Doug Brunk

SAN DIEGO – Patients with atopic dermatitis should routinely receive the intramuscular form of the influenza vaccine Fluzone unless the affected area of skin has been swabbed and found to have normal skin flora, data from a controlled study suggested.

"The original studies leading to approval of intradermal vaccination with Fluzone were done only in normal subjects," Dr. Donald Y.M. Leung said in an interview prior to the annual meeting of the American Academy of Allergy, Asthma, and Immunology, where the findings were presented. "Patients with atopic dermatitis [AD], the most common skin disease in the general population, were not included in previous studies. AD patients are prone to skin infection and may have an abnormal immune response in their skin."

To determine whether patients with AD had a normal skin immune response to Fluzone, Dr. Leung and his associates at five medical centers measured hemagglutination inhibition antibody (HAI) titers at baseline and 28 days post vaccination in 223 subjects with AD (including a subset with Staphylococcus aureus colonization) and 135 nonatopic controls after administration per label of either a single dose of the seasonal 2012-2013 intradermal Fluzone or Fluzone for intramuscular injection. They excluded subjects who were seroprotected at baseline (defined as an HAI of greater than 1:40).

Dr. Leung, who heads the division of pediatric allergy and immunology at National Jewish Health, Denver, reported that seroprotection and seroconversion rates for the three influenza strains included in the vaccine (B, H1N1, and H3N2) were not significantly different for AD and control subjects who received intradermal vaccination. Seroprotection and seroconversion rates were similar for AD subjects who received intradermal vaccination compared with AD subjects who received intramuscular vaccination.

Following intradermal vaccination, AD patients colonized with S. aureus had notably lower seroprotection and seroconversion rates to the B strain (12% vs. 47%, P less than .001, and 21% vs. 51%, P = .002, respectively) and a lower seroconversion rate for H1N1 (77% vs. 95%, P = .029) compared with subjects with uncolonized AD. There were no notable differences for H3N2. No differences were observed between AD subjects colonized with S. aureus and uncolonized AD subjects following intramuscular Fluzone for any strain.

"Although the AD group as a whole had a normal response to Fluzone given in the skin, the large subset of AD patients who were colonized with Staphylococcus aureus had a reduced response to Fluzone vaccination when the vaccine was introduced into the skin as opposed to the conventional intramuscular injection," Dr. Leung said. "Studies are needed to find out why colonization of the skin with S. aureus is associated with reduced skin immune responses."

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Leung said he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Patients with atopic dermatitis should routinely receive the intramuscular form of the influenza vaccine Fluzone unless the affected area of skin has been swabbed and found to have normal skin flora, data from a controlled study suggested.

"The original studies leading to approval of intradermal vaccination with Fluzone were done only in normal subjects," Dr. Donald Y.M. Leung said in an interview prior to the annual meeting of the American Academy of Allergy, Asthma, and Immunology, where the findings were presented. "Patients with atopic dermatitis [AD], the most common skin disease in the general population, were not included in previous studies. AD patients are prone to skin infection and may have an abnormal immune response in their skin."

To determine whether patients with AD had a normal skin immune response to Fluzone, Dr. Leung and his associates at five medical centers measured hemagglutination inhibition antibody (HAI) titers at baseline and 28 days post vaccination in 223 subjects with AD (including a subset with Staphylococcus aureus colonization) and 135 nonatopic controls after administration per label of either a single dose of the seasonal 2012-2013 intradermal Fluzone or Fluzone for intramuscular injection. They excluded subjects who were seroprotected at baseline (defined as an HAI of greater than 1:40).

Dr. Leung, who heads the division of pediatric allergy and immunology at National Jewish Health, Denver, reported that seroprotection and seroconversion rates for the three influenza strains included in the vaccine (B, H1N1, and H3N2) were not significantly different for AD and control subjects who received intradermal vaccination. Seroprotection and seroconversion rates were similar for AD subjects who received intradermal vaccination compared with AD subjects who received intramuscular vaccination.

Following intradermal vaccination, AD patients colonized with S. aureus had notably lower seroprotection and seroconversion rates to the B strain (12% vs. 47%, P less than .001, and 21% vs. 51%, P = .002, respectively) and a lower seroconversion rate for H1N1 (77% vs. 95%, P = .029) compared with subjects with uncolonized AD. There were no notable differences for H3N2. No differences were observed between AD subjects colonized with S. aureus and uncolonized AD subjects following intramuscular Fluzone for any strain.

"Although the AD group as a whole had a normal response to Fluzone given in the skin, the large subset of AD patients who were colonized with Staphylococcus aureus had a reduced response to Fluzone vaccination when the vaccine was introduced into the skin as opposed to the conventional intramuscular injection," Dr. Leung said. "Studies are needed to find out why colonization of the skin with S. aureus is associated with reduced skin immune responses."

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Leung said he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Patients with atopic dermatitis should routinely receive the intramuscular form of the influenza vaccine Fluzone unless the affected area of skin has been swabbed and found to have normal skin flora, data from a controlled study suggested.

"The original studies leading to approval of intradermal vaccination with Fluzone were done only in normal subjects," Dr. Donald Y.M. Leung said in an interview prior to the annual meeting of the American Academy of Allergy, Asthma, and Immunology, where the findings were presented. "Patients with atopic dermatitis [AD], the most common skin disease in the general population, were not included in previous studies. AD patients are prone to skin infection and may have an abnormal immune response in their skin."

To determine whether patients with AD had a normal skin immune response to Fluzone, Dr. Leung and his associates at five medical centers measured hemagglutination inhibition antibody (HAI) titers at baseline and 28 days post vaccination in 223 subjects with AD (including a subset with Staphylococcus aureus colonization) and 135 nonatopic controls after administration per label of either a single dose of the seasonal 2012-2013 intradermal Fluzone or Fluzone for intramuscular injection. They excluded subjects who were seroprotected at baseline (defined as an HAI of greater than 1:40).

Dr. Leung, who heads the division of pediatric allergy and immunology at National Jewish Health, Denver, reported that seroprotection and seroconversion rates for the three influenza strains included in the vaccine (B, H1N1, and H3N2) were not significantly different for AD and control subjects who received intradermal vaccination. Seroprotection and seroconversion rates were similar for AD subjects who received intradermal vaccination compared with AD subjects who received intramuscular vaccination.

Following intradermal vaccination, AD patients colonized with S. aureus had notably lower seroprotection and seroconversion rates to the B strain (12% vs. 47%, P less than .001, and 21% vs. 51%, P = .002, respectively) and a lower seroconversion rate for H1N1 (77% vs. 95%, P = .029) compared with subjects with uncolonized AD. There were no notable differences for H3N2. No differences were observed between AD subjects colonized with S. aureus and uncolonized AD subjects following intramuscular Fluzone for any strain.

"Although the AD group as a whole had a normal response to Fluzone given in the skin, the large subset of AD patients who were colonized with Staphylococcus aureus had a reduced response to Fluzone vaccination when the vaccine was introduced into the skin as opposed to the conventional intramuscular injection," Dr. Leung said. "Studies are needed to find out why colonization of the skin with S. aureus is associated with reduced skin immune responses."

The study was funded by the National Institute of Allergy and Infectious Diseases. Dr. Leung said he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO– Twenty-one years after the National Research Council published its first report on child abuse and neglect, clinicians and researchers in the field wrestle with many of the same issues today as they did in 1993, according to Anne C. Petersen, Ph.D.

"Significant progress has been made since 1993, but significant gaps still remain," said Dr. Petersen, who chaired the Institute of Medicine and National Research Council report entitled "New Directions in Child Abuse and Neglect Research," which was released on Sept. 12, 2013. "That was disheartening to us as a committee to realize that many of the things we noticed in the first report 20 years ago still exist, especially in research infrastructure."

At the San Diego International Conference on Child and Family Maltreatment, she characterized child abuse and neglect as "a devastating health problem that affects victims throughout their lives in every aspect of human function. It’s a very serious public health issue that carries an annual cost to society of $80.3 billion. Addressing this problem requires an immediate, coordinated response with high-level federal support."

Fiscal year 2011 data from the National Child Abuse and Neglect Data System (NCANDS) reported 3.4 million referrals of child abuse and neglect involving 6.2 million children. Of these, 75% were classified as neglect, about 15% were physical abuse, and about 10% were sexual abuse. The highest rates of child abuse and neglect occurred in children younger than 3 years old.

Since 1993, sexual abuse has declined by as much as 62%, according to NCANDS and other data, while physical abuse – especially less serious forms – has declined by as much as 56%, although the data are less consistent, Dr. Petersen said at the meeting, which was sponsored by Rady Children’s Hospital, San Diego. At the same time, neglect statistics vary significantly across states with no evidence of decline.

Understanding what drives such trends remains elusive. "Why do physical and sexual abuse appear to be going down, whereas neglect may not be going down?" she asked. "Until we get a grip on that, we really are going to be handicapped in our capacity to treat these issues, prevent them, and develop sensible policies. There are too few people looking at this bigger issue."

Although there has been a threefold increase in scientific publications related to child abuse and neglect over the past 2 decades, research in the field "continues to be disjointed and fragmented across multiple disciplines," said Dr. Petersen, a research professor in the University of Michigan’s Center for Human Growth and Development, Ann Arbor. "The field continues to be set apart from mainstream studies of child and adolescent health and development. Improved infrastructure, support, and coordination are needed for the research field to be an efficient, productive scientific enterprise."

The 365-page IOM-NRC report calls for rigorous research to further explore the process and outcomes of both screening and medical evaluation; to examine the validity of abusive head trauma diagnoses; to support the development of more uniform approaches to practice; and to arrive at a medical consensus regarding thresholds for reporting neglect. "There’s no definitive differential diagnostic technique to say that it’s been child abuse," Dr. Petersen said. "We need good diagnostic tools, for treatment and for designing effective prevention programs."

In terms of causality, parental substance abuse, depression, and a history of child abuse and neglect have the strongest evidentiary support as risk factors, according to the report. Some children who suffer from abuse and neglect "seem to do better than others," she added. "One of the approaches to studying this is looking at resilience: why some children are more resilient than others. If the problem is less chronic, there is less severity and better outcomes. Having a support figure is crucial for children who have been abused and neglected."

While much has been learned generally about pervasive consequences of child abuse and neglect, the report’s authors recommend that future research focus on improved understanding of the consequences of sexual abuse vs. physical abuse vs. neglect. "We don’t have much differential research yet to really help us understand whether different kinds of abuse and neglect have different consequences," Dr. Petersen explained. "We need a better understanding of mechanisms. There is a lot of research emerging [that] suggests that interventions can help those who have been severely abused and neglected. We don’t know if that’s true for all cases. My guess is it won’t be, but there’s research showing that interventions can generally help these young people."

Successful and promising programs related to prevention of child abuse and neglect illuminated in the report include early home-visit programs, public awareness campaigns, parenting education programs, and professional practice reforms such as screening. "One question that we can’t answer definitively is whether the rates of physical and sexual abuse have gone down because of these efforts," Dr. Petersen said. "It would be wonderful to conclude that’s the case. We hope it is."

The report can be downloaded for free at the IOM reports page.

Dr. Petersen reported no relevant financial conflicts.

dbrunk@frontlinemedcom.com

SAN DIEGO– Twenty-one years after the National Research Council published its first report on child abuse and neglect, clinicians and researchers in the field wrestle with many of the same issues today as they did in 1993, according to Anne C. Petersen, Ph.D.

"Significant progress has been made since 1993, but significant gaps still remain," said Dr. Petersen, who chaired the Institute of Medicine and National Research Council report entitled "New Directions in Child Abuse and Neglect Research," which was released on Sept. 12, 2013. "That was disheartening to us as a committee to realize that many of the things we noticed in the first report 20 years ago still exist, especially in research infrastructure."

At the San Diego International Conference on Child and Family Maltreatment, she characterized child abuse and neglect as "a devastating health problem that affects victims throughout their lives in every aspect of human function. It’s a very serious public health issue that carries an annual cost to society of $80.3 billion. Addressing this problem requires an immediate, coordinated response with high-level federal support."

Fiscal year 2011 data from the National Child Abuse and Neglect Data System (NCANDS) reported 3.4 million referrals of child abuse and neglect involving 6.2 million children. Of these, 75% were classified as neglect, about 15% were physical abuse, and about 10% were sexual abuse. The highest rates of child abuse and neglect occurred in children younger than 3 years old.

Since 1993, sexual abuse has declined by as much as 62%, according to NCANDS and other data, while physical abuse – especially less serious forms – has declined by as much as 56%, although the data are less consistent, Dr. Petersen said at the meeting, which was sponsored by Rady Children’s Hospital, San Diego. At the same time, neglect statistics vary significantly across states with no evidence of decline.

Understanding what drives such trends remains elusive. "Why do physical and sexual abuse appear to be going down, whereas neglect may not be going down?" she asked. "Until we get a grip on that, we really are going to be handicapped in our capacity to treat these issues, prevent them, and develop sensible policies. There are too few people looking at this bigger issue."

Although there has been a threefold increase in scientific publications related to child abuse and neglect over the past 2 decades, research in the field "continues to be disjointed and fragmented across multiple disciplines," said Dr. Petersen, a research professor in the University of Michigan’s Center for Human Growth and Development, Ann Arbor. "The field continues to be set apart from mainstream studies of child and adolescent health and development. Improved infrastructure, support, and coordination are needed for the research field to be an efficient, productive scientific enterprise."

The 365-page IOM-NRC report calls for rigorous research to further explore the process and outcomes of both screening and medical evaluation; to examine the validity of abusive head trauma diagnoses; to support the development of more uniform approaches to practice; and to arrive at a medical consensus regarding thresholds for reporting neglect. "There’s no definitive differential diagnostic technique to say that it’s been child abuse," Dr. Petersen said. "We need good diagnostic tools, for treatment and for designing effective prevention programs."

In terms of causality, parental substance abuse, depression, and a history of child abuse and neglect have the strongest evidentiary support as risk factors, according to the report. Some children who suffer from abuse and neglect "seem to do better than others," she added. "One of the approaches to studying this is looking at resilience: why some children are more resilient than others. If the problem is less chronic, there is less severity and better outcomes. Having a support figure is crucial for children who have been abused and neglected."

While much has been learned generally about pervasive consequences of child abuse and neglect, the report’s authors recommend that future research focus on improved understanding of the consequences of sexual abuse vs. physical abuse vs. neglect. "We don’t have much differential research yet to really help us understand whether different kinds of abuse and neglect have different consequences," Dr. Petersen explained. "We need a better understanding of mechanisms. There is a lot of research emerging [that] suggests that interventions can help those who have been severely abused and neglected. We don’t know if that’s true for all cases. My guess is it won’t be, but there’s research showing that interventions can generally help these young people."

Successful and promising programs related to prevention of child abuse and neglect illuminated in the report include early home-visit programs, public awareness campaigns, parenting education programs, and professional practice reforms such as screening. "One question that we can’t answer definitively is whether the rates of physical and sexual abuse have gone down because of these efforts," Dr. Petersen said. "It would be wonderful to conclude that’s the case. We hope it is."

The report can be downloaded for free at the IOM reports page.

Dr. Petersen reported no relevant financial conflicts.

dbrunk@frontlinemedcom.com

SAN DIEGO– Twenty-one years after the National Research Council published its first report on child abuse and neglect, clinicians and researchers in the field wrestle with many of the same issues today as they did in 1993, according to Anne C. Petersen, Ph.D.

"Significant progress has been made since 1993, but significant gaps still remain," said Dr. Petersen, who chaired the Institute of Medicine and National Research Council report entitled "New Directions in Child Abuse and Neglect Research," which was released on Sept. 12, 2013. "That was disheartening to us as a committee to realize that many of the things we noticed in the first report 20 years ago still exist, especially in research infrastructure."

At the San Diego International Conference on Child and Family Maltreatment, she characterized child abuse and neglect as "a devastating health problem that affects victims throughout their lives in every aspect of human function. It’s a very serious public health issue that carries an annual cost to society of $80.3 billion. Addressing this problem requires an immediate, coordinated response with high-level federal support."

Fiscal year 2011 data from the National Child Abuse and Neglect Data System (NCANDS) reported 3.4 million referrals of child abuse and neglect involving 6.2 million children. Of these, 75% were classified as neglect, about 15% were physical abuse, and about 10% were sexual abuse. The highest rates of child abuse and neglect occurred in children younger than 3 years old.

Since 1993, sexual abuse has declined by as much as 62%, according to NCANDS and other data, while physical abuse – especially less serious forms – has declined by as much as 56%, although the data are less consistent, Dr. Petersen said at the meeting, which was sponsored by Rady Children’s Hospital, San Diego. At the same time, neglect statistics vary significantly across states with no evidence of decline.

Understanding what drives such trends remains elusive. "Why do physical and sexual abuse appear to be going down, whereas neglect may not be going down?" she asked. "Until we get a grip on that, we really are going to be handicapped in our capacity to treat these issues, prevent them, and develop sensible policies. There are too few people looking at this bigger issue."

Although there has been a threefold increase in scientific publications related to child abuse and neglect over the past 2 decades, research in the field "continues to be disjointed and fragmented across multiple disciplines," said Dr. Petersen, a research professor in the University of Michigan’s Center for Human Growth and Development, Ann Arbor. "The field continues to be set apart from mainstream studies of child and adolescent health and development. Improved infrastructure, support, and coordination are needed for the research field to be an efficient, productive scientific enterprise."

The 365-page IOM-NRC report calls for rigorous research to further explore the process and outcomes of both screening and medical evaluation; to examine the validity of abusive head trauma diagnoses; to support the development of more uniform approaches to practice; and to arrive at a medical consensus regarding thresholds for reporting neglect. "There’s no definitive differential diagnostic technique to say that it’s been child abuse," Dr. Petersen said. "We need good diagnostic tools, for treatment and for designing effective prevention programs."

In terms of causality, parental substance abuse, depression, and a history of child abuse and neglect have the strongest evidentiary support as risk factors, according to the report. Some children who suffer from abuse and neglect "seem to do better than others," she added. "One of the approaches to studying this is looking at resilience: why some children are more resilient than others. If the problem is less chronic, there is less severity and better outcomes. Having a support figure is crucial for children who have been abused and neglected."

While much has been learned generally about pervasive consequences of child abuse and neglect, the report’s authors recommend that future research focus on improved understanding of the consequences of sexual abuse vs. physical abuse vs. neglect. "We don’t have much differential research yet to really help us understand whether different kinds of abuse and neglect have different consequences," Dr. Petersen explained. "We need a better understanding of mechanisms. There is a lot of research emerging [that] suggests that interventions can help those who have been severely abused and neglected. We don’t know if that’s true for all cases. My guess is it won’t be, but there’s research showing that interventions can generally help these young people."

Successful and promising programs related to prevention of child abuse and neglect illuminated in the report include early home-visit programs, public awareness campaigns, parenting education programs, and professional practice reforms such as screening. "One question that we can’t answer definitively is whether the rates of physical and sexual abuse have gone down because of these efforts," Dr. Petersen said. "It would be wonderful to conclude that’s the case. We hope it is."

The report can be downloaded for free at the IOM reports page.

Dr. Petersen reported no relevant financial conflicts.

dbrunk@frontlinemedcom.com

LAS VEGAS – Despite your best efforts at treating patients newly diagnosed with major depressive disorder, only about 1 in 3 patients achieves remission on the first antidepressant and almost 50% subsequently relapse.

"Our work is cut out for is," Dr. Jonathan E. Alpert said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

Factors associated with nonremission in major depressive disorder (MDD) include a history of chronic or recurrent depression; anxious, melancholic, or psychotic features; psychiatric or general medical comorbidity; minority ethnic/racial status; and lower quality of life and function prior to treatment. When a patient fails to remit, Dr. Alpert recommends a checklist of four basic factors to consider before rushing to the next medication or to the next form of psychotherapy.

"It’s important to step back for a moment and recheck what you think you know about that particular patient," said Dr. Alpert, associate chief of psychiatry for clinical services at Massachusetts General Hospital (MGH), Boston.

One factor on the checklist is adherence. Some patients – and sometimes their significant others – are ambivalent about pursuing depression treatment, which could interfere with adherence. "Other patients are confused about the instructions we’ve given them, or they might have cognitive problems that make it difficult for them to stick with the complex regimens we might be prescribing," he explained. "Access to health care and cost of medications can also play a role."

Another factor on the checklist is to be sure of your primary diagnosis. Is it MDD, or is it MDD with psychotic features? Is it bipolar disorder or mood dysregulation in the context of personality disorder? "It can be difficult to separate these," he said.

A third factor on the checklist is to assess for comorbidities such as substance abuse; obsessive-compulsive disorder; posttraumatic stress disorder; and general medical conditions that can mimic MDD symptoms, such as hypothyroidism.

A fourth factor to consider is drug-drug interactions and pharmacokinetics. For example, rapid/fast metabolizers and smokers "may require high doses of medication to achieve a benefit," said Dr. Alpert, who also serves as associate director of the MGH Depression Clinical and Research Program.

After you’ve run through the checklist and you’re confident that a patient has MDD, consider switch, augmentation, and combination strategies to improve response. "Typically we switch from one antidepressant to another in the setting of nonresponse or intolerance to the first agent," he said. "It’s been difficult to see differential effects of different classes of antidepressants. There are some limited data that show the inferiority of tricyclic antidepressants compared with monoamine oxidase inhibitors in patients with atypical features – the kind of depression characterized by pronounced rejection, sensitivity, and mood reactivity."

Dr. Alpert noted that some data support selective norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants as being superior to selective serotonin reuptake inhibitors (SSRIs) in MDD complicated by comorbid pain syndrome such as fibromyalgia. "Bupropion is clearly better than SSRIs and SNRIs for MDD with antidepressant-related sexual dysfunction, nicotine dependence, or ADHD," he said. "Consider broad-spectrum agents such as clomipramine in the setting of persistent refractory depression."

For patients who have only achieved partial response to an antidepressant, consider augmenting with a nonantidepressant such as atypical antipsychotics; dopamine agonists and psychostimulants; lithium; thyroid (T3); buspirone; and natural agents such as l-methylfolate, S-adenosyl-l-methionine (SAMe), creatinine, and omega-3 fatty acids.

Another strategy is to combine antidepressants together in the context of partial response and tolerability of the initial agent. Examples of combination therapy include an SSRI or SNRI plus bupropion, or an SNRI plus mirtazapine.

As for future directions in the psychopharmacology of depression, important recent targets in drug development include mitochondrial function, inflammation processes, and neurogenesis. "Non-monoaminergic mechanisms including kappa and NK1 antagonists and a range of glutamatergic agents are a continued and growing focus," Dr. Alpert concluded. "Rapid-acting antidepressants such as intravenous ketamine and scopolamine promise novel strategies for jump-starting treatment."

Dr. Alpert said he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

LAS VEGAS – Despite your best efforts at treating patients newly diagnosed with major depressive disorder, only about 1 in 3 patients achieves remission on the first antidepressant and almost 50% subsequently relapse.

"Our work is cut out for is," Dr. Jonathan E. Alpert said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

Factors associated with nonremission in major depressive disorder (MDD) include a history of chronic or recurrent depression; anxious, melancholic, or psychotic features; psychiatric or general medical comorbidity; minority ethnic/racial status; and lower quality of life and function prior to treatment. When a patient fails to remit, Dr. Alpert recommends a checklist of four basic factors to consider before rushing to the next medication or to the next form of psychotherapy.

"It’s important to step back for a moment and recheck what you think you know about that particular patient," said Dr. Alpert, associate chief of psychiatry for clinical services at Massachusetts General Hospital (MGH), Boston.

One factor on the checklist is adherence. Some patients – and sometimes their significant others – are ambivalent about pursuing depression treatment, which could interfere with adherence. "Other patients are confused about the instructions we’ve given them, or they might have cognitive problems that make it difficult for them to stick with the complex regimens we might be prescribing," he explained. "Access to health care and cost of medications can also play a role."

Another factor on the checklist is to be sure of your primary diagnosis. Is it MDD, or is it MDD with psychotic features? Is it bipolar disorder or mood dysregulation in the context of personality disorder? "It can be difficult to separate these," he said.

A third factor on the checklist is to assess for comorbidities such as substance abuse; obsessive-compulsive disorder; posttraumatic stress disorder; and general medical conditions that can mimic MDD symptoms, such as hypothyroidism.

A fourth factor to consider is drug-drug interactions and pharmacokinetics. For example, rapid/fast metabolizers and smokers "may require high doses of medication to achieve a benefit," said Dr. Alpert, who also serves as associate director of the MGH Depression Clinical and Research Program.

After you’ve run through the checklist and you’re confident that a patient has MDD, consider switch, augmentation, and combination strategies to improve response. "Typically we switch from one antidepressant to another in the setting of nonresponse or intolerance to the first agent," he said. "It’s been difficult to see differential effects of different classes of antidepressants. There are some limited data that show the inferiority of tricyclic antidepressants compared with monoamine oxidase inhibitors in patients with atypical features – the kind of depression characterized by pronounced rejection, sensitivity, and mood reactivity."

Dr. Alpert noted that some data support selective norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants as being superior to selective serotonin reuptake inhibitors (SSRIs) in MDD complicated by comorbid pain syndrome such as fibromyalgia. "Bupropion is clearly better than SSRIs and SNRIs for MDD with antidepressant-related sexual dysfunction, nicotine dependence, or ADHD," he said. "Consider broad-spectrum agents such as clomipramine in the setting of persistent refractory depression."

For patients who have only achieved partial response to an antidepressant, consider augmenting with a nonantidepressant such as atypical antipsychotics; dopamine agonists and psychostimulants; lithium; thyroid (T3); buspirone; and natural agents such as l-methylfolate, S-adenosyl-l-methionine (SAMe), creatinine, and omega-3 fatty acids.

Another strategy is to combine antidepressants together in the context of partial response and tolerability of the initial agent. Examples of combination therapy include an SSRI or SNRI plus bupropion, or an SNRI plus mirtazapine.

As for future directions in the psychopharmacology of depression, important recent targets in drug development include mitochondrial function, inflammation processes, and neurogenesis. "Non-monoaminergic mechanisms including kappa and NK1 antagonists and a range of glutamatergic agents are a continued and growing focus," Dr. Alpert concluded. "Rapid-acting antidepressants such as intravenous ketamine and scopolamine promise novel strategies for jump-starting treatment."

Dr. Alpert said he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

LAS VEGAS – Despite your best efforts at treating patients newly diagnosed with major depressive disorder, only about 1 in 3 patients achieves remission on the first antidepressant and almost 50% subsequently relapse.

"Our work is cut out for is," Dr. Jonathan E. Alpert said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

Factors associated with nonremission in major depressive disorder (MDD) include a history of chronic or recurrent depression; anxious, melancholic, or psychotic features; psychiatric or general medical comorbidity; minority ethnic/racial status; and lower quality of life and function prior to treatment. When a patient fails to remit, Dr. Alpert recommends a checklist of four basic factors to consider before rushing to the next medication or to the next form of psychotherapy.

"It’s important to step back for a moment and recheck what you think you know about that particular patient," said Dr. Alpert, associate chief of psychiatry for clinical services at Massachusetts General Hospital (MGH), Boston.

One factor on the checklist is adherence. Some patients – and sometimes their significant others – are ambivalent about pursuing depression treatment, which could interfere with adherence. "Other patients are confused about the instructions we’ve given them, or they might have cognitive problems that make it difficult for them to stick with the complex regimens we might be prescribing," he explained. "Access to health care and cost of medications can also play a role."

Another factor on the checklist is to be sure of your primary diagnosis. Is it MDD, or is it MDD with psychotic features? Is it bipolar disorder or mood dysregulation in the context of personality disorder? "It can be difficult to separate these," he said.

A third factor on the checklist is to assess for comorbidities such as substance abuse; obsessive-compulsive disorder; posttraumatic stress disorder; and general medical conditions that can mimic MDD symptoms, such as hypothyroidism.

A fourth factor to consider is drug-drug interactions and pharmacokinetics. For example, rapid/fast metabolizers and smokers "may require high doses of medication to achieve a benefit," said Dr. Alpert, who also serves as associate director of the MGH Depression Clinical and Research Program.

After you’ve run through the checklist and you’re confident that a patient has MDD, consider switch, augmentation, and combination strategies to improve response. "Typically we switch from one antidepressant to another in the setting of nonresponse or intolerance to the first agent," he said. "It’s been difficult to see differential effects of different classes of antidepressants. There are some limited data that show the inferiority of tricyclic antidepressants compared with monoamine oxidase inhibitors in patients with atypical features – the kind of depression characterized by pronounced rejection, sensitivity, and mood reactivity."

Dr. Alpert noted that some data support selective norepinephrine reuptake inhibitors (SNRIs) and tricyclic antidepressants as being superior to selective serotonin reuptake inhibitors (SSRIs) in MDD complicated by comorbid pain syndrome such as fibromyalgia. "Bupropion is clearly better than SSRIs and SNRIs for MDD with antidepressant-related sexual dysfunction, nicotine dependence, or ADHD," he said. "Consider broad-spectrum agents such as clomipramine in the setting of persistent refractory depression."

For patients who have only achieved partial response to an antidepressant, consider augmenting with a nonantidepressant such as atypical antipsychotics; dopamine agonists and psychostimulants; lithium; thyroid (T3); buspirone; and natural agents such as l-methylfolate, S-adenosyl-l-methionine (SAMe), creatinine, and omega-3 fatty acids.

Another strategy is to combine antidepressants together in the context of partial response and tolerability of the initial agent. Examples of combination therapy include an SSRI or SNRI plus bupropion, or an SNRI plus mirtazapine.

As for future directions in the psychopharmacology of depression, important recent targets in drug development include mitochondrial function, inflammation processes, and neurogenesis. "Non-monoaminergic mechanisms including kappa and NK1 antagonists and a range of glutamatergic agents are a continued and growing focus," Dr. Alpert concluded. "Rapid-acting antidepressants such as intravenous ketamine and scopolamine promise novel strategies for jump-starting treatment."

Dr. Alpert said he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

LAS VEGAS – With the exception of memantine, about 30 clinical trials of agents intended to halt the progression of Alzheimer’s disease have failed in the past decade.

"We’ve attacked every process you can think of in the amyloid cascade, but it’s possible that maybe these were just the wrong medications," Dr. Dylan P. Wint said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

According to retrospective analyses, 20-30% of people diagnosed with Alzheimer’s disease (AD) turned out to not have the condition, said Dr. Wint, director of the fellowship in behavioral neurology and neuropsychiatry at the Las Vegas–based Cleveland Clinic’s Lou Ruvo Center for Brain Health. This suggests that "we may be doing trials on the wrong patients because of inadequate identification of the underlying pathology," he said. The focus on beta-amyloid also could be misguided, he suggested. "There is a strong possibility that we have the wrong hypothesis. Maybe attacking the amyloid is not going to make a dent in what happens with the disease overall. It turns out that amyloid pathology doesn’t correlate very well with symptoms of AD. Tau is much more associated with AD symptoms in terms of its distribution, compared with amyloid."

On the other hand, Dr. Wint pointed out that genetic mutations that cause Alzheimer’s disease are related to amyloid processing. Other processes that could have an impact on AD and warrant investigation include quality of cerebral cells, viability of neurons, and outgrowth of neurites, he added.

Promising AD biomarkers being studied in clinical trials such as brain imaging techniques, blood tests, and genetic-risk profiling might help clinicians identify the disease before symptoms start. "Biomarkers can help us to [recruit] patients who are more suited for clinical trials," added Dr. Wint, who is also director of education in neurodegeneration at the center. "They can help us verify the disease process and measure the severity of the disease – not just symptoms – and we can classify patients by the biomarker."

Emerging AD therapies in the pipeline can be classified as symptomatic (targeting cognition and behavior), disease-modifying (anti–beta-amyloid, anti-tau, and promoting neuroprotection), and regenerative (reversing the disease with stem cells and growth factors). According to Dr. Wint, disease-modifying treatments currently or recently in phase III trials include solanezumab, gantenerumab, albumin plus immunoglobulin, thalidomide, TRx0237, masitinib, and epigallocatechin gallate. Behavioral management agents in phase III trials include bupropion (targeting apathy), mirtazapine (insomnia), citalopram (agitation), and brexpiprazole (agitation). Meanwhile, cognitive enhancement agents being studied in phase III trials include nasal insulin, caprylic triglyceride, and coconut oil.

Dr. Wint said he and other researchers currently take "a multiple shots on goal approach" to advancing the understanding of AD. "That means trying things from all of these categories," he said. "At the Lou Ruvo Center, we’re looking at diagnosis through blood testing, studying the impact of the oral cancer drug bexarotene on amyloid, medical foods, IV [intravenous] medications, the impact of a magnetic stimulation device on information processing, and brain imaging as a way to diagnose candidates for clinical trials."

Dr. Wint disclosed that he has received speakers fees from Accera and has consulted for Teva Pharmaceutical Industries.

dbrunk@frontlinemedcom.com

LAS VEGAS – With the exception of memantine, about 30 clinical trials of agents intended to halt the progression of Alzheimer’s disease have failed in the past decade.

"We’ve attacked every process you can think of in the amyloid cascade, but it’s possible that maybe these were just the wrong medications," Dr. Dylan P. Wint said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

According to retrospective analyses, 20-30% of people diagnosed with Alzheimer’s disease (AD) turned out to not have the condition, said Dr. Wint, director of the fellowship in behavioral neurology and neuropsychiatry at the Las Vegas–based Cleveland Clinic’s Lou Ruvo Center for Brain Health. This suggests that "we may be doing trials on the wrong patients because of inadequate identification of the underlying pathology," he said. The focus on beta-amyloid also could be misguided, he suggested. "There is a strong possibility that we have the wrong hypothesis. Maybe attacking the amyloid is not going to make a dent in what happens with the disease overall. It turns out that amyloid pathology doesn’t correlate very well with symptoms of AD. Tau is much more associated with AD symptoms in terms of its distribution, compared with amyloid."

On the other hand, Dr. Wint pointed out that genetic mutations that cause Alzheimer’s disease are related to amyloid processing. Other processes that could have an impact on AD and warrant investigation include quality of cerebral cells, viability of neurons, and outgrowth of neurites, he added.

Promising AD biomarkers being studied in clinical trials such as brain imaging techniques, blood tests, and genetic-risk profiling might help clinicians identify the disease before symptoms start. "Biomarkers can help us to [recruit] patients who are more suited for clinical trials," added Dr. Wint, who is also director of education in neurodegeneration at the center. "They can help us verify the disease process and measure the severity of the disease – not just symptoms – and we can classify patients by the biomarker."

Emerging AD therapies in the pipeline can be classified as symptomatic (targeting cognition and behavior), disease-modifying (anti–beta-amyloid, anti-tau, and promoting neuroprotection), and regenerative (reversing the disease with stem cells and growth factors). According to Dr. Wint, disease-modifying treatments currently or recently in phase III trials include solanezumab, gantenerumab, albumin plus immunoglobulin, thalidomide, TRx0237, masitinib, and epigallocatechin gallate. Behavioral management agents in phase III trials include bupropion (targeting apathy), mirtazapine (insomnia), citalopram (agitation), and brexpiprazole (agitation). Meanwhile, cognitive enhancement agents being studied in phase III trials include nasal insulin, caprylic triglyceride, and coconut oil.

Dr. Wint said he and other researchers currently take "a multiple shots on goal approach" to advancing the understanding of AD. "That means trying things from all of these categories," he said. "At the Lou Ruvo Center, we’re looking at diagnosis through blood testing, studying the impact of the oral cancer drug bexarotene on amyloid, medical foods, IV [intravenous] medications, the impact of a magnetic stimulation device on information processing, and brain imaging as a way to diagnose candidates for clinical trials."

Dr. Wint disclosed that he has received speakers fees from Accera and has consulted for Teva Pharmaceutical Industries.

dbrunk@frontlinemedcom.com

LAS VEGAS – With the exception of memantine, about 30 clinical trials of agents intended to halt the progression of Alzheimer’s disease have failed in the past decade.

"We’ve attacked every process you can think of in the amyloid cascade, but it’s possible that maybe these were just the wrong medications," Dr. Dylan P. Wint said at the annual psychopharmacology update held by the Nevada Psychiatric Association.

According to retrospective analyses, 20-30% of people diagnosed with Alzheimer’s disease (AD) turned out to not have the condition, said Dr. Wint, director of the fellowship in behavioral neurology and neuropsychiatry at the Las Vegas–based Cleveland Clinic’s Lou Ruvo Center for Brain Health. This suggests that "we may be doing trials on the wrong patients because of inadequate identification of the underlying pathology," he said. The focus on beta-amyloid also could be misguided, he suggested. "There is a strong possibility that we have the wrong hypothesis. Maybe attacking the amyloid is not going to make a dent in what happens with the disease overall. It turns out that amyloid pathology doesn’t correlate very well with symptoms of AD. Tau is much more associated with AD symptoms in terms of its distribution, compared with amyloid."

On the other hand, Dr. Wint pointed out that genetic mutations that cause Alzheimer’s disease are related to amyloid processing. Other processes that could have an impact on AD and warrant investigation include quality of cerebral cells, viability of neurons, and outgrowth of neurites, he added.

Promising AD biomarkers being studied in clinical trials such as brain imaging techniques, blood tests, and genetic-risk profiling might help clinicians identify the disease before symptoms start. "Biomarkers can help us to [recruit] patients who are more suited for clinical trials," added Dr. Wint, who is also director of education in neurodegeneration at the center. "They can help us verify the disease process and measure the severity of the disease – not just symptoms – and we can classify patients by the biomarker."

Emerging AD therapies in the pipeline can be classified as symptomatic (targeting cognition and behavior), disease-modifying (anti–beta-amyloid, anti-tau, and promoting neuroprotection), and regenerative (reversing the disease with stem cells and growth factors). According to Dr. Wint, disease-modifying treatments currently or recently in phase III trials include solanezumab, gantenerumab, albumin plus immunoglobulin, thalidomide, TRx0237, masitinib, and epigallocatechin gallate. Behavioral management agents in phase III trials include bupropion (targeting apathy), mirtazapine (insomnia), citalopram (agitation), and brexpiprazole (agitation). Meanwhile, cognitive enhancement agents being studied in phase III trials include nasal insulin, caprylic triglyceride, and coconut oil.

Dr. Wint said he and other researchers currently take "a multiple shots on goal approach" to advancing the understanding of AD. "That means trying things from all of these categories," he said. "At the Lou Ruvo Center, we’re looking at diagnosis through blood testing, studying the impact of the oral cancer drug bexarotene on amyloid, medical foods, IV [intravenous] medications, the impact of a magnetic stimulation device on information processing, and brain imaging as a way to diagnose candidates for clinical trials."

Dr. Wint disclosed that he has received speakers fees from Accera and has consulted for Teva Pharmaceutical Industries.

dbrunk@frontlinemedcom.com

LAS VEGAS – A growing body of evidence suggests that a high proportion of men with hypersexual disorder have an axis I psychiatric comorbidity such as attention-deficit/hyperactivity disorder, an association that can easily fly under a clinician’s radar.

"ADHD is very prominent in men with hypersexual disorder who come to see me now, occurring about 45% of the time," Dr. Martin Kafka said at the annual psychopharmacology update held by the Nevada Psychiatric Association. "I spend half of my time trying to get authorizations for them to be prescribed stimulants."

Men with ADHD tend to "look for something novel when they’re feeling dysphoric affect like boredom or when they’re depressed," continued Dr. Kafka, clinical associate professor of psychiatry at Harvard Medical School, Boston, and an authority on hypersexual disorder (HD). "They procrastinate, so when they’re facing stressful events they escape through their sexual behavior. Pornography is very tempting, because it can be viewed with just the click of a button."

He based his remarks on an analysis of medical records from about 150 HD patients he’s treated in recent years, with a goal of expanding that data set to at least 300. Previous studies he published from 1994 to 2002 suggested that the association between HD and ADHD ranged from 17% to 19%. Those studies also found that dysthymia was the most common coexisting axis I disorder in HD patients, occurring 61%-62% of the time, followed by alcohol abuse (25%-39%) and social phobia (22%-25%).

In Dr. Kafka’s current clinical practice, about 26% of men with HD that he counsels also have bipolar spectrum disorder. "What’s interesting is that this tends to occur in patients with cyclothymic disorder or bipolar disorder not otherwise specified," he said. "It’s the ones who have hypomanias lasting 1-2 days, but repetitively, who have a family history of the illness. In community samples, about 5% of the population meets criteria for hypomania if you shorten the duration to 1-2 days. We really need to be sensitive about brief, recurrent hypomanias and things like cyclothymic disorder, where you’re not depressed for that long."

Though one hallmark symptom of major depressive disorder (MDD) is decreased sexual interest, a small body of literature suggests that the opposite might be true. "This sounds counterintuitive, but subgroups of patients with MDD can have increased sexual behavior," Dr. Kafka said. "Some can have chronically increased sexual behavior." In one 1993 study of cognitive therapy in 40 subjects who were having problems with sexual arousal, 28 got better. The 12 who didn’t get better had chronic low-grade depression" (Arch. Gen. Psychiatry 1993;50:24-30).

Other investigators have reported that when men are depressed, they are more likely to respond to dysphoric affect through action and impulsivity (Arch. Sexual Behav. 2003; 32:217-30). "So even though it’s counterintuitive, depressive disorders can be associated with hypersexuality," Dr. Kafka said.

Treatment of axis I disorders, when executed properly, can positively affect outcomes for patients with HD. "Consider doing a thorough diagnostic evaluation," Dr. Kafka advised. "If they’re not getting better with nonpharmacological treatments, or their behavior is endangering them, then medications could be indicated." He went on to note that the medical model "goes a long way to destigmatize behavior in patients with HD. Yes, there are people who do immoral acts. Promiscuous behavior is an immoral act. But it could be embedded in a psychiatric disorder, which makes it much more complex. It makes it much more understandable; it can destigmatize the person. The person is not just a philanderer; the person is somebody who has an affliction, whose symptom is philandering. They will connect with you if you say this is a medical psychiatric disorder and not just a moral issue."

Though no controlled studies exist on treatment strategies for HD, Dr. Kafka recommended integrating psychiatric diagnosis into the treatment of HD. He also recommended proactive communication with other mental health professionals in helping derive "a good diagnostic picture" of certain patients and educating them about subthreshold adult manifestations of psychiatric diagnoses. "Of course, they can’t really help you with identifying bipolar spectrum disorder or ADHD unless they’re educated about it, but it’s helpful when a psychotherapist tells you that a patient looked hypomanic to him," Dr. Kafka explained. "The next time you see that patient, you might want to ask about that."

He also recommended educating HD patients as much as possible about their illness from resources such as the Society for the Advancement of Sexual Health (www.sash.net) "because these are chronic, early-onset disorders. They’re going to have them for the rest of their lives. Unless they understand them, they’re going to use medication inappropriately, they’re not going to be as treatment compliant and collaborative, and they’re going to relapse."

As to treatment approaches for HD itself, Dr. Kafka recommended a "here and now" approach that involves external interventions to limit access to computers and smart phones, such as phone block, Internet filters with kept passwords, moving the computer to a more public location, changing Internet service providers, and removing credit cards. He acknowledged that disclosing HD to an unsuspecting spouse can be "a minefield. Unless a spouse is prepared to find out about this, it’s devastating, because this is a secret disorder. Many times the spouse has no clue. I’m not going to say don’t tell the spouse, I’m going to say be very careful with your patient about what might be a strategy and when a spouse should find out. When the spouse finds out, it’s important that the spouse be in treatment, that they know how to get some help."

Frequent 12-step meetings that include daily contact with a sponsor are typically indicated for patients with HD, he added, along with individual psychotherapy and some cognitive-behavioral therapy.

"Hypersexuality is a dimension of human behavior; it can be treated," Dr. Kafka concluded. "The psychiatrist is an important player in all this."

Dr. Kafka said that he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

LAS VEGAS – A growing body of evidence suggests that a high proportion of men with hypersexual disorder have an axis I psychiatric comorbidity such as attention-deficit/hyperactivity disorder, an association that can easily fly under a clinician’s radar.

"ADHD is very prominent in men with hypersexual disorder who come to see me now, occurring about 45% of the time," Dr. Martin Kafka said at the annual psychopharmacology update held by the Nevada Psychiatric Association. "I spend half of my time trying to get authorizations for them to be prescribed stimulants."

Men with ADHD tend to "look for something novel when they’re feeling dysphoric affect like boredom or when they’re depressed," continued Dr. Kafka, clinical associate professor of psychiatry at Harvard Medical School, Boston, and an authority on hypersexual disorder (HD). "They procrastinate, so when they’re facing stressful events they escape through their sexual behavior. Pornography is very tempting, because it can be viewed with just the click of a button."

He based his remarks on an analysis of medical records from about 150 HD patients he’s treated in recent years, with a goal of expanding that data set to at least 300. Previous studies he published from 1994 to 2002 suggested that the association between HD and ADHD ranged from 17% to 19%. Those studies also found that dysthymia was the most common coexisting axis I disorder in HD patients, occurring 61%-62% of the time, followed by alcohol abuse (25%-39%) and social phobia (22%-25%).

In Dr. Kafka’s current clinical practice, about 26% of men with HD that he counsels also have bipolar spectrum disorder. "What’s interesting is that this tends to occur in patients with cyclothymic disorder or bipolar disorder not otherwise specified," he said. "It’s the ones who have hypomanias lasting 1-2 days, but repetitively, who have a family history of the illness. In community samples, about 5% of the population meets criteria for hypomania if you shorten the duration to 1-2 days. We really need to be sensitive about brief, recurrent hypomanias and things like cyclothymic disorder, where you’re not depressed for that long."

Though one hallmark symptom of major depressive disorder (MDD) is decreased sexual interest, a small body of literature suggests that the opposite might be true. "This sounds counterintuitive, but subgroups of patients with MDD can have increased sexual behavior," Dr. Kafka said. "Some can have chronically increased sexual behavior." In one 1993 study of cognitive therapy in 40 subjects who were having problems with sexual arousal, 28 got better. The 12 who didn’t get better had chronic low-grade depression" (Arch. Gen. Psychiatry 1993;50:24-30).

Other investigators have reported that when men are depressed, they are more likely to respond to dysphoric affect through action and impulsivity (Arch. Sexual Behav. 2003; 32:217-30). "So even though it’s counterintuitive, depressive disorders can be associated with hypersexuality," Dr. Kafka said.

Treatment of axis I disorders, when executed properly, can positively affect outcomes for patients with HD. "Consider doing a thorough diagnostic evaluation," Dr. Kafka advised. "If they’re not getting better with nonpharmacological treatments, or their behavior is endangering them, then medications could be indicated." He went on to note that the medical model "goes a long way to destigmatize behavior in patients with HD. Yes, there are people who do immoral acts. Promiscuous behavior is an immoral act. But it could be embedded in a psychiatric disorder, which makes it much more complex. It makes it much more understandable; it can destigmatize the person. The person is not just a philanderer; the person is somebody who has an affliction, whose symptom is philandering. They will connect with you if you say this is a medical psychiatric disorder and not just a moral issue."

Though no controlled studies exist on treatment strategies for HD, Dr. Kafka recommended integrating psychiatric diagnosis into the treatment of HD. He also recommended proactive communication with other mental health professionals in helping derive "a good diagnostic picture" of certain patients and educating them about subthreshold adult manifestations of psychiatric diagnoses. "Of course, they can’t really help you with identifying bipolar spectrum disorder or ADHD unless they’re educated about it, but it’s helpful when a psychotherapist tells you that a patient looked hypomanic to him," Dr. Kafka explained. "The next time you see that patient, you might want to ask about that."

He also recommended educating HD patients as much as possible about their illness from resources such as the Society for the Advancement of Sexual Health (www.sash.net) "because these are chronic, early-onset disorders. They’re going to have them for the rest of their lives. Unless they understand them, they’re going to use medication inappropriately, they’re not going to be as treatment compliant and collaborative, and they’re going to relapse."

As to treatment approaches for HD itself, Dr. Kafka recommended a "here and now" approach that involves external interventions to limit access to computers and smart phones, such as phone block, Internet filters with kept passwords, moving the computer to a more public location, changing Internet service providers, and removing credit cards. He acknowledged that disclosing HD to an unsuspecting spouse can be "a minefield. Unless a spouse is prepared to find out about this, it’s devastating, because this is a secret disorder. Many times the spouse has no clue. I’m not going to say don’t tell the spouse, I’m going to say be very careful with your patient about what might be a strategy and when a spouse should find out. When the spouse finds out, it’s important that the spouse be in treatment, that they know how to get some help."

Frequent 12-step meetings that include daily contact with a sponsor are typically indicated for patients with HD, he added, along with individual psychotherapy and some cognitive-behavioral therapy.

"Hypersexuality is a dimension of human behavior; it can be treated," Dr. Kafka concluded. "The psychiatrist is an important player in all this."

Dr. Kafka said that he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

LAS VEGAS – A growing body of evidence suggests that a high proportion of men with hypersexual disorder have an axis I psychiatric comorbidity such as attention-deficit/hyperactivity disorder, an association that can easily fly under a clinician’s radar.

"ADHD is very prominent in men with hypersexual disorder who come to see me now, occurring about 45% of the time," Dr. Martin Kafka said at the annual psychopharmacology update held by the Nevada Psychiatric Association. "I spend half of my time trying to get authorizations for them to be prescribed stimulants."

Men with ADHD tend to "look for something novel when they’re feeling dysphoric affect like boredom or when they’re depressed," continued Dr. Kafka, clinical associate professor of psychiatry at Harvard Medical School, Boston, and an authority on hypersexual disorder (HD). "They procrastinate, so when they’re facing stressful events they escape through their sexual behavior. Pornography is very tempting, because it can be viewed with just the click of a button."

He based his remarks on an analysis of medical records from about 150 HD patients he’s treated in recent years, with a goal of expanding that data set to at least 300. Previous studies he published from 1994 to 2002 suggested that the association between HD and ADHD ranged from 17% to 19%. Those studies also found that dysthymia was the most common coexisting axis I disorder in HD patients, occurring 61%-62% of the time, followed by alcohol abuse (25%-39%) and social phobia (22%-25%).

In Dr. Kafka’s current clinical practice, about 26% of men with HD that he counsels also have bipolar spectrum disorder. "What’s interesting is that this tends to occur in patients with cyclothymic disorder or bipolar disorder not otherwise specified," he said. "It’s the ones who have hypomanias lasting 1-2 days, but repetitively, who have a family history of the illness. In community samples, about 5% of the population meets criteria for hypomania if you shorten the duration to 1-2 days. We really need to be sensitive about brief, recurrent hypomanias and things like cyclothymic disorder, where you’re not depressed for that long."

Though one hallmark symptom of major depressive disorder (MDD) is decreased sexual interest, a small body of literature suggests that the opposite might be true. "This sounds counterintuitive, but subgroups of patients with MDD can have increased sexual behavior," Dr. Kafka said. "Some can have chronically increased sexual behavior." In one 1993 study of cognitive therapy in 40 subjects who were having problems with sexual arousal, 28 got better. The 12 who didn’t get better had chronic low-grade depression" (Arch. Gen. Psychiatry 1993;50:24-30).

Other investigators have reported that when men are depressed, they are more likely to respond to dysphoric affect through action and impulsivity (Arch. Sexual Behav. 2003; 32:217-30). "So even though it’s counterintuitive, depressive disorders can be associated with hypersexuality," Dr. Kafka said.

Treatment of axis I disorders, when executed properly, can positively affect outcomes for patients with HD. "Consider doing a thorough diagnostic evaluation," Dr. Kafka advised. "If they’re not getting better with nonpharmacological treatments, or their behavior is endangering them, then medications could be indicated." He went on to note that the medical model "goes a long way to destigmatize behavior in patients with HD. Yes, there are people who do immoral acts. Promiscuous behavior is an immoral act. But it could be embedded in a psychiatric disorder, which makes it much more complex. It makes it much more understandable; it can destigmatize the person. The person is not just a philanderer; the person is somebody who has an affliction, whose symptom is philandering. They will connect with you if you say this is a medical psychiatric disorder and not just a moral issue."

Though no controlled studies exist on treatment strategies for HD, Dr. Kafka recommended integrating psychiatric diagnosis into the treatment of HD. He also recommended proactive communication with other mental health professionals in helping derive "a good diagnostic picture" of certain patients and educating them about subthreshold adult manifestations of psychiatric diagnoses. "Of course, they can’t really help you with identifying bipolar spectrum disorder or ADHD unless they’re educated about it, but it’s helpful when a psychotherapist tells you that a patient looked hypomanic to him," Dr. Kafka explained. "The next time you see that patient, you might want to ask about that."

He also recommended educating HD patients as much as possible about their illness from resources such as the Society for the Advancement of Sexual Health (www.sash.net) "because these are chronic, early-onset disorders. They’re going to have them for the rest of their lives. Unless they understand them, they’re going to use medication inappropriately, they’re not going to be as treatment compliant and collaborative, and they’re going to relapse."

As to treatment approaches for HD itself, Dr. Kafka recommended a "here and now" approach that involves external interventions to limit access to computers and smart phones, such as phone block, Internet filters with kept passwords, moving the computer to a more public location, changing Internet service providers, and removing credit cards. He acknowledged that disclosing HD to an unsuspecting spouse can be "a minefield. Unless a spouse is prepared to find out about this, it’s devastating, because this is a secret disorder. Many times the spouse has no clue. I’m not going to say don’t tell the spouse, I’m going to say be very careful with your patient about what might be a strategy and when a spouse should find out. When the spouse finds out, it’s important that the spouse be in treatment, that they know how to get some help."

Frequent 12-step meetings that include daily contact with a sponsor are typically indicated for patients with HD, he added, along with individual psychotherapy and some cognitive-behavioral therapy.

"Hypersexuality is a dimension of human behavior; it can be treated," Dr. Kafka concluded. "The psychiatrist is an important player in all this."

Dr. Kafka said that he had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

The most common skin manifestation of epidermal growth factor receptor inhibitors is a papulopustular eruption that typically develops 8-10 days after the beginning of therapy, mainly on the scalp and in other areas with a high concentration of sebaceous glands, according to a review of the topic.

"Although the eruption typically spontaneously resolves after 12 weeks of EGFR inhibitor therapy, long-term postinflammatory erythema or hyperpigmentation is not unusual and may last for years after therapy has been discontinued," Rachel L. Kyllo and Dr. Milan J. Anadkat wrote in Seminars in Cutaneous Medicine and Surgery (in press).

As part of a larger review of the cutaneous manifestations of chemotherapeutic agents, Ms. Kyllo and Dr. Anadkat of the division of dermatology at Washington University, St. Louis, noted that EGFR receptor inhibitors have been approved for treating solid tumors including pancreatic cancer, non–small cell lung cancer, colorectal cancer, head and neck squamous cell cancer, and breast cancer. The two main types are small molecule inhibitors, including gefitinib, erlotinib,and lapatinib, and the monoclonal antibodies cetuximab and panitumumab.

Monoclonal antibodies are associated with a higher incidence of papulopustular eruption. Histology "demonstrates a mixed superficial inflammatory infiltrate which leads to follicular rupture and acantholysis," the authors wrote. "These findings are consistent with dysregulation of molecular pathways downstream from EGFR signaling, which are known to be important in keratinocyte migration, maturation, and survival."

Although having an EGFR inhibitor–related papulopustular eruption appears to be associated with an increased median survival time, high-grade rash often leads to treatment modification or dose adjustment. "Prophylactic treatment with systemic tetracycline antibiotics for the first 8 weeks of EGFR inhibitor therapy significantly reduces the severity of the papulopustular eruption, theoretically decreasing the need for dosage adjustment," the authors wrote. "Severe cases should prompt consideration of systemic therapy with corticosteroids, low-dose isotretinoin, or acitretin."

EGFR inhibitor therapy also can affect the hair, most commonly causing a change in hair texture with increased breakability and curliness. This side effect is more likely with long-term exposure and can appear months after treatment begins. "Nonscarring alopecia typically develops 8-12 weeks after initiation of EGFR inhibitor therapy in 5% of patients and resolves spontaneously after discontinuation of the drug," the authors added. "Rarely, scarring alopecia results in permanent hair loss; prophylactic doxycycline to reduce papulopustular eruption severity ... and topical high-dose corticosteroid preparations reduce the likelihood of subsequent scarring."

They went on to note that 12%-16% of patients develop paronychia 8-12 weeks after initiation of EGFR therapy, with local trauma believed to be an aggravating factor. A course of antibiotics is warranted only in cases of culture-proven bacterial superinfection.

Another potential side effect of EGFR therapy, xerosis, occurs in 4%-35% of patients, usually 4-8 weeks after initiation of treatment. It most commonly affects elderly patients, as well as those with preexisting eczema and those who have undergone prior treatment with cytotoxic agents. "Treatments include topical emollients and keratolytics; use of topical retinoids or benzoyl peroxide is not recommended as they may exacerbate skin dryness," the authors wrote. "Use of topical corticosteroids is reserved for cases of frank dermatitis."

Dr. Anadkat disclosed having received honoraria as a consultant and/or speaker from ImClone, Genentech, AstraZeneca, Therakos, Eisai, and Bristol-Myers Squibb.

dbrunk@frontlinemedcom.com

The most common skin manifestation of epidermal growth factor receptor inhibitors is a papulopustular eruption that typically develops 8-10 days after the beginning of therapy, mainly on the scalp and in other areas with a high concentration of sebaceous glands, according to a review of the topic.

"Although the eruption typically spontaneously resolves after 12 weeks of EGFR inhibitor therapy, long-term postinflammatory erythema or hyperpigmentation is not unusual and may last for years after therapy has been discontinued," Rachel L. Kyllo and Dr. Milan J. Anadkat wrote in Seminars in Cutaneous Medicine and Surgery (in press).

As part of a larger review of the cutaneous manifestations of chemotherapeutic agents, Ms. Kyllo and Dr. Anadkat of the division of dermatology at Washington University, St. Louis, noted that EGFR receptor inhibitors have been approved for treating solid tumors including pancreatic cancer, non–small cell lung cancer, colorectal cancer, head and neck squamous cell cancer, and breast cancer. The two main types are small molecule inhibitors, including gefitinib, erlotinib,and lapatinib, and the monoclonal antibodies cetuximab and panitumumab.

Monoclonal antibodies are associated with a higher incidence of papulopustular eruption. Histology "demonstrates a mixed superficial inflammatory infiltrate which leads to follicular rupture and acantholysis," the authors wrote. "These findings are consistent with dysregulation of molecular pathways downstream from EGFR signaling, which are known to be important in keratinocyte migration, maturation, and survival."

Although having an EGFR inhibitor–related papulopustular eruption appears to be associated with an increased median survival time, high-grade rash often leads to treatment modification or dose adjustment. "Prophylactic treatment with systemic tetracycline antibiotics for the first 8 weeks of EGFR inhibitor therapy significantly reduces the severity of the papulopustular eruption, theoretically decreasing the need for dosage adjustment," the authors wrote. "Severe cases should prompt consideration of systemic therapy with corticosteroids, low-dose isotretinoin, or acitretin."

EGFR inhibitor therapy also can affect the hair, most commonly causing a change in hair texture with increased breakability and curliness. This side effect is more likely with long-term exposure and can appear months after treatment begins. "Nonscarring alopecia typically develops 8-12 weeks after initiation of EGFR inhibitor therapy in 5% of patients and resolves spontaneously after discontinuation of the drug," the authors added. "Rarely, scarring alopecia results in permanent hair loss; prophylactic doxycycline to reduce papulopustular eruption severity ... and topical high-dose corticosteroid preparations reduce the likelihood of subsequent scarring."

They went on to note that 12%-16% of patients develop paronychia 8-12 weeks after initiation of EGFR therapy, with local trauma believed to be an aggravating factor. A course of antibiotics is warranted only in cases of culture-proven bacterial superinfection.

Another potential side effect of EGFR therapy, xerosis, occurs in 4%-35% of patients, usually 4-8 weeks after initiation of treatment. It most commonly affects elderly patients, as well as those with preexisting eczema and those who have undergone prior treatment with cytotoxic agents. "Treatments include topical emollients and keratolytics; use of topical retinoids or benzoyl peroxide is not recommended as they may exacerbate skin dryness," the authors wrote. "Use of topical corticosteroids is reserved for cases of frank dermatitis."

Dr. Anadkat disclosed having received honoraria as a consultant and/or speaker from ImClone, Genentech, AstraZeneca, Therakos, Eisai, and Bristol-Myers Squibb.

dbrunk@frontlinemedcom.com

The most common skin manifestation of epidermal growth factor receptor inhibitors is a papulopustular eruption that typically develops 8-10 days after the beginning of therapy, mainly on the scalp and in other areas with a high concentration of sebaceous glands, according to a review of the topic.

"Although the eruption typically spontaneously resolves after 12 weeks of EGFR inhibitor therapy, long-term postinflammatory erythema or hyperpigmentation is not unusual and may last for years after therapy has been discontinued," Rachel L. Kyllo and Dr. Milan J. Anadkat wrote in Seminars in Cutaneous Medicine and Surgery (in press).

As part of a larger review of the cutaneous manifestations of chemotherapeutic agents, Ms. Kyllo and Dr. Anadkat of the division of dermatology at Washington University, St. Louis, noted that EGFR receptor inhibitors have been approved for treating solid tumors including pancreatic cancer, non–small cell lung cancer, colorectal cancer, head and neck squamous cell cancer, and breast cancer. The two main types are small molecule inhibitors, including gefitinib, erlotinib,and lapatinib, and the monoclonal antibodies cetuximab and panitumumab.

Monoclonal antibodies are associated with a higher incidence of papulopustular eruption. Histology "demonstrates a mixed superficial inflammatory infiltrate which leads to follicular rupture and acantholysis," the authors wrote. "These findings are consistent with dysregulation of molecular pathways downstream from EGFR signaling, which are known to be important in keratinocyte migration, maturation, and survival."

Although having an EGFR inhibitor–related papulopustular eruption appears to be associated with an increased median survival time, high-grade rash often leads to treatment modification or dose adjustment. "Prophylactic treatment with systemic tetracycline antibiotics for the first 8 weeks of EGFR inhibitor therapy significantly reduces the severity of the papulopustular eruption, theoretically decreasing the need for dosage adjustment," the authors wrote. "Severe cases should prompt consideration of systemic therapy with corticosteroids, low-dose isotretinoin, or acitretin."

EGFR inhibitor therapy also can affect the hair, most commonly causing a change in hair texture with increased breakability and curliness. This side effect is more likely with long-term exposure and can appear months after treatment begins. "Nonscarring alopecia typically develops 8-12 weeks after initiation of EGFR inhibitor therapy in 5% of patients and resolves spontaneously after discontinuation of the drug," the authors added. "Rarely, scarring alopecia results in permanent hair loss; prophylactic doxycycline to reduce papulopustular eruption severity ... and topical high-dose corticosteroid preparations reduce the likelihood of subsequent scarring."

They went on to note that 12%-16% of patients develop paronychia 8-12 weeks after initiation of EGFR therapy, with local trauma believed to be an aggravating factor. A course of antibiotics is warranted only in cases of culture-proven bacterial superinfection.

Another potential side effect of EGFR therapy, xerosis, occurs in 4%-35% of patients, usually 4-8 weeks after initiation of treatment. It most commonly affects elderly patients, as well as those with preexisting eczema and those who have undergone prior treatment with cytotoxic agents. "Treatments include topical emollients and keratolytics; use of topical retinoids or benzoyl peroxide is not recommended as they may exacerbate skin dryness," the authors wrote. "Use of topical corticosteroids is reserved for cases of frank dermatitis."

Dr. Anadkat disclosed having received honoraria as a consultant and/or speaker from ImClone, Genentech, AstraZeneca, Therakos, Eisai, and Bristol-Myers Squibb.

dbrunk@frontlinemedcom.com

SAN DIEGO – Although the release of the U.S. Preventive Services Task Force grade B recommendations on lung cancer screening in December 2013 marked an important advance in the field, they are not the last words on the issue.

"There are innumerable other questions for which we don’t have great answers," Dr. Denise R. Aberle said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

These include lack of data on the optimal screening population, interpretation algorithms, and cost effectiveness, said Dr. Aberle, professor of radiology and bioengineering at the University of California, Los Angeles. "Because there remain many unanswered questions, and the implementation process is not standardized, the single most important thing we can do in screening programs is to collect the data that would be necessary to inform these questions."

The primary difference between the recommendations of the U.S. Preventive Services Task Force and those of the National Lung Screening Trial (NLST) is the USPSTF’s expanded age range of 55-80 years. The USPSTF "also added the caveat that screenings should be discontinued once patients are beyond the age of 80, if there is a smoking cessation history of greater than 15 years, or in the face of significant comorbidity that would likely be a factor in competing mortality or would render that person unable to tolerate treatment," she said.

USPSTF investigators used data from the Cancer Intervention and Surveillance Modeling Network (CISNET) to inform their decision-making. CISNET consists of investigators from five different institutions who have each developed independent, natural histories of lung cancer in modeling exercises. They used each of their five models, and tested at least 500 different strategies for screening based on differences in the frequency of screening (anywhere from annually to once every 3 years), start and stop ages, pack-year intensity, and the number of years since quitting smoking. By doing so, the USPSTF investigators determined that mortality reduction with screening was 15%, estimated that 50% of cancers would be early stage, and projected that 497 per 100,000 lung cancer deaths would be averted.

"We now have guidelines that we can build on," Dr. Aberle said of the USPSTF recommendations.

She characterized false positivity rates as "probably the most significant downside of CT screening" for lung cancer. "It results in unnecessary follow-up imaging and excess radiation, [and] unnecessary biopsies and surgical procedures with their attendant complications, costs, and unnecessary anxiety," she said.

In a study of NLST participants led by Dr. Aberle, 24% of all screens were positive based on the observation of a nodule of 4 mm or larger (N. Engl. J. Med. 2011;365:395-409). "It turns out that about two-thirds of positive screens were for a nodule that was 7 mm or smaller in size," she said. "Finally, 96% of positive screens were not associated with a lung cancer diagnosis. How do we address this? The easiest way to look at this is to look at nodule size, which remains the most durable of imaging biomarkers that we have thus far."

About 7% of all lung cancers occurred in nodules between 4 and 6 mm in diameter, but Dr. Aberle and her associates noticed two inflection points. First, relative to nodules 4-6 mm in diameter, nodules in the 7- to 10-mm diameter range translate into about a threefold increase in the numbers of lung cancers observed. Second, nodules greater than 10 mm in diameter roughly translate into a doubling in the number of lung cancers observed. "After 20 mm, the numbers of cancers decrease, as do the number of nodules," she said.

In subsequent analyses, Dr. Aberle and her associates found that using a 7-mm nodule as the threshold size for screen positivity would result in a delay in diagnosis of perhaps 2% of lung cancers relative to first observation. "This is clearly an area that we’ll be looking at when we look toward screening implementation," she said.

With respect to diagnostic algorithms, a number of organizations are looking to standardize interpretations, including the American College of Radiology, which is developing a standardized reporting system called LUNG-RADS. In this algorithm, category 1 = negative, 2 = benign, 3 = likely benign (not actionable), 4 = suspicious, 5 = highly suspicious, and S = significant/other. In categories 1-3, annual screening would be recommended. "Level 4 screens would dictate an early follow-up, generally within 4-6 months of the baseline CT scan," Dr. Aberle explained. "Nodules that are highly suspicious typically undergo some form of additional tissue sampling."

Dr. Aberle said that she had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Although the release of the U.S. Preventive Services Task Force grade B recommendations on lung cancer screening in December 2013 marked an important advance in the field, they are not the last words on the issue.

"There are innumerable other questions for which we don’t have great answers," Dr. Denise R. Aberle said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

These include lack of data on the optimal screening population, interpretation algorithms, and cost effectiveness, said Dr. Aberle, professor of radiology and bioengineering at the University of California, Los Angeles. "Because there remain many unanswered questions, and the implementation process is not standardized, the single most important thing we can do in screening programs is to collect the data that would be necessary to inform these questions."

The primary difference between the recommendations of the U.S. Preventive Services Task Force and those of the National Lung Screening Trial (NLST) is the USPSTF’s expanded age range of 55-80 years. The USPSTF "also added the caveat that screenings should be discontinued once patients are beyond the age of 80, if there is a smoking cessation history of greater than 15 years, or in the face of significant comorbidity that would likely be a factor in competing mortality or would render that person unable to tolerate treatment," she said.

USPSTF investigators used data from the Cancer Intervention and Surveillance Modeling Network (CISNET) to inform their decision-making. CISNET consists of investigators from five different institutions who have each developed independent, natural histories of lung cancer in modeling exercises. They used each of their five models, and tested at least 500 different strategies for screening based on differences in the frequency of screening (anywhere from annually to once every 3 years), start and stop ages, pack-year intensity, and the number of years since quitting smoking. By doing so, the USPSTF investigators determined that mortality reduction with screening was 15%, estimated that 50% of cancers would be early stage, and projected that 497 per 100,000 lung cancer deaths would be averted.

"We now have guidelines that we can build on," Dr. Aberle said of the USPSTF recommendations.

She characterized false positivity rates as "probably the most significant downside of CT screening" for lung cancer. "It results in unnecessary follow-up imaging and excess radiation, [and] unnecessary biopsies and surgical procedures with their attendant complications, costs, and unnecessary anxiety," she said.

In a study of NLST participants led by Dr. Aberle, 24% of all screens were positive based on the observation of a nodule of 4 mm or larger (N. Engl. J. Med. 2011;365:395-409). "It turns out that about two-thirds of positive screens were for a nodule that was 7 mm or smaller in size," she said. "Finally, 96% of positive screens were not associated with a lung cancer diagnosis. How do we address this? The easiest way to look at this is to look at nodule size, which remains the most durable of imaging biomarkers that we have thus far."

About 7% of all lung cancers occurred in nodules between 4 and 6 mm in diameter, but Dr. Aberle and her associates noticed two inflection points. First, relative to nodules 4-6 mm in diameter, nodules in the 7- to 10-mm diameter range translate into about a threefold increase in the numbers of lung cancers observed. Second, nodules greater than 10 mm in diameter roughly translate into a doubling in the number of lung cancers observed. "After 20 mm, the numbers of cancers decrease, as do the number of nodules," she said.

In subsequent analyses, Dr. Aberle and her associates found that using a 7-mm nodule as the threshold size for screen positivity would result in a delay in diagnosis of perhaps 2% of lung cancers relative to first observation. "This is clearly an area that we’ll be looking at when we look toward screening implementation," she said.

With respect to diagnostic algorithms, a number of organizations are looking to standardize interpretations, including the American College of Radiology, which is developing a standardized reporting system called LUNG-RADS. In this algorithm, category 1 = negative, 2 = benign, 3 = likely benign (not actionable), 4 = suspicious, 5 = highly suspicious, and S = significant/other. In categories 1-3, annual screening would be recommended. "Level 4 screens would dictate an early follow-up, generally within 4-6 months of the baseline CT scan," Dr. Aberle explained. "Nodules that are highly suspicious typically undergo some form of additional tissue sampling."

Dr. Aberle said that she had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Although the release of the U.S. Preventive Services Task Force grade B recommendations on lung cancer screening in December 2013 marked an important advance in the field, they are not the last words on the issue.

"There are innumerable other questions for which we don’t have great answers," Dr. Denise R. Aberle said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

These include lack of data on the optimal screening population, interpretation algorithms, and cost effectiveness, said Dr. Aberle, professor of radiology and bioengineering at the University of California, Los Angeles. "Because there remain many unanswered questions, and the implementation process is not standardized, the single most important thing we can do in screening programs is to collect the data that would be necessary to inform these questions."

The primary difference between the recommendations of the U.S. Preventive Services Task Force and those of the National Lung Screening Trial (NLST) is the USPSTF’s expanded age range of 55-80 years. The USPSTF "also added the caveat that screenings should be discontinued once patients are beyond the age of 80, if there is a smoking cessation history of greater than 15 years, or in the face of significant comorbidity that would likely be a factor in competing mortality or would render that person unable to tolerate treatment," she said.

USPSTF investigators used data from the Cancer Intervention and Surveillance Modeling Network (CISNET) to inform their decision-making. CISNET consists of investigators from five different institutions who have each developed independent, natural histories of lung cancer in modeling exercises. They used each of their five models, and tested at least 500 different strategies for screening based on differences in the frequency of screening (anywhere from annually to once every 3 years), start and stop ages, pack-year intensity, and the number of years since quitting smoking. By doing so, the USPSTF investigators determined that mortality reduction with screening was 15%, estimated that 50% of cancers would be early stage, and projected that 497 per 100,000 lung cancer deaths would be averted.

"We now have guidelines that we can build on," Dr. Aberle said of the USPSTF recommendations.

She characterized false positivity rates as "probably the most significant downside of CT screening" for lung cancer. "It results in unnecessary follow-up imaging and excess radiation, [and] unnecessary biopsies and surgical procedures with their attendant complications, costs, and unnecessary anxiety," she said.

In a study of NLST participants led by Dr. Aberle, 24% of all screens were positive based on the observation of a nodule of 4 mm or larger (N. Engl. J. Med. 2011;365:395-409). "It turns out that about two-thirds of positive screens were for a nodule that was 7 mm or smaller in size," she said. "Finally, 96% of positive screens were not associated with a lung cancer diagnosis. How do we address this? The easiest way to look at this is to look at nodule size, which remains the most durable of imaging biomarkers that we have thus far."

About 7% of all lung cancers occurred in nodules between 4 and 6 mm in diameter, but Dr. Aberle and her associates noticed two inflection points. First, relative to nodules 4-6 mm in diameter, nodules in the 7- to 10-mm diameter range translate into about a threefold increase in the numbers of lung cancers observed. Second, nodules greater than 10 mm in diameter roughly translate into a doubling in the number of lung cancers observed. "After 20 mm, the numbers of cancers decrease, as do the number of nodules," she said.

In subsequent analyses, Dr. Aberle and her associates found that using a 7-mm nodule as the threshold size for screen positivity would result in a delay in diagnosis of perhaps 2% of lung cancers relative to first observation. "This is clearly an area that we’ll be looking at when we look toward screening implementation," she said.

With respect to diagnostic algorithms, a number of organizations are looking to standardize interpretations, including the American College of Radiology, which is developing a standardized reporting system called LUNG-RADS. In this algorithm, category 1 = negative, 2 = benign, 3 = likely benign (not actionable), 4 = suspicious, 5 = highly suspicious, and S = significant/other. In categories 1-3, annual screening would be recommended. "Level 4 screens would dictate an early follow-up, generally within 4-6 months of the baseline CT scan," Dr. Aberle explained. "Nodules that are highly suspicious typically undergo some form of additional tissue sampling."

Dr. Aberle said that she had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

SAN DIEGO – Results from studies conducted to date indicate that anti-PD-L1 therapy is well tolerated in patients with non–small cell lung cancer, with rapid response rates.

In fact, responses are "not only very rapid, they’re also very durable," Dr. Leora Horn said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

"We’re seeing continued responses even when treatment is discontinued. The response rates appear to be somewhat higher in tumors that express PD-L1, and we see no pneumonitis or treatment-related grade 5 adverse events to date."

The four anti-PD-L1 agents that have been investigated or are currently being investigated in patients with non–small cell lung cancer (NSCLC) are BMS-936559, MPDL3280A, MEDI-4736, and MSB0010718C, according to Dr. Horn, clinical director of the thoracic oncology research program at Vanderbilt University, Nashville, Tenn.

BMS-936559, developed by Bristol Myers-Squibb, was part of a phase IA dose study at 0.3, 1, 3, and 10 mg/kg in patients with multiple tumor types including NSCLC. Of the 207 patients enrolled, 75 had NSCLC (N. Engl. J. Med 2012;366:2455-65).

More than half of all patients (61%) had treatment-related adverse events, with fatigue the most common (16%), followed by infusion reaction (10%) and diarrhea (9%). Grade 3 and 4 adverse events occurred in 9% of patients. "One of the themes with anti-PD-L1 therapy is that we’re not seeing grade 3-5 pneumonitis in these like we have seen with anti-PD-1 agents," said Dr. Horn. "This may have to do with different expression of PD-1 and PD-2 within the body and the targets of PD-1 compared to anti-PD-L1 antibodies."

The response rate among NSCLC patients treated in the trial reached about 10%, and responses were seen in squamous and nonsquamous NSCLC. "This agent is not being further developed in NSCLC patients," Dr. Horn said. "Nivolumab, a PD-1 blocking antibody, has really taken over as far as development for Bristol-Myers Squibb."

The next agent she discussed, MPDL3280A, is being developed by Roche and Genentech. A phase I trial presented at the 2013 European Society for Medical Oncology (ESMO) Congress examined different doses in 85 patients with NSCLC ranging from 10 to 20 mg/kg once every week for just under 1 year. Key eligibility criteria were measurable disease per Response Evaluation Criteria in Solid Tumors v1.1 and Eastern Cooperative Oncology Group Performance Status 0 or 1. Dr. Horn said that the majority of adverse events were grade 1-2 and did not require intervention. "There was also no maximum tolerated dose or dose-limiting toxicities, and no grade 3-5 pneumonitis was observed," she said.

In a study of MPDL3280A presented by Dr. Horn and her associates at the 2013 World Conference on Lung Cancer, the clinical impact was assessed in 53 patients with NSCLC. Patients first dosed at 1-20 mg/kg by Oct. 1, 2012, with data cutoff on April 30, 2013. The response rate was 83% among patients who had an immunohistochemistry (IHC) score of 3, 46% among those who were IHC 2 and 3, and 31% among those who were IHC 1, 2, and 3. "In all-comers the response rate was 23%," Dr. Horn said. "The responses in these patients are very rapid. We see them by their first or second CT [computed tomography] scan. The responses are also very durable regardless of their IHC status and in patients who are PD-L1 negative. They’ve also been responding even after treatment has been discontinued."

She and her associates examined the response rate to MPDL3280A based on smoking status and mutational status. The response rate was higher in patients who were current or former smokers compared with never smokers (26% vs. 10%, respectively). By molecular status, the response rate in EGFR [epidermal growth factor receptor] wild-type patients was 26%, compared with 17% in EGFR mutant patients. In addition, there was a 30% response rate in patients who were KRAS wild-type and a 10% response rate in KRAS mutant patients, although the numbers are very small, she noted.

According to Dr. Horn, there are three separate, ongoing studies looking at MPDL3280A in NSCLC patients: one in patients with PD-L1–positive NSCLC, one in combination with bevacizumab and/or chemotherapy, and one randomized phase III trial comparing the agent with docetaxel in patients after platinum failure.

Data on the next agent Dr. Horn discussed, MEDI4736 from MedImmune, are limited. A study of this agent was presented at the 2013 ESMO Congress and included 11 patients who received doses of 0.1, 0.3, and 1.0 mg/kg. The most common treatment-related adverse events were diarrhea, vomiting, and dizziness (18% each), and no grade 3 or 4 adverse events or pneumonitis have been reported to date.

Pharmacokinetic studies of MEDI4736 indicate a dose-dependent increase in target engagement, consistent with binding of the agent to PD-L1. Initial clinical data on eight patients demonstrated response at all different dose levels, ranging from 42% to 80%. "This involves small subsets of patients, so hopefully we’ll see more data on this agent in the next couple of years," Dr. Horn said.

The final anti-PD-L1 in clinical development is MSB0010718C from EMD Serono, but no data are available yet. A three-dose escalation study up to 10 mg/kg is underway. "Hopefully, we’ll see some data on this later this year," Dr. Horn said.

She concluded her remarks by noting that future directions in anti-PD-L1 therapy will involve determining its role in specific molecular cohorts and in patients with PD-L1–negative tumors; combination therapy with chemotherapy, other immune therapy, and targeted therapies; patients with prior radiation therapy to the chest; and patients with early-stage disease.

Dr. Horn disclosed that she is a speaker for Bristol-Myers Squibb, Theradex, and other companies.

dbrunk@frontlinemedcom.com

SAN DIEGO – Results from studies conducted to date indicate that anti-PD-L1 therapy is well tolerated in patients with non–small cell lung cancer, with rapid response rates.

In fact, responses are "not only very rapid, they’re also very durable," Dr. Leora Horn said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

"We’re seeing continued responses even when treatment is discontinued. The response rates appear to be somewhat higher in tumors that express PD-L1, and we see no pneumonitis or treatment-related grade 5 adverse events to date."

The four anti-PD-L1 agents that have been investigated or are currently being investigated in patients with non–small cell lung cancer (NSCLC) are BMS-936559, MPDL3280A, MEDI-4736, and MSB0010718C, according to Dr. Horn, clinical director of the thoracic oncology research program at Vanderbilt University, Nashville, Tenn.

BMS-936559, developed by Bristol Myers-Squibb, was part of a phase IA dose study at 0.3, 1, 3, and 10 mg/kg in patients with multiple tumor types including NSCLC. Of the 207 patients enrolled, 75 had NSCLC (N. Engl. J. Med 2012;366:2455-65).

More than half of all patients (61%) had treatment-related adverse events, with fatigue the most common (16%), followed by infusion reaction (10%) and diarrhea (9%). Grade 3 and 4 adverse events occurred in 9% of patients. "One of the themes with anti-PD-L1 therapy is that we’re not seeing grade 3-5 pneumonitis in these like we have seen with anti-PD-1 agents," said Dr. Horn. "This may have to do with different expression of PD-1 and PD-2 within the body and the targets of PD-1 compared to anti-PD-L1 antibodies."

The response rate among NSCLC patients treated in the trial reached about 10%, and responses were seen in squamous and nonsquamous NSCLC. "This agent is not being further developed in NSCLC patients," Dr. Horn said. "Nivolumab, a PD-1 blocking antibody, has really taken over as far as development for Bristol-Myers Squibb."

The next agent she discussed, MPDL3280A, is being developed by Roche and Genentech. A phase I trial presented at the 2013 European Society for Medical Oncology (ESMO) Congress examined different doses in 85 patients with NSCLC ranging from 10 to 20 mg/kg once every week for just under 1 year. Key eligibility criteria were measurable disease per Response Evaluation Criteria in Solid Tumors v1.1 and Eastern Cooperative Oncology Group Performance Status 0 or 1. Dr. Horn said that the majority of adverse events were grade 1-2 and did not require intervention. "There was also no maximum tolerated dose or dose-limiting toxicities, and no grade 3-5 pneumonitis was observed," she said.

In a study of MPDL3280A presented by Dr. Horn and her associates at the 2013 World Conference on Lung Cancer, the clinical impact was assessed in 53 patients with NSCLC. Patients first dosed at 1-20 mg/kg by Oct. 1, 2012, with data cutoff on April 30, 2013. The response rate was 83% among patients who had an immunohistochemistry (IHC) score of 3, 46% among those who were IHC 2 and 3, and 31% among those who were IHC 1, 2, and 3. "In all-comers the response rate was 23%," Dr. Horn said. "The responses in these patients are very rapid. We see them by their first or second CT [computed tomography] scan. The responses are also very durable regardless of their IHC status and in patients who are PD-L1 negative. They’ve also been responding even after treatment has been discontinued."

She and her associates examined the response rate to MPDL3280A based on smoking status and mutational status. The response rate was higher in patients who were current or former smokers compared with never smokers (26% vs. 10%, respectively). By molecular status, the response rate in EGFR [epidermal growth factor receptor] wild-type patients was 26%, compared with 17% in EGFR mutant patients. In addition, there was a 30% response rate in patients who were KRAS wild-type and a 10% response rate in KRAS mutant patients, although the numbers are very small, she noted.

According to Dr. Horn, there are three separate, ongoing studies looking at MPDL3280A in NSCLC patients: one in patients with PD-L1–positive NSCLC, one in combination with bevacizumab and/or chemotherapy, and one randomized phase III trial comparing the agent with docetaxel in patients after platinum failure.

Data on the next agent Dr. Horn discussed, MEDI4736 from MedImmune, are limited. A study of this agent was presented at the 2013 ESMO Congress and included 11 patients who received doses of 0.1, 0.3, and 1.0 mg/kg. The most common treatment-related adverse events were diarrhea, vomiting, and dizziness (18% each), and no grade 3 or 4 adverse events or pneumonitis have been reported to date.

Pharmacokinetic studies of MEDI4736 indicate a dose-dependent increase in target engagement, consistent with binding of the agent to PD-L1. Initial clinical data on eight patients demonstrated response at all different dose levels, ranging from 42% to 80%. "This involves small subsets of patients, so hopefully we’ll see more data on this agent in the next couple of years," Dr. Horn said.

The final anti-PD-L1 in clinical development is MSB0010718C from EMD Serono, but no data are available yet. A three-dose escalation study up to 10 mg/kg is underway. "Hopefully, we’ll see some data on this later this year," Dr. Horn said.

She concluded her remarks by noting that future directions in anti-PD-L1 therapy will involve determining its role in specific molecular cohorts and in patients with PD-L1–negative tumors; combination therapy with chemotherapy, other immune therapy, and targeted therapies; patients with prior radiation therapy to the chest; and patients with early-stage disease.

Dr. Horn disclosed that she is a speaker for Bristol-Myers Squibb, Theradex, and other companies.

dbrunk@frontlinemedcom.com

SAN DIEGO – Results from studies conducted to date indicate that anti-PD-L1 therapy is well tolerated in patients with non–small cell lung cancer, with rapid response rates.

In fact, responses are "not only very rapid, they’re also very durable," Dr. Leora Horn said at the Joint Conference on the Molecular Origins of Lung Cancer sponsored by the American Association for Cancer Research and the International Association for the Study of Lung Cancer.

"We’re seeing continued responses even when treatment is discontinued. The response rates appear to be somewhat higher in tumors that express PD-L1, and we see no pneumonitis or treatment-related grade 5 adverse events to date."

The four anti-PD-L1 agents that have been investigated or are currently being investigated in patients with non–small cell lung cancer (NSCLC) are BMS-936559, MPDL3280A, MEDI-4736, and MSB0010718C, according to Dr. Horn, clinical director of the thoracic oncology research program at Vanderbilt University, Nashville, Tenn.

BMS-936559, developed by Bristol Myers-Squibb, was part of a phase IA dose study at 0.3, 1, 3, and 10 mg/kg in patients with multiple tumor types including NSCLC. Of the 207 patients enrolled, 75 had NSCLC (N. Engl. J. Med 2012;366:2455-65).

More than half of all patients (61%) had treatment-related adverse events, with fatigue the most common (16%), followed by infusion reaction (10%) and diarrhea (9%). Grade 3 and 4 adverse events occurred in 9% of patients. "One of the themes with anti-PD-L1 therapy is that we’re not seeing grade 3-5 pneumonitis in these like we have seen with anti-PD-1 agents," said Dr. Horn. "This may have to do with different expression of PD-1 and PD-2 within the body and the targets of PD-1 compared to anti-PD-L1 antibodies."

The response rate among NSCLC patients treated in the trial reached about 10%, and responses were seen in squamous and nonsquamous NSCLC. "This agent is not being further developed in NSCLC patients," Dr. Horn said. "Nivolumab, a PD-1 blocking antibody, has really taken over as far as development for Bristol-Myers Squibb."

The next agent she discussed, MPDL3280A, is being developed by Roche and Genentech. A phase I trial presented at the 2013 European Society for Medical Oncology (ESMO) Congress examined different doses in 85 patients with NSCLC ranging from 10 to 20 mg/kg once every week for just under 1 year. Key eligibility criteria were measurable disease per Response Evaluation Criteria in Solid Tumors v1.1 and Eastern Cooperative Oncology Group Performance Status 0 or 1. Dr. Horn said that the majority of adverse events were grade 1-2 and did not require intervention. "There was also no maximum tolerated dose or dose-limiting toxicities, and no grade 3-5 pneumonitis was observed," she said.

In a study of MPDL3280A presented by Dr. Horn and her associates at the 2013 World Conference on Lung Cancer, the clinical impact was assessed in 53 patients with NSCLC. Patients first dosed at 1-20 mg/kg by Oct. 1, 2012, with data cutoff on April 30, 2013. The response rate was 83% among patients who had an immunohistochemistry (IHC) score of 3, 46% among those who were IHC 2 and 3, and 31% among those who were IHC 1, 2, and 3. "In all-comers the response rate was 23%," Dr. Horn said. "The responses in these patients are very rapid. We see them by their first or second CT [computed tomography] scan. The responses are also very durable regardless of their IHC status and in patients who are PD-L1 negative. They’ve also been responding even after treatment has been discontinued."

She and her associates examined the response rate to MPDL3280A based on smoking status and mutational status. The response rate was higher in patients who were current or former smokers compared with never smokers (26% vs. 10%, respectively). By molecular status, the response rate in EGFR [epidermal growth factor receptor] wild-type patients was 26%, compared with 17% in EGFR mutant patients. In addition, there was a 30% response rate in patients who were KRAS wild-type and a 10% response rate in KRAS mutant patients, although the numbers are very small, she noted.

According to Dr. Horn, there are three separate, ongoing studies looking at MPDL3280A in NSCLC patients: one in patients with PD-L1–positive NSCLC, one in combination with bevacizumab and/or chemotherapy, and one randomized phase III trial comparing the agent with docetaxel in patients after platinum failure.

Data on the next agent Dr. Horn discussed, MEDI4736 from MedImmune, are limited. A study of this agent was presented at the 2013 ESMO Congress and included 11 patients who received doses of 0.1, 0.3, and 1.0 mg/kg. The most common treatment-related adverse events were diarrhea, vomiting, and dizziness (18% each), and no grade 3 or 4 adverse events or pneumonitis have been reported to date.

Pharmacokinetic studies of MEDI4736 indicate a dose-dependent increase in target engagement, consistent with binding of the agent to PD-L1. Initial clinical data on eight patients demonstrated response at all different dose levels, ranging from 42% to 80%. "This involves small subsets of patients, so hopefully we’ll see more data on this agent in the next couple of years," Dr. Horn said.

The final anti-PD-L1 in clinical development is MSB0010718C from EMD Serono, but no data are available yet. A three-dose escalation study up to 10 mg/kg is underway. "Hopefully, we’ll see some data on this later this year," Dr. Horn said.

She concluded her remarks by noting that future directions in anti-PD-L1 therapy will involve determining its role in specific molecular cohorts and in patients with PD-L1–negative tumors; combination therapy with chemotherapy, other immune therapy, and targeted therapies; patients with prior radiation therapy to the chest; and patients with early-stage disease.

Dr. Horn disclosed that she is a speaker for Bristol-Myers Squibb, Theradex, and other companies.

dbrunk@frontlinemedcom.com

As the practice of fecal microbiota transplantation to treat recurrent Clostridium difficile infection continues to evolve, a growing number of researchers have expressed interest in studying the procedure for other conditions, according to an article published in the February issue of Clinical Gastroenterology and Hepatology.

Even though the mechanism of action behind fecal microbiota transplantation (FMT) remains unclear, "the procedure results in restoration of normal microbial gut ecology," wrote Dr. Colleen Kelly, a gastroenterologist at the Women’s Medicine Collaborative, Providence, R.I., and her coinvestigators. "Therefore, it is possible that FMT may become applicable to other conditions associated with intestinal dysbiosis, including inflammatory bowel disease, irritable bowel syndrome, antibiotic-associated diarrhea, and components of metabolic syndrome such as obesity and diabetes."

Source: American Gastroenterological Association

With this in mind and noting that FMT is considered an investigational agent by the Food and Drug Administration, Dr. Kelly and her associates set out to provide guidance to other investigators and clinicians on how to prepare an investigational new drug application (IND) for the Center for Biologics Evaluation and Research to study FMT for recurrent C. difficile infection (R-CDI). "Because of the complexity of IND applications and their burden on a physician, the FDA announced its intention to exercise enforcement discretion regarding IND applications for use of FMT to treat R-CDI," the authors explained (doi:10.1016/j.cgh.2013.09.060). "In these cases, an IND is encouraged but not required. At this time, this decision decreases the need for INDs to treat individual patients with R-CDI. However, an IND for the use of FMT is still required for indications other than CDI for research purposes."

The IND application can have only one sponsor: the investigator or clinician who applies for it. After that is secured, 10 basic elements are required to complete the IND application, according to the authors. These include product name/chemical structure, proposed indications, dosage and route of administration, background about the therapy, and information regarding chemistry, manufacturing, and controls. "The contents of this section vary depending on the source/form of donor material," wrote the authors, who indicated that they hold approved INDs to use FMT in patients with CDI and inflammatory bowel disease. For example, "if the sponsor decides to seek an IND for frozen material, they will need to provide detail about how donor stool will be processed and stored."

Other basic elements of an IND application, according to the article, include a clinical data summary, an FMT treatment protocol that includes plans for clinical follow-up of treated patients and adverse event reporting, an explanation of the risks associated with FMT, and a safety-monitoring protocol that "may consist of symptom diaries maintained by patients/subjects and follow-up telephone contacts and clinic visits."

Dr. Kelly and her associates emphasized that their recommendations are "only a guide to all the elements necessary to put together a protocol and an FDA application and a starting point for the new IND sponsor." They added that minimal requirements for donor testing "are likely to change over time. Some testing that is currently merely recommended may become absolute requirements or may be found unnecessary."

The National Institutes of Health provided funding support for the article. One of the authors, Dr. Alexander Khoruts, has received research funding from CIPAC LLC. The other authors said they had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

As the practice of fecal microbiota transplantation to treat recurrent Clostridium difficile infection continues to evolve, a growing number of researchers have expressed interest in studying the procedure for other conditions, according to an article published in the February issue of Clinical Gastroenterology and Hepatology.

Even though the mechanism of action behind fecal microbiota transplantation (FMT) remains unclear, "the procedure results in restoration of normal microbial gut ecology," wrote Dr. Colleen Kelly, a gastroenterologist at the Women’s Medicine Collaborative, Providence, R.I., and her coinvestigators. "Therefore, it is possible that FMT may become applicable to other conditions associated with intestinal dysbiosis, including inflammatory bowel disease, irritable bowel syndrome, antibiotic-associated diarrhea, and components of metabolic syndrome such as obesity and diabetes."

Source: American Gastroenterological Association

With this in mind and noting that FMT is considered an investigational agent by the Food and Drug Administration, Dr. Kelly and her associates set out to provide guidance to other investigators and clinicians on how to prepare an investigational new drug application (IND) for the Center for Biologics Evaluation and Research to study FMT for recurrent C. difficile infection (R-CDI). "Because of the complexity of IND applications and their burden on a physician, the FDA announced its intention to exercise enforcement discretion regarding IND applications for use of FMT to treat R-CDI," the authors explained (doi:10.1016/j.cgh.2013.09.060). "In these cases, an IND is encouraged but not required. At this time, this decision decreases the need for INDs to treat individual patients with R-CDI. However, an IND for the use of FMT is still required for indications other than CDI for research purposes."

The IND application can have only one sponsor: the investigator or clinician who applies for it. After that is secured, 10 basic elements are required to complete the IND application, according to the authors. These include product name/chemical structure, proposed indications, dosage and route of administration, background about the therapy, and information regarding chemistry, manufacturing, and controls. "The contents of this section vary depending on the source/form of donor material," wrote the authors, who indicated that they hold approved INDs to use FMT in patients with CDI and inflammatory bowel disease. For example, "if the sponsor decides to seek an IND for frozen material, they will need to provide detail about how donor stool will be processed and stored."

Other basic elements of an IND application, according to the article, include a clinical data summary, an FMT treatment protocol that includes plans for clinical follow-up of treated patients and adverse event reporting, an explanation of the risks associated with FMT, and a safety-monitoring protocol that "may consist of symptom diaries maintained by patients/subjects and follow-up telephone contacts and clinic visits."

Dr. Kelly and her associates emphasized that their recommendations are "only a guide to all the elements necessary to put together a protocol and an FDA application and a starting point for the new IND sponsor." They added that minimal requirements for donor testing "are likely to change over time. Some testing that is currently merely recommended may become absolute requirements or may be found unnecessary."

The National Institutes of Health provided funding support for the article. One of the authors, Dr. Alexander Khoruts, has received research funding from CIPAC LLC. The other authors said they had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

As the practice of fecal microbiota transplantation to treat recurrent Clostridium difficile infection continues to evolve, a growing number of researchers have expressed interest in studying the procedure for other conditions, according to an article published in the February issue of Clinical Gastroenterology and Hepatology.

Even though the mechanism of action behind fecal microbiota transplantation (FMT) remains unclear, "the procedure results in restoration of normal microbial gut ecology," wrote Dr. Colleen Kelly, a gastroenterologist at the Women’s Medicine Collaborative, Providence, R.I., and her coinvestigators. "Therefore, it is possible that FMT may become applicable to other conditions associated with intestinal dysbiosis, including inflammatory bowel disease, irritable bowel syndrome, antibiotic-associated diarrhea, and components of metabolic syndrome such as obesity and diabetes."

Source: American Gastroenterological Association

With this in mind and noting that FMT is considered an investigational agent by the Food and Drug Administration, Dr. Kelly and her associates set out to provide guidance to other investigators and clinicians on how to prepare an investigational new drug application (IND) for the Center for Biologics Evaluation and Research to study FMT for recurrent C. difficile infection (R-CDI). "Because of the complexity of IND applications and their burden on a physician, the FDA announced its intention to exercise enforcement discretion regarding IND applications for use of FMT to treat R-CDI," the authors explained (doi:10.1016/j.cgh.2013.09.060). "In these cases, an IND is encouraged but not required. At this time, this decision decreases the need for INDs to treat individual patients with R-CDI. However, an IND for the use of FMT is still required for indications other than CDI for research purposes."

The IND application can have only one sponsor: the investigator or clinician who applies for it. After that is secured, 10 basic elements are required to complete the IND application, according to the authors. These include product name/chemical structure, proposed indications, dosage and route of administration, background about the therapy, and information regarding chemistry, manufacturing, and controls. "The contents of this section vary depending on the source/form of donor material," wrote the authors, who indicated that they hold approved INDs to use FMT in patients with CDI and inflammatory bowel disease. For example, "if the sponsor decides to seek an IND for frozen material, they will need to provide detail about how donor stool will be processed and stored."

Other basic elements of an IND application, according to the article, include a clinical data summary, an FMT treatment protocol that includes plans for clinical follow-up of treated patients and adverse event reporting, an explanation of the risks associated with FMT, and a safety-monitoring protocol that "may consist of symptom diaries maintained by patients/subjects and follow-up telephone contacts and clinic visits."

Dr. Kelly and her associates emphasized that their recommendations are "only a guide to all the elements necessary to put together a protocol and an FDA application and a starting point for the new IND sponsor." They added that minimal requirements for donor testing "are likely to change over time. Some testing that is currently merely recommended may become absolute requirements or may be found unnecessary."

The National Institutes of Health provided funding support for the article. One of the authors, Dr. Alexander Khoruts, has received research funding from CIPAC LLC. The other authors said they had no relevant financial conflicts to disclose.

dbrunk@frontlinemedcom.com

Children with Crohn’s disease who received antitumor necrosis factor-alpha within 3 months of diagnosis experienced better overall clinical and growth outcomes at 1 year, compared with their counterparts who received an immunomodulator or those who received no immunomodulator therapy, results from an observational study demonstrated.

Although the current standard of practice for children recently diagnosed with Crohn’s disease (CD) involves early administration of immunomodulators after initial treatment with corticosteroids, some pediatric gastroenterologists, inspired by data from adult trials, "are adopting earlier introduction of anti-TNF-alpha therapy (without a trial of immunomodulators alone) in patients with inflammatory luminal CD judged to be at risk of serious chronically active disease," researchers led by Dr. Thomas D. Walters wrote in the February issue of Gastroenterology.

Source: American Gastroenterological Association

Dr. Walters of the Hospital for Sick Children in Toronto and his associates went on to note that while the efficacy of anti-TNF-alpha therapy is well established, "it has yet to be shown that the early use of this therapy in a specific group of pediatric patients (those with inflammatory luminal disease) is any more effective at improving patient outcomes than the classic step-up approach." In an effort to answer this question, the researchers analyzed data from the ongoing Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children With Crohn’s Disease (RS) trial, which was launched in 2008 at 28 pediatric gastroenterology centers in North America. The purpose of the current study was to determine whether anti-TNF-alpha monotherapy started within 3 months of diagnosis improves 1-year outcomes, compared with clinically similar patients who were treated with immunomodulator monotherapy started within 3 months of diagnosis or those who were treated with no immunotherapy during that time frame.

The researchers evaluated data from 552 patients who participated in the trial RISK between 2008 and 2012. They used propensity score matching "to avoid the usual problem of confounding by indication when using observational cohort data to explore differences in treatment response." More than half of the patients (61%) were male, their mean age was 11.8 years, and 63% had a Pediatric Crohn’s Disease Activity Index (PCDAI) score of greater than 30. The primary outcome of interest was corticosteroid-free clinical remission (defined as a PCDAI of 10 or less) at 1 year after diagnosis without luminal resection (Gastroenterology 2013 [doi: 10.1053/j.gastro.2013.10.027]).

Of the 552 patients, 68 received early anti-TNF-alpha monotherapy, 248 received early immunomodulator therapy, and 236 received no early immunotherapy. After propensity score matching, 85% of patients treated with early anti-TNF-alpha monotherapy achieved remission at 1 year, compared with 60% of those who were treated with early immunomodulator monotherapy and 54% of those who received no early immunotherapy, a difference that reached statistical significance (P =.0003). When the researchers factored in therapy after 3 months as a covariate, the results did not change; treatment with anti-TNF-alpha monotherapy remained significantly superior to early immunomodulator monotherapy (risk ratio, 1.51; P =.0004), while early immunomodulator monotherapy was no different from no early immunotherapy (RR, 1.00; P =.99).

Dr. Walters and his associates also observed that while weight and body mass index scores improved in all three groups, the height z score only showed improvement in the early anti-TNF-alpha group.

"Although our data clearly have added to the evidence base guiding treatment decisions after a diagnosis of Crohn’s disease in children, they should not be taken as an endorsement of one early therapeutic regimen over another," the authors concluded. "We were not able to identify any common clinical or laboratory characteristic that predicted response or failure with a particular approach. Further genetic, serologic, and microbiome analysis of our study cohort in conjunction with comparative efficacy results will better elucidate the value of different treatment decisions."

The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Walters and many of his coauthors disclosed having received research support, consulting fees, or being on the speakers bureau for numerous pharmaceutical companies.

dbrunk@frontlinemedcom.com

Children with Crohn’s disease who received antitumor necrosis factor-alpha within 3 months of diagnosis experienced better overall clinical and growth outcomes at 1 year, compared with their counterparts who received an immunomodulator or those who received no immunomodulator therapy, results from an observational study demonstrated.

Although the current standard of practice for children recently diagnosed with Crohn’s disease (CD) involves early administration of immunomodulators after initial treatment with corticosteroids, some pediatric gastroenterologists, inspired by data from adult trials, "are adopting earlier introduction of anti-TNF-alpha therapy (without a trial of immunomodulators alone) in patients with inflammatory luminal CD judged to be at risk of serious chronically active disease," researchers led by Dr. Thomas D. Walters wrote in the February issue of Gastroenterology.

Source: American Gastroenterological Association

Dr. Walters of the Hospital for Sick Children in Toronto and his associates went on to note that while the efficacy of anti-TNF-alpha therapy is well established, "it has yet to be shown that the early use of this therapy in a specific group of pediatric patients (those with inflammatory luminal disease) is any more effective at improving patient outcomes than the classic step-up approach." In an effort to answer this question, the researchers analyzed data from the ongoing Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children With Crohn’s Disease (RS) trial, which was launched in 2008 at 28 pediatric gastroenterology centers in North America. The purpose of the current study was to determine whether anti-TNF-alpha monotherapy started within 3 months of diagnosis improves 1-year outcomes, compared with clinically similar patients who were treated with immunomodulator monotherapy started within 3 months of diagnosis or those who were treated with no immunotherapy during that time frame.

The researchers evaluated data from 552 patients who participated in the trial RISK between 2008 and 2012. They used propensity score matching "to avoid the usual problem of confounding by indication when using observational cohort data to explore differences in treatment response." More than half of the patients (61%) were male, their mean age was 11.8 years, and 63% had a Pediatric Crohn’s Disease Activity Index (PCDAI) score of greater than 30. The primary outcome of interest was corticosteroid-free clinical remission (defined as a PCDAI of 10 or less) at 1 year after diagnosis without luminal resection (Gastroenterology 2013 [doi: 10.1053/j.gastro.2013.10.027]).

Of the 552 patients, 68 received early anti-TNF-alpha monotherapy, 248 received early immunomodulator therapy, and 236 received no early immunotherapy. After propensity score matching, 85% of patients treated with early anti-TNF-alpha monotherapy achieved remission at 1 year, compared with 60% of those who were treated with early immunomodulator monotherapy and 54% of those who received no early immunotherapy, a difference that reached statistical significance (P =.0003). When the researchers factored in therapy after 3 months as a covariate, the results did not change; treatment with anti-TNF-alpha monotherapy remained significantly superior to early immunomodulator monotherapy (risk ratio, 1.51; P =.0004), while early immunomodulator monotherapy was no different from no early immunotherapy (RR, 1.00; P =.99).

Dr. Walters and his associates also observed that while weight and body mass index scores improved in all three groups, the height z score only showed improvement in the early anti-TNF-alpha group.

"Although our data clearly have added to the evidence base guiding treatment decisions after a diagnosis of Crohn’s disease in children, they should not be taken as an endorsement of one early therapeutic regimen over another," the authors concluded. "We were not able to identify any common clinical or laboratory characteristic that predicted response or failure with a particular approach. Further genetic, serologic, and microbiome analysis of our study cohort in conjunction with comparative efficacy results will better elucidate the value of different treatment decisions."

The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Walters and many of his coauthors disclosed having received research support, consulting fees, or being on the speakers bureau for numerous pharmaceutical companies.

dbrunk@frontlinemedcom.com

Children with Crohn’s disease who received antitumor necrosis factor-alpha within 3 months of diagnosis experienced better overall clinical and growth outcomes at 1 year, compared with their counterparts who received an immunomodulator or those who received no immunomodulator therapy, results from an observational study demonstrated.

Although the current standard of practice for children recently diagnosed with Crohn’s disease (CD) involves early administration of immunomodulators after initial treatment with corticosteroids, some pediatric gastroenterologists, inspired by data from adult trials, "are adopting earlier introduction of anti-TNF-alpha therapy (without a trial of immunomodulators alone) in patients with inflammatory luminal CD judged to be at risk of serious chronically active disease," researchers led by Dr. Thomas D. Walters wrote in the February issue of Gastroenterology.

Source: American Gastroenterological Association

Dr. Walters of the Hospital for Sick Children in Toronto and his associates went on to note that while the efficacy of anti-TNF-alpha therapy is well established, "it has yet to be shown that the early use of this therapy in a specific group of pediatric patients (those with inflammatory luminal disease) is any more effective at improving patient outcomes than the classic step-up approach." In an effort to answer this question, the researchers analyzed data from the ongoing Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children With Crohn’s Disease (RS) trial, which was launched in 2008 at 28 pediatric gastroenterology centers in North America. The purpose of the current study was to determine whether anti-TNF-alpha monotherapy started within 3 months of diagnosis improves 1-year outcomes, compared with clinically similar patients who were treated with immunomodulator monotherapy started within 3 months of diagnosis or those who were treated with no immunotherapy during that time frame.

The researchers evaluated data from 552 patients who participated in the trial RISK between 2008 and 2012. They used propensity score matching "to avoid the usual problem of confounding by indication when using observational cohort data to explore differences in treatment response." More than half of the patients (61%) were male, their mean age was 11.8 years, and 63% had a Pediatric Crohn’s Disease Activity Index (PCDAI) score of greater than 30. The primary outcome of interest was corticosteroid-free clinical remission (defined as a PCDAI of 10 or less) at 1 year after diagnosis without luminal resection (Gastroenterology 2013 [doi: 10.1053/j.gastro.2013.10.027]).

Of the 552 patients, 68 received early anti-TNF-alpha monotherapy, 248 received early immunomodulator therapy, and 236 received no early immunotherapy. After propensity score matching, 85% of patients treated with early anti-TNF-alpha monotherapy achieved remission at 1 year, compared with 60% of those who were treated with early immunomodulator monotherapy and 54% of those who received no early immunotherapy, a difference that reached statistical significance (P =.0003). When the researchers factored in therapy after 3 months as a covariate, the results did not change; treatment with anti-TNF-alpha monotherapy remained significantly superior to early immunomodulator monotherapy (risk ratio, 1.51; P =.0004), while early immunomodulator monotherapy was no different from no early immunotherapy (RR, 1.00; P =.99).

Dr. Walters and his associates also observed that while weight and body mass index scores improved in all three groups, the height z score only showed improvement in the early anti-TNF-alpha group.

"Although our data clearly have added to the evidence base guiding treatment decisions after a diagnosis of Crohn’s disease in children, they should not be taken as an endorsement of one early therapeutic regimen over another," the authors concluded. "We were not able to identify any common clinical or laboratory characteristic that predicted response or failure with a particular approach. Further genetic, serologic, and microbiome analysis of our study cohort in conjunction with comparative efficacy results will better elucidate the value of different treatment decisions."

The study was supported by the Crohn’s and Colitis Foundation of America. Dr. Walters and many of his coauthors disclosed having received research support, consulting fees, or being on the speakers bureau for numerous pharmaceutical companies.

dbrunk@frontlinemedcom.com