KEYSTONE, COLO. – Research-minded otolaryngologists have gotten serious about conducting high-quality, patient-centered outcomes studies of endoscopic sinus surgery for chronic rhinosinusitis, which more than 250,000 Americans undergo each year. And the results are eye opening.

Mounting evidence documents that endoscopic sinus surgery (ESS) in properly selected patients with chronic rhinosinusitis (CRS) results in markedly improved quality of life, functional status, and reduced use of medications, compared with medical management, Dr. Todd T. Kingdom said at a meeting on allergy and respiratory diseases sponsored by National Jewish Health.

These studies utilize validated measures of patient-centered quality of life and symptoms. They are nothing like the lightweight, less-than-persuasive ESS research published in the 1990s, which reported glowing ‘success’ rates of 80%-97% in single-institution retrospective studies using variable inclusion criteria and often-sketchy definitions of success.

"Those data are not acceptable, but that’s what we had. This was before evidence-based medicine with an emphasis on rigorously designed studies took hold," explained Dr. Kingdom, professor and vice chairman of the department of otolaryngology – head and neck surgery, at the University of Colorado, Denver, and immediate past president of the American Rhinologic Society.

Current research emphasizes the use of modern, validated patient-centered quality of life tools and symptom scores because CRS is a symptom-based diagnosis and it is symptom severity that drives patients to seek treatment. Also, objective measures, such as the Lund-Mackay CT staging system, fail to capture the full experience of disease burden. Nor do objective measures necessarily correlate with patient symptoms, according to the otolaryngologist.

A low point in the field of sinus surgery, in Dr. Kingdom’s view, was the 2006 Cochrane systematic review which concluded ESS "has not been demonstrated to confer additional benefit to that obtained by medical therapy" (Cochrane Database Syst. Rev. 2006:CD004458).

"This review was a disservice," he asserted.

The review was based entirely on three older randomized trials, which not only did not use current treatment paradigms but also did not study the key research question, which Dr. Kingdom believes is this: What’s the comparative effectiveness of ESS vs. continued medical therapy in patients who’ve failed initial medical therapy?

He offered as an example of the contemporary approach to comparative outcomes research in the field of ESS a recent multicenter prospective study led by otolaryngologists at Oregon Health and Science University, Portland. It involved 1 year of prospective follow-up of patients with CRS who had failed initial medical therapy, at which point they elected to undergo ESS or further medical management.

The 65 patients who opted for ESS and the 50 whose chose more medical management were comparable in terms of baseline CRS severity and comorbidities. Both groups showed durable improvement at 12 months, compared with baseline. But ESS was the clear winner, with a mean 71% improvement in the validated Chronic Sinusitis Survey total score, compared with a 46% improvement in the medically managed group. Moreover, during the year of follow-up 17 patients switched over from medical management to ESS and they, too, showed significantly greater improvement than those who remained on medical management (Int. Forum Allergy Rhinol. 2013;3:236-41).

An earlier interim report featuring 6 months of followup showed the surgical group experienced roughly twofold greater improvement, compared with the medical cohort in endpoints including number of days on oral antibiotics or oral corticosteroids and missed days of work or school (Int. Forum Allergy Rhinol. 2011;1:235-41).

Cost-effectiveness studies by various research groups are in the pipeline. The early indication is that the data will show an economic advantage for ESS over medical therapy in patients with recalcitrant disease, according to Dr. Kingdom.

The next research frontier in surgical outcomes in CRS is identification of cellular and molecular markers of disease activity and their genetic underpinnings, which it’s hoped can be used to select the best candidates for ESS, he added.

Dr. Kingdom reported having no financial conflicts of interest.

[email protected]

KEYSTONE, COLO. – Research-minded otolaryngologists have gotten serious about conducting high-quality, patient-centered outcomes studies of endoscopic sinus surgery for chronic rhinosinusitis, which more than 250,000 Americans undergo each year. And the results are eye opening.

Mounting evidence documents that endoscopic sinus surgery (ESS) in properly selected patients with chronic rhinosinusitis (CRS) results in markedly improved quality of life, functional status, and reduced use of medications, compared with medical management, Dr. Todd T. Kingdom said at a meeting on allergy and respiratory diseases sponsored by National Jewish Health.

These studies utilize validated measures of patient-centered quality of life and symptoms. They are nothing like the lightweight, less-than-persuasive ESS research published in the 1990s, which reported glowing ‘success’ rates of 80%-97% in single-institution retrospective studies using variable inclusion criteria and often-sketchy definitions of success.

"Those data are not acceptable, but that’s what we had. This was before evidence-based medicine with an emphasis on rigorously designed studies took hold," explained Dr. Kingdom, professor and vice chairman of the department of otolaryngology – head and neck surgery, at the University of Colorado, Denver, and immediate past president of the American Rhinologic Society.

Current research emphasizes the use of modern, validated patient-centered quality of life tools and symptom scores because CRS is a symptom-based diagnosis and it is symptom severity that drives patients to seek treatment. Also, objective measures, such as the Lund-Mackay CT staging system, fail to capture the full experience of disease burden. Nor do objective measures necessarily correlate with patient symptoms, according to the otolaryngologist.

A low point in the field of sinus surgery, in Dr. Kingdom’s view, was the 2006 Cochrane systematic review which concluded ESS "has not been demonstrated to confer additional benefit to that obtained by medical therapy" (Cochrane Database Syst. Rev. 2006:CD004458).

"This review was a disservice," he asserted.

The review was based entirely on three older randomized trials, which not only did not use current treatment paradigms but also did not study the key research question, which Dr. Kingdom believes is this: What’s the comparative effectiveness of ESS vs. continued medical therapy in patients who’ve failed initial medical therapy?

He offered as an example of the contemporary approach to comparative outcomes research in the field of ESS a recent multicenter prospective study led by otolaryngologists at Oregon Health and Science University, Portland. It involved 1 year of prospective follow-up of patients with CRS who had failed initial medical therapy, at which point they elected to undergo ESS or further medical management.

The 65 patients who opted for ESS and the 50 whose chose more medical management were comparable in terms of baseline CRS severity and comorbidities. Both groups showed durable improvement at 12 months, compared with baseline. But ESS was the clear winner, with a mean 71% improvement in the validated Chronic Sinusitis Survey total score, compared with a 46% improvement in the medically managed group. Moreover, during the year of follow-up 17 patients switched over from medical management to ESS and they, too, showed significantly greater improvement than those who remained on medical management (Int. Forum Allergy Rhinol. 2013;3:236-41).

An earlier interim report featuring 6 months of followup showed the surgical group experienced roughly twofold greater improvement, compared with the medical cohort in endpoints including number of days on oral antibiotics or oral corticosteroids and missed days of work or school (Int. Forum Allergy Rhinol. 2011;1:235-41).

Cost-effectiveness studies by various research groups are in the pipeline. The early indication is that the data will show an economic advantage for ESS over medical therapy in patients with recalcitrant disease, according to Dr. Kingdom.

The next research frontier in surgical outcomes in CRS is identification of cellular and molecular markers of disease activity and their genetic underpinnings, which it’s hoped can be used to select the best candidates for ESS, he added.

Dr. Kingdom reported having no financial conflicts of interest.

[email protected]

KEYSTONE, COLO. – Research-minded otolaryngologists have gotten serious about conducting high-quality, patient-centered outcomes studies of endoscopic sinus surgery for chronic rhinosinusitis, which more than 250,000 Americans undergo each year. And the results are eye opening.

Mounting evidence documents that endoscopic sinus surgery (ESS) in properly selected patients with chronic rhinosinusitis (CRS) results in markedly improved quality of life, functional status, and reduced use of medications, compared with medical management, Dr. Todd T. Kingdom said at a meeting on allergy and respiratory diseases sponsored by National Jewish Health.

These studies utilize validated measures of patient-centered quality of life and symptoms. They are nothing like the lightweight, less-than-persuasive ESS research published in the 1990s, which reported glowing ‘success’ rates of 80%-97% in single-institution retrospective studies using variable inclusion criteria and often-sketchy definitions of success.

"Those data are not acceptable, but that’s what we had. This was before evidence-based medicine with an emphasis on rigorously designed studies took hold," explained Dr. Kingdom, professor and vice chairman of the department of otolaryngology – head and neck surgery, at the University of Colorado, Denver, and immediate past president of the American Rhinologic Society.

Current research emphasizes the use of modern, validated patient-centered quality of life tools and symptom scores because CRS is a symptom-based diagnosis and it is symptom severity that drives patients to seek treatment. Also, objective measures, such as the Lund-Mackay CT staging system, fail to capture the full experience of disease burden. Nor do objective measures necessarily correlate with patient symptoms, according to the otolaryngologist.

A low point in the field of sinus surgery, in Dr. Kingdom’s view, was the 2006 Cochrane systematic review which concluded ESS "has not been demonstrated to confer additional benefit to that obtained by medical therapy" (Cochrane Database Syst. Rev. 2006:CD004458).

"This review was a disservice," he asserted.

The review was based entirely on three older randomized trials, which not only did not use current treatment paradigms but also did not study the key research question, which Dr. Kingdom believes is this: What’s the comparative effectiveness of ESS vs. continued medical therapy in patients who’ve failed initial medical therapy?

He offered as an example of the contemporary approach to comparative outcomes research in the field of ESS a recent multicenter prospective study led by otolaryngologists at Oregon Health and Science University, Portland. It involved 1 year of prospective follow-up of patients with CRS who had failed initial medical therapy, at which point they elected to undergo ESS or further medical management.

The 65 patients who opted for ESS and the 50 whose chose more medical management were comparable in terms of baseline CRS severity and comorbidities. Both groups showed durable improvement at 12 months, compared with baseline. But ESS was the clear winner, with a mean 71% improvement in the validated Chronic Sinusitis Survey total score, compared with a 46% improvement in the medically managed group. Moreover, during the year of follow-up 17 patients switched over from medical management to ESS and they, too, showed significantly greater improvement than those who remained on medical management (Int. Forum Allergy Rhinol. 2013;3:236-41).

An earlier interim report featuring 6 months of followup showed the surgical group experienced roughly twofold greater improvement, compared with the medical cohort in endpoints including number of days on oral antibiotics or oral corticosteroids and missed days of work or school (Int. Forum Allergy Rhinol. 2011;1:235-41).

Cost-effectiveness studies by various research groups are in the pipeline. The early indication is that the data will show an economic advantage for ESS over medical therapy in patients with recalcitrant disease, according to Dr. Kingdom.

The next research frontier in surgical outcomes in CRS is identification of cellular and molecular markers of disease activity and their genetic underpinnings, which it’s hoped can be used to select the best candidates for ESS, he added.

Dr. Kingdom reported having no financial conflicts of interest.

[email protected]

In the jail cell I had appropriated as an office, the toilet was broken. The metal toilet bowl was wrapped carelessly in heavy plastic and the plastic was anchored in place by gray duct tape. The window opened hopefully to about 4 inches, just enough to let in the August humidity. Outside, the temperature reached 90 F. Inside the cell, the temperature was easily over 100° F. I was wilting, my patients were wilting, and I left the building at the end of the morning soaked in sweat carrying stacks of damp paper. For the first time since I was an intern, I donned a pair of surgical scrubs because the building was too intolerable for wearing street clothes. This was the legacy of my jail. The facility was opened in 1859, well before the invention of modern heating and air conditioning.

Thanks to the intervention of the Department of Justice, some improvements were made. Certain tiers were given air-conditioning units and designated for the housing of inmates vulnerable to heat exhaustion. Intake procedures were modified to identify and stratify new detainees according to their medical needs and heat tolerance. Inmates were given education on the symptoms of heat exhaustion and how to prevent it. Eventually summer passed, and I was able to lose the surgical scrubs and slip back into street clothes.

Yet the remaining need for a new jail was obvious to anyone working in the facility or incarcerated there. A recent legislative inquiry pointed out the security risks posed by the antiquated tier structures and other hazards. In the report published later, the cost of a new jail was estimated to be $553 million.

The protest started almost immediately. People wrote to the local newspaper to object to the idea of spending money on incarceration rather than crime prevention. Advocacy groups carved out territorial niches to promote diversion of juveniles, pregnant women, and the mentally ill, apparently leaving any prisoner who didn’t fit into one of those categories to fend for himself. In the end, the jail – which opened at a time when there were only 33 states in the union, the year that "A Tale of Two Cities" and "On the Origin of Species" were published, and when the works of Johannes Brahms were being heard for the first time – remained untouched.

These memories returned quickly after reading a recent New York Times story about a homeless veteran with mental illness who died in his jail cell, presumably because of excessive heat. The man had been incarcerated for a misdemeanor and held only because he couldn’t make bail. The fact that this happened in winter tells me a lot about the nature of the facility’s heating and ventilation system.

The first thing that struck me about this story was the need to invoke certain adjectives, as though readers would not care about the story if the prisoner who died was not mentally ill or was not a veteran. There may be some truth to that concern. When it comes to prison reform, I’ve seen the tendency within psychiatry to limit discussions only to conditions as they affect the mentally ill. This was not always the case. Dr. Benjamin Rush, founder of Pennsylvania Hospital, also founded one of the first prison reformation societies. He advocated humane care for everyone in the facility, not just a certain faction.

Unless someone figures out how to "cure" crime, we will always need jails and prisons. Building a new facility is neither a failure nor a waste of resources. It may be the beginning of a long-term commitment to rehabilitation.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work." The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

In the jail cell I had appropriated as an office, the toilet was broken. The metal toilet bowl was wrapped carelessly in heavy plastic and the plastic was anchored in place by gray duct tape. The window opened hopefully to about 4 inches, just enough to let in the August humidity. Outside, the temperature reached 90 F. Inside the cell, the temperature was easily over 100° F. I was wilting, my patients were wilting, and I left the building at the end of the morning soaked in sweat carrying stacks of damp paper. For the first time since I was an intern, I donned a pair of surgical scrubs because the building was too intolerable for wearing street clothes. This was the legacy of my jail. The facility was opened in 1859, well before the invention of modern heating and air conditioning.

Thanks to the intervention of the Department of Justice, some improvements were made. Certain tiers were given air-conditioning units and designated for the housing of inmates vulnerable to heat exhaustion. Intake procedures were modified to identify and stratify new detainees according to their medical needs and heat tolerance. Inmates were given education on the symptoms of heat exhaustion and how to prevent it. Eventually summer passed, and I was able to lose the surgical scrubs and slip back into street clothes.

Yet the remaining need for a new jail was obvious to anyone working in the facility or incarcerated there. A recent legislative inquiry pointed out the security risks posed by the antiquated tier structures and other hazards. In the report published later, the cost of a new jail was estimated to be $553 million.

The protest started almost immediately. People wrote to the local newspaper to object to the idea of spending money on incarceration rather than crime prevention. Advocacy groups carved out territorial niches to promote diversion of juveniles, pregnant women, and the mentally ill, apparently leaving any prisoner who didn’t fit into one of those categories to fend for himself. In the end, the jail – which opened at a time when there were only 33 states in the union, the year that "A Tale of Two Cities" and "On the Origin of Species" were published, and when the works of Johannes Brahms were being heard for the first time – remained untouched.

These memories returned quickly after reading a recent New York Times story about a homeless veteran with mental illness who died in his jail cell, presumably because of excessive heat. The man had been incarcerated for a misdemeanor and held only because he couldn’t make bail. The fact that this happened in winter tells me a lot about the nature of the facility’s heating and ventilation system.

The first thing that struck me about this story was the need to invoke certain adjectives, as though readers would not care about the story if the prisoner who died was not mentally ill or was not a veteran. There may be some truth to that concern. When it comes to prison reform, I’ve seen the tendency within psychiatry to limit discussions only to conditions as they affect the mentally ill. This was not always the case. Dr. Benjamin Rush, founder of Pennsylvania Hospital, also founded one of the first prison reformation societies. He advocated humane care for everyone in the facility, not just a certain faction.

Unless someone figures out how to "cure" crime, we will always need jails and prisons. Building a new facility is neither a failure nor a waste of resources. It may be the beginning of a long-term commitment to rehabilitation.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work." The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

In the jail cell I had appropriated as an office, the toilet was broken. The metal toilet bowl was wrapped carelessly in heavy plastic and the plastic was anchored in place by gray duct tape. The window opened hopefully to about 4 inches, just enough to let in the August humidity. Outside, the temperature reached 90 F. Inside the cell, the temperature was easily over 100° F. I was wilting, my patients were wilting, and I left the building at the end of the morning soaked in sweat carrying stacks of damp paper. For the first time since I was an intern, I donned a pair of surgical scrubs because the building was too intolerable for wearing street clothes. This was the legacy of my jail. The facility was opened in 1859, well before the invention of modern heating and air conditioning.

Thanks to the intervention of the Department of Justice, some improvements were made. Certain tiers were given air-conditioning units and designated for the housing of inmates vulnerable to heat exhaustion. Intake procedures were modified to identify and stratify new detainees according to their medical needs and heat tolerance. Inmates were given education on the symptoms of heat exhaustion and how to prevent it. Eventually summer passed, and I was able to lose the surgical scrubs and slip back into street clothes.

Yet the remaining need for a new jail was obvious to anyone working in the facility or incarcerated there. A recent legislative inquiry pointed out the security risks posed by the antiquated tier structures and other hazards. In the report published later, the cost of a new jail was estimated to be $553 million.

The protest started almost immediately. People wrote to the local newspaper to object to the idea of spending money on incarceration rather than crime prevention. Advocacy groups carved out territorial niches to promote diversion of juveniles, pregnant women, and the mentally ill, apparently leaving any prisoner who didn’t fit into one of those categories to fend for himself. In the end, the jail – which opened at a time when there were only 33 states in the union, the year that "A Tale of Two Cities" and "On the Origin of Species" were published, and when the works of Johannes Brahms were being heard for the first time – remained untouched.

These memories returned quickly after reading a recent New York Times story about a homeless veteran with mental illness who died in his jail cell, presumably because of excessive heat. The man had been incarcerated for a misdemeanor and held only because he couldn’t make bail. The fact that this happened in winter tells me a lot about the nature of the facility’s heating and ventilation system.

The first thing that struck me about this story was the need to invoke certain adjectives, as though readers would not care about the story if the prisoner who died was not mentally ill or was not a veteran. There may be some truth to that concern. When it comes to prison reform, I’ve seen the tendency within psychiatry to limit discussions only to conditions as they affect the mentally ill. This was not always the case. Dr. Benjamin Rush, founder of Pennsylvania Hospital, also founded one of the first prison reformation societies. He advocated humane care for everyone in the facility, not just a certain faction.

Unless someone figures out how to "cure" crime, we will always need jails and prisons. Building a new facility is neither a failure nor a waste of resources. It may be the beginning of a long-term commitment to rehabilitation.

Dr. Hanson is a forensic psychiatrist and coauthor of "Shrink Rap: Three Psychiatrists Explain Their Work." The opinions expressed are those of the author only, and do not represent those of any of Dr. Hanson’s employers or consultees, including the Maryland Department of Health and Mental Hygiene or the Maryland Division of Correction.

Mr. V, age 29, is a US Army veteran who presents to the psychiatric emergen­cy department because of increasing aggression. He recently returned from deployment overseas and lives with his parents. Mr. V’s mother reports that he has been in­creasingly “unstable” and describes an inci­dent during which he punched a hole in his bedroom window after a temporary slow-down in the home’s Internet connection.

The workup and review of the history rules out substance abuse, posttraumatic stress dis­order, bipolar disorder, seizure disorder, and personality disorders. He is currently taking only omeprazole, 40 mg/d, for acid reflux. The psychiatrist considers prescribing an antiepi­leptic medication to treat the agitation. Why this choice of agent?

According to DSM-5, patients who have re­peated episodes of aggression can be given a diagnosis of intermittent explosive disor­der, but such behavior can occur secondary to other psychiatric diagnoses (Table 1). No medications are FDA approved for aggression.¹

Aggression and associated verbal and physical acts fall into 2 subtypes: impulsive type and premeditated (predatory) type. Impulsive aggression generally is described as an emotionally charged aggressive response characterized by a loss of behavioral control.

Premeditated aggression

Pharmacotherapy is directed primarily at treating impulsive aggression because this subtype is thought to be caused by neurologic deficits that can affect a person’s ability to process, and react appropriately to, external stimuli. Agitation can result from neuronal hyperactivity.² Agents such as antiepileptic drugs (AEDs) have the potential to reduce the intensity and frequency of such behaviors.²

In this article, we focus on the use of AEDs for treating impulsive aggression in adults.

Reviewing the evidence for AEDs
The neurobiology of aggression involves multiple neurotransmitters, intracellular pathways, and ion channels.³ AEDs have several mechanisms of action, however; pri­mary mechanisms include action on sodium and calcium channels and modulation of γ-aminobutyric acid (GABA), glutamate, and carbonic anhydrase.^2,3 Agent-specific mecha­nisms of actions are listed in Table 2.

Phenytoin. Several double-blind, placebo-controlled trials have found a statistically significant difference between phenytoin and placebo for treating impulsive aggres­sion, as measured by the Overt Aggression Scale (OAS)a or a modified version (MOAS/ OAS-M).^1,2,4 Researchers found that phenyt­oin, 300 mg/d, but not 100 mg/d, decreased impulsive aggression.<sup>4

a</sup> Studies generally used the OAS, or one of its modifications, to evaluate aggressive behavior.^2,4

Valproate. Trials of valproate for decreasing aggressive behaviors have produced mixed results with regard to primary outcome when used at standard dosages and within the ther­apeutic range measured by serum concentra­tion.^2,3 In a pooled analysis of studies that met stringent criteria (randomized, controlled tri­al, aggressive behavior as primary outcome, patients free of organic illness or neurologic illness), Jones and colleagues¹ reported that valproate/divalproex did not produce statis­tically significant results compared with pla­cebo for treating impulsive aggression. 

Carbamazepine and oxcarbazepine. Double-blind, placebo-controlled trials and case studies of carbamazepine have shown mixed results. In contrast, oxcarbazepine has been found to significantly decrease aggres­sive behavior, measured by OAS/MOAS/ OAS-M scores.^2,3 Total daily dosages of ox­carbazepine ranged from 1,500 to 2,400 mg.^2-4 It has been speculated that oxcarbazepine might be a useful option for treating impul­sive aggression because of its therapeutic val­ue in temporal lobe seizures—a subtype of seizure disorder that involves the limbic sys­tem, which also modulates aggressiveness.⁵

Additionally, when compared with carba­mazepine, oxcarbazepine has a lower risk of cardiotoxicity, neurotoxicity, and blood dys­crasia. Oxcarbazepine has fewer drug-drug interactions because of a lower degree of he­patic enzyme induction.

Topiramate. Several studies have confirmed the efficacy of topiramate for aggressive be­havior.^2,3 However, there have been reports that topiramate can induce or exacerbate aggression in some patients, an effect that might be dose-related. Aggression might respond better to a higher, short-term dos­age (eg, 400 mg/d) than to lower (100 to 300 mg/d) dosages, which might exacerbate aggression.³

Gabapentin. Research on using gabapen­tin for aggression is limited. Speculation is that the combined activity of gabapentin on GABA and glutamate give the drug its anti­aggressive effect.³ No randomized, double-blind, placebo-controlled trials are underway comparing gabapentin and placebo or other active medication for impulsive aggression.

Some case reports and small-scale, open-label studies report a decrease in aggression with gabapentin. As is the case with topira­mate, a lower dosage (200 mg to 400 mg) has been reported to result in increased aggres­sion—whereas a higher dosages (800 mg) decreases aggressive behavior.^2,3

Lamotrigine. The results of several studies, including double-blind, placebo-controlled trials, support the use of lamotrigine for ag­gressive behavior. A number of these studies, however, used scales other than OAS (or its modifications) to determine this outcome. One trial showed increased aggression in several patients on lower-dosage lamotrigine (100 mg/d) that resolved when the dosage was increased.^2,3

Treatment recommendations
Although all AEDs have some documented efficacy against aggression, choosing the ap­propriate agent depends on patient-specific variables. Avoiding divalproex in patients with liver dysfunction, for example, or car­bamazepine in those with a preexisting car­diac conduction abnormality will improve outcomes by avoiding complications.

It is important to rule out all other causes of aggression before selecting a treatment. The presence of one or more of the diagnoses listed in Table 1 could lead to selection of an alternate class of medication. Nondrug ther­apies, such as cognitive-behavioral therapy, also should be considered.
 

Related Resources
• Coccaro EF. Aggression. Psychiatric assessment and treat­ment. Chicago, IL: Marcel Dekker, Inc.; 2003.
• Citrome LL. Aggression. http://emedicine.medscape.com/article/288689-overview. Updated June 18, 2012. Accessed February 28, 2014.
 

Drug Brand Names
Carbamazepine • Tegretol                 Phenytoin • Dilantin
Gabapentin • Neurontin                    Topiramate • Topamax
Lamotrigine • Lamictal                      Valproate/Divalproex
Omeprazole • Prilosec                          • Depakote           
Oxcarbazepine • Trileptal

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. V, age 29, is a US Army veteran who presents to the psychiatric emergen­cy department because of increasing aggression. He recently returned from deployment overseas and lives with his parents. Mr. V’s mother reports that he has been in­creasingly “unstable” and describes an inci­dent during which he punched a hole in his bedroom window after a temporary slow-down in the home’s Internet connection.

The workup and review of the history rules out substance abuse, posttraumatic stress dis­order, bipolar disorder, seizure disorder, and personality disorders. He is currently taking only omeprazole, 40 mg/d, for acid reflux. The psychiatrist considers prescribing an antiepi­leptic medication to treat the agitation. Why this choice of agent?

According to DSM-5, patients who have re­peated episodes of aggression can be given a diagnosis of intermittent explosive disor­der, but such behavior can occur secondary to other psychiatric diagnoses (Table 1). No medications are FDA approved for aggression.¹

Aggression and associated verbal and physical acts fall into 2 subtypes: impulsive type and premeditated (predatory) type. Impulsive aggression generally is described as an emotionally charged aggressive response characterized by a loss of behavioral control.

Premeditated aggression

Pharmacotherapy is directed primarily at treating impulsive aggression because this subtype is thought to be caused by neurologic deficits that can affect a person’s ability to process, and react appropriately to, external stimuli. Agitation can result from neuronal hyperactivity.² Agents such as antiepileptic drugs (AEDs) have the potential to reduce the intensity and frequency of such behaviors.²

In this article, we focus on the use of AEDs for treating impulsive aggression in adults.

Reviewing the evidence for AEDs
The neurobiology of aggression involves multiple neurotransmitters, intracellular pathways, and ion channels.³ AEDs have several mechanisms of action, however; pri­mary mechanisms include action on sodium and calcium channels and modulation of γ-aminobutyric acid (GABA), glutamate, and carbonic anhydrase.^2,3 Agent-specific mecha­nisms of actions are listed in Table 2.

Phenytoin. Several double-blind, placebo-controlled trials have found a statistically significant difference between phenytoin and placebo for treating impulsive aggres­sion, as measured by the Overt Aggression Scale (OAS)a or a modified version (MOAS/ OAS-M).^1,2,4 Researchers found that phenyt­oin, 300 mg/d, but not 100 mg/d, decreased impulsive aggression.<sup>4

a</sup> Studies generally used the OAS, or one of its modifications, to evaluate aggressive behavior.^2,4

Valproate. Trials of valproate for decreasing aggressive behaviors have produced mixed results with regard to primary outcome when used at standard dosages and within the ther­apeutic range measured by serum concentra­tion.^2,3 In a pooled analysis of studies that met stringent criteria (randomized, controlled tri­al, aggressive behavior as primary outcome, patients free of organic illness or neurologic illness), Jones and colleagues¹ reported that valproate/divalproex did not produce statis­tically significant results compared with pla­cebo for treating impulsive aggression. 

Carbamazepine and oxcarbazepine. Double-blind, placebo-controlled trials and case studies of carbamazepine have shown mixed results. In contrast, oxcarbazepine has been found to significantly decrease aggres­sive behavior, measured by OAS/MOAS/ OAS-M scores.^2,3 Total daily dosages of ox­carbazepine ranged from 1,500 to 2,400 mg.^2-4 It has been speculated that oxcarbazepine might be a useful option for treating impul­sive aggression because of its therapeutic val­ue in temporal lobe seizures—a subtype of seizure disorder that involves the limbic sys­tem, which also modulates aggressiveness.⁵

Additionally, when compared with carba­mazepine, oxcarbazepine has a lower risk of cardiotoxicity, neurotoxicity, and blood dys­crasia. Oxcarbazepine has fewer drug-drug interactions because of a lower degree of he­patic enzyme induction.

Topiramate. Several studies have confirmed the efficacy of topiramate for aggressive be­havior.^2,3 However, there have been reports that topiramate can induce or exacerbate aggression in some patients, an effect that might be dose-related. Aggression might respond better to a higher, short-term dos­age (eg, 400 mg/d) than to lower (100 to 300 mg/d) dosages, which might exacerbate aggression.³

Gabapentin. Research on using gabapen­tin for aggression is limited. Speculation is that the combined activity of gabapentin on GABA and glutamate give the drug its anti­aggressive effect.³ No randomized, double-blind, placebo-controlled trials are underway comparing gabapentin and placebo or other active medication for impulsive aggression.

Some case reports and small-scale, open-label studies report a decrease in aggression with gabapentin. As is the case with topira­mate, a lower dosage (200 mg to 400 mg) has been reported to result in increased aggres­sion—whereas a higher dosages (800 mg) decreases aggressive behavior.^2,3

Lamotrigine. The results of several studies, including double-blind, placebo-controlled trials, support the use of lamotrigine for ag­gressive behavior. A number of these studies, however, used scales other than OAS (or its modifications) to determine this outcome. One trial showed increased aggression in several patients on lower-dosage lamotrigine (100 mg/d) that resolved when the dosage was increased.^2,3

Treatment recommendations
Although all AEDs have some documented efficacy against aggression, choosing the ap­propriate agent depends on patient-specific variables. Avoiding divalproex in patients with liver dysfunction, for example, or car­bamazepine in those with a preexisting car­diac conduction abnormality will improve outcomes by avoiding complications.

It is important to rule out all other causes of aggression before selecting a treatment. The presence of one or more of the diagnoses listed in Table 1 could lead to selection of an alternate class of medication. Nondrug ther­apies, such as cognitive-behavioral therapy, also should be considered.
 

Related Resources
• Coccaro EF. Aggression. Psychiatric assessment and treat­ment. Chicago, IL: Marcel Dekker, Inc.; 2003.
• Citrome LL. Aggression. http://emedicine.medscape.com/article/288689-overview. Updated June 18, 2012. Accessed February 28, 2014.
 

Drug Brand Names
Carbamazepine • Tegretol                 Phenytoin • Dilantin
Gabapentin • Neurontin                    Topiramate • Topamax
Lamotrigine • Lamictal                      Valproate/Divalproex
Omeprazole • Prilosec                          • Depakote           
Oxcarbazepine • Trileptal

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

Mr. V, age 29, is a US Army veteran who presents to the psychiatric emergen­cy department because of increasing aggression. He recently returned from deployment overseas and lives with his parents. Mr. V’s mother reports that he has been in­creasingly “unstable” and describes an inci­dent during which he punched a hole in his bedroom window after a temporary slow-down in the home’s Internet connection.

The workup and review of the history rules out substance abuse, posttraumatic stress dis­order, bipolar disorder, seizure disorder, and personality disorders. He is currently taking only omeprazole, 40 mg/d, for acid reflux. The psychiatrist considers prescribing an antiepi­leptic medication to treat the agitation. Why this choice of agent?

According to DSM-5, patients who have re­peated episodes of aggression can be given a diagnosis of intermittent explosive disor­der, but such behavior can occur secondary to other psychiatric diagnoses (Table 1). No medications are FDA approved for aggression.¹

Aggression and associated verbal and physical acts fall into 2 subtypes: impulsive type and premeditated (predatory) type. Impulsive aggression generally is described as an emotionally charged aggressive response characterized by a loss of behavioral control.

Premeditated aggression

Pharmacotherapy is directed primarily at treating impulsive aggression because this subtype is thought to be caused by neurologic deficits that can affect a person’s ability to process, and react appropriately to, external stimuli. Agitation can result from neuronal hyperactivity.² Agents such as antiepileptic drugs (AEDs) have the potential to reduce the intensity and frequency of such behaviors.²

In this article, we focus on the use of AEDs for treating impulsive aggression in adults.

Reviewing the evidence for AEDs
The neurobiology of aggression involves multiple neurotransmitters, intracellular pathways, and ion channels.³ AEDs have several mechanisms of action, however; pri­mary mechanisms include action on sodium and calcium channels and modulation of γ-aminobutyric acid (GABA), glutamate, and carbonic anhydrase.^2,3 Agent-specific mecha­nisms of actions are listed in Table 2.

Phenytoin. Several double-blind, placebo-controlled trials have found a statistically significant difference between phenytoin and placebo for treating impulsive aggres­sion, as measured by the Overt Aggression Scale (OAS)a or a modified version (MOAS/ OAS-M).^1,2,4 Researchers found that phenyt­oin, 300 mg/d, but not 100 mg/d, decreased impulsive aggression.<sup>4

a</sup> Studies generally used the OAS, or one of its modifications, to evaluate aggressive behavior.^2,4

Valproate. Trials of valproate for decreasing aggressive behaviors have produced mixed results with regard to primary outcome when used at standard dosages and within the ther­apeutic range measured by serum concentra­tion.^2,3 In a pooled analysis of studies that met stringent criteria (randomized, controlled tri­al, aggressive behavior as primary outcome, patients free of organic illness or neurologic illness), Jones and colleagues¹ reported that valproate/divalproex did not produce statis­tically significant results compared with pla­cebo for treating impulsive aggression. 

Carbamazepine and oxcarbazepine. Double-blind, placebo-controlled trials and case studies of carbamazepine have shown mixed results. In contrast, oxcarbazepine has been found to significantly decrease aggres­sive behavior, measured by OAS/MOAS/ OAS-M scores.^2,3 Total daily dosages of ox­carbazepine ranged from 1,500 to 2,400 mg.^2-4 It has been speculated that oxcarbazepine might be a useful option for treating impul­sive aggression because of its therapeutic val­ue in temporal lobe seizures—a subtype of seizure disorder that involves the limbic sys­tem, which also modulates aggressiveness.⁵

Additionally, when compared with carba­mazepine, oxcarbazepine has a lower risk of cardiotoxicity, neurotoxicity, and blood dys­crasia. Oxcarbazepine has fewer drug-drug interactions because of a lower degree of he­patic enzyme induction.

Topiramate. Several studies have confirmed the efficacy of topiramate for aggressive be­havior.^2,3 However, there have been reports that topiramate can induce or exacerbate aggression in some patients, an effect that might be dose-related. Aggression might respond better to a higher, short-term dos­age (eg, 400 mg/d) than to lower (100 to 300 mg/d) dosages, which might exacerbate aggression.³

Gabapentin. Research on using gabapen­tin for aggression is limited. Speculation is that the combined activity of gabapentin on GABA and glutamate give the drug its anti­aggressive effect.³ No randomized, double-blind, placebo-controlled trials are underway comparing gabapentin and placebo or other active medication for impulsive aggression.

Some case reports and small-scale, open-label studies report a decrease in aggression with gabapentin. As is the case with topira­mate, a lower dosage (200 mg to 400 mg) has been reported to result in increased aggres­sion—whereas a higher dosages (800 mg) decreases aggressive behavior.^2,3

Lamotrigine. The results of several studies, including double-blind, placebo-controlled trials, support the use of lamotrigine for ag­gressive behavior. A number of these studies, however, used scales other than OAS (or its modifications) to determine this outcome. One trial showed increased aggression in several patients on lower-dosage lamotrigine (100 mg/d) that resolved when the dosage was increased.^2,3

Treatment recommendations
Although all AEDs have some documented efficacy against aggression, choosing the ap­propriate agent depends on patient-specific variables. Avoiding divalproex in patients with liver dysfunction, for example, or car­bamazepine in those with a preexisting car­diac conduction abnormality will improve outcomes by avoiding complications.

It is important to rule out all other causes of aggression before selecting a treatment. The presence of one or more of the diagnoses listed in Table 1 could lead to selection of an alternate class of medication. Nondrug ther­apies, such as cognitive-behavioral therapy, also should be considered.
 

Related Resources
• Coccaro EF. Aggression. Psychiatric assessment and treat­ment. Chicago, IL: Marcel Dekker, Inc.; 2003.
• Citrome LL. Aggression. http://emedicine.medscape.com/article/288689-overview. Updated June 18, 2012. Accessed February 28, 2014.
 

Drug Brand Names
Carbamazepine • Tegretol                 Phenytoin • Dilantin
Gabapentin • Neurontin                    Topiramate • Topamax
Lamotrigine • Lamictal                      Valproate/Divalproex
Omeprazole • Prilosec                          • Depakote           
Oxcarbazepine • Trileptal

Disclosure
The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

WASHINGTON – Obesity requires a medical definition that goes beyond gauging a person’s body mass index if cost-effective care is to be delivered in an integrated fashion, according to a consensus statement issued by the American Association of Clinical Endocrinologists and the American College of Endocrinology.

"The definition of obesity as a disease is not perfect," Dr. W. Timothy Garvey, who chaired the AACE/ACE Obesity Consensus Conference, said in a media briefing. "We rely upon an [anthropometric] measure of body mass index, which is a measure of height versus weight, and there was consensus that this was ... divorced from the impact of weight gain on the health of the individual. This imprecision in our diagnosis of obesity was constraining us."

In 2013, the American Medical Association officially recognized obesity as a disease. Better codification of what actually constitutes "obesity, the disease," will allow a more integrated and effective approach to treating it, said Dr. Garvey, professor of medicine and chair of the department of nutrition sciences at the University of Alabama at Birmingham. To do so, the AACE/ACE held an intensive, 2-day session that largely featured spontaneous discussions between panelists and audience members representing four specific obesity "pillars": biomedical, government and regulation, health industry and economics, and research and education sectors.

A constant theme across the sectors was the need for a definition of obesity that accounts for cultural differences, ethnicity, and the presence or absence of cardiometabolic markers of disease in persons who are overweight or obese.

The conference’s multidisciplined approach informed the consensus statement that obesity is a chronic disease that should be treated with the established AACE/ACE obesity algorithm and met with lifestyle interventions. The consensus statement also addressed our current "obesogenic" environment, which many participants said was created in part by the abundance of nonnutritious foods.

In an interview, Dr. Susan Kansagra, deputy commissioner of the New York City Department of Health and Mental Hygiene, said that by working with local vendors and their suppliers, among other actions, her agency is focused on increasing access to more nutritious foods in neighborhoods across the city as a way to shape the food environment. "It’s not people who’ve changed over the past 30 years; it’s the environment," Dr. Kansagra said at the conference.

Also addressed by the consensus statement was the need for preventive care, particularly at the pediatric level, and more cohesive public awareness campaigns that could affect how private payers develop their reimbursement strategies. Audience member Dr. Robert Silverman, medical director of CIGNA Healthcare, said that payers would respond to the need for obesity care, but that what currently is missing is "a tie between the evidence and the complications [of obesity]."

"We learned that different stakeholders require different levels of evidence," AACE President Jeffrey I. Mechanick said in the media briefing. "So, we’re going to be able come up with a more efficient way to make recommendations about research so that private insurance carriers, the Centers for Medicare & Medicaid Services, or regulatory agencies have the type of data they require to facilitate the action [they need]."

These differences were brought to light during the conference as various audience members representing the Centers for Disease Control and Prevention, the Food and Drug Administration, the CMS, the National Institutes of Health, and others involved in research and policy making, addressed the panel to either explain or defend why their agency operates as it does.

In the case of the CMS, a statutory organization, it can apply coverage only according to what the agency is mandated to do, said Dr. Elizabeth Koller of the CMS. The level of evidence the agency looks for, she said, includes "hard endpoints of clinical relevance, like reductions in sleep apnea and degenerative joint disease." The CMS is also concerned about the lack of long-term data on interventions, the durability of interventions, and which characteristics are common in people who relapse in their disease, said Dr. Koller, who addressed the group as an audience member.

"Hearing from the CMS was incredibly helpful. We learned so much," said Dr. Mechanick, director of metabolic support at the Mt. Sinai School of Medicine in New York, in an interview.

Dr. Mechanick also said this was the first of three meetings, the next to be held in about a year, where the ultimate goal would be to use the evidence base they will have created to develop recommendations for all involved in delivering obesity care.

The talk was "polite," Dr. John Morton, chief of bariatric surgery at Stanford (Calif.) University and president of the American Society of Bariatric and Metabolic Surgery, said in an interview, but he said he thinks there is bias against people with obesity. "We wouldn’t be having this discussion if it were about cancer," he said in the interview. "Sometimes we think the consequences of obesity are the result of a personal decision, and that may skew people in a direction where they don’t necessarily want to provide help."

Regardless, Dr. Garvey said at the briefing, "the ‘old world’ thinking that obesity is a lifestyle choice has failed us."

Dr. Mechanick is a consultant for Abbott Nutrition. Dr. Garvey has multiple industry relationships, including with Merck, Vivus, and Eisai.

[email protected]

WASHINGTON – Obesity requires a medical definition that goes beyond gauging a person’s body mass index if cost-effective care is to be delivered in an integrated fashion, according to a consensus statement issued by the American Association of Clinical Endocrinologists and the American College of Endocrinology.

"The definition of obesity as a disease is not perfect," Dr. W. Timothy Garvey, who chaired the AACE/ACE Obesity Consensus Conference, said in a media briefing. "We rely upon an [anthropometric] measure of body mass index, which is a measure of height versus weight, and there was consensus that this was ... divorced from the impact of weight gain on the health of the individual. This imprecision in our diagnosis of obesity was constraining us."

In 2013, the American Medical Association officially recognized obesity as a disease. Better codification of what actually constitutes "obesity, the disease," will allow a more integrated and effective approach to treating it, said Dr. Garvey, professor of medicine and chair of the department of nutrition sciences at the University of Alabama at Birmingham. To do so, the AACE/ACE held an intensive, 2-day session that largely featured spontaneous discussions between panelists and audience members representing four specific obesity "pillars": biomedical, government and regulation, health industry and economics, and research and education sectors.

A constant theme across the sectors was the need for a definition of obesity that accounts for cultural differences, ethnicity, and the presence or absence of cardiometabolic markers of disease in persons who are overweight or obese.

The conference’s multidisciplined approach informed the consensus statement that obesity is a chronic disease that should be treated with the established AACE/ACE obesity algorithm and met with lifestyle interventions. The consensus statement also addressed our current "obesogenic" environment, which many participants said was created in part by the abundance of nonnutritious foods.

In an interview, Dr. Susan Kansagra, deputy commissioner of the New York City Department of Health and Mental Hygiene, said that by working with local vendors and their suppliers, among other actions, her agency is focused on increasing access to more nutritious foods in neighborhoods across the city as a way to shape the food environment. "It’s not people who’ve changed over the past 30 years; it’s the environment," Dr. Kansagra said at the conference.

Also addressed by the consensus statement was the need for preventive care, particularly at the pediatric level, and more cohesive public awareness campaigns that could affect how private payers develop their reimbursement strategies. Audience member Dr. Robert Silverman, medical director of CIGNA Healthcare, said that payers would respond to the need for obesity care, but that what currently is missing is "a tie between the evidence and the complications [of obesity]."

"We learned that different stakeholders require different levels of evidence," AACE President Jeffrey I. Mechanick said in the media briefing. "So, we’re going to be able come up with a more efficient way to make recommendations about research so that private insurance carriers, the Centers for Medicare & Medicaid Services, or regulatory agencies have the type of data they require to facilitate the action [they need]."

These differences were brought to light during the conference as various audience members representing the Centers for Disease Control and Prevention, the Food and Drug Administration, the CMS, the National Institutes of Health, and others involved in research and policy making, addressed the panel to either explain or defend why their agency operates as it does.

In the case of the CMS, a statutory organization, it can apply coverage only according to what the agency is mandated to do, said Dr. Elizabeth Koller of the CMS. The level of evidence the agency looks for, she said, includes "hard endpoints of clinical relevance, like reductions in sleep apnea and degenerative joint disease." The CMS is also concerned about the lack of long-term data on interventions, the durability of interventions, and which characteristics are common in people who relapse in their disease, said Dr. Koller, who addressed the group as an audience member.

"Hearing from the CMS was incredibly helpful. We learned so much," said Dr. Mechanick, director of metabolic support at the Mt. Sinai School of Medicine in New York, in an interview.

Dr. Mechanick also said this was the first of three meetings, the next to be held in about a year, where the ultimate goal would be to use the evidence base they will have created to develop recommendations for all involved in delivering obesity care.

The talk was "polite," Dr. John Morton, chief of bariatric surgery at Stanford (Calif.) University and president of the American Society of Bariatric and Metabolic Surgery, said in an interview, but he said he thinks there is bias against people with obesity. "We wouldn’t be having this discussion if it were about cancer," he said in the interview. "Sometimes we think the consequences of obesity are the result of a personal decision, and that may skew people in a direction where they don’t necessarily want to provide help."

Regardless, Dr. Garvey said at the briefing, "the ‘old world’ thinking that obesity is a lifestyle choice has failed us."

Dr. Mechanick is a consultant for Abbott Nutrition. Dr. Garvey has multiple industry relationships, including with Merck, Vivus, and Eisai.

[email protected]

WASHINGTON – Obesity requires a medical definition that goes beyond gauging a person’s body mass index if cost-effective care is to be delivered in an integrated fashion, according to a consensus statement issued by the American Association of Clinical Endocrinologists and the American College of Endocrinology.

"The definition of obesity as a disease is not perfect," Dr. W. Timothy Garvey, who chaired the AACE/ACE Obesity Consensus Conference, said in a media briefing. "We rely upon an [anthropometric] measure of body mass index, which is a measure of height versus weight, and there was consensus that this was ... divorced from the impact of weight gain on the health of the individual. This imprecision in our diagnosis of obesity was constraining us."

In 2013, the American Medical Association officially recognized obesity as a disease. Better codification of what actually constitutes "obesity, the disease," will allow a more integrated and effective approach to treating it, said Dr. Garvey, professor of medicine and chair of the department of nutrition sciences at the University of Alabama at Birmingham. To do so, the AACE/ACE held an intensive, 2-day session that largely featured spontaneous discussions between panelists and audience members representing four specific obesity "pillars": biomedical, government and regulation, health industry and economics, and research and education sectors.

A constant theme across the sectors was the need for a definition of obesity that accounts for cultural differences, ethnicity, and the presence or absence of cardiometabolic markers of disease in persons who are overweight or obese.

The conference’s multidisciplined approach informed the consensus statement that obesity is a chronic disease that should be treated with the established AACE/ACE obesity algorithm and met with lifestyle interventions. The consensus statement also addressed our current "obesogenic" environment, which many participants said was created in part by the abundance of nonnutritious foods.

In an interview, Dr. Susan Kansagra, deputy commissioner of the New York City Department of Health and Mental Hygiene, said that by working with local vendors and their suppliers, among other actions, her agency is focused on increasing access to more nutritious foods in neighborhoods across the city as a way to shape the food environment. "It’s not people who’ve changed over the past 30 years; it’s the environment," Dr. Kansagra said at the conference.

Also addressed by the consensus statement was the need for preventive care, particularly at the pediatric level, and more cohesive public awareness campaigns that could affect how private payers develop their reimbursement strategies. Audience member Dr. Robert Silverman, medical director of CIGNA Healthcare, said that payers would respond to the need for obesity care, but that what currently is missing is "a tie between the evidence and the complications [of obesity]."

"We learned that different stakeholders require different levels of evidence," AACE President Jeffrey I. Mechanick said in the media briefing. "So, we’re going to be able come up with a more efficient way to make recommendations about research so that private insurance carriers, the Centers for Medicare & Medicaid Services, or regulatory agencies have the type of data they require to facilitate the action [they need]."

These differences were brought to light during the conference as various audience members representing the Centers for Disease Control and Prevention, the Food and Drug Administration, the CMS, the National Institutes of Health, and others involved in research and policy making, addressed the panel to either explain or defend why their agency operates as it does.

In the case of the CMS, a statutory organization, it can apply coverage only according to what the agency is mandated to do, said Dr. Elizabeth Koller of the CMS. The level of evidence the agency looks for, she said, includes "hard endpoints of clinical relevance, like reductions in sleep apnea and degenerative joint disease." The CMS is also concerned about the lack of long-term data on interventions, the durability of interventions, and which characteristics are common in people who relapse in their disease, said Dr. Koller, who addressed the group as an audience member.

"Hearing from the CMS was incredibly helpful. We learned so much," said Dr. Mechanick, director of metabolic support at the Mt. Sinai School of Medicine in New York, in an interview.

Dr. Mechanick also said this was the first of three meetings, the next to be held in about a year, where the ultimate goal would be to use the evidence base they will have created to develop recommendations for all involved in delivering obesity care.

The talk was "polite," Dr. John Morton, chief of bariatric surgery at Stanford (Calif.) University and president of the American Society of Bariatric and Metabolic Surgery, said in an interview, but he said he thinks there is bias against people with obesity. "We wouldn’t be having this discussion if it were about cancer," he said in the interview. "Sometimes we think the consequences of obesity are the result of a personal decision, and that may skew people in a direction where they don’t necessarily want to provide help."

Regardless, Dr. Garvey said at the briefing, "the ‘old world’ thinking that obesity is a lifestyle choice has failed us."

Dr. Mechanick is a consultant for Abbott Nutrition. Dr. Garvey has multiple industry relationships, including with Merck, Vivus, and Eisai.

[email protected]

At a recent surgical Morbidity and Mortality Conference, we discussed a tragic case of an elderly gentleman who had been explored for a gastric outlet obstruction. He was found to have a widely metastatic malignancy of unknown primary that was clearly unresectable. Biopsies were taken, a bypass was performed to alleviate the obstruction, and the patient was closed. The surgeon subsequently discussed the findings with the patient and his family. They were understandably upset after getting the news, but plans were made for follow-up and possible treatment when the final pathology was back. During several days in the hospital, the patient seemed to be in good spirits and was seen regularly, encouraging his family not to worry. However, on the day of discharge, the patient went home and committed suicide.

This case raised a series of important questions at the Morbidity and Mortality (M&M) Conference. Had the patient shown signs of depression? Should he have been evaluated by psychiatry? Did the surgical team miss any signs of his impending actions? In the tradition of M&M Conferences, the discussion focused on the question, "What would you have done differently?"

One issue repeatedly raised in the discussions at conference given the patient’s response was whether he should have been told his diagnosis. Such a consideration is a radical idea today when no physician would argue against telling a patient a diagnosis of cancer. But this consensus of full disclosure is relatively new in the medical profession. In 1961, 88% of physicians surveyed at Michael Reese Hospital in Chicago stated that their general policy was not to disclose a cancer diagnosis to the patient (JAMA 1961;175:1120-8). Certainly, this view among physicians has changed dramatically in recent decades. By 1979, the same survey at the same hospital revealed that 98% of physicians said that they tell patients that when the diagnosis is cancer (JAMA 1979;241:897-900).

In the medical profession, a diagnosis is no longer seen as information that can be withheld from a patient. The idea of respecting the patient as a person means that the patient must have the information necessary to make decisions about his or her future.

In this context, the recent New York Times article entitled "When Doctors Need to Lie" (Feb. 22, 2014) is provocative. Dr. Sandeep Jauhar suggests that sometimes there are situations in which doctors need to exercise a form of paternalism and lie to patients for their own benefit. Dr. Jauhar described a case in which he informed the family of a young patient of the true diagnosis, but only gradually and gently told the young man of his true condition.

Informing the elderly gentleman of his diagnosis may well have triggered his suicide. If the patient had not known that he had unresectable cancer, he could well still be alive. Nevertheless, no one at the M&M conference thought that lying about the diagnosis could be justified. Knowing the diagnosis is the fundamental basis for a patient to project a future existence. The ability to make the best medical and nonmedical decisions is dependent on having valid information. Without truthful information, the decisions made are uninformed and no better than guesses. It is not the physician’s role to guess the reaction of a patient to a diagnosis or project a future circumstance that may result from the patient learning the truth.

While the outcome of the transmission of knowledge to the patient may at times be unfortunate, the ethical implications of not telling patients the truth are potentially even more unfortunate. How can a surgeon establish a relationship of trust while also lying to a patient or withholding important information? Even though the choice made by this particular patient was tragic, to have lied to him is contrary to the physician’s role. Truth is the basis of trust, and trust in turn must be the basis of the relationship between doctor and patient.

Dr. Angelos is an ACS Fellow; the Linda Kohler Anderson Professor of Surgery and Surgical Ethics; chief, endocrine surgery; and associate director of the MacLean Center for Clinical Medical Ethics at the University of Chicago.

At a recent surgical Morbidity and Mortality Conference, we discussed a tragic case of an elderly gentleman who had been explored for a gastric outlet obstruction. He was found to have a widely metastatic malignancy of unknown primary that was clearly unresectable. Biopsies were taken, a bypass was performed to alleviate the obstruction, and the patient was closed. The surgeon subsequently discussed the findings with the patient and his family. They were understandably upset after getting the news, but plans were made for follow-up and possible treatment when the final pathology was back. During several days in the hospital, the patient seemed to be in good spirits and was seen regularly, encouraging his family not to worry. However, on the day of discharge, the patient went home and committed suicide.

This case raised a series of important questions at the Morbidity and Mortality (M&M) Conference. Had the patient shown signs of depression? Should he have been evaluated by psychiatry? Did the surgical team miss any signs of his impending actions? In the tradition of M&M Conferences, the discussion focused on the question, "What would you have done differently?"

One issue repeatedly raised in the discussions at conference given the patient’s response was whether he should have been told his diagnosis. Such a consideration is a radical idea today when no physician would argue against telling a patient a diagnosis of cancer. But this consensus of full disclosure is relatively new in the medical profession. In 1961, 88% of physicians surveyed at Michael Reese Hospital in Chicago stated that their general policy was not to disclose a cancer diagnosis to the patient (JAMA 1961;175:1120-8). Certainly, this view among physicians has changed dramatically in recent decades. By 1979, the same survey at the same hospital revealed that 98% of physicians said that they tell patients that when the diagnosis is cancer (JAMA 1979;241:897-900).

In the medical profession, a diagnosis is no longer seen as information that can be withheld from a patient. The idea of respecting the patient as a person means that the patient must have the information necessary to make decisions about his or her future.

In this context, the recent New York Times article entitled "When Doctors Need to Lie" (Feb. 22, 2014) is provocative. Dr. Sandeep Jauhar suggests that sometimes there are situations in which doctors need to exercise a form of paternalism and lie to patients for their own benefit. Dr. Jauhar described a case in which he informed the family of a young patient of the true diagnosis, but only gradually and gently told the young man of his true condition.

Informing the elderly gentleman of his diagnosis may well have triggered his suicide. If the patient had not known that he had unresectable cancer, he could well still be alive. Nevertheless, no one at the M&M conference thought that lying about the diagnosis could be justified. Knowing the diagnosis is the fundamental basis for a patient to project a future existence. The ability to make the best medical and nonmedical decisions is dependent on having valid information. Without truthful information, the decisions made are uninformed and no better than guesses. It is not the physician’s role to guess the reaction of a patient to a diagnosis or project a future circumstance that may result from the patient learning the truth.

While the outcome of the transmission of knowledge to the patient may at times be unfortunate, the ethical implications of not telling patients the truth are potentially even more unfortunate. How can a surgeon establish a relationship of trust while also lying to a patient or withholding important information? Even though the choice made by this particular patient was tragic, to have lied to him is contrary to the physician’s role. Truth is the basis of trust, and trust in turn must be the basis of the relationship between doctor and patient.

Dr. Angelos is an ACS Fellow; the Linda Kohler Anderson Professor of Surgery and Surgical Ethics; chief, endocrine surgery; and associate director of the MacLean Center for Clinical Medical Ethics at the University of Chicago.

At a recent surgical Morbidity and Mortality Conference, we discussed a tragic case of an elderly gentleman who had been explored for a gastric outlet obstruction. He was found to have a widely metastatic malignancy of unknown primary that was clearly unresectable. Biopsies were taken, a bypass was performed to alleviate the obstruction, and the patient was closed. The surgeon subsequently discussed the findings with the patient and his family. They were understandably upset after getting the news, but plans were made for follow-up and possible treatment when the final pathology was back. During several days in the hospital, the patient seemed to be in good spirits and was seen regularly, encouraging his family not to worry. However, on the day of discharge, the patient went home and committed suicide.

This case raised a series of important questions at the Morbidity and Mortality (M&M) Conference. Had the patient shown signs of depression? Should he have been evaluated by psychiatry? Did the surgical team miss any signs of his impending actions? In the tradition of M&M Conferences, the discussion focused on the question, "What would you have done differently?"

One issue repeatedly raised in the discussions at conference given the patient’s response was whether he should have been told his diagnosis. Such a consideration is a radical idea today when no physician would argue against telling a patient a diagnosis of cancer. But this consensus of full disclosure is relatively new in the medical profession. In 1961, 88% of physicians surveyed at Michael Reese Hospital in Chicago stated that their general policy was not to disclose a cancer diagnosis to the patient (JAMA 1961;175:1120-8). Certainly, this view among physicians has changed dramatically in recent decades. By 1979, the same survey at the same hospital revealed that 98% of physicians said that they tell patients that when the diagnosis is cancer (JAMA 1979;241:897-900).

In the medical profession, a diagnosis is no longer seen as information that can be withheld from a patient. The idea of respecting the patient as a person means that the patient must have the information necessary to make decisions about his or her future.

In this context, the recent New York Times article entitled "When Doctors Need to Lie" (Feb. 22, 2014) is provocative. Dr. Sandeep Jauhar suggests that sometimes there are situations in which doctors need to exercise a form of paternalism and lie to patients for their own benefit. Dr. Jauhar described a case in which he informed the family of a young patient of the true diagnosis, but only gradually and gently told the young man of his true condition.

Informing the elderly gentleman of his diagnosis may well have triggered his suicide. If the patient had not known that he had unresectable cancer, he could well still be alive. Nevertheless, no one at the M&M conference thought that lying about the diagnosis could be justified. Knowing the diagnosis is the fundamental basis for a patient to project a future existence. The ability to make the best medical and nonmedical decisions is dependent on having valid information. Without truthful information, the decisions made are uninformed and no better than guesses. It is not the physician’s role to guess the reaction of a patient to a diagnosis or project a future circumstance that may result from the patient learning the truth.

While the outcome of the transmission of knowledge to the patient may at times be unfortunate, the ethical implications of not telling patients the truth are potentially even more unfortunate. How can a surgeon establish a relationship of trust while also lying to a patient or withholding important information? Even though the choice made by this particular patient was tragic, to have lied to him is contrary to the physician’s role. Truth is the basis of trust, and trust in turn must be the basis of the relationship between doctor and patient.

Dr. Angelos is an ACS Fellow; the Linda Kohler Anderson Professor of Surgery and Surgical Ethics; chief, endocrine surgery; and associate director of the MacLean Center for Clinical Medical Ethics at the University of Chicago.

Obesity rates in the United States have skyrocketed over the last 30 years, with rates for adults having doubled and rates for children tripled from 1980 to 2010. Approximately one-third of the U.S adult population is obese; that’s 72 million people. The consequences of obesity include an increased risk for stroke, hypertension, type 2 diabetes, liver and gallbladder disease, orthopedic complications, mental health conditions, cancers, elevated lipids, obstructive sleep apnea (OSA), and reproductive complications such as infertility.

There is now solid evidence that we can intervene to help patient lose weight and decrease the complications that result from obesity. To this end, the American Association of Clinical Endocrinology (AACE) has issued recommendations giving guidance for clinicians about how to approach this issue. Intensive approaches to lifestyle modification with diet and exercise can help patients lose 7% or more of their body weight and have been show to decrease progression from prediabetes to diabetes. Two new medications, lorcaserin and phentermine/topiramate ER, have received Food and Drug Administration approval over the past 2 years as an adjunct to diet for weight loss. Bariatric surgery has emerged as a safe and effective method of weight loss as well.

The AACE guidelines focus on a "complications-centric model" as opposed to a body mass index–driven approach. The guidelines recommend treating obesity to decrease the risk of developing adverse metabolic consequences such as diabetes and metabolic syndrome, and to decrease disability from mechanical comorbidities such as osteoarthritis and obstructive sleep apnea. The AACE guidelines place obese patients into two categories: those that have obesity-related comorbidities and those that do not. The guidelines recommend a graded approach to treatment. All overweight and obese patients should receive therapeutic lifestyle counseling focusing on diet and exercise. Medical or surgical treatment is then recommended for the patients who stand to benefit the most, those with obesity-related comorbidities and those with more severe obesity who have not been able to lose weight using lifestyle modification alone.

In the initial evaluation of overweight and obese patients, the patients should be assessed for cardiometabolic and mechanical complications of obesity, as well as the severity of those complications in order to determine the level of treatment that is appropriate. Patients with obesity-related comorbidities are classified into two groups. The first group includes those with insulin resistance and/or cardiovascular consequences. For this group, evaluation should include waist circumference, fasting, and 2-hour glucose tolerance testing, and lipids, blood pressure, and liver function testing. The second group is composed of people with mechanical consequences including OSA, stress incontinence, orthopedic complications, and chronic pulmonary diseases.

It is important to determine target goals for weight loss to improve mechanical and cardiometabolic complications. Weight loss of 5% or more is enough to affect improvement in metabolic parameters such as glucose and lipids, decrease progression to diabetes, and improve mechanical complications such as knee and hip pain in osteoarthritis. The next step in the approach to treatment is to determine the type and intensity. Therapeutic lifestyle changes (TLC) are important for all patients with diabetes and prediabetes, regardless of risk factors. TLC recommendations include smoking cessation, physical activity, weight management, and healthy eating. Exercise is recommended 5 days/week for more than 30 minutes of moderate intensity activity, to achieve a more than 60% age-related heart rate. The diet recommended reduced saturated fat to less than 7% of calories, reduced cholesterol intake to 200 mg/day, increased fiber to 10-25 g/day, increased plant sterols/stanol esters to 2 g/day, caloric restriction, reduced simple carbohydrates and sugars, increased intake of unsaturated fats, elimination of trans fats, increased marine-based omega-3 ethyl esters, and restriction of alcohol to 20-30 g/day.

For patients with comorbidities and with a BMI of 27 kg/m² or more, consideration should be given to weight-loss medication in addition to lifestyle intervention. The currently approved medications for long-term weight loss include lorcaserin and phentermine/topiramate ER. In the FDA registration studies, the lorcaserin group had an average weight loss of 5.8% after 1 year vs. 2.2% in the placebo group. Phentermine/topiramate ER had an average weight loss of 10% at 1 year vs. 1.2% in the placebo group. These medications are FDA approved as adjuncts to lifestyle modification for the treatment of overweight patients with a BMI greater than 27 kg/m² with comorbidities and for obese patients with a BMI greater than 30 kg/m² regardless of comorbidities. Both medications improve blood pressure, triglycerides, and insulin sensitivity and prevent the progression to diabetes in patients with diabetes. Bariatric surgery should be considered for those with a BMI of 35 kg/m² or morewith comorbidities, especially if they have failed using other methods.

Once goals are reached, reassess the patient to evaluate for more interventions, if needed. If the targets for improvement in complications were not reached, then the weight loss therapy should become more intense.

Bottom line

The AACE recommendations recognize obesity as a disease and have formulated guidelines using a "complications-centric model." Patients should be assessed for obesity and related complications. Lifestyle counseling should be provided for all overweight and obese individuals, with the addition of weight loss medications for individuals with a BMI of 27 kg/m² or more who have obesity-related comorbidities, and the consideration of bariatric surgery for those with a BMI of 35 kg/m² or more with comorbidities.

Reference

American Association of Clinical Endocrinologists’ Comprehensive Diabetes Management Algorithm 2013 Consensus Statement. Published May/June 2013, Endocrine Practice, Vol. 19 (Suppl. 2).

Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University, Philadelphia. Dr. McDonald is a second-year resident in the Family Medicine Residency Program at Abington Memorial Hospital.

[email protected]

Obesity rates in the United States have skyrocketed over the last 30 years, with rates for adults having doubled and rates for children tripled from 1980 to 2010. Approximately one-third of the U.S adult population is obese; that’s 72 million people. The consequences of obesity include an increased risk for stroke, hypertension, type 2 diabetes, liver and gallbladder disease, orthopedic complications, mental health conditions, cancers, elevated lipids, obstructive sleep apnea (OSA), and reproductive complications such as infertility.

There is now solid evidence that we can intervene to help patient lose weight and decrease the complications that result from obesity. To this end, the American Association of Clinical Endocrinology (AACE) has issued recommendations giving guidance for clinicians about how to approach this issue. Intensive approaches to lifestyle modification with diet and exercise can help patients lose 7% or more of their body weight and have been show to decrease progression from prediabetes to diabetes. Two new medications, lorcaserin and phentermine/topiramate ER, have received Food and Drug Administration approval over the past 2 years as an adjunct to diet for weight loss. Bariatric surgery has emerged as a safe and effective method of weight loss as well.

The AACE guidelines focus on a "complications-centric model" as opposed to a body mass index–driven approach. The guidelines recommend treating obesity to decrease the risk of developing adverse metabolic consequences such as diabetes and metabolic syndrome, and to decrease disability from mechanical comorbidities such as osteoarthritis and obstructive sleep apnea. The AACE guidelines place obese patients into two categories: those that have obesity-related comorbidities and those that do not. The guidelines recommend a graded approach to treatment. All overweight and obese patients should receive therapeutic lifestyle counseling focusing on diet and exercise. Medical or surgical treatment is then recommended for the patients who stand to benefit the most, those with obesity-related comorbidities and those with more severe obesity who have not been able to lose weight using lifestyle modification alone.

In the initial evaluation of overweight and obese patients, the patients should be assessed for cardiometabolic and mechanical complications of obesity, as well as the severity of those complications in order to determine the level of treatment that is appropriate. Patients with obesity-related comorbidities are classified into two groups. The first group includes those with insulin resistance and/or cardiovascular consequences. For this group, evaluation should include waist circumference, fasting, and 2-hour glucose tolerance testing, and lipids, blood pressure, and liver function testing. The second group is composed of people with mechanical consequences including OSA, stress incontinence, orthopedic complications, and chronic pulmonary diseases.

It is important to determine target goals for weight loss to improve mechanical and cardiometabolic complications. Weight loss of 5% or more is enough to affect improvement in metabolic parameters such as glucose and lipids, decrease progression to diabetes, and improve mechanical complications such as knee and hip pain in osteoarthritis. The next step in the approach to treatment is to determine the type and intensity. Therapeutic lifestyle changes (TLC) are important for all patients with diabetes and prediabetes, regardless of risk factors. TLC recommendations include smoking cessation, physical activity, weight management, and healthy eating. Exercise is recommended 5 days/week for more than 30 minutes of moderate intensity activity, to achieve a more than 60% age-related heart rate. The diet recommended reduced saturated fat to less than 7% of calories, reduced cholesterol intake to 200 mg/day, increased fiber to 10-25 g/day, increased plant sterols/stanol esters to 2 g/day, caloric restriction, reduced simple carbohydrates and sugars, increased intake of unsaturated fats, elimination of trans fats, increased marine-based omega-3 ethyl esters, and restriction of alcohol to 20-30 g/day.

For patients with comorbidities and with a BMI of 27 kg/m² or more, consideration should be given to weight-loss medication in addition to lifestyle intervention. The currently approved medications for long-term weight loss include lorcaserin and phentermine/topiramate ER. In the FDA registration studies, the lorcaserin group had an average weight loss of 5.8% after 1 year vs. 2.2% in the placebo group. Phentermine/topiramate ER had an average weight loss of 10% at 1 year vs. 1.2% in the placebo group. These medications are FDA approved as adjuncts to lifestyle modification for the treatment of overweight patients with a BMI greater than 27 kg/m² with comorbidities and for obese patients with a BMI greater than 30 kg/m² regardless of comorbidities. Both medications improve blood pressure, triglycerides, and insulin sensitivity and prevent the progression to diabetes in patients with diabetes. Bariatric surgery should be considered for those with a BMI of 35 kg/m² or morewith comorbidities, especially if they have failed using other methods.

Once goals are reached, reassess the patient to evaluate for more interventions, if needed. If the targets for improvement in complications were not reached, then the weight loss therapy should become more intense.

Bottom line

The AACE recommendations recognize obesity as a disease and have formulated guidelines using a "complications-centric model." Patients should be assessed for obesity and related complications. Lifestyle counseling should be provided for all overweight and obese individuals, with the addition of weight loss medications for individuals with a BMI of 27 kg/m² or more who have obesity-related comorbidities, and the consideration of bariatric surgery for those with a BMI of 35 kg/m² or more with comorbidities.

Reference

American Association of Clinical Endocrinologists’ Comprehensive Diabetes Management Algorithm 2013 Consensus Statement. Published May/June 2013, Endocrine Practice, Vol. 19 (Suppl. 2).

Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University, Philadelphia. Dr. McDonald is a second-year resident in the Family Medicine Residency Program at Abington Memorial Hospital.

[email protected]

Obesity rates in the United States have skyrocketed over the last 30 years, with rates for adults having doubled and rates for children tripled from 1980 to 2010. Approximately one-third of the U.S adult population is obese; that’s 72 million people. The consequences of obesity include an increased risk for stroke, hypertension, type 2 diabetes, liver and gallbladder disease, orthopedic complications, mental health conditions, cancers, elevated lipids, obstructive sleep apnea (OSA), and reproductive complications such as infertility.

There is now solid evidence that we can intervene to help patient lose weight and decrease the complications that result from obesity. To this end, the American Association of Clinical Endocrinology (AACE) has issued recommendations giving guidance for clinicians about how to approach this issue. Intensive approaches to lifestyle modification with diet and exercise can help patients lose 7% or more of their body weight and have been show to decrease progression from prediabetes to diabetes. Two new medications, lorcaserin and phentermine/topiramate ER, have received Food and Drug Administration approval over the past 2 years as an adjunct to diet for weight loss. Bariatric surgery has emerged as a safe and effective method of weight loss as well.

The AACE guidelines focus on a "complications-centric model" as opposed to a body mass index–driven approach. The guidelines recommend treating obesity to decrease the risk of developing adverse metabolic consequences such as diabetes and metabolic syndrome, and to decrease disability from mechanical comorbidities such as osteoarthritis and obstructive sleep apnea. The AACE guidelines place obese patients into two categories: those that have obesity-related comorbidities and those that do not. The guidelines recommend a graded approach to treatment. All overweight and obese patients should receive therapeutic lifestyle counseling focusing on diet and exercise. Medical or surgical treatment is then recommended for the patients who stand to benefit the most, those with obesity-related comorbidities and those with more severe obesity who have not been able to lose weight using lifestyle modification alone.

In the initial evaluation of overweight and obese patients, the patients should be assessed for cardiometabolic and mechanical complications of obesity, as well as the severity of those complications in order to determine the level of treatment that is appropriate. Patients with obesity-related comorbidities are classified into two groups. The first group includes those with insulin resistance and/or cardiovascular consequences. For this group, evaluation should include waist circumference, fasting, and 2-hour glucose tolerance testing, and lipids, blood pressure, and liver function testing. The second group is composed of people with mechanical consequences including OSA, stress incontinence, orthopedic complications, and chronic pulmonary diseases.

It is important to determine target goals for weight loss to improve mechanical and cardiometabolic complications. Weight loss of 5% or more is enough to affect improvement in metabolic parameters such as glucose and lipids, decrease progression to diabetes, and improve mechanical complications such as knee and hip pain in osteoarthritis. The next step in the approach to treatment is to determine the type and intensity. Therapeutic lifestyle changes (TLC) are important for all patients with diabetes and prediabetes, regardless of risk factors. TLC recommendations include smoking cessation, physical activity, weight management, and healthy eating. Exercise is recommended 5 days/week for more than 30 minutes of moderate intensity activity, to achieve a more than 60% age-related heart rate. The diet recommended reduced saturated fat to less than 7% of calories, reduced cholesterol intake to 200 mg/day, increased fiber to 10-25 g/day, increased plant sterols/stanol esters to 2 g/day, caloric restriction, reduced simple carbohydrates and sugars, increased intake of unsaturated fats, elimination of trans fats, increased marine-based omega-3 ethyl esters, and restriction of alcohol to 20-30 g/day.

For patients with comorbidities and with a BMI of 27 kg/m² or more, consideration should be given to weight-loss medication in addition to lifestyle intervention. The currently approved medications for long-term weight loss include lorcaserin and phentermine/topiramate ER. In the FDA registration studies, the lorcaserin group had an average weight loss of 5.8% after 1 year vs. 2.2% in the placebo group. Phentermine/topiramate ER had an average weight loss of 10% at 1 year vs. 1.2% in the placebo group. These medications are FDA approved as adjuncts to lifestyle modification for the treatment of overweight patients with a BMI greater than 27 kg/m² with comorbidities and for obese patients with a BMI greater than 30 kg/m² regardless of comorbidities. Both medications improve blood pressure, triglycerides, and insulin sensitivity and prevent the progression to diabetes in patients with diabetes. Bariatric surgery should be considered for those with a BMI of 35 kg/m² or morewith comorbidities, especially if they have failed using other methods.

Once goals are reached, reassess the patient to evaluate for more interventions, if needed. If the targets for improvement in complications were not reached, then the weight loss therapy should become more intense.

Bottom line

The AACE recommendations recognize obesity as a disease and have formulated guidelines using a "complications-centric model." Patients should be assessed for obesity and related complications. Lifestyle counseling should be provided for all overweight and obese individuals, with the addition of weight loss medications for individuals with a BMI of 27 kg/m² or more who have obesity-related comorbidities, and the consideration of bariatric surgery for those with a BMI of 35 kg/m² or more with comorbidities.

Reference

American Association of Clinical Endocrinologists’ Comprehensive Diabetes Management Algorithm 2013 Consensus Statement. Published May/June 2013, Endocrine Practice, Vol. 19 (Suppl. 2).

Dr. Skolnik is associate director of the family medicine residency program at Abington (Pa.) Memorial Hospital and professor of family and community medicine at Temple University, Philadelphia. Dr. McDonald is a second-year resident in the Family Medicine Residency Program at Abington Memorial Hospital.

[email protected]

The prevailing view among many psy­chiatrists and mental health profession­als is that borderline personality disorder (BPD) is a “psychological” condition. BPD often is conceptualized as a behav­ioral consequence of childhood trauma; treatment approaches have emphasized intensive psychotherapeutic modali­ties, less so biologic interventions. You might not be aware that a large body of research over the past decade provides strong evidence that BPD is a neuro­biological illness—a finding that would drastically alter how the disorder should be conceptualized and managed.

Neuropathology underpins the personality disorder
Foremost, BPD must be regarded as a serious, disabling brain disorder, not simply an aberration of personality. In DSM-5, symptoms of BPD are listed as: feelings of abandonment; unstable and intense interpersonal relationships; un­stable sense of self; impulsivity; suicidal or self-mutilating behavior; affective in­stability (dysphoria, irritability, anxiety); chronic feelings of emptiness; intense anger episodes; and transient paranoid or dissociative symptoms. Clearly, these clusters of psychopathological and be­havioral symptoms reflect a pervasive brain disorder associated with abnormal neurobiology and neural circuitry that might, at times, stubbornly defy thera­peutic intervention.

No wonder that 42 published stud­ies report that, compared with healthy controls, people who have BPD display extensive cortical and subcortical abnor­malities in brain structure and function.¹ These anomalous patterns have been detected across all 4 available neuroim­aging techniques.

Magnetic resonance imaging. MRI studies have revealed the following abnormalities in BPD:
   • hypoplasia of the hippocampus, caudate, and dorsolateral prefrontal cortex
   • variations in the CA1 region of the hippocampus and subiculum
   • smaller-than-normal orbitofrontal cortex (by 24%, compared with healthy controls) and the mid-temporal and left cingulate gyrii (by 26%)
   • larger-than-normal volume of the right inferior parietal cortex and the right parahippocampal gyrus
   • loss of gray matter in the frontal, temporal, and parietal cortices
   • an enlarged third cerebral ventricle
   • in women, reduced size of the me­dial temporal lobe and amygdala
   • in men, a decreased concentra­tion of gray matter in the anterior cingulate
   • reversal of normal right-greater-than-left asymmetry of the orbitofron­tal cortex gray matter, reflecting loss of gray matter on the right side
   • a lower concentration of gray mat­ter in the rostral/subgenual anterior cin­gulate cortex
   • a  smaller frontal lobe.

In an analysis of MRI studies,2 cor­relation was found between structural brain abnormalities and specific symp­toms of BPD, such as impulsivity, sui­cidality, and aggression. These findings might someday guide personalized in­terventions—for example, using neuro­stimulation techniques such as repetitive transcranial magnetic stimulation and deep brain stimulation—to modulate the activity of a given region of the brain (depending on which symptom is most prominent or disabling).
 

Magnetic resonance spectroscopy. In BPD, MRS studies reveal:
   • compared with controls, a higher glutamate level in the anterior cingulate cortex
   • reduced levels of N-acetyl aspar­tate (NAA; found in neurons) and cre­atinine in the left amygdala
   • a reduction (on average, 19%) in the NAA concentration in the dorsolat­eral prefrontal cortex.

Functional magnetic resonance im­aging. From fMRI studies, there is evi­dence in BPD of:
   • greater activation of the amygdala and prolonged return to baseline
   • increased functional connectiv­ity in the left frontopolar cortex and left insula
   • decreased connectivity in the left cuneus and left inferior parietal and the right middle temporal lobes
   • marked frontal hypometabolism
   • hypermetabolism in the motor cor­tex, medial and anterior cingulate, and occipital and temporal poles
   • lower connectivity between the amygdala during a neutral stimulus
   • higher connectivity between the amygdala during fear stimulus
   • higher connectivity between the amygdala during fear stimulus
   • deactivation of the opioid system in the left nucleus accumbens, hypothal­amus, and hippocampus
   • hyperactivation of the left medial prefrontal cortex during social exclusion
   • more mistakes made in differenti­ating an emotional and a neutral facial expression.
 

Diffusion tensor imaging. DTI white-matter integrity studies of BPD show:
   • a bilateral decrease in fractional an­isotropy (FA) in frontal, uncinated, and occipitalfrontal fasciculi
   • a decrease in FA in the genu and rostrum of the corpus callosum
   • a decrease in inter-hemispheric connectivity between right and left ante­rior cigulate cortices.

Genetic Studies
There is substantial scientific evidence that BPD is highly heritable—a finding that suggests that brain abnormalities of this disorder are a consequence of genes involved in brain development (similar to what is known about schizophrenia, bipolar disorder, and autism).

A systematic review of the heritabil­ity of BPD examined 59 published stud­ies that were categorized into 12 family studies, 18 twin studies, 24 association studies, and 5 gene-environment inter­action studies.3 The authors concluded that BPD has a strong genetic compo­nent, although there also is evidence of gene-environment (G.E) interactions (ie, how nature and nurture influence each other).

The G.E interaction model appears to be consistent with the theory that ex­pression of plasticity genes is modified by childhood experiences and environ­ment, such as physical or sexual abuse. Some studies have found evidence of hypermethylation in BPD, which can ex­ert epigenetic effects. Childhood abuse might, therefore, disrupt certain neuro­plasticity genes, culminating in morpho­logical, neurochemical, metabolic, and white-matter aberrations—leading to pathological behavioral patterns identi­fied as BPD.
 

The neuropsychiatric basis of BPD must guide treatment
There is no such thing as a purely psycho­logical disorder: Invariably, it is an abnor­mality of brain circuits that disrupts normal development of emotions, thought, behavior, and social cognition. BPD is an exemplar of such neuropsychiatric illness, and treat­ment should support psychotherapeutic ap­proaches to mend the mind at the same time it moves aggressively to repair the brain.

The prevailing view among many psy­chiatrists and mental health profession­als is that borderline personality disorder (BPD) is a “psychological” condition. BPD often is conceptualized as a behav­ioral consequence of childhood trauma; treatment approaches have emphasized intensive psychotherapeutic modali­ties, less so biologic interventions. You might not be aware that a large body of research over the past decade provides strong evidence that BPD is a neuro­biological illness—a finding that would drastically alter how the disorder should be conceptualized and managed.

Neuropathology underpins the personality disorder
Foremost, BPD must be regarded as a serious, disabling brain disorder, not simply an aberration of personality. In DSM-5, symptoms of BPD are listed as: feelings of abandonment; unstable and intense interpersonal relationships; un­stable sense of self; impulsivity; suicidal or self-mutilating behavior; affective in­stability (dysphoria, irritability, anxiety); chronic feelings of emptiness; intense anger episodes; and transient paranoid or dissociative symptoms. Clearly, these clusters of psychopathological and be­havioral symptoms reflect a pervasive brain disorder associated with abnormal neurobiology and neural circuitry that might, at times, stubbornly defy thera­peutic intervention.

No wonder that 42 published stud­ies report that, compared with healthy controls, people who have BPD display extensive cortical and subcortical abnor­malities in brain structure and function.¹ These anomalous patterns have been detected across all 4 available neuroim­aging techniques.

Magnetic resonance imaging. MRI studies have revealed the following abnormalities in BPD:
   • hypoplasia of the hippocampus, caudate, and dorsolateral prefrontal cortex
   • variations in the CA1 region of the hippocampus and subiculum
   • smaller-than-normal orbitofrontal cortex (by 24%, compared with healthy controls) and the mid-temporal and left cingulate gyrii (by 26%)
   • larger-than-normal volume of the right inferior parietal cortex and the right parahippocampal gyrus
   • loss of gray matter in the frontal, temporal, and parietal cortices
   • an enlarged third cerebral ventricle
   • in women, reduced size of the me­dial temporal lobe and amygdala
   • in men, a decreased concentra­tion of gray matter in the anterior cingulate
   • reversal of normal right-greater-than-left asymmetry of the orbitofron­tal cortex gray matter, reflecting loss of gray matter on the right side
   • a lower concentration of gray mat­ter in the rostral/subgenual anterior cin­gulate cortex
   • a  smaller frontal lobe.

In an analysis of MRI studies,2 cor­relation was found between structural brain abnormalities and specific symp­toms of BPD, such as impulsivity, sui­cidality, and aggression. These findings might someday guide personalized in­terventions—for example, using neuro­stimulation techniques such as repetitive transcranial magnetic stimulation and deep brain stimulation—to modulate the activity of a given region of the brain (depending on which symptom is most prominent or disabling).
 

Magnetic resonance spectroscopy. In BPD, MRS studies reveal:
   • compared with controls, a higher glutamate level in the anterior cingulate cortex
   • reduced levels of N-acetyl aspar­tate (NAA; found in neurons) and cre­atinine in the left amygdala
   • a reduction (on average, 19%) in the NAA concentration in the dorsolat­eral prefrontal cortex.

Functional magnetic resonance im­aging. From fMRI studies, there is evi­dence in BPD of:
   • greater activation of the amygdala and prolonged return to baseline
   • increased functional connectiv­ity in the left frontopolar cortex and left insula
   • decreased connectivity in the left cuneus and left inferior parietal and the right middle temporal lobes
   • marked frontal hypometabolism
   • hypermetabolism in the motor cor­tex, medial and anterior cingulate, and occipital and temporal poles
   • lower connectivity between the amygdala during a neutral stimulus
   • higher connectivity between the amygdala during fear stimulus
   • higher connectivity between the amygdala during fear stimulus
   • deactivation of the opioid system in the left nucleus accumbens, hypothal­amus, and hippocampus
   • hyperactivation of the left medial prefrontal cortex during social exclusion
   • more mistakes made in differenti­ating an emotional and a neutral facial expression.
 

Diffusion tensor imaging. DTI white-matter integrity studies of BPD show:
   • a bilateral decrease in fractional an­isotropy (FA) in frontal, uncinated, and occipitalfrontal fasciculi
   • a decrease in FA in the genu and rostrum of the corpus callosum
   • a decrease in inter-hemispheric connectivity between right and left ante­rior cigulate cortices.

Genetic Studies
There is substantial scientific evidence that BPD is highly heritable—a finding that suggests that brain abnormalities of this disorder are a consequence of genes involved in brain development (similar to what is known about schizophrenia, bipolar disorder, and autism).

A systematic review of the heritabil­ity of BPD examined 59 published stud­ies that were categorized into 12 family studies, 18 twin studies, 24 association studies, and 5 gene-environment inter­action studies.3 The authors concluded that BPD has a strong genetic compo­nent, although there also is evidence of gene-environment (G.E) interactions (ie, how nature and nurture influence each other).

The G.E interaction model appears to be consistent with the theory that ex­pression of plasticity genes is modified by childhood experiences and environ­ment, such as physical or sexual abuse. Some studies have found evidence of hypermethylation in BPD, which can ex­ert epigenetic effects. Childhood abuse might, therefore, disrupt certain neuro­plasticity genes, culminating in morpho­logical, neurochemical, metabolic, and white-matter aberrations—leading to pathological behavioral patterns identi­fied as BPD.
 

The neuropsychiatric basis of BPD must guide treatment
There is no such thing as a purely psycho­logical disorder: Invariably, it is an abnor­mality of brain circuits that disrupts normal development of emotions, thought, behavior, and social cognition. BPD is an exemplar of such neuropsychiatric illness, and treat­ment should support psychotherapeutic ap­proaches to mend the mind at the same time it moves aggressively to repair the brain.

The prevailing view among many psy­chiatrists and mental health profession­als is that borderline personality disorder (BPD) is a “psychological” condition. BPD often is conceptualized as a behav­ioral consequence of childhood trauma; treatment approaches have emphasized intensive psychotherapeutic modali­ties, less so biologic interventions. You might not be aware that a large body of research over the past decade provides strong evidence that BPD is a neuro­biological illness—a finding that would drastically alter how the disorder should be conceptualized and managed.

Neuropathology underpins the personality disorder
Foremost, BPD must be regarded as a serious, disabling brain disorder, not simply an aberration of personality. In DSM-5, symptoms of BPD are listed as: feelings of abandonment; unstable and intense interpersonal relationships; un­stable sense of self; impulsivity; suicidal or self-mutilating behavior; affective in­stability (dysphoria, irritability, anxiety); chronic feelings of emptiness; intense anger episodes; and transient paranoid or dissociative symptoms. Clearly, these clusters of psychopathological and be­havioral symptoms reflect a pervasive brain disorder associated with abnormal neurobiology and neural circuitry that might, at times, stubbornly defy thera­peutic intervention.

No wonder that 42 published stud­ies report that, compared with healthy controls, people who have BPD display extensive cortical and subcortical abnor­malities in brain structure and function.¹ These anomalous patterns have been detected across all 4 available neuroim­aging techniques.

Magnetic resonance imaging. MRI studies have revealed the following abnormalities in BPD:
   • hypoplasia of the hippocampus, caudate, and dorsolateral prefrontal cortex
   • variations in the CA1 region of the hippocampus and subiculum
   • smaller-than-normal orbitofrontal cortex (by 24%, compared with healthy controls) and the mid-temporal and left cingulate gyrii (by 26%)
   • larger-than-normal volume of the right inferior parietal cortex and the right parahippocampal gyrus
   • loss of gray matter in the frontal, temporal, and parietal cortices
   • an enlarged third cerebral ventricle
   • in women, reduced size of the me­dial temporal lobe and amygdala
   • in men, a decreased concentra­tion of gray matter in the anterior cingulate
   • reversal of normal right-greater-than-left asymmetry of the orbitofron­tal cortex gray matter, reflecting loss of gray matter on the right side
   • a lower concentration of gray mat­ter in the rostral/subgenual anterior cin­gulate cortex
   • a  smaller frontal lobe.

In an analysis of MRI studies,2 cor­relation was found between structural brain abnormalities and specific symp­toms of BPD, such as impulsivity, sui­cidality, and aggression. These findings might someday guide personalized in­terventions—for example, using neuro­stimulation techniques such as repetitive transcranial magnetic stimulation and deep brain stimulation—to modulate the activity of a given region of the brain (depending on which symptom is most prominent or disabling).
 

Magnetic resonance spectroscopy. In BPD, MRS studies reveal:
   • compared with controls, a higher glutamate level in the anterior cingulate cortex
   • reduced levels of N-acetyl aspar­tate (NAA; found in neurons) and cre­atinine in the left amygdala
   • a reduction (on average, 19%) in the NAA concentration in the dorsolat­eral prefrontal cortex.

Functional magnetic resonance im­aging. From fMRI studies, there is evi­dence in BPD of:
   • greater activation of the amygdala and prolonged return to baseline
   • increased functional connectiv­ity in the left frontopolar cortex and left insula
   • decreased connectivity in the left cuneus and left inferior parietal and the right middle temporal lobes
   • marked frontal hypometabolism
   • hypermetabolism in the motor cor­tex, medial and anterior cingulate, and occipital and temporal poles
   • lower connectivity between the amygdala during a neutral stimulus
   • higher connectivity between the amygdala during fear stimulus
   • higher connectivity between the amygdala during fear stimulus
   • deactivation of the opioid system in the left nucleus accumbens, hypothal­amus, and hippocampus
   • hyperactivation of the left medial prefrontal cortex during social exclusion
   • more mistakes made in differenti­ating an emotional and a neutral facial expression.
 

Diffusion tensor imaging. DTI white-matter integrity studies of BPD show:
   • a bilateral decrease in fractional an­isotropy (FA) in frontal, uncinated, and occipitalfrontal fasciculi
   • a decrease in FA in the genu and rostrum of the corpus callosum
   • a decrease in inter-hemispheric connectivity between right and left ante­rior cigulate cortices.

Genetic Studies
There is substantial scientific evidence that BPD is highly heritable—a finding that suggests that brain abnormalities of this disorder are a consequence of genes involved in brain development (similar to what is known about schizophrenia, bipolar disorder, and autism).

A systematic review of the heritabil­ity of BPD examined 59 published stud­ies that were categorized into 12 family studies, 18 twin studies, 24 association studies, and 5 gene-environment inter­action studies.3 The authors concluded that BPD has a strong genetic compo­nent, although there also is evidence of gene-environment (G.E) interactions (ie, how nature and nurture influence each other).

The G.E interaction model appears to be consistent with the theory that ex­pression of plasticity genes is modified by childhood experiences and environ­ment, such as physical or sexual abuse. Some studies have found evidence of hypermethylation in BPD, which can ex­ert epigenetic effects. Childhood abuse might, therefore, disrupt certain neuro­plasticity genes, culminating in morpho­logical, neurochemical, metabolic, and white-matter aberrations—leading to pathological behavioral patterns identi­fied as BPD.
 

The neuropsychiatric basis of BPD must guide treatment
There is no such thing as a purely psycho­logical disorder: Invariably, it is an abnor­mality of brain circuits that disrupts normal development of emotions, thought, behavior, and social cognition. BPD is an exemplar of such neuropsychiatric illness, and treat­ment should support psychotherapeutic ap­proaches to mend the mind at the same time it moves aggressively to repair the brain.

Doctor and patient

Credit: CDC

SAN DIEGO—Watching videos through special glasses can calm patients undergoing a biopsy or other minimally invasive treatment, according to research presented at the Society of Interventional Radiology’s 39th Annual Scientific Meeting.

Researchers have explored strategies other than medication to reduce anxiety in these patients, including having patients listen to music or undergo hypnosis. But these methods have had modest benefits.

“Our study—the first of its kind for interventional radiology treatments—puts a spin on using modern technology to provide a safe, potentially cost-effective strategy of reducing anxiety, which can help and improve patient care,” said David L. Waldman, MD, PhD, of the University of Rochester Medical Center in New York.

“Whether they were watching a children’s movie or a nature show, patients wearing video glasses were successful at tuning out their surroundings. It’s an effective distraction technique that helps focus the individual’s attention away from the treatment.”

The study involved 49 patients (33 men and 16 women, ages 18-87) who were undergoing an outpatient interventional radiology treatment, such as a biopsy or placement of a catheter in the arm or chest to receive medication for treating cancer or infection.

Twenty-five of the patients donned video glasses prior to undergoing the treatment, and 24 did not. The video viewers chose from 20 videos, none of which were violent.

All of the patients filled out a standard 20-question test called the State-Trait Anxiety Inventory Form Y before and after the procedure to assess their level of anxiety.

Patients who wore the video glasses were 18.1% less anxious after the treatment than they were before, while those who didn’t wear video glasses were 7.5% less anxious afterward.

And the presence of the video glasses did not bother either the patient or the doctor, Dr Waldman said.

The glasses had no significant effect on blood pressure, heart rate, respiratory rate, pain, procedure time, or the amount of sedation or pain medication used.

“Patients told us the video glasses really helped calm them down and took their mind off the treatment, and we now offer video glasses to help distract patients from medical treatment going on mere inches away,” Dr Waldman said. “It is really comforting for patients, especially the ones who tend to be more nervous.

Dr Waldman and his colleagues presented these results at the meeting as abstract 126.

Doctor and patient

Credit: CDC

SAN DIEGO—Watching videos through special glasses can calm patients undergoing a biopsy or other minimally invasive treatment, according to research presented at the Society of Interventional Radiology’s 39th Annual Scientific Meeting.

Researchers have explored strategies other than medication to reduce anxiety in these patients, including having patients listen to music or undergo hypnosis. But these methods have had modest benefits.

“Our study—the first of its kind for interventional radiology treatments—puts a spin on using modern technology to provide a safe, potentially cost-effective strategy of reducing anxiety, which can help and improve patient care,” said David L. Waldman, MD, PhD, of the University of Rochester Medical Center in New York.

“Whether they were watching a children’s movie or a nature show, patients wearing video glasses were successful at tuning out their surroundings. It’s an effective distraction technique that helps focus the individual’s attention away from the treatment.”

The study involved 49 patients (33 men and 16 women, ages 18-87) who were undergoing an outpatient interventional radiology treatment, such as a biopsy or placement of a catheter in the arm or chest to receive medication for treating cancer or infection.

Twenty-five of the patients donned video glasses prior to undergoing the treatment, and 24 did not. The video viewers chose from 20 videos, none of which were violent.

All of the patients filled out a standard 20-question test called the State-Trait Anxiety Inventory Form Y before and after the procedure to assess their level of anxiety.

Patients who wore the video glasses were 18.1% less anxious after the treatment than they were before, while those who didn’t wear video glasses were 7.5% less anxious afterward.

And the presence of the video glasses did not bother either the patient or the doctor, Dr Waldman said.

The glasses had no significant effect on blood pressure, heart rate, respiratory rate, pain, procedure time, or the amount of sedation or pain medication used.

“Patients told us the video glasses really helped calm them down and took their mind off the treatment, and we now offer video glasses to help distract patients from medical treatment going on mere inches away,” Dr Waldman said. “It is really comforting for patients, especially the ones who tend to be more nervous.

Dr Waldman and his colleagues presented these results at the meeting as abstract 126.

Doctor and patient

Credit: CDC

SAN DIEGO—Watching videos through special glasses can calm patients undergoing a biopsy or other minimally invasive treatment, according to research presented at the Society of Interventional Radiology’s 39th Annual Scientific Meeting.

Researchers have explored strategies other than medication to reduce anxiety in these patients, including having patients listen to music or undergo hypnosis. But these methods have had modest benefits.

“Our study—the first of its kind for interventional radiology treatments—puts a spin on using modern technology to provide a safe, potentially cost-effective strategy of reducing anxiety, which can help and improve patient care,” said David L. Waldman, MD, PhD, of the University of Rochester Medical Center in New York.

“Whether they were watching a children’s movie or a nature show, patients wearing video glasses were successful at tuning out their surroundings. It’s an effective distraction technique that helps focus the individual’s attention away from the treatment.”

The study involved 49 patients (33 men and 16 women, ages 18-87) who were undergoing an outpatient interventional radiology treatment, such as a biopsy or placement of a catheter in the arm or chest to receive medication for treating cancer or infection.

Twenty-five of the patients donned video glasses prior to undergoing the treatment, and 24 did not. The video viewers chose from 20 videos, none of which were violent.

All of the patients filled out a standard 20-question test called the State-Trait Anxiety Inventory Form Y before and after the procedure to assess their level of anxiety.

Patients who wore the video glasses were 18.1% less anxious after the treatment than they were before, while those who didn’t wear video glasses were 7.5% less anxious afterward.

And the presence of the video glasses did not bother either the patient or the doctor, Dr Waldman said.

The glasses had no significant effect on blood pressure, heart rate, respiratory rate, pain, procedure time, or the amount of sedation or pain medication used.

“Patients told us the video glasses really helped calm them down and took their mind off the treatment, and we now offer video glasses to help distract patients from medical treatment going on mere inches away,” Dr Waldman said. “It is really comforting for patients, especially the ones who tend to be more nervous.

Dr Waldman and his colleagues presented these results at the meeting as abstract 126.

 

 

Micrograph showing FL

 

Single-agent treatment with the HDAC inhibitor vorinostat can be effective in certain patients with indolent non-Hodgkin lymphoma (NHL), according to research published in the British Journal of Haematology.

In the phase 2 study, vorinostat prompted a 49% overall response rate among 39 patients with relapsed or refractory follicular lymphoma (FL).

However, none of the 4 patients with previously treated mantle cell lymphoma (MCL) achieved a response.

Michinori Ogura, MD, PhD, of Nagoya Daini Red Cross Hospital in Japan, and his colleagues set out to analyze the effects of vorinostat in 56 patients with indolent NHL. Six patients were excluded from the final analysis, as their diseases could not be classified.

Thirty-nine patients had FL, 4 had extranodal marginal zone lymphoma (MZL) of MALT type, 4 had MCL, 2 had small B-cell lymphoma not otherwise specified (NOS), and 1 had small lymphocytic lymphoma.

The median age was 60 years (range, 33-75), and the median number of prior therapies was 2 (range, 1-4). These therapies included rituximab (n=40), alkylating agents (n=7), purine analogs (n=5), and radioimmunotherapy (n=3).

The patients received vorinostat for a median of 8 months. The planned dosage was 200 mg twice daily for 14 consecutive days in a 21-day cycle.

At the first data cutoff point (1 year from the last patient’s enrollment), 18 patients remained on treatment. Thirty-eight had discontinued due to disease progression (n=25), drug-related adverse events (n=9), or withdrawn consent (n=4).

The overall response rate was 49% among FL patients. Ten percent (n=4) achieved a complete response, 8% (n=3) achieved an unconfirmed complete response, and 31% (n=12) achieved a partial response.

None of the patients with MCL responded, but 3 of the 7 (43%) patients with other indolent NHLs achieved a response.

That included 2 patients with small B-cell lymphoma NOS and 1 with extranodal MZL of MALT type. One of the patients with small B-cell lymphoma NOS achieved a complete response.

Approximately 81% of all 56 patients remained alive at 2 years after the last patients had enrolled (the second data cutoff point).

At that point, the median overall survival had not been reached. And the median progression-free survival was 26 months among the FL patients who responded.

There were no treatment-related deaths. The most common drug-related events (in all 56 patients) were thrombocytopenia (93%), diarrhea (68%), neutropenia (68%), decreased appetite (63%), nausea (61%), leukopenia (55%), and fatigue (52%).

Eighty percent of patients (n=45) experienced grade 3/4 adverse events, the most common of which were thrombocytopenia (23% grade 3; 25% grade 4) and neutropenia (36% grade 3; 5% grade 4).

However, all of the patients with thrombocytopenia or neutropenia recovered after they received adequate supportive care and their vorinostat dose was reduced or treatment was interrupted or discontinued.

Taking these results together, the researchers concluded that vorinostat offers sustained antitumor activity and has an acceptable safety profile for patients with relapsed or refractory FL. The team noted, however, that because this was a single-arm study with limited data, a comparative study is needed.

 

 

Micrograph showing FL

 

Single-agent treatment with the HDAC inhibitor vorinostat can be effective in certain patients with indolent non-Hodgkin lymphoma (NHL), according to research published in the British Journal of Haematology.

In the phase 2 study, vorinostat prompted a 49% overall response rate among 39 patients with relapsed or refractory follicular lymphoma (FL).

However, none of the 4 patients with previously treated mantle cell lymphoma (MCL) achieved a response.

Michinori Ogura, MD, PhD, of Nagoya Daini Red Cross Hospital in Japan, and his colleagues set out to analyze the effects of vorinostat in 56 patients with indolent NHL. Six patients were excluded from the final analysis, as their diseases could not be classified.

Thirty-nine patients had FL, 4 had extranodal marginal zone lymphoma (MZL) of MALT type, 4 had MCL, 2 had small B-cell lymphoma not otherwise specified (NOS), and 1 had small lymphocytic lymphoma.

The median age was 60 years (range, 33-75), and the median number of prior therapies was 2 (range, 1-4). These therapies included rituximab (n=40), alkylating agents (n=7), purine analogs (n=5), and radioimmunotherapy (n=3).

The patients received vorinostat for a median of 8 months. The planned dosage was 200 mg twice daily for 14 consecutive days in a 21-day cycle.

At the first data cutoff point (1 year from the last patient’s enrollment), 18 patients remained on treatment. Thirty-eight had discontinued due to disease progression (n=25), drug-related adverse events (n=9), or withdrawn consent (n=4).

The overall response rate was 49% among FL patients. Ten percent (n=4) achieved a complete response, 8% (n=3) achieved an unconfirmed complete response, and 31% (n=12) achieved a partial response.

None of the patients with MCL responded, but 3 of the 7 (43%) patients with other indolent NHLs achieved a response.

That included 2 patients with small B-cell lymphoma NOS and 1 with extranodal MZL of MALT type. One of the patients with small B-cell lymphoma NOS achieved a complete response.

Approximately 81% of all 56 patients remained alive at 2 years after the last patients had enrolled (the second data cutoff point).

At that point, the median overall survival had not been reached. And the median progression-free survival was 26 months among the FL patients who responded.

There were no treatment-related deaths. The most common drug-related events (in all 56 patients) were thrombocytopenia (93%), diarrhea (68%), neutropenia (68%), decreased appetite (63%), nausea (61%), leukopenia (55%), and fatigue (52%).

Eighty percent of patients (n=45) experienced grade 3/4 adverse events, the most common of which were thrombocytopenia (23% grade 3; 25% grade 4) and neutropenia (36% grade 3; 5% grade 4).

However, all of the patients with thrombocytopenia or neutropenia recovered after they received adequate supportive care and their vorinostat dose was reduced or treatment was interrupted or discontinued.

Taking these results together, the researchers concluded that vorinostat offers sustained antitumor activity and has an acceptable safety profile for patients with relapsed or refractory FL. The team noted, however, that because this was a single-arm study with limited data, a comparative study is needed.

 

 

Micrograph showing FL

 

Single-agent treatment with the HDAC inhibitor vorinostat can be effective in certain patients with indolent non-Hodgkin lymphoma (NHL), according to research published in the British Journal of Haematology.

In the phase 2 study, vorinostat prompted a 49% overall response rate among 39 patients with relapsed or refractory follicular lymphoma (FL).

However, none of the 4 patients with previously treated mantle cell lymphoma (MCL) achieved a response.

Michinori Ogura, MD, PhD, of Nagoya Daini Red Cross Hospital in Japan, and his colleagues set out to analyze the effects of vorinostat in 56 patients with indolent NHL. Six patients were excluded from the final analysis, as their diseases could not be classified.

Thirty-nine patients had FL, 4 had extranodal marginal zone lymphoma (MZL) of MALT type, 4 had MCL, 2 had small B-cell lymphoma not otherwise specified (NOS), and 1 had small lymphocytic lymphoma.

The median age was 60 years (range, 33-75), and the median number of prior therapies was 2 (range, 1-4). These therapies included rituximab (n=40), alkylating agents (n=7), purine analogs (n=5), and radioimmunotherapy (n=3).

The patients received vorinostat for a median of 8 months. The planned dosage was 200 mg twice daily for 14 consecutive days in a 21-day cycle.

At the first data cutoff point (1 year from the last patient’s enrollment), 18 patients remained on treatment. Thirty-eight had discontinued due to disease progression (n=25), drug-related adverse events (n=9), or withdrawn consent (n=4).

The overall response rate was 49% among FL patients. Ten percent (n=4) achieved a complete response, 8% (n=3) achieved an unconfirmed complete response, and 31% (n=12) achieved a partial response.

None of the patients with MCL responded, but 3 of the 7 (43%) patients with other indolent NHLs achieved a response.

That included 2 patients with small B-cell lymphoma NOS and 1 with extranodal MZL of MALT type. One of the patients with small B-cell lymphoma NOS achieved a complete response.

Approximately 81% of all 56 patients remained alive at 2 years after the last patients had enrolled (the second data cutoff point).

At that point, the median overall survival had not been reached. And the median progression-free survival was 26 months among the FL patients who responded.

There were no treatment-related deaths. The most common drug-related events (in all 56 patients) were thrombocytopenia (93%), diarrhea (68%), neutropenia (68%), decreased appetite (63%), nausea (61%), leukopenia (55%), and fatigue (52%).

Eighty percent of patients (n=45) experienced grade 3/4 adverse events, the most common of which were thrombocytopenia (23% grade 3; 25% grade 4) and neutropenia (36% grade 3; 5% grade 4).

However, all of the patients with thrombocytopenia or neutropenia recovered after they received adequate supportive care and their vorinostat dose was reduced or treatment was interrupted or discontinued.

Taking these results together, the researchers concluded that vorinostat offers sustained antitumor activity and has an acceptable safety profile for patients with relapsed or refractory FL. The team noted, however, that because this was a single-arm study with limited data, a comparative study is needed.

Micrograph showing cutaneous

diffuse large B-cell lymphoma

Credit: Leszek Woźniak

& Krzysztof W. Zieliński

An immunotherapeutic agent can confer clinical benefit in patients with relapsed cutaneous B-cell lymphoma (CBCL), results of a small phase 2 study suggest.

The therapy, TG1042, is human adenovirus type 5 engineered to express interferon-gamma.

Repeat injections of TG1042 elicited responses in 11 of 12 evaluable patients, with complete responses in 7.

All 13 of the patients enrolled on the study experienced an adverse event that may have been related to TG1042, but most were grade 1 or 2 in severity.

“Intralesional TG1042 therapy is well-tolerated and results in lasting tumor regressions,” said study author Reinhard Dummer, MD, of the University of Zurich in Switzerland.

He and his colleagues reported these results in PLOS ONE. The study was sponsored by Transgene SA, makers of TG1042.

The trial consisted of 13 patients with primary CBCL, including primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center B-cell lymphoma, primary cutaneous diffuse large B-cell lymphoma other than leg type, and T-cell/histiocyte-rich B-cell lymphoma.

Patients were required to have either relapsed or active disease after at least 1 first-line treatment.

The patients received intralesional injections of TG1042 at 5 x 10¹⁰ viral particles per lesion. They could receive injections in up to 6 lesions, which were treated simultaneously on days 1, 8, and 15 of a 4-week cycle.

Patients did not receive treatment during the fourth week. At the end of the cycle, the researchers evaluated tumors for response.

If patients’ disease did not progress, they could receive an additional cycle, up to a maximum of 4. If patients responded to treatment and their lesions disappeared, they were eligible to receive a second series of injections in untreated lesions.

Of the 13 patients treated, 12 were evaluable for response. Eleven of the patients (85%) achieved an objective response—7 complete responses and 4 partial responses. One patient had stable disease.

All reviewed skin biopsies showed that lesions improved after treatment, with a decrease of the lymphoid infiltrate.

The median time to first objective response was 3.2 months (rage, 1-17.5 months). Among complete responders, the median time to response was 4.3 months (range, 1.4-17.5 months).

The median time to progression was 23.5 months (range, 6.5-26.4+ months).

All 13 patients were included in the safety evaluation, and all experienced 1 or more adverse events that were considered possibly or probably related to the treatment.

One patient discontinued treatment due to influenza-like illness, pyrexia, headache, and skin blisters that were possibly related to TG1042.

Another patient had grade 3 increased lipase, but this was thought to be unrelated to TG1042. And it resolved without treatment.

All other adverse events were grade 1 or 2 in nature. They included fatigue, headache, pyrexia, chills, influenza-like illness, injection site irritation, injection site erythema, and injection site pain.

All of these reactions resolved after treatment discontinuation.

Micrograph showing cutaneous

diffuse large B-cell lymphoma

Credit: Leszek Woźniak

& Krzysztof W. Zieliński

An immunotherapeutic agent can confer clinical benefit in patients with relapsed cutaneous B-cell lymphoma (CBCL), results of a small phase 2 study suggest.

The therapy, TG1042, is human adenovirus type 5 engineered to express interferon-gamma.

Repeat injections of TG1042 elicited responses in 11 of 12 evaluable patients, with complete responses in 7.

All 13 of the patients enrolled on the study experienced an adverse event that may have been related to TG1042, but most were grade 1 or 2 in severity.

“Intralesional TG1042 therapy is well-tolerated and results in lasting tumor regressions,” said study author Reinhard Dummer, MD, of the University of Zurich in Switzerland.

He and his colleagues reported these results in PLOS ONE. The study was sponsored by Transgene SA, makers of TG1042.

The trial consisted of 13 patients with primary CBCL, including primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center B-cell lymphoma, primary cutaneous diffuse large B-cell lymphoma other than leg type, and T-cell/histiocyte-rich B-cell lymphoma.

Patients were required to have either relapsed or active disease after at least 1 first-line treatment.

The patients received intralesional injections of TG1042 at 5 x 10¹⁰ viral particles per lesion. They could receive injections in up to 6 lesions, which were treated simultaneously on days 1, 8, and 15 of a 4-week cycle.

Patients did not receive treatment during the fourth week. At the end of the cycle, the researchers evaluated tumors for response.

If patients’ disease did not progress, they could receive an additional cycle, up to a maximum of 4. If patients responded to treatment and their lesions disappeared, they were eligible to receive a second series of injections in untreated lesions.

Of the 13 patients treated, 12 were evaluable for response. Eleven of the patients (85%) achieved an objective response—7 complete responses and 4 partial responses. One patient had stable disease.

All reviewed skin biopsies showed that lesions improved after treatment, with a decrease of the lymphoid infiltrate.

The median time to first objective response was 3.2 months (rage, 1-17.5 months). Among complete responders, the median time to response was 4.3 months (range, 1.4-17.5 months).

The median time to progression was 23.5 months (range, 6.5-26.4+ months).

All 13 patients were included in the safety evaluation, and all experienced 1 or more adverse events that were considered possibly or probably related to the treatment.

One patient discontinued treatment due to influenza-like illness, pyrexia, headache, and skin blisters that were possibly related to TG1042.

Another patient had grade 3 increased lipase, but this was thought to be unrelated to TG1042. And it resolved without treatment.

All other adverse events were grade 1 or 2 in nature. They included fatigue, headache, pyrexia, chills, influenza-like illness, injection site irritation, injection site erythema, and injection site pain.

All of these reactions resolved after treatment discontinuation.

Micrograph showing cutaneous

diffuse large B-cell lymphoma

Credit: Leszek Woźniak

& Krzysztof W. Zieliński

An immunotherapeutic agent can confer clinical benefit in patients with relapsed cutaneous B-cell lymphoma (CBCL), results of a small phase 2 study suggest.

The therapy, TG1042, is human adenovirus type 5 engineered to express interferon-gamma.

Repeat injections of TG1042 elicited responses in 11 of 12 evaluable patients, with complete responses in 7.

All 13 of the patients enrolled on the study experienced an adverse event that may have been related to TG1042, but most were grade 1 or 2 in severity.

“Intralesional TG1042 therapy is well-tolerated and results in lasting tumor regressions,” said study author Reinhard Dummer, MD, of the University of Zurich in Switzerland.

He and his colleagues reported these results in PLOS ONE. The study was sponsored by Transgene SA, makers of TG1042.

The trial consisted of 13 patients with primary CBCL, including primary cutaneous marginal zone B-cell lymphoma, primary cutaneous follicle center B-cell lymphoma, primary cutaneous diffuse large B-cell lymphoma other than leg type, and T-cell/histiocyte-rich B-cell lymphoma.

Patients were required to have either relapsed or active disease after at least 1 first-line treatment.

The patients received intralesional injections of TG1042 at 5 x 10¹⁰ viral particles per lesion. They could receive injections in up to 6 lesions, which were treated simultaneously on days 1, 8, and 15 of a 4-week cycle.

Patients did not receive treatment during the fourth week. At the end of the cycle, the researchers evaluated tumors for response.

If patients’ disease did not progress, they could receive an additional cycle, up to a maximum of 4. If patients responded to treatment and their lesions disappeared, they were eligible to receive a second series of injections in untreated lesions.

Of the 13 patients treated, 12 were evaluable for response. Eleven of the patients (85%) achieved an objective response—7 complete responses and 4 partial responses. One patient had stable disease.

All reviewed skin biopsies showed that lesions improved after treatment, with a decrease of the lymphoid infiltrate.

The median time to first objective response was 3.2 months (rage, 1-17.5 months). Among complete responders, the median time to response was 4.3 months (range, 1.4-17.5 months).

The median time to progression was 23.5 months (range, 6.5-26.4+ months).

All 13 patients were included in the safety evaluation, and all experienced 1 or more adverse events that were considered possibly or probably related to the treatment.

One patient discontinued treatment due to influenza-like illness, pyrexia, headache, and skin blisters that were possibly related to TG1042.

Another patient had grade 3 increased lipase, but this was thought to be unrelated to TG1042. And it resolved without treatment.

All other adverse events were grade 1 or 2 in nature. They included fatigue, headache, pyrexia, chills, influenza-like illness, injection site irritation, injection site erythema, and injection site pain.

All of these reactions resolved after treatment discontinuation.