nutrition is associated with increased permeability, a lack of peristaltic stimulation, changes in intestinal flora, and an increased risk of infection.
“More recently, enteral nutrition has been used, despite a potential for pancreatic stimulation,” she said. “From 16 randomized, controlled trials with 847 patients, it was associated with decreased mortality, decreased infectious complications, decreased length of hospital stay, and a trend toward decreased rate of organ failure. Based on those findings, enteral nutrition has become the standard of care in acute pancreatitis. The optimal enteral nutrition route, however, is still debated. The traditional route is the nasojejunal [NJ] tube. Its placement is noninvasive, but it is associated with discomfort for the patient, dislodgement in 16%-63% of cases, and potentially sinusitis. Conversely, percutaneous gastrostomy with jejunal extension [PEG-J] is beneficial for patient comfort but has the drawbacks of being an invasive procedure with the risk of cellulitis and more severe complications.”
The aim of the current study was to compare the safety and efficacy of NJ tube and PEG-J enteral nutrition delivery before surgical debridement in patients with necrotizing pancreatitis. Dr. Roch and her associates hypothesized that NJ tube and PEG-J would have a similar complication profile. They retrospectively reviewed the medical records of all patients who underwent surgical debridement for necrotizing pancreatitis at Indiana University Medical Center between 2005 and 2015. Patients with exclusive total parenteral nutrition were excluded from the study, as were those who had incomplete data.
Dr. Roch reported results from 242 patients with a mean age of 54 years. More than half (64%) were men and the main etiology was biliary (47%), followed by alcohol (16%). The median duration of preoperative enteral nutrition was 29 days. Of the 242 patients, 187 had an NJ tube only, 25 had PEG-J only, and 30 patients had an NJ tube followed by PEG-J. More than half of PEG-Js were placed under fluoroscopic guidance, while the remaining 41% were placed endoscopically.
In terms of safety, patients in the NJ tube group had a significantly higher rate of all complications, compared with those in the PEG-J group (52% vs. 27%, respectively; P = .0015). Conversely, there was a significantly higher rate of serious complications among patients in the PEG-J group, compared with the NJ group (11% vs. 0%; P less than .0001). The researchers also found that compared with patients in the PEG-J group, those in the NJ group were more prone to mechanical complications such as difficulty to place (5% vs. 0%, respectively), replacement (30% vs. 5.5%), and repositioning (30% vs. 2%), while PEG-J patients were more prone to infectious complications such as skin infections/cellulitis (4% vs. 0%) and perforation/leakage/peritonitis (11% vs. 0%). When they limited the analysis to grade III or IV complications, the mechanism was always the same: early dislodgement from the GI tract. “The presentation ranged from asymptomatic patients to severe peritonitis,” Dr. Roch said. “Two patients out of the six with severe complications required emergent laparotomy.”
In terms of efficacy, the NJ and PEG-J groups were equivalent in achieving enteral nutrition (67% vs. 68%, respectively). There were also no differences between the two groups in nutritional status when assessed by an increase of serum albumin (38% vs. 36%; P = .87), normalization of serum albumin (9% vs. 16%; P = .14), or in the prevalence of infected necrosis (53% vs. 49%; P = .64).
Dr. Roch acknowledged certain limitations of the study, including its single-center, retrospective design. “Furthermore, we are a tertiary care center, and most patients are referred to us late in the course of their disease,” she said. “Finally, no PEG-Js were placed outside of our institution, raising the question of a selection bias. She reported having no financial disclosures.
CORONADO, CALIF. – Percutaneous gastrostomy with jejunal extension (PEG-J) is an appealing and effective method for delivery of enteral nutrition in necrotizing pancreatitis patients, without the mechanical issues and discomfort associated with nasojejunal (NJ) tube, results from a single-center retrospective study showed.
“The advantages of PEG-J route for enteral nutrition in necrotizing pancreatitis patients must be weighed carefully against the potentially severe complication profile,” study author Alexandra M. Roch, MD, said at the annual meeting of the Western Surgical Association.
Historically, the preferred way to manage patients with necrotizing pancreatitis was via parenteral nutrition with a lack of pancreatic stimulation, said Dr. Roch, of the department of surgery at Indiana University, Indianapolis. However, parenteral nutrition is associated with increased permeability, a lack of peristaltic stimulation, changes in intestinal flora, and an increased risk of infection.
“More recently, enteral nutrition has been used, despite a potential for pancreatic stimulation,” she said. “From 16 randomized, controlled trials with 847 patients, it was associated with decreased mortality, decreased infectious complications, decreased length of hospital stay, and a trend toward decreased rate of organ failure. Based on those findings, enteral nutrition has become the standard of care in acute pancreatitis. The optimal enteral nutrition route, however, is still debated. The traditional route is the nasojejunal [NJ] tube. Its placement is noninvasive, but it is associated with discomfort for the patient, dislodgement in 16%-63% of cases, and potentially sinusitis. Conversely, percutaneous gastrostomy with jejunal extension [PEG-J] is beneficial for patient comfort but has the drawbacks of being an invasive procedure with the risk of cellulitis and more severe complications.”
The aim of the current study was to compare the safety and efficacy of NJ tube and PEG-J enteral nutrition delivery before surgical debridement in patients with necrotizing pancreatitis. Dr. Roch and her associates hypothesized that NJ tube and PEG-J would have a similar complication profile. They retrospectively reviewed the medical records of all patients who underwent surgical debridement for necrotizing pancreatitis at Indiana University Medical Center between 2005 and 2015. Patients with exclusive total parenteral nutrition were excluded from the study, as were those who had incomplete data.
Dr. Roch reported results from 242 patients with a mean age of 54 years. More than half (64%) were men and the main etiology was biliary (47%), followed by alcohol (16%). The median duration of preoperative enteral nutrition was 29 days. Of the 242 patients, 187 had an NJ tube only, 25 had PEG-J only, and 30 patients had an NJ tube followed by PEG-J. More than half of PEG-Js were placed under fluoroscopic guidance, while the remaining 41% were placed endoscopically.
In terms of safety, patients in the NJ tube group had a significantly higher rate of all complications, compared with those in the PEG-J group (52% vs. 27%, respectively; P = .0015). Conversely, there was a significantly higher rate of serious complications among patients in the PEG-J group, compared with the NJ group (11% vs. 0%; P less than .0001). The researchers also found that compared with patients in the PEG-J group, those in the NJ group were more prone to mechanical complications such as difficulty to place (5% vs. 0%, respectively), replacement (30% vs. 5.5%), and repositioning (30% vs. 2%), while PEG-J patients were more prone to infectious complications such as skin infections/cellulitis (4% vs. 0%) and perforation/leakage/peritonitis (11% vs. 0%). When they limited the analysis to grade III or IV complications, the mechanism was always the same: early dislodgement from the GI tract. “The presentation ranged from asymptomatic patients to severe peritonitis,” Dr. Roch said. “Two patients out of the six with severe complications required emergent laparotomy.”
In terms of efficacy, the NJ and PEG-J groups were equivalent in achieving enteral nutrition (67% vs. 68%, respectively). There were also no differences between the two groups in nutritional status when assessed by an increase of serum albumin (38% vs. 36%; P = .87), normalization of serum albumin (9% vs. 16%; P = .14), or in the prevalence of infected necrosis (53% vs. 49%; P = .64).
Dr. Roch acknowledged certain limitations of the study, including its single-center, retrospective design. “Furthermore, we are a tertiary care center, and most patients are referred to us late in the course of their disease,” she said. “Finally, no PEG-Js were placed outside of our institution, raising the question of a selection bias. She reported having no financial disclosures.
CORONADO, CALIF. – Percutaneous gastrostomy with jejunal extension (PEG-J) is an appealing and effective method for delivery of enteral nutrition in necrotizing pancreatitis patients, without the mechanical issues and discomfort associated with nasojejunal (NJ) tube, results from a single-center retrospective study showed.
“The advantages of PEG-J route for enteral nutrition in necrotizing pancreatitis patients must be weighed carefully against the potentially severe complication profile,” study author Alexandra M. Roch, MD, said at the annual meeting of the Western Surgical Association.
Historically, the preferred way to manage patients with necrotizing pancreatitis was via parenteral nutrition with a lack of pancreatic stimulation, said Dr. Roch, of the department of surgery at Indiana University, Indianapolis. However, parenteral nutrition is associated with increased permeability, a lack of peristaltic stimulation, changes in intestinal flora, and an increased risk of infection.
“More recently, enteral nutrition has been used, despite a potential for pancreatic stimulation,” she said. “From 16 randomized, controlled trials with 847 patients, it was associated with decreased mortality, decreased infectious complications, decreased length of hospital stay, and a trend toward decreased rate of organ failure. Based on those findings, enteral nutrition has become the standard of care in acute pancreatitis. The optimal enteral nutrition route, however, is still debated. The traditional route is the nasojejunal [NJ] tube. Its placement is noninvasive, but it is associated with discomfort for the patient, dislodgement in 16%-63% of cases, and potentially sinusitis. Conversely, percutaneous gastrostomy with jejunal extension [PEG-J] is beneficial for patient comfort but has the drawbacks of being an invasive procedure with the risk of cellulitis and more severe complications.”
The aim of the current study was to compare the safety and efficacy of NJ tube and PEG-J enteral nutrition delivery before surgical debridement in patients with necrotizing pancreatitis. Dr. Roch and her associates hypothesized that NJ tube and PEG-J would have a similar complication profile. They retrospectively reviewed the medical records of all patients who underwent surgical debridement for necrotizing pancreatitis at Indiana University Medical Center between 2005 and 2015. Patients with exclusive total parenteral nutrition were excluded from the study, as were those who had incomplete data.
Dr. Roch reported results from 242 patients with a mean age of 54 years. More than half (64%) were men and the main etiology was biliary (47%), followed by alcohol (16%). The median duration of preoperative enteral nutrition was 29 days. Of the 242 patients, 187 had an NJ tube only, 25 had PEG-J only, and 30 patients had an NJ tube followed by PEG-J. More than half of PEG-Js were placed under fluoroscopic guidance, while the remaining 41% were placed endoscopically.
In terms of safety, patients in the NJ tube group had a significantly higher rate of all complications, compared with those in the PEG-J group (52% vs. 27%, respectively; P = .0015). Conversely, there was a significantly higher rate of serious complications among patients in the PEG-J group, compared with the NJ group (11% vs. 0%; P less than .0001). The researchers also found that compared with patients in the PEG-J group, those in the NJ group were more prone to mechanical complications such as difficulty to place (5% vs. 0%, respectively), replacement (30% vs. 5.5%), and repositioning (30% vs. 2%), while PEG-J patients were more prone to infectious complications such as skin infections/cellulitis (4% vs. 0%) and perforation/leakage/peritonitis (11% vs. 0%). When they limited the analysis to grade III or IV complications, the mechanism was always the same: early dislodgement from the GI tract. “The presentation ranged from asymptomatic patients to severe peritonitis,” Dr. Roch said. “Two patients out of the six with severe complications required emergent laparotomy.”
In terms of efficacy, the NJ and PEG-J groups were equivalent in achieving enteral nutrition (67% vs. 68%, respectively). There were also no differences between the two groups in nutritional status when assessed by an increase of serum albumin (38% vs. 36%; P = .87), normalization of serum albumin (9% vs. 16%; P = .14), or in the prevalence of infected necrosis (53% vs. 49%; P = .64).
Dr. Roch acknowledged certain limitations of the study, including its single-center, retrospective design. “Furthermore, we are a tertiary care center, and most patients are referred to us late in the course of their disease,” she said. “Finally, no PEG-Js were placed outside of our institution, raising the question of a selection bias. She reported having no financial disclosures.
AT WSA 2016
Key clinical point:
Major finding: In terms of efficacy, the NJ and PEG-J groups were equivalent in achieving enteral nutrition (67% vs. 68%, respectively).
Data source: A retrospective review of 242 patients who underwent surgical debridement for necrotizing pancreatitis at Indiana University Medical Center between 2005 and 2015.
Disclosures: Dr. Roch reported having no financial disclosures.
DBS and Optimal Therapy May Have Long-Term Benefit in Early Parkinson’s Disease
BALTIMORE—Deep brain stimulation (DBS) of the subthalamic nucleus, along with optimal drug therapy (ODT), produces clinically meaningful improvements in clinician-assessed motor control for at least five years in patients with early-stage Parkinson’s disease, according to a prospective pilot study. If the findings are confirmed in a phase III trial that has been approved, DBS may become a valuable method to achieve long-term improvement in motor skills in patients with Parkinson’s disease.
Mallory Hacker, PhD, Research Assistant Professor of Neurology at Vanderbilt University in Nashville, presented the latest results of a subanalysis of a randomized, controlled, single-blind clinical trial at the 141st Annual Meeting of the American Neurological Association. 
The pilot trial included 30 patients with Parkinson’s disease between ages 50 and 75 and demonstrated the safety and benefit of DBS in conjunction with ODT—which includes drugs such as carbidopa–levodopa, pramipexole, ropinirole, and selegiline—compared with ODT alone in improving motor scores of the patients through two years. The latest subanalysis of the trial data examined the effect of DBS for at least five years.
The subanalysis included 28 patients: 14 in the DBS and ODT group and 14 in the ODT-only group. Both groups were predominantly male and were similar in age (about 61) at baseline. Motor control was assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III (clinician assessed) and the Hoehn and Yahr scale.
Over the five-year period, mean UPDRS motor scores progressively worsened for the ODT group, but improved for patients who received DBS. Compared with patients who received ODT only, patients who received DBS plus ODT had UPDRS improvements of 4.6 points at 1.5 years, 5.8 points at two years, 8.9 points at four years, and 10.1 points at five years.
“These results demonstrate that subthalamic nucleus DBS applied in early-stage Parkinson’s disease may provide long-term, clinically meaningful improvement in motor function over standard clinical therapy,” Dr. Hacker said.
The exact mechanism of DBS is still unknown, but evidence suggests that synaptic plasticity is involved. Results from the pilot trial led to FDA approval of a large-scale, multicenter clinical trial. Participants will be implanted with a DBS device and will receive ODT. Some subjects will be randomized to receive DBS during the first two years, along with ODT, and the remainder will receive ODT only. In the following two years, all subjects will receive DBS and ODT.
—Brian Hoyle
BALTIMORE—Deep brain stimulation (DBS) of the subthalamic nucleus, along with optimal drug therapy (ODT), produces clinically meaningful improvements in clinician-assessed motor control for at least five years in patients with early-stage Parkinson’s disease, according to a prospective pilot study. If the findings are confirmed in a phase III trial that has been approved, DBS may become a valuable method to achieve long-term improvement in motor skills in patients with Parkinson’s disease.
Mallory Hacker, PhD, Research Assistant Professor of Neurology at Vanderbilt University in Nashville, presented the latest results of a subanalysis of a randomized, controlled, single-blind clinical trial at the 141st Annual Meeting of the American Neurological Association.
The pilot trial included 30 patients with Parkinson’s disease between ages 50 and 75 and demonstrated the safety and benefit of DBS in conjunction with ODT—which includes drugs such as carbidopa–levodopa, pramipexole, ropinirole, and selegiline—compared with ODT alone in improving motor scores of the patients through two years. The latest subanalysis of the trial data examined the effect of DBS for at least five years.
The subanalysis included 28 patients: 14 in the DBS and ODT group and 14 in the ODT-only group. Both groups were predominantly male and were similar in age (about 61) at baseline. Motor control was assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III (clinician assessed) and the Hoehn and Yahr scale.
Over the five-year period, mean UPDRS motor scores progressively worsened for the ODT group, but improved for patients who received DBS. Compared with patients who received ODT only, patients who received DBS plus ODT had UPDRS improvements of 4.6 points at 1.5 years, 5.8 points at two years, 8.9 points at four years, and 10.1 points at five years.
“These results demonstrate that subthalamic nucleus DBS applied in early-stage Parkinson’s disease may provide long-term, clinically meaningful improvement in motor function over standard clinical therapy,” Dr. Hacker said.
The exact mechanism of DBS is still unknown, but evidence suggests that synaptic plasticity is involved. Results from the pilot trial led to FDA approval of a large-scale, multicenter clinical trial. Participants will be implanted with a DBS device and will receive ODT. Some subjects will be randomized to receive DBS during the first two years, along with ODT, and the remainder will receive ODT only. In the following two years, all subjects will receive DBS and ODT.
—Brian Hoyle
BALTIMORE—Deep brain stimulation (DBS) of the subthalamic nucleus, along with optimal drug therapy (ODT), produces clinically meaningful improvements in clinician-assessed motor control for at least five years in patients with early-stage Parkinson’s disease, according to a prospective pilot study. If the findings are confirmed in a phase III trial that has been approved, DBS may become a valuable method to achieve long-term improvement in motor skills in patients with Parkinson’s disease.
Mallory Hacker, PhD, Research Assistant Professor of Neurology at Vanderbilt University in Nashville, presented the latest results of a subanalysis of a randomized, controlled, single-blind clinical trial at the 141st Annual Meeting of the American Neurological Association.
The pilot trial included 30 patients with Parkinson’s disease between ages 50 and 75 and demonstrated the safety and benefit of DBS in conjunction with ODT—which includes drugs such as carbidopa–levodopa, pramipexole, ropinirole, and selegiline—compared with ODT alone in improving motor scores of the patients through two years. The latest subanalysis of the trial data examined the effect of DBS for at least five years.
The subanalysis included 28 patients: 14 in the DBS and ODT group and 14 in the ODT-only group. Both groups were predominantly male and were similar in age (about 61) at baseline. Motor control was assessed using the Unified Parkinson’s Disease Rating Scale (UPDRS) Part III (clinician assessed) and the Hoehn and Yahr scale.
Over the five-year period, mean UPDRS motor scores progressively worsened for the ODT group, but improved for patients who received DBS. Compared with patients who received ODT only, patients who received DBS plus ODT had UPDRS improvements of 4.6 points at 1.5 years, 5.8 points at two years, 8.9 points at four years, and 10.1 points at five years.
“These results demonstrate that subthalamic nucleus DBS applied in early-stage Parkinson’s disease may provide long-term, clinically meaningful improvement in motor function over standard clinical therapy,” Dr. Hacker said.
The exact mechanism of DBS is still unknown, but evidence suggests that synaptic plasticity is involved. Results from the pilot trial led to FDA approval of a large-scale, multicenter clinical trial. Participants will be implanted with a DBS device and will receive ODT. Some subjects will be randomized to receive DBS during the first two years, along with ODT, and the remainder will receive ODT only. In the following two years, all subjects will receive DBS and ODT.
—Brian Hoyle
PINK1 Mutation Raises Risk of Early-Onset Parkinson’s Disease
The rare p.G411S mutation of PINK1 greatly increases the risk of early-onset Parkinson’s disease, even if present in only one allele, according to a genetic association study published online ahead of print November 2 in Brain. By reducing kinase activity towards ubiquitin, the mutation impairs the elimination of damaged mitochondria from cells.
Previous data had indicated that mutations in both PINK1 alleles confer a risk of early-onset Parkinson’s disease (age younger than 45). Genetic studies had suggested that a single mutated PINK1 allele also might increase the risk of developing the disease.
Wolfdieter Springer, PhD, Associate Professor of Neuroscience at Mayo Clinic in Jacksonville, Florida, and colleagues examined DNA samples from 2,560 patients with Parkinson’s disease and 2,145 controls from the United States, Poland, Norway, Ireland, and Sweden. Patients were included in the study irrespective of age at disease onset. The controls included the patients’ spouses and caregivers, as well as unrelated individuals. Dr. Springer and colleagues also searched the literature for previous studies that identified or excluded PINK1 p.G411S mutations in cases of Parkinson’s disease and controls. 
The investigators found PINK1 p.G411S substitution in 19 cases (0.74%) and five control subjects (0.23%), indicating a significant association with an intermediate effect size between heterozygous PINK1 p.G411S carrier status and Parkinson’s disease (odds ratio [OR], 2.92). The median age at disease onset was significantly lower in the 19 cases carrying PINK1 p.G411S than in noncarrier cases (59 vs 64). When the researchers combined their data with those of six studies that they had identified in the literature review, the increased risk of Parkinson’s disease associated with the p.G411S mutation remained evident (OR, 2.89).
Levels of PINK1 protein, which helps selectively eliminate damaged mitochondria from cells, were similar in p.G411S heterozygous cells and in wild-type controls. Levels of p-Ser65-Ub, a marker of mitochondrial stress, were persistently lower, however, and were significantly reduced at later time points. In a HeLa cell model, the researchers observed that p.G411S overexpressing cells had reduced p-Ser65-Ub levels, compared with PINK1 wild-type cells. Furthermore, p.G411S showed strongly reduced kinase activity towards ubiquitin, compared with PINK1 wild-type. Coexpression of p.G411S along with PINK1 wild-type significantly impaired ubiquitin phosphorylation.
“Genetic analyses, as well as functional, cell-based and structural, computational characterization, for the first time provided evidence for a partial dominant-negative function of the heterozygous PINK1 p.G411S mutation that confers a markedly increased risk for Parkinson’s disease,” said Dr. Springer. “The low frequency of homozygote p.G411S carriers may be due to the rarity of the mutation or could indicate [that] it is particularly damaging or clinically manifests with an alternate phenotypic presentation. Replication of our genetic association in other case–control series and further clinical studies is now warranted.”
—Erik Greb
Suggested Reading
Puschmann A, Fiesel FC, Caulfield TR, et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain. 2016 Nov 2 [Epub ahead of print].
The rare p.G411S mutation of PINK1 greatly increases the risk of early-onset Parkinson’s disease, even if present in only one allele, according to a genetic association study published online ahead of print November 2 in Brain. By reducing kinase activity towards ubiquitin, the mutation impairs the elimination of damaged mitochondria from cells.
Previous data had indicated that mutations in both PINK1 alleles confer a risk of early-onset Parkinson’s disease (age younger than 45). Genetic studies had suggested that a single mutated PINK1 allele also might increase the risk of developing the disease.
Wolfdieter Springer, PhD, Associate Professor of Neuroscience at Mayo Clinic in Jacksonville, Florida, and colleagues examined DNA samples from 2,560 patients with Parkinson’s disease and 2,145 controls from the United States, Poland, Norway, Ireland, and Sweden. Patients were included in the study irrespective of age at disease onset. The controls included the patients’ spouses and caregivers, as well as unrelated individuals. Dr. Springer and colleagues also searched the literature for previous studies that identified or excluded PINK1 p.G411S mutations in cases of Parkinson’s disease and controls.
The investigators found PINK1 p.G411S substitution in 19 cases (0.74%) and five control subjects (0.23%), indicating a significant association with an intermediate effect size between heterozygous PINK1 p.G411S carrier status and Parkinson’s disease (odds ratio [OR], 2.92). The median age at disease onset was significantly lower in the 19 cases carrying PINK1 p.G411S than in noncarrier cases (59 vs 64). When the researchers combined their data with those of six studies that they had identified in the literature review, the increased risk of Parkinson’s disease associated with the p.G411S mutation remained evident (OR, 2.89).
Levels of PINK1 protein, which helps selectively eliminate damaged mitochondria from cells, were similar in p.G411S heterozygous cells and in wild-type controls. Levels of p-Ser65-Ub, a marker of mitochondrial stress, were persistently lower, however, and were significantly reduced at later time points. In a HeLa cell model, the researchers observed that p.G411S overexpressing cells had reduced p-Ser65-Ub levels, compared with PINK1 wild-type cells. Furthermore, p.G411S showed strongly reduced kinase activity towards ubiquitin, compared with PINK1 wild-type. Coexpression of p.G411S along with PINK1 wild-type significantly impaired ubiquitin phosphorylation.
“Genetic analyses, as well as functional, cell-based and structural, computational characterization, for the first time provided evidence for a partial dominant-negative function of the heterozygous PINK1 p.G411S mutation that confers a markedly increased risk for Parkinson’s disease,” said Dr. Springer. “The low frequency of homozygote p.G411S carriers may be due to the rarity of the mutation or could indicate [that] it is particularly damaging or clinically manifests with an alternate phenotypic presentation. Replication of our genetic association in other case–control series and further clinical studies is now warranted.”
—Erik Greb
Suggested Reading
Puschmann A, Fiesel FC, Caulfield TR, et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain. 2016 Nov 2 [Epub ahead of print].
The rare p.G411S mutation of PINK1 greatly increases the risk of early-onset Parkinson’s disease, even if present in only one allele, according to a genetic association study published online ahead of print November 2 in Brain. By reducing kinase activity towards ubiquitin, the mutation impairs the elimination of damaged mitochondria from cells.
Previous data had indicated that mutations in both PINK1 alleles confer a risk of early-onset Parkinson’s disease (age younger than 45). Genetic studies had suggested that a single mutated PINK1 allele also might increase the risk of developing the disease.
Wolfdieter Springer, PhD, Associate Professor of Neuroscience at Mayo Clinic in Jacksonville, Florida, and colleagues examined DNA samples from 2,560 patients with Parkinson’s disease and 2,145 controls from the United States, Poland, Norway, Ireland, and Sweden. Patients were included in the study irrespective of age at disease onset. The controls included the patients’ spouses and caregivers, as well as unrelated individuals. Dr. Springer and colleagues also searched the literature for previous studies that identified or excluded PINK1 p.G411S mutations in cases of Parkinson’s disease and controls.
The investigators found PINK1 p.G411S substitution in 19 cases (0.74%) and five control subjects (0.23%), indicating a significant association with an intermediate effect size between heterozygous PINK1 p.G411S carrier status and Parkinson’s disease (odds ratio [OR], 2.92). The median age at disease onset was significantly lower in the 19 cases carrying PINK1 p.G411S than in noncarrier cases (59 vs 64). When the researchers combined their data with those of six studies that they had identified in the literature review, the increased risk of Parkinson’s disease associated with the p.G411S mutation remained evident (OR, 2.89).
Levels of PINK1 protein, which helps selectively eliminate damaged mitochondria from cells, were similar in p.G411S heterozygous cells and in wild-type controls. Levels of p-Ser65-Ub, a marker of mitochondrial stress, were persistently lower, however, and were significantly reduced at later time points. In a HeLa cell model, the researchers observed that p.G411S overexpressing cells had reduced p-Ser65-Ub levels, compared with PINK1 wild-type cells. Furthermore, p.G411S showed strongly reduced kinase activity towards ubiquitin, compared with PINK1 wild-type. Coexpression of p.G411S along with PINK1 wild-type significantly impaired ubiquitin phosphorylation.
“Genetic analyses, as well as functional, cell-based and structural, computational characterization, for the first time provided evidence for a partial dominant-negative function of the heterozygous PINK1 p.G411S mutation that confers a markedly increased risk for Parkinson’s disease,” said Dr. Springer. “The low frequency of homozygote p.G411S carriers may be due to the rarity of the mutation or could indicate [that] it is particularly damaging or clinically manifests with an alternate phenotypic presentation. Replication of our genetic association in other case–control series and further clinical studies is now warranted.”
—Erik Greb
Suggested Reading
Puschmann A, Fiesel FC, Caulfield TR, et al. Heterozygous PINK1 p.G411S increases risk of Parkinson’s disease via a dominant-negative mechanism. Brain. 2016 Nov 2 [Epub ahead of print].
Bone marrow cells prove limb-saving for some
NEW ORLEANS – Treatment with autologous bone marrow cells can avert amputation in selected patients who have critical limb ischemia and are not candidates for revascularization surgery, based on results from the randomized phase III MOBILE trial.
Critical limb ischemia, the end stage of peripheral arterial disease, accounts for more than 53,000 major limb amputations in the United States annually, noted principal investigator Dr. Michael P. Murphy, director of the Vascular and Cardiac Center for Adult Stem Cell Therapy at Indiana University, Indianapolis.
“About 30% of our patient population with critical limb ischemia have no options for the standard of care, such as surgical bypass, due to absence of a surgical target or chronic total occlusion, which mitigates an endovascular approach,” he said at the American Heart Association scientific sessions. “Thus, these no-option critical limb ischemia patients represent an unmet medical need for a novel agent that may promote limb salvage and prevent amputation and its associated disabilities.”
In the trial, investigators randomized 155 affected limbs (in 152 patients) 3:1 to receive double-blinded treatment with injections of concentrated autologous bone marrow aspirate or placebo.
Amputation-free survival 1 year after treatment, the trial’s primary endpoint, was not significantly better in the aspirate group than in the placebo group, according to the researchers. However, the aspirate reduced the risk of major amputation by 73% in the subgroup with less severe (Rutherford class 4) disease and by 67% in the subgroup of patients who did not have diabetes.
“Personally, I would recommend cell therapy for my Rutherford 4 patients and my nondiabetic Rutherford 5 patients,” Dr. Murphy said. “And one would say even for the Rutherford 5 diabetics, there were no safety concerns and there is hope for improvement rather than amputation – it might be worth the roll of the dice.”
The investigators are preparing a manuscript based on the full data and working with Biomet, the trial sponsor, to apply for Food and Drug Administration approval of the product for the treatment of critical limb ischemia, he said.
Lessons learned
A session attendee asked whether stronger demonstration of benefit in a larger trial is needed to justify the use and cost of such new cellular therapies.
“If we could go back and do it all over again, we would do things differently knowing what we know now,” Dr. Murphy replied, noting that the investigators had to stick to a trial design created more than a decade ago.
“We discovered that the event rate in patients with critical limb ischemia in the control group is actually 30% and not 40% because medical management has changed,” he said. “Secondly, we would do a 1:1 randomization and most likely would increase our sample size to 200, and we probably would have seen a difference overall. That difference overall would have been provided by, of course, increasing the Rutherford 4 and Rutherford 5 nondiabetics, which would overshadow the increased amputation rate in the diabetic group.”
“I think from this [experience], we can launch a much larger study, if there were funding for it, and look at autologous versus allogeneic cells in this domain,” Dr. Murphy concluded.
Identifying patients who benefit
Session panelist Roberto Bolli, MD, chief of the division of cardiovascular medicine at the University of Louisville (Ky.), commended the MOBILE trial for its study design and prespecified subgroup analyses.
“The whole problem we are coping with, not just in this trial, but in other studies, is that patients are different and some patients may respond better than others, or some patients may not respond at all. And really, we still don’t understand why some patients respond or not – it may have to do with their immune system, their regenerative capacity, as well as the type of cells that are being used,” he said.
“Even though it was in its entirety a negative study, it’s very important because it identified a possible target for future trials, which is patients without diabetes in Rutherford class 4, which may benefit from therapy,” Dr. Bolli concluded.
Trial details
Patients were enrolled in MOBILE from 24 U.S. centers. All had critical limb ischemia, were ineligible for revascularization, had an ankle-brachial index of less than 0.60 or a toe-brachial index of less than 0.40, and had Rutherford 4 disease (rest pain) or Rutherford 5 disease (tissue loss).
They received concentrated autologous bone marrow aspirate or placebo by intramuscular injection at 35-40 sites in the affected limb.
Results showed that the groups did not differ significantly with respect to the rates of adverse events or serious adverse events overall, Dr. Murphy reported. The aspirate group had lower rates of respiratory failure and fever; they also had a higher rate of anemia (68.9% vs. 36.1%, P less than .001) as expected, from the aspiration procedure, but with no associated complications.
The 1-year rate of amputation-free survival events, reflecting both major amputations and death, was lower with the aspirate, at 20.2%, than with placebo, at 30.5%, but not significantly so (P = .224). Findings were similar for major amputation in the entire trial population (16.0% vs. 22.2%, P = .392). However, this outcome was less common with the aspirate among patients with Rutherford 4 disease (7.7% vs. 26.3%, P = .041) and nondiabetic patients (10.0% vs. 27.7%, P = .046).
“Looking at these data, it became apparent to us that the Rutherford 5 diabetic was the outlying group,” said Dr. Murphy, who disclosed that he had no relevant conflicts of interest.
Considering all other patients – Rutherford 4 regardless of diabetes status and nondiabetic Rutherford 5 – the aspirate was associated with a dramatically lower rate of amputation compared with the placebo (9.6% vs. 26.7%, P = .021; hazard ratio, 0.33). In this subset, the number needed to treat with bone marrow aspirate to prevent a single amputation was just 6.
The aspirate and placebo groups did not differ with respect to ankle-brachial index, toe-brachial index, or 6-minute walk test distance in the entire trial population. Transcutaneous oxygen pressure (TcP02), an indicator of microvascular perfusion in the subcutaneous tissue of the ischemic limb, increased by 59% in the aspirate group but by only 7% in the placebo group.
NEW ORLEANS – Treatment with autologous bone marrow cells can avert amputation in selected patients who have critical limb ischemia and are not candidates for revascularization surgery, based on results from the randomized phase III MOBILE trial.
Critical limb ischemia, the end stage of peripheral arterial disease, accounts for more than 53,000 major limb amputations in the United States annually, noted principal investigator Dr. Michael P. Murphy, director of the Vascular and Cardiac Center for Adult Stem Cell Therapy at Indiana University, Indianapolis.
“About 30% of our patient population with critical limb ischemia have no options for the standard of care, such as surgical bypass, due to absence of a surgical target or chronic total occlusion, which mitigates an endovascular approach,” he said at the American Heart Association scientific sessions. “Thus, these no-option critical limb ischemia patients represent an unmet medical need for a novel agent that may promote limb salvage and prevent amputation and its associated disabilities.”
In the trial, investigators randomized 155 affected limbs (in 152 patients) 3:1 to receive double-blinded treatment with injections of concentrated autologous bone marrow aspirate or placebo.
Amputation-free survival 1 year after treatment, the trial’s primary endpoint, was not significantly better in the aspirate group than in the placebo group, according to the researchers. However, the aspirate reduced the risk of major amputation by 73% in the subgroup with less severe (Rutherford class 4) disease and by 67% in the subgroup of patients who did not have diabetes.
“Personally, I would recommend cell therapy for my Rutherford 4 patients and my nondiabetic Rutherford 5 patients,” Dr. Murphy said. “And one would say even for the Rutherford 5 diabetics, there were no safety concerns and there is hope for improvement rather than amputation – it might be worth the roll of the dice.”
The investigators are preparing a manuscript based on the full data and working with Biomet, the trial sponsor, to apply for Food and Drug Administration approval of the product for the treatment of critical limb ischemia, he said.
Lessons learned
A session attendee asked whether stronger demonstration of benefit in a larger trial is needed to justify the use and cost of such new cellular therapies.
“If we could go back and do it all over again, we would do things differently knowing what we know now,” Dr. Murphy replied, noting that the investigators had to stick to a trial design created more than a decade ago.
“We discovered that the event rate in patients with critical limb ischemia in the control group is actually 30% and not 40% because medical management has changed,” he said. “Secondly, we would do a 1:1 randomization and most likely would increase our sample size to 200, and we probably would have seen a difference overall. That difference overall would have been provided by, of course, increasing the Rutherford 4 and Rutherford 5 nondiabetics, which would overshadow the increased amputation rate in the diabetic group.”
“I think from this [experience], we can launch a much larger study, if there were funding for it, and look at autologous versus allogeneic cells in this domain,” Dr. Murphy concluded.
Identifying patients who benefit
Session panelist Roberto Bolli, MD, chief of the division of cardiovascular medicine at the University of Louisville (Ky.), commended the MOBILE trial for its study design and prespecified subgroup analyses.
“The whole problem we are coping with, not just in this trial, but in other studies, is that patients are different and some patients may respond better than others, or some patients may not respond at all. And really, we still don’t understand why some patients respond or not – it may have to do with their immune system, their regenerative capacity, as well as the type of cells that are being used,” he said.
“Even though it was in its entirety a negative study, it’s very important because it identified a possible target for future trials, which is patients without diabetes in Rutherford class 4, which may benefit from therapy,” Dr. Bolli concluded.
Trial details
Patients were enrolled in MOBILE from 24 U.S. centers. All had critical limb ischemia, were ineligible for revascularization, had an ankle-brachial index of less than 0.60 or a toe-brachial index of less than 0.40, and had Rutherford 4 disease (rest pain) or Rutherford 5 disease (tissue loss).
They received concentrated autologous bone marrow aspirate or placebo by intramuscular injection at 35-40 sites in the affected limb.
Results showed that the groups did not differ significantly with respect to the rates of adverse events or serious adverse events overall, Dr. Murphy reported. The aspirate group had lower rates of respiratory failure and fever; they also had a higher rate of anemia (68.9% vs. 36.1%, P less than .001) as expected, from the aspiration procedure, but with no associated complications.
The 1-year rate of amputation-free survival events, reflecting both major amputations and death, was lower with the aspirate, at 20.2%, than with placebo, at 30.5%, but not significantly so (P = .224). Findings were similar for major amputation in the entire trial population (16.0% vs. 22.2%, P = .392). However, this outcome was less common with the aspirate among patients with Rutherford 4 disease (7.7% vs. 26.3%, P = .041) and nondiabetic patients (10.0% vs. 27.7%, P = .046).
“Looking at these data, it became apparent to us that the Rutherford 5 diabetic was the outlying group,” said Dr. Murphy, who disclosed that he had no relevant conflicts of interest.
Considering all other patients – Rutherford 4 regardless of diabetes status and nondiabetic Rutherford 5 – the aspirate was associated with a dramatically lower rate of amputation compared with the placebo (9.6% vs. 26.7%, P = .021; hazard ratio, 0.33). In this subset, the number needed to treat with bone marrow aspirate to prevent a single amputation was just 6.
The aspirate and placebo groups did not differ with respect to ankle-brachial index, toe-brachial index, or 6-minute walk test distance in the entire trial population. Transcutaneous oxygen pressure (TcP02), an indicator of microvascular perfusion in the subcutaneous tissue of the ischemic limb, increased by 59% in the aspirate group but by only 7% in the placebo group.
NEW ORLEANS – Treatment with autologous bone marrow cells can avert amputation in selected patients who have critical limb ischemia and are not candidates for revascularization surgery, based on results from the randomized phase III MOBILE trial.
Critical limb ischemia, the end stage of peripheral arterial disease, accounts for more than 53,000 major limb amputations in the United States annually, noted principal investigator Dr. Michael P. Murphy, director of the Vascular and Cardiac Center for Adult Stem Cell Therapy at Indiana University, Indianapolis.
“About 30% of our patient population with critical limb ischemia have no options for the standard of care, such as surgical bypass, due to absence of a surgical target or chronic total occlusion, which mitigates an endovascular approach,” he said at the American Heart Association scientific sessions. “Thus, these no-option critical limb ischemia patients represent an unmet medical need for a novel agent that may promote limb salvage and prevent amputation and its associated disabilities.”
In the trial, investigators randomized 155 affected limbs (in 152 patients) 3:1 to receive double-blinded treatment with injections of concentrated autologous bone marrow aspirate or placebo.
Amputation-free survival 1 year after treatment, the trial’s primary endpoint, was not significantly better in the aspirate group than in the placebo group, according to the researchers. However, the aspirate reduced the risk of major amputation by 73% in the subgroup with less severe (Rutherford class 4) disease and by 67% in the subgroup of patients who did not have diabetes.
“Personally, I would recommend cell therapy for my Rutherford 4 patients and my nondiabetic Rutherford 5 patients,” Dr. Murphy said. “And one would say even for the Rutherford 5 diabetics, there were no safety concerns and there is hope for improvement rather than amputation – it might be worth the roll of the dice.”
The investigators are preparing a manuscript based on the full data and working with Biomet, the trial sponsor, to apply for Food and Drug Administration approval of the product for the treatment of critical limb ischemia, he said.
Lessons learned
A session attendee asked whether stronger demonstration of benefit in a larger trial is needed to justify the use and cost of such new cellular therapies.
“If we could go back and do it all over again, we would do things differently knowing what we know now,” Dr. Murphy replied, noting that the investigators had to stick to a trial design created more than a decade ago.
“We discovered that the event rate in patients with critical limb ischemia in the control group is actually 30% and not 40% because medical management has changed,” he said. “Secondly, we would do a 1:1 randomization and most likely would increase our sample size to 200, and we probably would have seen a difference overall. That difference overall would have been provided by, of course, increasing the Rutherford 4 and Rutherford 5 nondiabetics, which would overshadow the increased amputation rate in the diabetic group.”
“I think from this [experience], we can launch a much larger study, if there were funding for it, and look at autologous versus allogeneic cells in this domain,” Dr. Murphy concluded.
Identifying patients who benefit
Session panelist Roberto Bolli, MD, chief of the division of cardiovascular medicine at the University of Louisville (Ky.), commended the MOBILE trial for its study design and prespecified subgroup analyses.
“The whole problem we are coping with, not just in this trial, but in other studies, is that patients are different and some patients may respond better than others, or some patients may not respond at all. And really, we still don’t understand why some patients respond or not – it may have to do with their immune system, their regenerative capacity, as well as the type of cells that are being used,” he said.
“Even though it was in its entirety a negative study, it’s very important because it identified a possible target for future trials, which is patients without diabetes in Rutherford class 4, which may benefit from therapy,” Dr. Bolli concluded.
Trial details
Patients were enrolled in MOBILE from 24 U.S. centers. All had critical limb ischemia, were ineligible for revascularization, had an ankle-brachial index of less than 0.60 or a toe-brachial index of less than 0.40, and had Rutherford 4 disease (rest pain) or Rutherford 5 disease (tissue loss).
They received concentrated autologous bone marrow aspirate or placebo by intramuscular injection at 35-40 sites in the affected limb.
Results showed that the groups did not differ significantly with respect to the rates of adverse events or serious adverse events overall, Dr. Murphy reported. The aspirate group had lower rates of respiratory failure and fever; they also had a higher rate of anemia (68.9% vs. 36.1%, P less than .001) as expected, from the aspiration procedure, but with no associated complications.
The 1-year rate of amputation-free survival events, reflecting both major amputations and death, was lower with the aspirate, at 20.2%, than with placebo, at 30.5%, but not significantly so (P = .224). Findings were similar for major amputation in the entire trial population (16.0% vs. 22.2%, P = .392). However, this outcome was less common with the aspirate among patients with Rutherford 4 disease (7.7% vs. 26.3%, P = .041) and nondiabetic patients (10.0% vs. 27.7%, P = .046).
“Looking at these data, it became apparent to us that the Rutherford 5 diabetic was the outlying group,” said Dr. Murphy, who disclosed that he had no relevant conflicts of interest.
Considering all other patients – Rutherford 4 regardless of diabetes status and nondiabetic Rutherford 5 – the aspirate was associated with a dramatically lower rate of amputation compared with the placebo (9.6% vs. 26.7%, P = .021; hazard ratio, 0.33). In this subset, the number needed to treat with bone marrow aspirate to prevent a single amputation was just 6.
The aspirate and placebo groups did not differ with respect to ankle-brachial index, toe-brachial index, or 6-minute walk test distance in the entire trial population. Transcutaneous oxygen pressure (TcP02), an indicator of microvascular perfusion in the subcutaneous tissue of the ischemic limb, increased by 59% in the aspirate group but by only 7% in the placebo group.
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: The 52-week rate of amputation-free survival events was 20.2% with the aspirate and 30.5% with placebo (P = .224).
Data source: A randomized phase III trial among 152 patients with critical limb ischemia who were not candidates for revascularization surgery (MOBILE trial).
Disclosures: Dr. Murphy disclosed that he had no relevant conflicts of interest. The trial was sponsored by Biomet Biologics, LLC.
VIDEO: HeartMate 3 LVAD solves pump thrombosis
NEW ORLEANS – HeartMate 3, the latest left ventricular assist device in the HeartMate line, appears to have solved the problem of pump thrombosis, a complication that has dogged ventricular pumps since the issue leapt into medical awareness about 3 years ago (New Engl J Med. 2014 Jan 2;370:33-40).
During 6 months of follow-up, none of 152 heart failure patients assigned to receive a HeartMate 3 left ventricular assist device (LVAD) developed suspected or confirmed pump thrombosis, compared with 14 patients (10%) having pump thrombosis out of 138 recipients of the prior-generation HeartMate II LVAD who served as the control group for the study.
“Three years ago, when the issue of pump thrombosis was first revealed, there was a lot of consternation and some drop in LVAD use, especially as destination therapy. We think that seeing no pump thrombosis whatsoever will give people renewed confidence in this technology,” said Dr. Mehra, professor of medicine at Harvard Medical School and medical director of the Heart and Vascular Center of Brigham and Women’s Hospital, both in Boston.
Pump thrombosis has also been a problem for the patients who have received a competitor LVAD, the HeartWare HVAD device (Circulation. 2015 Nov 10;132[suppl 3]:A19675), approved for U.S. use as bridge to transplant. HeartMate II is approved for both bridge to transplant and for destination therapy.
In addition to apparently eliminating pump thrombosis, HeartMate 3’s size and potential implantation approach should make its placement during routine use as quick and minimally invasive as the HeartWare device, features that should further help broader use of HeartMate 3, commented Mark Slaughter, MD, professor and chairman of cardiovascular and thoracic surgery at the University of Louisville (Ky.). But Dr. Slaughter and others were also quick to highlight the shortcomings that remain with both devices that will continue to hamper a broader role for LVAD treatment of patients with advanced heart failure.
“We thought that if there was less pump thrombosis we’d see less stroke, but that is not what the data suggest. It’s the big puzzle we need to figure out before we see widespread acceptance of this treatment,” Dr. Sweitzer said.
“This will not shift LVAD use substantially,” commented Christopher B. Granger, MD, a professor of medicine and a heart failure specialist at Duke University, Durham, N.C. “Reducing the need for reoperation is good for the field, and is an incremental advance, but it is not transformational,” he said in an interview.
The MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial randomized 294 patients at 69 U.S. centers. The study’s primary endpoint of 6-month survival free from disabling stroke or reoperation to repair or replace the LVAD occurred in 86% of 152 patients who received a HeartMate 3 and 77% of 142 patients randomized to HeartMate II, a statistical difference that met the prespecified criteria for both noninferiority and superiority. Concurrently with Dr. Mehra’s report at the meeting, a journal article appeared online (New Engl J Med. 2016 Nov 16. doi: 10.1056/NEJMoa1610426). He stated that as far as he understood, St. Jude would submit the 6-month data he reported to the Food and Drug Administration in an application for marketing approval for HeartMate 3.
“I agree that there are still morbid evens [with HeartMate 3] that need to be surmounted, but this is a confidence-building step in the right direction,” Dr. Mehra said.
[email protected]
On Twitter @mitchelzoler
By eliminating all episodes of pump thrombosis during 6-month follow-up, the HeartMate 3 appeared to resolve one of the major issues that has stood in the way of patients and physicians feeling comfortable with left ventricular assist devices. The smaller size of the HeartMate 3 pump and its ability to be placed with minimally invasive and fairly rapid surgery is another big advance, putting this device on par with the rival pump, the HeartWare HVAD.
But the performance of the HeartMate 3 left ventricular assist device (LVAD) in MOMENTUM 3 also highlighted the shortcomings that still remain for these devices: the unchanged rates of stroke, gastrointestinal bleeds, and infections with HeartMate 3, compared with HeartMate II in this trial, and similar 6-month survival rates in the two arms of the study.
The HeartMate 3 can be implanted without sternotomy, using an 8 cm incision on the lateral chest wall, resulting in a shorter postoperative stay and fewer perisurgical adverse events. Despite the less invasive surgery and absence of pump thrombosis, some patients and physicians will remain hesitant to use an LVAD unless it is unavoidable because of concern about strokes. Until further design and procedural refinements change the rate of serious strokes and other adverse events, LVADs will not be fully competitive with heart transplantation.
The competition between HeartMate and the HeartWare devices will help drive this field forward, leading to further improvements in outcomes and expanded LVAD use.
Mark Slaughter, MD, is professor of surgery and chairman of cardiovascular and thoracic surgery at the University of Louisville (Ky.). He was an investigator in MOMENTUM 3, he has been a consultant to EvaHeart and Oregon Heart, and he has received research support from Carmat and HeartWare. He made these comments as designated discussant for the report and in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
By eliminating all episodes of pump thrombosis during 6-month follow-up, the HeartMate 3 appeared to resolve one of the major issues that has stood in the way of patients and physicians feeling comfortable with left ventricular assist devices. The smaller size of the HeartMate 3 pump and its ability to be placed with minimally invasive and fairly rapid surgery is another big advance, putting this device on par with the rival pump, the HeartWare HVAD.
But the performance of the HeartMate 3 left ventricular assist device (LVAD) in MOMENTUM 3 also highlighted the shortcomings that still remain for these devices: the unchanged rates of stroke, gastrointestinal bleeds, and infections with HeartMate 3, compared with HeartMate II in this trial, and similar 6-month survival rates in the two arms of the study.
The HeartMate 3 can be implanted without sternotomy, using an 8 cm incision on the lateral chest wall, resulting in a shorter postoperative stay and fewer perisurgical adverse events. Despite the less invasive surgery and absence of pump thrombosis, some patients and physicians will remain hesitant to use an LVAD unless it is unavoidable because of concern about strokes. Until further design and procedural refinements change the rate of serious strokes and other adverse events, LVADs will not be fully competitive with heart transplantation.
The competition between HeartMate and the HeartWare devices will help drive this field forward, leading to further improvements in outcomes and expanded LVAD use.
Mark Slaughter, MD, is professor of surgery and chairman of cardiovascular and thoracic surgery at the University of Louisville (Ky.). He was an investigator in MOMENTUM 3, he has been a consultant to EvaHeart and Oregon Heart, and he has received research support from Carmat and HeartWare. He made these comments as designated discussant for the report and in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
By eliminating all episodes of pump thrombosis during 6-month follow-up, the HeartMate 3 appeared to resolve one of the major issues that has stood in the way of patients and physicians feeling comfortable with left ventricular assist devices. The smaller size of the HeartMate 3 pump and its ability to be placed with minimally invasive and fairly rapid surgery is another big advance, putting this device on par with the rival pump, the HeartWare HVAD.
But the performance of the HeartMate 3 left ventricular assist device (LVAD) in MOMENTUM 3 also highlighted the shortcomings that still remain for these devices: the unchanged rates of stroke, gastrointestinal bleeds, and infections with HeartMate 3, compared with HeartMate II in this trial, and similar 6-month survival rates in the two arms of the study.
The HeartMate 3 can be implanted without sternotomy, using an 8 cm incision on the lateral chest wall, resulting in a shorter postoperative stay and fewer perisurgical adverse events. Despite the less invasive surgery and absence of pump thrombosis, some patients and physicians will remain hesitant to use an LVAD unless it is unavoidable because of concern about strokes. Until further design and procedural refinements change the rate of serious strokes and other adverse events, LVADs will not be fully competitive with heart transplantation.
The competition between HeartMate and the HeartWare devices will help drive this field forward, leading to further improvements in outcomes and expanded LVAD use.
Mark Slaughter, MD, is professor of surgery and chairman of cardiovascular and thoracic surgery at the University of Louisville (Ky.). He was an investigator in MOMENTUM 3, he has been a consultant to EvaHeart and Oregon Heart, and he has received research support from Carmat and HeartWare. He made these comments as designated discussant for the report and in a video interview.
The video associated with this article is no longer available on this site. Please view all of our videos on the MDedge YouTube channel
NEW ORLEANS – HeartMate 3, the latest left ventricular assist device in the HeartMate line, appears to have solved the problem of pump thrombosis, a complication that has dogged ventricular pumps since the issue leapt into medical awareness about 3 years ago (New Engl J Med. 2014 Jan 2;370:33-40).
During 6 months of follow-up, none of 152 heart failure patients assigned to receive a HeartMate 3 left ventricular assist device (LVAD) developed suspected or confirmed pump thrombosis, compared with 14 patients (10%) having pump thrombosis out of 138 recipients of the prior-generation HeartMate II LVAD who served as the control group for the study.
“Three years ago, when the issue of pump thrombosis was first revealed, there was a lot of consternation and some drop in LVAD use, especially as destination therapy. We think that seeing no pump thrombosis whatsoever will give people renewed confidence in this technology,” said Dr. Mehra, professor of medicine at Harvard Medical School and medical director of the Heart and Vascular Center of Brigham and Women’s Hospital, both in Boston.
Pump thrombosis has also been a problem for the patients who have received a competitor LVAD, the HeartWare HVAD device (Circulation. 2015 Nov 10;132[suppl 3]:A19675), approved for U.S. use as bridge to transplant. HeartMate II is approved for both bridge to transplant and for destination therapy.
In addition to apparently eliminating pump thrombosis, HeartMate 3’s size and potential implantation approach should make its placement during routine use as quick and minimally invasive as the HeartWare device, features that should further help broader use of HeartMate 3, commented Mark Slaughter, MD, professor and chairman of cardiovascular and thoracic surgery at the University of Louisville (Ky.). But Dr. Slaughter and others were also quick to highlight the shortcomings that remain with both devices that will continue to hamper a broader role for LVAD treatment of patients with advanced heart failure.
“We thought that if there was less pump thrombosis we’d see less stroke, but that is not what the data suggest. It’s the big puzzle we need to figure out before we see widespread acceptance of this treatment,” Dr. Sweitzer said.
“This will not shift LVAD use substantially,” commented Christopher B. Granger, MD, a professor of medicine and a heart failure specialist at Duke University, Durham, N.C. “Reducing the need for reoperation is good for the field, and is an incremental advance, but it is not transformational,” he said in an interview.
The MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial randomized 294 patients at 69 U.S. centers. The study’s primary endpoint of 6-month survival free from disabling stroke or reoperation to repair or replace the LVAD occurred in 86% of 152 patients who received a HeartMate 3 and 77% of 142 patients randomized to HeartMate II, a statistical difference that met the prespecified criteria for both noninferiority and superiority. Concurrently with Dr. Mehra’s report at the meeting, a journal article appeared online (New Engl J Med. 2016 Nov 16. doi: 10.1056/NEJMoa1610426). He stated that as far as he understood, St. Jude would submit the 6-month data he reported to the Food and Drug Administration in an application for marketing approval for HeartMate 3.
“I agree that there are still morbid evens [with HeartMate 3] that need to be surmounted, but this is a confidence-building step in the right direction,” Dr. Mehra said.
[email protected]
On Twitter @mitchelzoler
NEW ORLEANS – HeartMate 3, the latest left ventricular assist device in the HeartMate line, appears to have solved the problem of pump thrombosis, a complication that has dogged ventricular pumps since the issue leapt into medical awareness about 3 years ago (New Engl J Med. 2014 Jan 2;370:33-40).
During 6 months of follow-up, none of 152 heart failure patients assigned to receive a HeartMate 3 left ventricular assist device (LVAD) developed suspected or confirmed pump thrombosis, compared with 14 patients (10%) having pump thrombosis out of 138 recipients of the prior-generation HeartMate II LVAD who served as the control group for the study.
“Three years ago, when the issue of pump thrombosis was first revealed, there was a lot of consternation and some drop in LVAD use, especially as destination therapy. We think that seeing no pump thrombosis whatsoever will give people renewed confidence in this technology,” said Dr. Mehra, professor of medicine at Harvard Medical School and medical director of the Heart and Vascular Center of Brigham and Women’s Hospital, both in Boston.
Pump thrombosis has also been a problem for the patients who have received a competitor LVAD, the HeartWare HVAD device (Circulation. 2015 Nov 10;132[suppl 3]:A19675), approved for U.S. use as bridge to transplant. HeartMate II is approved for both bridge to transplant and for destination therapy.
In addition to apparently eliminating pump thrombosis, HeartMate 3’s size and potential implantation approach should make its placement during routine use as quick and minimally invasive as the HeartWare device, features that should further help broader use of HeartMate 3, commented Mark Slaughter, MD, professor and chairman of cardiovascular and thoracic surgery at the University of Louisville (Ky.). But Dr. Slaughter and others were also quick to highlight the shortcomings that remain with both devices that will continue to hamper a broader role for LVAD treatment of patients with advanced heart failure.
“We thought that if there was less pump thrombosis we’d see less stroke, but that is not what the data suggest. It’s the big puzzle we need to figure out before we see widespread acceptance of this treatment,” Dr. Sweitzer said.
“This will not shift LVAD use substantially,” commented Christopher B. Granger, MD, a professor of medicine and a heart failure specialist at Duke University, Durham, N.C. “Reducing the need for reoperation is good for the field, and is an incremental advance, but it is not transformational,” he said in an interview.
The MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial randomized 294 patients at 69 U.S. centers. The study’s primary endpoint of 6-month survival free from disabling stroke or reoperation to repair or replace the LVAD occurred in 86% of 152 patients who received a HeartMate 3 and 77% of 142 patients randomized to HeartMate II, a statistical difference that met the prespecified criteria for both noninferiority and superiority. Concurrently with Dr. Mehra’s report at the meeting, a journal article appeared online (New Engl J Med. 2016 Nov 16. doi: 10.1056/NEJMoa1610426). He stated that as far as he understood, St. Jude would submit the 6-month data he reported to the Food and Drug Administration in an application for marketing approval for HeartMate 3.
“I agree that there are still morbid evens [with HeartMate 3] that need to be surmounted, but this is a confidence-building step in the right direction,” Dr. Mehra said.
[email protected]
On Twitter @mitchelzoler
AT THE AHA SCIENTIFIC SESSIONS
Key clinical point:
Major finding: During 6 months, suspected or confirmed pump thrombosis occurred in no HeartMate 3 patients and in 10% of HeartMate II recipients.
Data source: The MOMENTUM 3 trial, which randomized 294 patients at 69 U.S. centers.
Disclosures: MOMENTUM 3 was sponsored by St. Jude, the company developing the HeartMate 3 LVAD. Dr. Mehra has received travel reimbursements from St. Jude and has been a consultant to Medtronic, Stealth, and Teva. Dr. Sweitzer was an investigator in MOMENTUM 3 and has been a consultant to Acorda and Medtronic and received research support from Bayer, Corvia, and Novartis. Dr. Granger has been a consultant to Boehringer Ingelheim, and received research support from Medtronic and several other drug and device companies. Dr. Slaughter was an investigator in MOMENTUM 3, has been a consultant to EvaHeart and Oregon Heart, and has received research support from Carmat and HeartWare.
Tips for Living With Myasthenia Gravis
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Time to consider cirrhosis medical homes
BOSTON – As part of the push to create value-based care across the specialties, hepatologists should consider medical homes for their patients, such as those with cirrhosis, according to experts.
“Cirrhosis is a chronic condition, highly symptomatic, and occurs in highly comorbid individuals. Treating them in a medical home scenario means we can offer services that we don’t otherwise do, but which are associated with better outcomes for our patients,” Fasiha Kanwal, MD, of the department of medicine at Baylor College of Medicine, Houston, said in a panel presentation at the annual meeting of the American Association for the Study of Liver Diseases.
Essentially, value-based care is the evolution of evidence-based medicine, according to Zobair M. Younossi, MD, AGAF, FAASLD, chair of the department of medicine at Inova Fairfax (Va.) Hospital. With value-based care, aligned incentives across all the specialties will lead to more precise accounting and efficiencies of care, said Dr. Younossi, who was also on the panel. “It would be very difficult right now to ask a hospital to tell you exactly what the cost of their liver care would be,” he said.
However, at present there are no true value-based models for hepatology in the United States, according to Dr. Kanwal, so clinicians should start by defining what will “truly constitute value for our patients.”
Because psychosocial support is essential to improved outcomes in patients with cirrhosis, she suggested adding case managers in practice, as they can help coordinate with services in the community at large. Other suggestions she offered included extending office hours, operating an after-hours hotline, and building teams that include general internists, additional nursing staff, and nutritionists.
Even though such changes in clinical practice models now are inevitable, Dr. Kanwal said there are few data at present that support how to innovate care in hospitalized patients with cirrhosis. This matters, as how patients present for outpatient follow-up care will impact reimbursements to the clinicians who treat them.
Some possible ways to improve hospital outcomes for patients with cirrhosis include creating a “best practice alert” that prompts a hepatology consult and triggers the implementation of a standardized set of guidelines for addressing ascites, bleeding, acute kidney injury, encephalopathy, and hepatorenal syndrome. For those with decompensated cirrhosis or for those who need transplants, a similar standardized checklist can be systematized between the hospital and clinic, emphasizing inpatient rifaximin and prophylactic antibiotics in case of spontaneous bacterial peritonitis.
With an overt emphasis on the needs of patients and payers, clinicians now must compete with one another to offer the most comprehensive, cost-effective care supported by information technology structures that can assess real time costs and outcomes, said Dr. Younossi. “Hepatology is lagging behind other fields in all this,” he added.
This worries Dr. Kanwal: “We should be the ones to determine what the value should be. We should be the ones to decide what the model will be and to engage with other fields, and the payers. Otherwise we will not have a seat at the table.”
Dr. Kanwal and Dr. Younossi did not have any relevant financial disclosures.
On Twitter @whitneymcknight
BOSTON – As part of the push to create value-based care across the specialties, hepatologists should consider medical homes for their patients, such as those with cirrhosis, according to experts.
“Cirrhosis is a chronic condition, highly symptomatic, and occurs in highly comorbid individuals. Treating them in a medical home scenario means we can offer services that we don’t otherwise do, but which are associated with better outcomes for our patients,” Fasiha Kanwal, MD, of the department of medicine at Baylor College of Medicine, Houston, said in a panel presentation at the annual meeting of the American Association for the Study of Liver Diseases.
Essentially, value-based care is the evolution of evidence-based medicine, according to Zobair M. Younossi, MD, AGAF, FAASLD, chair of the department of medicine at Inova Fairfax (Va.) Hospital. With value-based care, aligned incentives across all the specialties will lead to more precise accounting and efficiencies of care, said Dr. Younossi, who was also on the panel. “It would be very difficult right now to ask a hospital to tell you exactly what the cost of their liver care would be,” he said.
However, at present there are no true value-based models for hepatology in the United States, according to Dr. Kanwal, so clinicians should start by defining what will “truly constitute value for our patients.”
Because psychosocial support is essential to improved outcomes in patients with cirrhosis, she suggested adding case managers in practice, as they can help coordinate with services in the community at large. Other suggestions she offered included extending office hours, operating an after-hours hotline, and building teams that include general internists, additional nursing staff, and nutritionists.
Even though such changes in clinical practice models now are inevitable, Dr. Kanwal said there are few data at present that support how to innovate care in hospitalized patients with cirrhosis. This matters, as how patients present for outpatient follow-up care will impact reimbursements to the clinicians who treat them.
Some possible ways to improve hospital outcomes for patients with cirrhosis include creating a “best practice alert” that prompts a hepatology consult and triggers the implementation of a standardized set of guidelines for addressing ascites, bleeding, acute kidney injury, encephalopathy, and hepatorenal syndrome. For those with decompensated cirrhosis or for those who need transplants, a similar standardized checklist can be systematized between the hospital and clinic, emphasizing inpatient rifaximin and prophylactic antibiotics in case of spontaneous bacterial peritonitis.
With an overt emphasis on the needs of patients and payers, clinicians now must compete with one another to offer the most comprehensive, cost-effective care supported by information technology structures that can assess real time costs and outcomes, said Dr. Younossi. “Hepatology is lagging behind other fields in all this,” he added.
This worries Dr. Kanwal: “We should be the ones to determine what the value should be. We should be the ones to decide what the model will be and to engage with other fields, and the payers. Otherwise we will not have a seat at the table.”
Dr. Kanwal and Dr. Younossi did not have any relevant financial disclosures.
On Twitter @whitneymcknight
BOSTON – As part of the push to create value-based care across the specialties, hepatologists should consider medical homes for their patients, such as those with cirrhosis, according to experts.
“Cirrhosis is a chronic condition, highly symptomatic, and occurs in highly comorbid individuals. Treating them in a medical home scenario means we can offer services that we don’t otherwise do, but which are associated with better outcomes for our patients,” Fasiha Kanwal, MD, of the department of medicine at Baylor College of Medicine, Houston, said in a panel presentation at the annual meeting of the American Association for the Study of Liver Diseases.
Essentially, value-based care is the evolution of evidence-based medicine, according to Zobair M. Younossi, MD, AGAF, FAASLD, chair of the department of medicine at Inova Fairfax (Va.) Hospital. With value-based care, aligned incentives across all the specialties will lead to more precise accounting and efficiencies of care, said Dr. Younossi, who was also on the panel. “It would be very difficult right now to ask a hospital to tell you exactly what the cost of their liver care would be,” he said.
However, at present there are no true value-based models for hepatology in the United States, according to Dr. Kanwal, so clinicians should start by defining what will “truly constitute value for our patients.”
Because psychosocial support is essential to improved outcomes in patients with cirrhosis, she suggested adding case managers in practice, as they can help coordinate with services in the community at large. Other suggestions she offered included extending office hours, operating an after-hours hotline, and building teams that include general internists, additional nursing staff, and nutritionists.
Even though such changes in clinical practice models now are inevitable, Dr. Kanwal said there are few data at present that support how to innovate care in hospitalized patients with cirrhosis. This matters, as how patients present for outpatient follow-up care will impact reimbursements to the clinicians who treat them.
Some possible ways to improve hospital outcomes for patients with cirrhosis include creating a “best practice alert” that prompts a hepatology consult and triggers the implementation of a standardized set of guidelines for addressing ascites, bleeding, acute kidney injury, encephalopathy, and hepatorenal syndrome. For those with decompensated cirrhosis or for those who need transplants, a similar standardized checklist can be systematized between the hospital and clinic, emphasizing inpatient rifaximin and prophylactic antibiotics in case of spontaneous bacterial peritonitis.
With an overt emphasis on the needs of patients and payers, clinicians now must compete with one another to offer the most comprehensive, cost-effective care supported by information technology structures that can assess real time costs and outcomes, said Dr. Younossi. “Hepatology is lagging behind other fields in all this,” he added.
This worries Dr. Kanwal: “We should be the ones to determine what the value should be. We should be the ones to decide what the model will be and to engage with other fields, and the payers. Otherwise we will not have a seat at the table.”
Dr. Kanwal and Dr. Younossi did not have any relevant financial disclosures.
On Twitter @whitneymcknight
EXPERT ANALYSIS FROM THE LIVER MEETING 2016
Recognizing, addressing giftedness can be challenging
SAN FRANCISCO – Gifted children are far too commonly misunderstood, mislabeled, and misdiagnosed, leading to a mismatch between their needs and others’ perceptions of their needs, Dan Peters, PhD, a licensed psychologist and executive director of the Summit Center in the greater San Francisco and Los Angeles areas, explained at the annual meeting of the American Academy of Pediatrics.
Too often, one or more of these children’s health, developmental, social-emotional or learning needs are overlooked, or they receive an inappropriate mental health, developmental and/or learning disorder diagnosis. In fact, many of the risk factors for giftedness resemble those of other conditions: underachievement, difficulties with peers, social isolation, power struggles, perfectionism, anxiety, and depression.
Further, those who are culturally or linguistically diverse may not be recognized if a non-English first language obscures their performance ability or their socioeconomic status or lack of resources and enrichment opportunities leads them to be overlooked. It’s therefore important that practitioners understand what giftedness actually is and the characteristics gifted children might exhibit.
Understanding giftedness
A simple definition of giftedness is demonstrating a performance or the capacity for performance that significantly exceeds age or grade-level expectations, according to one school district’s gifted and talented education program.
A more involved description provided by the Columbus Group in 1991 defines giftedness as an “asynchronous development in which advanced cognitive abilities and heightened intensity combine to create inner experiences and awareness that are qualitatively different from the norm.” This asynchrony increases with higher intellectual capacity, they wrote. “The uniqueness of the gifted renders them vulnerable and requires modifications in parenting, teaching, and counseling in order for them to develop optimally.”
The level of a child’s giftedness makes a difference in their needs as well; these levels include advanced learners (IQ of 120-129), moderately gifted (130-144), highly gifted (145-159), exceptionally gifted (160-179), and profoundly gifted (180 and greater). Different spheres of giftedness can include intellectual ability, creative or productive thinking, leadership ability, and visual or performing arts. Consider the list of common characteristics of gifted children that Dr. Peters provided:
- Rapid learners.
- Strong memory.
- Large vocabulary.
- Advanced comprehension of nuances.
- Largely self-taught.
- Unusual emotional depth.
- Abstract/complex/logical/insightful thinking.
- Idealism and a sense of justice.
- Intense feelings and reactions.
- Highly sensitive.
- Long attention span and persistence.
- Preoccupied with own thoughts.
- Impatient with self and others’ inabilities and slowness.
- Asks probing questions (able to go beyond what is taught).
- Wide range of interests.
- Highly developed curiosity.
- Interest in experimenting and doing things differently.
- Divergent thinking.
- Keen and unusual sense of humor.
Dr. Peters cited Kazimierz Dabrowski, MD, PhD, a Polish psychiatrist of the mid-20th century, as explaining the sensitivity and intensity experienced by many gifted individuals in terms of overexcitabilities – a “greater capacity to be stimulated by and respond to external and internal stimuli.”
“Overexcitability permeates a gifted person’s existence and gives energy to their intelligence, talents, and personality,” Dr. Peters explained of Dabrowski’s ideas. This enhancement manifests in psychomotor terms as a strong drive, a lot of energy or movement, or extended bouts of activity. Intellectually, gifted children have an “insatiable curiosity, and voracious appetite and capacity for intellectual effort and stimulation,” Dr. Peters said. They may have heightened sensual experience in seeing, smelling, tasting, touching, or hearing, and they have an active imaginary and fantasy life. They also exhibit a capacity for great emotional depth and empathy – they deeply feel their own and others’ emotions.
How giftedness can be misdiagnosed
It is the combination of these very characteristics that can lead gifted children to receive an inappropriate mental or developmental diagnosis instead of being recognized as gifted.
“By current estimates, at any given time, approximately 11%-20% of children in the United States have a behavioral or emotional disorder as defined in the DSM-5,” Dr. Peters cited. Further, one study found that diagnoses of attention-deficit/hyperactivity disorder have increased 66% between 2000 and 2010, with 90% of those children taking psychostimulant medications – yet a study in the Journal of Health Economics estimated that one in five children diagnosed with ADHD are probably misdiagnosed and are receiving those medications.
Other incorrect diagnoses besides ADHD that gifted youth may commonly receive include anger diagnoses, ideational or anxiety disorders, developmental and personality disorders, mood disorders, and learning disorders.
Twice exceptionalism (2e)
Even more challenging are twice exceptional children, or 2e, those who are both gifted and have a learning or emotional disability or challenge. Common dual diagnoses in gifted children include anxiety disorders, depression (or existential depression), sleep disorders (such as nightmares, night terrors, or sleep walking), allergies, asthma, ADHD, oppositional-defiant disorder, obsessive-compulsive personality disorder, autism spectrum disorder, nonverbal learning disability, social/pragmatic communication disorder, and learning disorders such as dyslexia, dyscalculia, central auditory processing disorder, or sensory-motor integration disorder.
“It’s very complex. What happens is, a lot of people think you’re either gifted or not,” Dr. Peters said. “In the classroom, sometimes the advanced ability overshadows the weakness and so we get a lot of readers with an IQ of 130-150 and reading at the 50% percentile, and everyone says they’re fine, but they’re dyslexic.”
Other times, the weakness overshadows the strength, and sometimes they’re right in the middle where neither their giftedness nor their disability is recognized or addressed, Peters said. 2e children are very difficult to diagnose but also at higher risk for difficulties if one or both (or more) of their diagnoses are missed.
Maximizing gifted children’s developmental potential
Pediatricians have an opportunity to support gifted children by recognizing and accepting them for who they are, while also acknowledging that they want to feel “normal,” and therefore need extra reassurance and support from adults. Pediatricians should seek information about giftedness and 2e children from state and national gifted organizations, and, in the office, frame conversations with families and children’s differential diagnoses in terms of a child’s giftedness. If a pediatrician is themself gifted, they may be “a supportive and kindred spirit” to the child, Dr. Peters said.
In daily life, as well, gifted children need to be accepted for who they are, provided opportunities to be with their intellectual and academic peers, and provided challenges in their areas of strength, interests, or passions. Parents and teachers should follow their lead in learning: Keep up the pace for those who want to learn fast, and go deeper for those who want slower, more in-depth learning. Adults also need to understand their intensities and sensitivities and lead with their strengths in discussions.
Dr. Peters reported no disclosures.
SAN FRANCISCO – Gifted children are far too commonly misunderstood, mislabeled, and misdiagnosed, leading to a mismatch between their needs and others’ perceptions of their needs, Dan Peters, PhD, a licensed psychologist and executive director of the Summit Center in the greater San Francisco and Los Angeles areas, explained at the annual meeting of the American Academy of Pediatrics.
Too often, one or more of these children’s health, developmental, social-emotional or learning needs are overlooked, or they receive an inappropriate mental health, developmental and/or learning disorder diagnosis. In fact, many of the risk factors for giftedness resemble those of other conditions: underachievement, difficulties with peers, social isolation, power struggles, perfectionism, anxiety, and depression.
Further, those who are culturally or linguistically diverse may not be recognized if a non-English first language obscures their performance ability or their socioeconomic status or lack of resources and enrichment opportunities leads them to be overlooked. It’s therefore important that practitioners understand what giftedness actually is and the characteristics gifted children might exhibit.
Understanding giftedness
A simple definition of giftedness is demonstrating a performance or the capacity for performance that significantly exceeds age or grade-level expectations, according to one school district’s gifted and talented education program.
A more involved description provided by the Columbus Group in 1991 defines giftedness as an “asynchronous development in which advanced cognitive abilities and heightened intensity combine to create inner experiences and awareness that are qualitatively different from the norm.” This asynchrony increases with higher intellectual capacity, they wrote. “The uniqueness of the gifted renders them vulnerable and requires modifications in parenting, teaching, and counseling in order for them to develop optimally.”
The level of a child’s giftedness makes a difference in their needs as well; these levels include advanced learners (IQ of 120-129), moderately gifted (130-144), highly gifted (145-159), exceptionally gifted (160-179), and profoundly gifted (180 and greater). Different spheres of giftedness can include intellectual ability, creative or productive thinking, leadership ability, and visual or performing arts. Consider the list of common characteristics of gifted children that Dr. Peters provided:
- Rapid learners.
- Strong memory.
- Large vocabulary.
- Advanced comprehension of nuances.
- Largely self-taught.
- Unusual emotional depth.
- Abstract/complex/logical/insightful thinking.
- Idealism and a sense of justice.
- Intense feelings and reactions.
- Highly sensitive.
- Long attention span and persistence.
- Preoccupied with own thoughts.
- Impatient with self and others’ inabilities and slowness.
- Asks probing questions (able to go beyond what is taught).
- Wide range of interests.
- Highly developed curiosity.
- Interest in experimenting and doing things differently.
- Divergent thinking.
- Keen and unusual sense of humor.
Dr. Peters cited Kazimierz Dabrowski, MD, PhD, a Polish psychiatrist of the mid-20th century, as explaining the sensitivity and intensity experienced by many gifted individuals in terms of overexcitabilities – a “greater capacity to be stimulated by and respond to external and internal stimuli.”
“Overexcitability permeates a gifted person’s existence and gives energy to their intelligence, talents, and personality,” Dr. Peters explained of Dabrowski’s ideas. This enhancement manifests in psychomotor terms as a strong drive, a lot of energy or movement, or extended bouts of activity. Intellectually, gifted children have an “insatiable curiosity, and voracious appetite and capacity for intellectual effort and stimulation,” Dr. Peters said. They may have heightened sensual experience in seeing, smelling, tasting, touching, or hearing, and they have an active imaginary and fantasy life. They also exhibit a capacity for great emotional depth and empathy – they deeply feel their own and others’ emotions.
How giftedness can be misdiagnosed
It is the combination of these very characteristics that can lead gifted children to receive an inappropriate mental or developmental diagnosis instead of being recognized as gifted.
“By current estimates, at any given time, approximately 11%-20% of children in the United States have a behavioral or emotional disorder as defined in the DSM-5,” Dr. Peters cited. Further, one study found that diagnoses of attention-deficit/hyperactivity disorder have increased 66% between 2000 and 2010, with 90% of those children taking psychostimulant medications – yet a study in the Journal of Health Economics estimated that one in five children diagnosed with ADHD are probably misdiagnosed and are receiving those medications.
Other incorrect diagnoses besides ADHD that gifted youth may commonly receive include anger diagnoses, ideational or anxiety disorders, developmental and personality disorders, mood disorders, and learning disorders.
Twice exceptionalism (2e)
Even more challenging are twice exceptional children, or 2e, those who are both gifted and have a learning or emotional disability or challenge. Common dual diagnoses in gifted children include anxiety disorders, depression (or existential depression), sleep disorders (such as nightmares, night terrors, or sleep walking), allergies, asthma, ADHD, oppositional-defiant disorder, obsessive-compulsive personality disorder, autism spectrum disorder, nonverbal learning disability, social/pragmatic communication disorder, and learning disorders such as dyslexia, dyscalculia, central auditory processing disorder, or sensory-motor integration disorder.
“It’s very complex. What happens is, a lot of people think you’re either gifted or not,” Dr. Peters said. “In the classroom, sometimes the advanced ability overshadows the weakness and so we get a lot of readers with an IQ of 130-150 and reading at the 50% percentile, and everyone says they’re fine, but they’re dyslexic.”
Other times, the weakness overshadows the strength, and sometimes they’re right in the middle where neither their giftedness nor their disability is recognized or addressed, Peters said. 2e children are very difficult to diagnose but also at higher risk for difficulties if one or both (or more) of their diagnoses are missed.
Maximizing gifted children’s developmental potential
Pediatricians have an opportunity to support gifted children by recognizing and accepting them for who they are, while also acknowledging that they want to feel “normal,” and therefore need extra reassurance and support from adults. Pediatricians should seek information about giftedness and 2e children from state and national gifted organizations, and, in the office, frame conversations with families and children’s differential diagnoses in terms of a child’s giftedness. If a pediatrician is themself gifted, they may be “a supportive and kindred spirit” to the child, Dr. Peters said.
In daily life, as well, gifted children need to be accepted for who they are, provided opportunities to be with their intellectual and academic peers, and provided challenges in their areas of strength, interests, or passions. Parents and teachers should follow their lead in learning: Keep up the pace for those who want to learn fast, and go deeper for those who want slower, more in-depth learning. Adults also need to understand their intensities and sensitivities and lead with their strengths in discussions.
Dr. Peters reported no disclosures.
SAN FRANCISCO – Gifted children are far too commonly misunderstood, mislabeled, and misdiagnosed, leading to a mismatch between their needs and others’ perceptions of their needs, Dan Peters, PhD, a licensed psychologist and executive director of the Summit Center in the greater San Francisco and Los Angeles areas, explained at the annual meeting of the American Academy of Pediatrics.
Too often, one or more of these children’s health, developmental, social-emotional or learning needs are overlooked, or they receive an inappropriate mental health, developmental and/or learning disorder diagnosis. In fact, many of the risk factors for giftedness resemble those of other conditions: underachievement, difficulties with peers, social isolation, power struggles, perfectionism, anxiety, and depression.
Further, those who are culturally or linguistically diverse may not be recognized if a non-English first language obscures their performance ability or their socioeconomic status or lack of resources and enrichment opportunities leads them to be overlooked. It’s therefore important that practitioners understand what giftedness actually is and the characteristics gifted children might exhibit.
Understanding giftedness
A simple definition of giftedness is demonstrating a performance or the capacity for performance that significantly exceeds age or grade-level expectations, according to one school district’s gifted and talented education program.
A more involved description provided by the Columbus Group in 1991 defines giftedness as an “asynchronous development in which advanced cognitive abilities and heightened intensity combine to create inner experiences and awareness that are qualitatively different from the norm.” This asynchrony increases with higher intellectual capacity, they wrote. “The uniqueness of the gifted renders them vulnerable and requires modifications in parenting, teaching, and counseling in order for them to develop optimally.”
The level of a child’s giftedness makes a difference in their needs as well; these levels include advanced learners (IQ of 120-129), moderately gifted (130-144), highly gifted (145-159), exceptionally gifted (160-179), and profoundly gifted (180 and greater). Different spheres of giftedness can include intellectual ability, creative or productive thinking, leadership ability, and visual or performing arts. Consider the list of common characteristics of gifted children that Dr. Peters provided:
- Rapid learners.
- Strong memory.
- Large vocabulary.
- Advanced comprehension of nuances.
- Largely self-taught.
- Unusual emotional depth.
- Abstract/complex/logical/insightful thinking.
- Idealism and a sense of justice.
- Intense feelings and reactions.
- Highly sensitive.
- Long attention span and persistence.
- Preoccupied with own thoughts.
- Impatient with self and others’ inabilities and slowness.
- Asks probing questions (able to go beyond what is taught).
- Wide range of interests.
- Highly developed curiosity.
- Interest in experimenting and doing things differently.
- Divergent thinking.
- Keen and unusual sense of humor.
Dr. Peters cited Kazimierz Dabrowski, MD, PhD, a Polish psychiatrist of the mid-20th century, as explaining the sensitivity and intensity experienced by many gifted individuals in terms of overexcitabilities – a “greater capacity to be stimulated by and respond to external and internal stimuli.”
“Overexcitability permeates a gifted person’s existence and gives energy to their intelligence, talents, and personality,” Dr. Peters explained of Dabrowski’s ideas. This enhancement manifests in psychomotor terms as a strong drive, a lot of energy or movement, or extended bouts of activity. Intellectually, gifted children have an “insatiable curiosity, and voracious appetite and capacity for intellectual effort and stimulation,” Dr. Peters said. They may have heightened sensual experience in seeing, smelling, tasting, touching, or hearing, and they have an active imaginary and fantasy life. They also exhibit a capacity for great emotional depth and empathy – they deeply feel their own and others’ emotions.
How giftedness can be misdiagnosed
It is the combination of these very characteristics that can lead gifted children to receive an inappropriate mental or developmental diagnosis instead of being recognized as gifted.
“By current estimates, at any given time, approximately 11%-20% of children in the United States have a behavioral or emotional disorder as defined in the DSM-5,” Dr. Peters cited. Further, one study found that diagnoses of attention-deficit/hyperactivity disorder have increased 66% between 2000 and 2010, with 90% of those children taking psychostimulant medications – yet a study in the Journal of Health Economics estimated that one in five children diagnosed with ADHD are probably misdiagnosed and are receiving those medications.
Other incorrect diagnoses besides ADHD that gifted youth may commonly receive include anger diagnoses, ideational or anxiety disorders, developmental and personality disorders, mood disorders, and learning disorders.
Twice exceptionalism (2e)
Even more challenging are twice exceptional children, or 2e, those who are both gifted and have a learning or emotional disability or challenge. Common dual diagnoses in gifted children include anxiety disorders, depression (or existential depression), sleep disorders (such as nightmares, night terrors, or sleep walking), allergies, asthma, ADHD, oppositional-defiant disorder, obsessive-compulsive personality disorder, autism spectrum disorder, nonverbal learning disability, social/pragmatic communication disorder, and learning disorders such as dyslexia, dyscalculia, central auditory processing disorder, or sensory-motor integration disorder.
“It’s very complex. What happens is, a lot of people think you’re either gifted or not,” Dr. Peters said. “In the classroom, sometimes the advanced ability overshadows the weakness and so we get a lot of readers with an IQ of 130-150 and reading at the 50% percentile, and everyone says they’re fine, but they’re dyslexic.”
Other times, the weakness overshadows the strength, and sometimes they’re right in the middle where neither their giftedness nor their disability is recognized or addressed, Peters said. 2e children are very difficult to diagnose but also at higher risk for difficulties if one or both (or more) of their diagnoses are missed.
Maximizing gifted children’s developmental potential
Pediatricians have an opportunity to support gifted children by recognizing and accepting them for who they are, while also acknowledging that they want to feel “normal,” and therefore need extra reassurance and support from adults. Pediatricians should seek information about giftedness and 2e children from state and national gifted organizations, and, in the office, frame conversations with families and children’s differential diagnoses in terms of a child’s giftedness. If a pediatrician is themself gifted, they may be “a supportive and kindred spirit” to the child, Dr. Peters said.
In daily life, as well, gifted children need to be accepted for who they are, provided opportunities to be with their intellectual and academic peers, and provided challenges in their areas of strength, interests, or passions. Parents and teachers should follow their lead in learning: Keep up the pace for those who want to learn fast, and go deeper for those who want slower, more in-depth learning. Adults also need to understand their intensities and sensitivities and lead with their strengths in discussions.
Dr. Peters reported no disclosures.
EXPERT ANALYSIS FROM AAP 16