Kari Oakes

For cancer patients and the surgeons who treat them, tumor margins matter. The amount of malignant tissue left behind after cancer surgery can make a profound difference in overall survival, but sparing healthy tissue while removing as much tumor as possible is limited by the surgeon’s ability to differentiate one from the other.

Now, new optical imaging techniques that deliver fluorescing molecules specifically to tumor targets show promise to allow both surgeons and pathologists to optimize cancer surgery. These intraoperative techniques use fluorescent molecules tagged to a ligand that binds to a target site on malignant cells. Thus, uptake occurs only in the malignant cells, highlighting them for the surgeon and for pathologists assessing margin adequacy.

Courtesy Emw/Wikicommons Creative Commons License

Dr. Sunil Singhal of the University of Pennsylvania, Philadelphia, has coined the term “optical biopsy” to describe what’s happening during optical imaging-guided surgery. “For so long, we as surgeons have just had our eyes and our hands – and our intuition – to guide us. This technology allows us to really focus our attention where it needs to be in surgery.”

Optical imaging in surgery uses a variety of fluorescing molecules, some of which were originally derived from sources as diverse as scorpions and fireflies. Some of these glow in the visible spectrum, but increasingly, optical imaging techniques are employing molecules that fluoresce when excited by light in the near-infrared spectrum.

Using the near-infrared spectrum, said Dr. Eben Rosenthal, the Anne and John Doerr Medical Director of the Stanford (Calif.) Cancer Center, does two things: it allows for visualization deeper into tissues – up to 1 or 2 cm – and it improves the signal-to-noise ratio that can be a problem in the visual spectrum, where tissue autofluorescence occurs.

Cameras, endoscopes, and surgical microscopes can all be equipped to display the fluorescence and coregister the image with the white-light view the surgeon or pathologist normally sees. Surgeons using optical imaging techniques can usually continue to use the same tools and the same interface they are accustomed to.

Ligands can be small molecules, such as folate, or complex glycoproteins, such as monoclonal antibodies: all will bind selectively to sites on tumor cells. Patients are infused with the fluorescence-tagged ligand complexes before surgery, with timing appropriate to the half-lives of the agents, so infusions may happen the day before or the day of surgery.

For Dr. Rosenthal, using monoclonal antibodies to target tumors for optical imaging techniques affords several advantages. The antibodies are approved by the Food and Drug Administration, with known safety and side effect profiles. The antibodies can be tagged with an FDA-approved fluorescing molecule, allowing an easier approval process for the compound agent. Finally, the epidermal growth factor receptor (EGFR) target of these monoclonal antibodies is well expressed in many target tumor cells, including melanoma, breast, glioma, and colorectal cancers.

Dr. Singhal’s group has been working with fluorescein-tagged folate to identify pulmonary adenocarcinomas and is exploring use of other agents as well. “We like small molecules,” he said. “We can avoid lots of problems with biotoxicity.”

Annexin A2 (ANXA2) is a molecule expressed on the surface of cancer cells but found intracellularly in healthy cells, and it is the target of the chlorotoxin conjugate used by Dr. Jim Olson of Seattle’s Fred Hutchinson Cancer Research Center. Target malignancies may include glioblastoma, medullablastoma, sarcoma, and prostate and intestinal cancers.

Regardless of the target, however, optical imaging techniques may be particularly well suited for tumors occurring in areas where a generous dissection can have potentially devastating consequences, as in the head and neck, and for brain tumors. By giving the surgeon a clear delineation of malignant tissue, optical imaging can help the surgeon strike a balance to achieve the most conservative dissection that still achieves a complete gross dissection of the malignancy.

Achieving gross total dissection during cancer surgery is an important goal, said Dr. Olson. Citing devastating childhood brain tumors such as medulloblastomas and gliomablastomas, he noted that optical imaging can help surgeons avoid leaving behind any bulk areas of tumor, where hypoxic regions and therapy-resistant changes in tumor physiology may reduce the chance for cure. “Surgery is one of the most important elements of curing cancer,” he said. He pointed out that, in children with medulloblastomas, if nearly all tumor tissue is removed, less radiation is needed and survival is improved, even with less radiation – even if very small amounts of cancer remain.

Limitations of these technologies depend, to some extent, on the tissue targets, on substrates used to deliver the fluorescing molecules, and on the fluorescent agents themselves. Even with the enhanced tissue penetration of near-infrared light, the surgeon can really only see a centimeter or two beneath the surface of a solid organ. Said Dr. Singhal, “The basic limitation is that we’re talking about light.” However, if presurgery imaging identifies an area of concern, the surgeon can direct his or her dissection more carefully when the malignant tissue glows during surgery.

Dr. Rosenthal noted that pathologists also are making use of optical imaging to guide their processes. Since only about 5% of most tumor margins are sampled, there is an inevitable chance of sampling error with the resulting potential for a false-negative pathology result. “This technique augments the pathologist’s role and allows for improved biopsy results,” he said. Using image-guided pathology offers a way to test the margins immediately, helping the pathologist ascertain where the surgeon’s attention should be focused. Optical imaging, he said, “will in many ways change and enhance the experience for everybody.”

Dr. Olson, looking forward, asked, “If we can deliver the ability to light up, why can’t we deliver chemotherapy?” He sees an optical imaging future that will make flexible use of ligands to delineate tumors and test drug delivery.

There are many ways optical imaging can improve the practice of cancer surgery, Dr. Rosenthal said. “Historically, surgery has been a hard area to study because it’s so variable.” Following results from optical imaging–guided precision surgery, he said, will allow surgeons to identify and achieve “the right margin for the right cancer.”

Looking to the future, Dr. Singhal said, “it won’t be an either/or scenario. I think there will be multiple targets, multiple agents for this technology. We, as surgeons, have an obligation to our profession to move ahead with this.”

[email protected]

On Twitter @karioakes

For cancer patients and the surgeons who treat them, tumor margins matter. The amount of malignant tissue left behind after cancer surgery can make a profound difference in overall survival, but sparing healthy tissue while removing as much tumor as possible is limited by the surgeon’s ability to differentiate one from the other.

Now, new optical imaging techniques that deliver fluorescing molecules specifically to tumor targets show promise to allow both surgeons and pathologists to optimize cancer surgery. These intraoperative techniques use fluorescent molecules tagged to a ligand that binds to a target site on malignant cells. Thus, uptake occurs only in the malignant cells, highlighting them for the surgeon and for pathologists assessing margin adequacy.

Courtesy Emw/Wikicommons Creative Commons License

Dr. Sunil Singhal of the University of Pennsylvania, Philadelphia, has coined the term “optical biopsy” to describe what’s happening during optical imaging-guided surgery. “For so long, we as surgeons have just had our eyes and our hands – and our intuition – to guide us. This technology allows us to really focus our attention where it needs to be in surgery.”

Optical imaging in surgery uses a variety of fluorescing molecules, some of which were originally derived from sources as diverse as scorpions and fireflies. Some of these glow in the visible spectrum, but increasingly, optical imaging techniques are employing molecules that fluoresce when excited by light in the near-infrared spectrum.

Using the near-infrared spectrum, said Dr. Eben Rosenthal, the Anne and John Doerr Medical Director of the Stanford (Calif.) Cancer Center, does two things: it allows for visualization deeper into tissues – up to 1 or 2 cm – and it improves the signal-to-noise ratio that can be a problem in the visual spectrum, where tissue autofluorescence occurs.

Cameras, endoscopes, and surgical microscopes can all be equipped to display the fluorescence and coregister the image with the white-light view the surgeon or pathologist normally sees. Surgeons using optical imaging techniques can usually continue to use the same tools and the same interface they are accustomed to.

Ligands can be small molecules, such as folate, or complex glycoproteins, such as monoclonal antibodies: all will bind selectively to sites on tumor cells. Patients are infused with the fluorescence-tagged ligand complexes before surgery, with timing appropriate to the half-lives of the agents, so infusions may happen the day before or the day of surgery.

For Dr. Rosenthal, using monoclonal antibodies to target tumors for optical imaging techniques affords several advantages. The antibodies are approved by the Food and Drug Administration, with known safety and side effect profiles. The antibodies can be tagged with an FDA-approved fluorescing molecule, allowing an easier approval process for the compound agent. Finally, the epidermal growth factor receptor (EGFR) target of these monoclonal antibodies is well expressed in many target tumor cells, including melanoma, breast, glioma, and colorectal cancers.

Dr. Singhal’s group has been working with fluorescein-tagged folate to identify pulmonary adenocarcinomas and is exploring use of other agents as well. “We like small molecules,” he said. “We can avoid lots of problems with biotoxicity.”

Annexin A2 (ANXA2) is a molecule expressed on the surface of cancer cells but found intracellularly in healthy cells, and it is the target of the chlorotoxin conjugate used by Dr. Jim Olson of Seattle’s Fred Hutchinson Cancer Research Center. Target malignancies may include glioblastoma, medullablastoma, sarcoma, and prostate and intestinal cancers.

Regardless of the target, however, optical imaging techniques may be particularly well suited for tumors occurring in areas where a generous dissection can have potentially devastating consequences, as in the head and neck, and for brain tumors. By giving the surgeon a clear delineation of malignant tissue, optical imaging can help the surgeon strike a balance to achieve the most conservative dissection that still achieves a complete gross dissection of the malignancy.

Achieving gross total dissection during cancer surgery is an important goal, said Dr. Olson. Citing devastating childhood brain tumors such as medulloblastomas and gliomablastomas, he noted that optical imaging can help surgeons avoid leaving behind any bulk areas of tumor, where hypoxic regions and therapy-resistant changes in tumor physiology may reduce the chance for cure. “Surgery is one of the most important elements of curing cancer,” he said. He pointed out that, in children with medulloblastomas, if nearly all tumor tissue is removed, less radiation is needed and survival is improved, even with less radiation – even if very small amounts of cancer remain.

Limitations of these technologies depend, to some extent, on the tissue targets, on substrates used to deliver the fluorescing molecules, and on the fluorescent agents themselves. Even with the enhanced tissue penetration of near-infrared light, the surgeon can really only see a centimeter or two beneath the surface of a solid organ. Said Dr. Singhal, “The basic limitation is that we’re talking about light.” However, if presurgery imaging identifies an area of concern, the surgeon can direct his or her dissection more carefully when the malignant tissue glows during surgery.

Dr. Rosenthal noted that pathologists also are making use of optical imaging to guide their processes. Since only about 5% of most tumor margins are sampled, there is an inevitable chance of sampling error with the resulting potential for a false-negative pathology result. “This technique augments the pathologist’s role and allows for improved biopsy results,” he said. Using image-guided pathology offers a way to test the margins immediately, helping the pathologist ascertain where the surgeon’s attention should be focused. Optical imaging, he said, “will in many ways change and enhance the experience for everybody.”

Dr. Olson, looking forward, asked, “If we can deliver the ability to light up, why can’t we deliver chemotherapy?” He sees an optical imaging future that will make flexible use of ligands to delineate tumors and test drug delivery.

There are many ways optical imaging can improve the practice of cancer surgery, Dr. Rosenthal said. “Historically, surgery has been a hard area to study because it’s so variable.” Following results from optical imaging–guided precision surgery, he said, will allow surgeons to identify and achieve “the right margin for the right cancer.”

Looking to the future, Dr. Singhal said, “it won’t be an either/or scenario. I think there will be multiple targets, multiple agents for this technology. We, as surgeons, have an obligation to our profession to move ahead with this.”

[email protected]

On Twitter @karioakes

For cancer patients and the surgeons who treat them, tumor margins matter. The amount of malignant tissue left behind after cancer surgery can make a profound difference in overall survival, but sparing healthy tissue while removing as much tumor as possible is limited by the surgeon’s ability to differentiate one from the other.

Now, new optical imaging techniques that deliver fluorescing molecules specifically to tumor targets show promise to allow both surgeons and pathologists to optimize cancer surgery. These intraoperative techniques use fluorescent molecules tagged to a ligand that binds to a target site on malignant cells. Thus, uptake occurs only in the malignant cells, highlighting them for the surgeon and for pathologists assessing margin adequacy.

Courtesy Emw/Wikicommons Creative Commons License

Dr. Sunil Singhal of the University of Pennsylvania, Philadelphia, has coined the term “optical biopsy” to describe what’s happening during optical imaging-guided surgery. “For so long, we as surgeons have just had our eyes and our hands – and our intuition – to guide us. This technology allows us to really focus our attention where it needs to be in surgery.”

Optical imaging in surgery uses a variety of fluorescing molecules, some of which were originally derived from sources as diverse as scorpions and fireflies. Some of these glow in the visible spectrum, but increasingly, optical imaging techniques are employing molecules that fluoresce when excited by light in the near-infrared spectrum.

Using the near-infrared spectrum, said Dr. Eben Rosenthal, the Anne and John Doerr Medical Director of the Stanford (Calif.) Cancer Center, does two things: it allows for visualization deeper into tissues – up to 1 or 2 cm – and it improves the signal-to-noise ratio that can be a problem in the visual spectrum, where tissue autofluorescence occurs.

Cameras, endoscopes, and surgical microscopes can all be equipped to display the fluorescence and coregister the image with the white-light view the surgeon or pathologist normally sees. Surgeons using optical imaging techniques can usually continue to use the same tools and the same interface they are accustomed to.

Ligands can be small molecules, such as folate, or complex glycoproteins, such as monoclonal antibodies: all will bind selectively to sites on tumor cells. Patients are infused with the fluorescence-tagged ligand complexes before surgery, with timing appropriate to the half-lives of the agents, so infusions may happen the day before or the day of surgery.

For Dr. Rosenthal, using monoclonal antibodies to target tumors for optical imaging techniques affords several advantages. The antibodies are approved by the Food and Drug Administration, with known safety and side effect profiles. The antibodies can be tagged with an FDA-approved fluorescing molecule, allowing an easier approval process for the compound agent. Finally, the epidermal growth factor receptor (EGFR) target of these monoclonal antibodies is well expressed in many target tumor cells, including melanoma, breast, glioma, and colorectal cancers.

Dr. Singhal’s group has been working with fluorescein-tagged folate to identify pulmonary adenocarcinomas and is exploring use of other agents as well. “We like small molecules,” he said. “We can avoid lots of problems with biotoxicity.”

Annexin A2 (ANXA2) is a molecule expressed on the surface of cancer cells but found intracellularly in healthy cells, and it is the target of the chlorotoxin conjugate used by Dr. Jim Olson of Seattle’s Fred Hutchinson Cancer Research Center. Target malignancies may include glioblastoma, medullablastoma, sarcoma, and prostate and intestinal cancers.

Regardless of the target, however, optical imaging techniques may be particularly well suited for tumors occurring in areas where a generous dissection can have potentially devastating consequences, as in the head and neck, and for brain tumors. By giving the surgeon a clear delineation of malignant tissue, optical imaging can help the surgeon strike a balance to achieve the most conservative dissection that still achieves a complete gross dissection of the malignancy.

Achieving gross total dissection during cancer surgery is an important goal, said Dr. Olson. Citing devastating childhood brain tumors such as medulloblastomas and gliomablastomas, he noted that optical imaging can help surgeons avoid leaving behind any bulk areas of tumor, where hypoxic regions and therapy-resistant changes in tumor physiology may reduce the chance for cure. “Surgery is one of the most important elements of curing cancer,” he said. He pointed out that, in children with medulloblastomas, if nearly all tumor tissue is removed, less radiation is needed and survival is improved, even with less radiation – even if very small amounts of cancer remain.

Limitations of these technologies depend, to some extent, on the tissue targets, on substrates used to deliver the fluorescing molecules, and on the fluorescent agents themselves. Even with the enhanced tissue penetration of near-infrared light, the surgeon can really only see a centimeter or two beneath the surface of a solid organ. Said Dr. Singhal, “The basic limitation is that we’re talking about light.” However, if presurgery imaging identifies an area of concern, the surgeon can direct his or her dissection more carefully when the malignant tissue glows during surgery.

Dr. Rosenthal noted that pathologists also are making use of optical imaging to guide their processes. Since only about 5% of most tumor margins are sampled, there is an inevitable chance of sampling error with the resulting potential for a false-negative pathology result. “This technique augments the pathologist’s role and allows for improved biopsy results,” he said. Using image-guided pathology offers a way to test the margins immediately, helping the pathologist ascertain where the surgeon’s attention should be focused. Optical imaging, he said, “will in many ways change and enhance the experience for everybody.”

Dr. Olson, looking forward, asked, “If we can deliver the ability to light up, why can’t we deliver chemotherapy?” He sees an optical imaging future that will make flexible use of ligands to delineate tumors and test drug delivery.

There are many ways optical imaging can improve the practice of cancer surgery, Dr. Rosenthal said. “Historically, surgery has been a hard area to study because it’s so variable.” Following results from optical imaging–guided precision surgery, he said, will allow surgeons to identify and achieve “the right margin for the right cancer.”

Looking to the future, Dr. Singhal said, “it won’t be an either/or scenario. I think there will be multiple targets, multiple agents for this technology. We, as surgeons, have an obligation to our profession to move ahead with this.”

[email protected]

On Twitter @karioakes

MIAMI BEACH – Researchers reporting early work in three areas of chronic mental illness or disability – autism spectrum disorder, schizophrenia, and bipolar disorder – shared the promising results of early detection and intervention programs during a plenary session at a meeting of the American Society for Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting. Common themes across research in these disparate illnesses included the benefit of early identification of at-risk individuals and the hope that early intervention might modify the disease course of lifelong illnesses.

Geraldine Dawson, Ph.D., of Duke University in Durham, N.C., shared the results of her early detection and intervention programs. Since siblings of individuals with autism spectrum disorders are at increased risk for autism spectrum disorder (ASD), researchers began using eye-tracking exercises in very young infants. Some studies have reported differences in attention and gaze in infants as young as 4 months old; infants who went on to develop ASD spent less time focusing on the eyes of faces. Infants who later developed ASD also showed less differential in EEG tracings to direct versus averted gaze than normally developing infants. Dr. Dawson’s work found that toddlers with ASD showed distinctly more EEG reactivity to familiar versus unfamiliar objects, but not faces, indicating a lack of ability to differentiate faces.

Courtesy Duke University

Those changes, said Dr. Dawson, might indicate a fundamental biologic underpinning to ASD. Further, the lack of interaction with the social environment that’s seen so early might result in overall reduced input and stimulation for the developing prefrontal cortex, influencing development. “We have a double whammy going on here,” said Dr. Dawson, professor in the department of psychiatry and behavioral sciences at Duke.

Dr. Dawson found that early intensive behavioral intervention that started before age 2 and lasted for 2 years resulted in improved cognitive, language, and social behavior. In addition, brain activity of these children in response to social stimuli by the age of 4 was indistinguishable from that of a typical 4-year-old, said Dr. Dawson, also a professor in the departments of psychology and neuroscience, and pediatrics at the university.

She also shared the results of a small pilot study with parents of infants at risk for ASD who were coached in strategies that promote interaction with the social environment. She found that among at-risk infants, by 12 months of age, they showed more normal EEG responses to social stimuli.

Dr. Dawson emphasized that it is not yet known whether the early stimulation reduces later symptoms of autism. She said she hopes that a combination of pharmacologic and behavioral interventions will emerge that will enhance synaptic plasticity and improve outcomes for greater numbers of children.

Dr. John M. Kane spoke to the effectiveness of the NAVIGATE structured team-based assessment and treatment program for individuals newly diagnosed with schizophrenia. The program also incorporated COMPASS, a web-based documentation, shared decision making, and decision support tool. Using a cluster-randomized protocol comparing NAVIGATE to community care for first-episode schizophrenia, Dr. Kane and his colleagues assessed 404 patients at 34 sites in 21 states over a 2-year-year period.

In early results, NAVIGATE enrollees were strikingly more likely to be asked regularly about medication use, side effects, and symptoms; to receive counseling about work or school options; and to have family counseling and support than those receiving usual treatment in the community-based centers participating in the program over the 2 years of the study period.

Early and standardized delivery of the coordinated specialty care model, said Dr. Kane, was associated with patients staying in treatment significantly longer, being more likely to be working or in school, and experiencing symptom improvement. Patients receiving the NAVIGATE intervention had significant improvement in the study’s primary outcome measure, quality of life, said Dr. Kane, professor of psychiatry, neurology, and neuroscience at the Albert Einstein College of Medicine, New York.

Ellen Frank, Ph.D., of the University of Pittsburgh, began her presentation by expressing frank envy for her colleagues’ relatively advanced understanding of the pathophysiology of autism and schizophrenia. By contrast, she said, very little is known about the bipolar disorders.

One thing that is known, however, is the high degree of heritability of bipolar disorder. Her work, she said, begins to assess whether prediagnosis behavioral interventions among children of parents with bipolar disorder might impact the course of the disorder or even prevent its development.

Building on the knowledge that anxiety, depression, and emotional ability in adolescence are predictors for the development of bipolar disorder, Dr. Frank developed and implemented an intervention that focused on regularizing sleep and social rhythms for these at-risk adolescents.

The open pilot study of 42 evenly split adolescents compared those who received the usual appropriate referrals alone with those who received these referrals, plus sleep and social rhythm–targeted education and support for families and the teens themselves. These interventions, dubbed interpersonal and social rhythm therapy (IPRST), have been shown to reduce illness recurrence in adults with bipolar disorder, said Dr. Frank, also director of the depression and manic-depression prevention program at the Western Psychiatric Institute and Clinic in Pittsburgh.

Over the 6-month follow-up period, Dr. Frank said, IPRST recipients had significantly fewer subclinical symptoms of depression and hypomania (P <.05 for both) than their controls, according to assessors who were blinded as to intervention. Participants and their families were satisfied overall with the IPRST therapy, and Dr. Frank noted that the adolescents were “remarkably willing to be open” during the sessions.

Dr. Frank reiterated the less mature state of knowledge about the etiology and natural history of bipolar disorders. Even so, she said, this small pilot study showed an encouraging improvement in sleep patterns and a global improvement in mood and functioning among teens at significantly increased risk for bipolar disorder.

Dr. Dawson serves on the scientific advisory boards of several entities, including Janssen Research and Development and Roche Pharmaceuticals. She also receives royalties from Guilford Press and Oxford University Press. Dr. Kane has served as a consultant to several companies, including Forest Pharmaceuticals. Dr. Frank’s disclosures include Guilford Press and Servier International.

[email protected]

On Twitter @karioakes

MIAMI BEACH – Researchers reporting early work in three areas of chronic mental illness or disability – autism spectrum disorder, schizophrenia, and bipolar disorder – shared the promising results of early detection and intervention programs during a plenary session at a meeting of the American Society for Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting. Common themes across research in these disparate illnesses included the benefit of early identification of at-risk individuals and the hope that early intervention might modify the disease course of lifelong illnesses.

Geraldine Dawson, Ph.D., of Duke University in Durham, N.C., shared the results of her early detection and intervention programs. Since siblings of individuals with autism spectrum disorders are at increased risk for autism spectrum disorder (ASD), researchers began using eye-tracking exercises in very young infants. Some studies have reported differences in attention and gaze in infants as young as 4 months old; infants who went on to develop ASD spent less time focusing on the eyes of faces. Infants who later developed ASD also showed less differential in EEG tracings to direct versus averted gaze than normally developing infants. Dr. Dawson’s work found that toddlers with ASD showed distinctly more EEG reactivity to familiar versus unfamiliar objects, but not faces, indicating a lack of ability to differentiate faces.

Courtesy Duke University

Those changes, said Dr. Dawson, might indicate a fundamental biologic underpinning to ASD. Further, the lack of interaction with the social environment that’s seen so early might result in overall reduced input and stimulation for the developing prefrontal cortex, influencing development. “We have a double whammy going on here,” said Dr. Dawson, professor in the department of psychiatry and behavioral sciences at Duke.

Dr. Dawson found that early intensive behavioral intervention that started before age 2 and lasted for 2 years resulted in improved cognitive, language, and social behavior. In addition, brain activity of these children in response to social stimuli by the age of 4 was indistinguishable from that of a typical 4-year-old, said Dr. Dawson, also a professor in the departments of psychology and neuroscience, and pediatrics at the university.

She also shared the results of a small pilot study with parents of infants at risk for ASD who were coached in strategies that promote interaction with the social environment. She found that among at-risk infants, by 12 months of age, they showed more normal EEG responses to social stimuli.

Dr. Dawson emphasized that it is not yet known whether the early stimulation reduces later symptoms of autism. She said she hopes that a combination of pharmacologic and behavioral interventions will emerge that will enhance synaptic plasticity and improve outcomes for greater numbers of children.

Dr. John M. Kane spoke to the effectiveness of the NAVIGATE structured team-based assessment and treatment program for individuals newly diagnosed with schizophrenia. The program also incorporated COMPASS, a web-based documentation, shared decision making, and decision support tool. Using a cluster-randomized protocol comparing NAVIGATE to community care for first-episode schizophrenia, Dr. Kane and his colleagues assessed 404 patients at 34 sites in 21 states over a 2-year-year period.

In early results, NAVIGATE enrollees were strikingly more likely to be asked regularly about medication use, side effects, and symptoms; to receive counseling about work or school options; and to have family counseling and support than those receiving usual treatment in the community-based centers participating in the program over the 2 years of the study period.

Early and standardized delivery of the coordinated specialty care model, said Dr. Kane, was associated with patients staying in treatment significantly longer, being more likely to be working or in school, and experiencing symptom improvement. Patients receiving the NAVIGATE intervention had significant improvement in the study’s primary outcome measure, quality of life, said Dr. Kane, professor of psychiatry, neurology, and neuroscience at the Albert Einstein College of Medicine, New York.

Ellen Frank, Ph.D., of the University of Pittsburgh, began her presentation by expressing frank envy for her colleagues’ relatively advanced understanding of the pathophysiology of autism and schizophrenia. By contrast, she said, very little is known about the bipolar disorders.

One thing that is known, however, is the high degree of heritability of bipolar disorder. Her work, she said, begins to assess whether prediagnosis behavioral interventions among children of parents with bipolar disorder might impact the course of the disorder or even prevent its development.

Building on the knowledge that anxiety, depression, and emotional ability in adolescence are predictors for the development of bipolar disorder, Dr. Frank developed and implemented an intervention that focused on regularizing sleep and social rhythms for these at-risk adolescents.

The open pilot study of 42 evenly split adolescents compared those who received the usual appropriate referrals alone with those who received these referrals, plus sleep and social rhythm–targeted education and support for families and the teens themselves. These interventions, dubbed interpersonal and social rhythm therapy (IPRST), have been shown to reduce illness recurrence in adults with bipolar disorder, said Dr. Frank, also director of the depression and manic-depression prevention program at the Western Psychiatric Institute and Clinic in Pittsburgh.

Over the 6-month follow-up period, Dr. Frank said, IPRST recipients had significantly fewer subclinical symptoms of depression and hypomania (P <.05 for both) than their controls, according to assessors who were blinded as to intervention. Participants and their families were satisfied overall with the IPRST therapy, and Dr. Frank noted that the adolescents were “remarkably willing to be open” during the sessions.

Dr. Frank reiterated the less mature state of knowledge about the etiology and natural history of bipolar disorders. Even so, she said, this small pilot study showed an encouraging improvement in sleep patterns and a global improvement in mood and functioning among teens at significantly increased risk for bipolar disorder.

Dr. Dawson serves on the scientific advisory boards of several entities, including Janssen Research and Development and Roche Pharmaceuticals. She also receives royalties from Guilford Press and Oxford University Press. Dr. Kane has served as a consultant to several companies, including Forest Pharmaceuticals. Dr. Frank’s disclosures include Guilford Press and Servier International.

[email protected]

On Twitter @karioakes

MIAMI BEACH – Researchers reporting early work in three areas of chronic mental illness or disability – autism spectrum disorder, schizophrenia, and bipolar disorder – shared the promising results of early detection and intervention programs during a plenary session at a meeting of the American Society for Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting. Common themes across research in these disparate illnesses included the benefit of early identification of at-risk individuals and the hope that early intervention might modify the disease course of lifelong illnesses.

Geraldine Dawson, Ph.D., of Duke University in Durham, N.C., shared the results of her early detection and intervention programs. Since siblings of individuals with autism spectrum disorders are at increased risk for autism spectrum disorder (ASD), researchers began using eye-tracking exercises in very young infants. Some studies have reported differences in attention and gaze in infants as young as 4 months old; infants who went on to develop ASD spent less time focusing on the eyes of faces. Infants who later developed ASD also showed less differential in EEG tracings to direct versus averted gaze than normally developing infants. Dr. Dawson’s work found that toddlers with ASD showed distinctly more EEG reactivity to familiar versus unfamiliar objects, but not faces, indicating a lack of ability to differentiate faces.

Courtesy Duke University

Those changes, said Dr. Dawson, might indicate a fundamental biologic underpinning to ASD. Further, the lack of interaction with the social environment that’s seen so early might result in overall reduced input and stimulation for the developing prefrontal cortex, influencing development. “We have a double whammy going on here,” said Dr. Dawson, professor in the department of psychiatry and behavioral sciences at Duke.

Dr. Dawson found that early intensive behavioral intervention that started before age 2 and lasted for 2 years resulted in improved cognitive, language, and social behavior. In addition, brain activity of these children in response to social stimuli by the age of 4 was indistinguishable from that of a typical 4-year-old, said Dr. Dawson, also a professor in the departments of psychology and neuroscience, and pediatrics at the university.

She also shared the results of a small pilot study with parents of infants at risk for ASD who were coached in strategies that promote interaction with the social environment. She found that among at-risk infants, by 12 months of age, they showed more normal EEG responses to social stimuli.

Dr. Dawson emphasized that it is not yet known whether the early stimulation reduces later symptoms of autism. She said she hopes that a combination of pharmacologic and behavioral interventions will emerge that will enhance synaptic plasticity and improve outcomes for greater numbers of children.

Dr. John M. Kane spoke to the effectiveness of the NAVIGATE structured team-based assessment and treatment program for individuals newly diagnosed with schizophrenia. The program also incorporated COMPASS, a web-based documentation, shared decision making, and decision support tool. Using a cluster-randomized protocol comparing NAVIGATE to community care for first-episode schizophrenia, Dr. Kane and his colleagues assessed 404 patients at 34 sites in 21 states over a 2-year-year period.

In early results, NAVIGATE enrollees were strikingly more likely to be asked regularly about medication use, side effects, and symptoms; to receive counseling about work or school options; and to have family counseling and support than those receiving usual treatment in the community-based centers participating in the program over the 2 years of the study period.

Early and standardized delivery of the coordinated specialty care model, said Dr. Kane, was associated with patients staying in treatment significantly longer, being more likely to be working or in school, and experiencing symptom improvement. Patients receiving the NAVIGATE intervention had significant improvement in the study’s primary outcome measure, quality of life, said Dr. Kane, professor of psychiatry, neurology, and neuroscience at the Albert Einstein College of Medicine, New York.

Ellen Frank, Ph.D., of the University of Pittsburgh, began her presentation by expressing frank envy for her colleagues’ relatively advanced understanding of the pathophysiology of autism and schizophrenia. By contrast, she said, very little is known about the bipolar disorders.

One thing that is known, however, is the high degree of heritability of bipolar disorder. Her work, she said, begins to assess whether prediagnosis behavioral interventions among children of parents with bipolar disorder might impact the course of the disorder or even prevent its development.

Building on the knowledge that anxiety, depression, and emotional ability in adolescence are predictors for the development of bipolar disorder, Dr. Frank developed and implemented an intervention that focused on regularizing sleep and social rhythms for these at-risk adolescents.

The open pilot study of 42 evenly split adolescents compared those who received the usual appropriate referrals alone with those who received these referrals, plus sleep and social rhythm–targeted education and support for families and the teens themselves. These interventions, dubbed interpersonal and social rhythm therapy (IPRST), have been shown to reduce illness recurrence in adults with bipolar disorder, said Dr. Frank, also director of the depression and manic-depression prevention program at the Western Psychiatric Institute and Clinic in Pittsburgh.

Over the 6-month follow-up period, Dr. Frank said, IPRST recipients had significantly fewer subclinical symptoms of depression and hypomania (P <.05 for both) than their controls, according to assessors who were blinded as to intervention. Participants and their families were satisfied overall with the IPRST therapy, and Dr. Frank noted that the adolescents were “remarkably willing to be open” during the sessions.

Dr. Frank reiterated the less mature state of knowledge about the etiology and natural history of bipolar disorders. Even so, she said, this small pilot study showed an encouraging improvement in sleep patterns and a global improvement in mood and functioning among teens at significantly increased risk for bipolar disorder.

Dr. Dawson serves on the scientific advisory boards of several entities, including Janssen Research and Development and Roche Pharmaceuticals. She also receives royalties from Guilford Press and Oxford University Press. Dr. Kane has served as a consultant to several companies, including Forest Pharmaceuticals. Dr. Frank’s disclosures include Guilford Press and Servier International.

[email protected]

On Twitter @karioakes

MIAMI BEACH – Implementing an online decision support tool was one pivotal component of a highly effective structured program to aid community-based prescribers treating those with their first episode of schizophrenia. Members of an investigative team comparing the structured program to usual care shared their findings during a panel session at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

The lifetime prevalence of schizophrenia is less than 1%, and the number of first episodes of schizophrenia each year also is low. This is a core challenge in treatment, said session leader Dr. Delbert G. Robinson of the Hofstra North Shore-LIJ School of Medicine, Glen Oaks, N.Y. Many community prescribers have experience treating schizophrenia as a chronic illness, but few will have much exposure to early-phase illness.

To determine the most effective way for these community prescribers to provide effective treatment for those newly diagnosed with schizophrenia, the National Institute of Mental Health tested usual care against a structured program in RAISE-ETP (Recovery After Initial Schizophrenia Episode–Early Treatment Program). The multistate, multisite controlled trial used cluster randomization at 34 community clinical sites in 21 states.

The study compared current care to the NAVIGATE model, a structured, team-based, multifaceted approach to treating newly diagnosed schizophrenia. Treatment protocols in early schizophrenia differ from more established disease, Dr. Robinson said. For example, recommended initial antipsychotic dosing is lower. Further, implementing NAVIGATE meant that investigators had to persuade prescribers at nonacademic community centers to change their habits – not an easy task.

During the study period, 3,939 visits occurred using COMPASS, the computerized encounter and decision support tool developed by the study team. This cloud-based online system included a comprehensive previsit questionnaire completed by patients, as well as an encounter form to be completed by the clinician with patient input during the visit. COMPASS emphasized shared decision making; for example, visit priorities were set jointly by prescriber and patient, said Dr. Eric D. Achtyes of Michigan State University, Grand Rapids.

Further, decision support tools prompt prescribers to turn first to evidence-based initial medication choices and doses for early schizophrenia, said Dr. Achtyes, director of the division of psychiatry and behavioral medicine at the university’s College of Human Medicine.

Overall, 404 subjects were enrolled in the two arms, of whom 223 were cluster-randomized to the NAVIGATE arm. Subjects aged 15-40 years who had experienced their first episode of psychosis and had a diagnosis in the schizophrenia spectrum were eligible if they had not taken more than 6 months of antipsychotic medication at enrollment. Mean age of the participants was 23, and about three-quarters of enrollments occurred subsequent to a psychiatric hospitalization. More than half of participants had dyslipidemia or were overweight or obese, about half smoked, and more than 10% had metabolic syndrome – numbers that are “very concerning” for such a young cohort, said Nina R. Schooler, Ph.D., professor of psychiatry and behavioral sciences at SUNY (State University of New York) Downstate Medical Center, Brooklyn.

Data analysis is ongoing, but initial results show that NAVIGATE participants stay in treatment significantly longer than do those receiving usual care. The research team is examining odds ratios for receiving a first-line antipsychotic in any given month and tracking trends in psychosocial care over time for the two study arms, Dr. Schooler said.

The cluster design had advantages in “the ease of operation” in terms of doing the study, Dr. Schooler said in an interview. “Each study site had only had one protocol to learn, one study design to run, and one set of trainings for staff to complete. However, data analysis is more complex with cluster randomization. Dr. Robinson noted that the design “vastly simplified the life of the site but shifted the burden to the central team.” The study used a blended assessment model, with some evaluations conducted on site and others conducted by centralized evaluators, another study strength, Dr. Schooler said.

Discussant Dr. Joseph P. McEvoy commended the panelists for their important work in this area. Especially important is the emphasis on rational implementation of evidence-based treatment in early schizophrenia within a framework achievable with current resources, said Dr. McEvoy, I.W. Case Distinguished Professor of Psychiatry at Georgia Regents University, Augusta. He noted that the Substance Abuse and Mental Health Services Administration has allocated per-state funding for demonstration projects that build on the NAVIGATE model.

The National Institute of Mental Health funded the study. Dr. Robinson reported ties with Otsuka; Dr. Achtyes disclosed ties with Roche, Janssen, AssurEx Health, and Otsuka; Dr. Schooler has ties with Roche, Sunovion, EnVivo/Forum, Genentech, Otsuka, and Neurocrine; and Dr. McEvoy reported ties with several pharmaceutical companies.

[email protected]

On Twitter @karioakes

MIAMI BEACH – Implementing an online decision support tool was one pivotal component of a highly effective structured program to aid community-based prescribers treating those with their first episode of schizophrenia. Members of an investigative team comparing the structured program to usual care shared their findings during a panel session at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

The lifetime prevalence of schizophrenia is less than 1%, and the number of first episodes of schizophrenia each year also is low. This is a core challenge in treatment, said session leader Dr. Delbert G. Robinson of the Hofstra North Shore-LIJ School of Medicine, Glen Oaks, N.Y. Many community prescribers have experience treating schizophrenia as a chronic illness, but few will have much exposure to early-phase illness.

To determine the most effective way for these community prescribers to provide effective treatment for those newly diagnosed with schizophrenia, the National Institute of Mental Health tested usual care against a structured program in RAISE-ETP (Recovery After Initial Schizophrenia Episode–Early Treatment Program). The multistate, multisite controlled trial used cluster randomization at 34 community clinical sites in 21 states.

The study compared current care to the NAVIGATE model, a structured, team-based, multifaceted approach to treating newly diagnosed schizophrenia. Treatment protocols in early schizophrenia differ from more established disease, Dr. Robinson said. For example, recommended initial antipsychotic dosing is lower. Further, implementing NAVIGATE meant that investigators had to persuade prescribers at nonacademic community centers to change their habits – not an easy task.

During the study period, 3,939 visits occurred using COMPASS, the computerized encounter and decision support tool developed by the study team. This cloud-based online system included a comprehensive previsit questionnaire completed by patients, as well as an encounter form to be completed by the clinician with patient input during the visit. COMPASS emphasized shared decision making; for example, visit priorities were set jointly by prescriber and patient, said Dr. Eric D. Achtyes of Michigan State University, Grand Rapids.

Further, decision support tools prompt prescribers to turn first to evidence-based initial medication choices and doses for early schizophrenia, said Dr. Achtyes, director of the division of psychiatry and behavioral medicine at the university’s College of Human Medicine.

Overall, 404 subjects were enrolled in the two arms, of whom 223 were cluster-randomized to the NAVIGATE arm. Subjects aged 15-40 years who had experienced their first episode of psychosis and had a diagnosis in the schizophrenia spectrum were eligible if they had not taken more than 6 months of antipsychotic medication at enrollment. Mean age of the participants was 23, and about three-quarters of enrollments occurred subsequent to a psychiatric hospitalization. More than half of participants had dyslipidemia or were overweight or obese, about half smoked, and more than 10% had metabolic syndrome – numbers that are “very concerning” for such a young cohort, said Nina R. Schooler, Ph.D., professor of psychiatry and behavioral sciences at SUNY (State University of New York) Downstate Medical Center, Brooklyn.

Data analysis is ongoing, but initial results show that NAVIGATE participants stay in treatment significantly longer than do those receiving usual care. The research team is examining odds ratios for receiving a first-line antipsychotic in any given month and tracking trends in psychosocial care over time for the two study arms, Dr. Schooler said.

The cluster design had advantages in “the ease of operation” in terms of doing the study, Dr. Schooler said in an interview. “Each study site had only had one protocol to learn, one study design to run, and one set of trainings for staff to complete. However, data analysis is more complex with cluster randomization. Dr. Robinson noted that the design “vastly simplified the life of the site but shifted the burden to the central team.” The study used a blended assessment model, with some evaluations conducted on site and others conducted by centralized evaluators, another study strength, Dr. Schooler said.

Discussant Dr. Joseph P. McEvoy commended the panelists for their important work in this area. Especially important is the emphasis on rational implementation of evidence-based treatment in early schizophrenia within a framework achievable with current resources, said Dr. McEvoy, I.W. Case Distinguished Professor of Psychiatry at Georgia Regents University, Augusta. He noted that the Substance Abuse and Mental Health Services Administration has allocated per-state funding for demonstration projects that build on the NAVIGATE model.

The National Institute of Mental Health funded the study. Dr. Robinson reported ties with Otsuka; Dr. Achtyes disclosed ties with Roche, Janssen, AssurEx Health, and Otsuka; Dr. Schooler has ties with Roche, Sunovion, EnVivo/Forum, Genentech, Otsuka, and Neurocrine; and Dr. McEvoy reported ties with several pharmaceutical companies.

[email protected]

On Twitter @karioakes

MIAMI BEACH – Implementing an online decision support tool was one pivotal component of a highly effective structured program to aid community-based prescribers treating those with their first episode of schizophrenia. Members of an investigative team comparing the structured program to usual care shared their findings during a panel session at a meeting of the American Society of Clinical Psychopharmacology, formerly known as the New Clinical Drug Evaluation Unit meeting.

The lifetime prevalence of schizophrenia is less than 1%, and the number of first episodes of schizophrenia each year also is low. This is a core challenge in treatment, said session leader Dr. Delbert G. Robinson of the Hofstra North Shore-LIJ School of Medicine, Glen Oaks, N.Y. Many community prescribers have experience treating schizophrenia as a chronic illness, but few will have much exposure to early-phase illness.

To determine the most effective way for these community prescribers to provide effective treatment for those newly diagnosed with schizophrenia, the National Institute of Mental Health tested usual care against a structured program in RAISE-ETP (Recovery After Initial Schizophrenia Episode–Early Treatment Program). The multistate, multisite controlled trial used cluster randomization at 34 community clinical sites in 21 states.

The study compared current care to the NAVIGATE model, a structured, team-based, multifaceted approach to treating newly diagnosed schizophrenia. Treatment protocols in early schizophrenia differ from more established disease, Dr. Robinson said. For example, recommended initial antipsychotic dosing is lower. Further, implementing NAVIGATE meant that investigators had to persuade prescribers at nonacademic community centers to change their habits – not an easy task.

During the study period, 3,939 visits occurred using COMPASS, the computerized encounter and decision support tool developed by the study team. This cloud-based online system included a comprehensive previsit questionnaire completed by patients, as well as an encounter form to be completed by the clinician with patient input during the visit. COMPASS emphasized shared decision making; for example, visit priorities were set jointly by prescriber and patient, said Dr. Eric D. Achtyes of Michigan State University, Grand Rapids.

Further, decision support tools prompt prescribers to turn first to evidence-based initial medication choices and doses for early schizophrenia, said Dr. Achtyes, director of the division of psychiatry and behavioral medicine at the university’s College of Human Medicine.

Overall, 404 subjects were enrolled in the two arms, of whom 223 were cluster-randomized to the NAVIGATE arm. Subjects aged 15-40 years who had experienced their first episode of psychosis and had a diagnosis in the schizophrenia spectrum were eligible if they had not taken more than 6 months of antipsychotic medication at enrollment. Mean age of the participants was 23, and about three-quarters of enrollments occurred subsequent to a psychiatric hospitalization. More than half of participants had dyslipidemia or were overweight or obese, about half smoked, and more than 10% had metabolic syndrome – numbers that are “very concerning” for such a young cohort, said Nina R. Schooler, Ph.D., professor of psychiatry and behavioral sciences at SUNY (State University of New York) Downstate Medical Center, Brooklyn.

Data analysis is ongoing, but initial results show that NAVIGATE participants stay in treatment significantly longer than do those receiving usual care. The research team is examining odds ratios for receiving a first-line antipsychotic in any given month and tracking trends in psychosocial care over time for the two study arms, Dr. Schooler said.

The cluster design had advantages in “the ease of operation” in terms of doing the study, Dr. Schooler said in an interview. “Each study site had only had one protocol to learn, one study design to run, and one set of trainings for staff to complete. However, data analysis is more complex with cluster randomization. Dr. Robinson noted that the design “vastly simplified the life of the site but shifted the burden to the central team.” The study used a blended assessment model, with some evaluations conducted on site and others conducted by centralized evaluators, another study strength, Dr. Schooler said.

Discussant Dr. Joseph P. McEvoy commended the panelists for their important work in this area. Especially important is the emphasis on rational implementation of evidence-based treatment in early schizophrenia within a framework achievable with current resources, said Dr. McEvoy, I.W. Case Distinguished Professor of Psychiatry at Georgia Regents University, Augusta. He noted that the Substance Abuse and Mental Health Services Administration has allocated per-state funding for demonstration projects that build on the NAVIGATE model.

The National Institute of Mental Health funded the study. Dr. Robinson reported ties with Otsuka; Dr. Achtyes disclosed ties with Roche, Janssen, AssurEx Health, and Otsuka; Dr. Schooler has ties with Roche, Sunovion, EnVivo/Forum, Genentech, Otsuka, and Neurocrine; and Dr. McEvoy reported ties with several pharmaceutical companies.

[email protected]

On Twitter @karioakes

Physicians seeking optimal body contouring results for their aesthetic medicine patients are increasingly turning to a variety of energy-based options. Newer technologies for body shaping deliver energy to heat or cool tissue, and each has its own side effect and tolerability profile. Finding the right technology fit for a practice and for a particular patient requires that clinicians understand how these technologies work and who is most likely to benefit.

Dr. Christopher Zachary, professor and chair of dermatology at the University of California, Irvine, reviewed current options for energy-based body sculpting at this year’s Summit in Aesthetic Medicine held in Dana Point, Calif. Current energy-based technologies, he said, either heat or cool tissue to achieve a deliberate panniculitis, followed by gradual apoptosis of fat cells. As adipocytes undergo apoptosis, intracellular contents are metabolized, so intact adipose tissue is not excreted as it is in liposuction, for example.

Dr. Zachary explained that fat destruction caused by cold was first noticed by physicians treating young children with cheek dimples after prolonged exposure to icy treats, a phenomenon they termed “Popsicle panniculitis.” However, heating fat tissue can have the same effect. Whether the technology uses heating or cooling to achieve body contouring, he said, is not as important as the volume and duration of treatment.

Ideally, energy-based contouring technologies should be able to achieve bulk treatment of a relatively large area for a significant amount of time, from 10 to 60 minutes. These criteria allow for the larger-scale controlled loss of cell viability critical for successful contouring, he said.

Zeltiq’s CoolSculpting has been a leader in body contouring using cold technologies, he continued. By achieving bulk cooling of adipose tissue, CoolSculpting can achieve both sculpting and debulking of abdominal, thigh, and flank problem areas. The procedure is generally well tolerated, and achieves gradual recontouring over the weeks following treatment.

Radiofrequency body contouring, said Dr. Zachary, has been led by Cutera. “Cutera has really done the best studies in this area,” he said. The technology uses large electrodes that heat tissue to 45-47° C for 3-6 minutes, “achieving some nice results.” This level of heating achieves significant apoptosis of adipose tissue but is well tolerated.

Near-infrared technology has been pioneered by Cynosure, which can be used to treat bulk areas of tissue. Again, said Dr. Zachary, “The company has done the right studies, using ultrasound and histology to measure results. They’re using the right parameters.”

Another technique is microfocused ultrasound, as pioneered by companies such as Liposonix. This technology creates a well-defined, focused injury and creates a painful acute necrosis. “This doesn’t fit my criteria for effective bulk heating or cooling,” he noted. Additionally, a significant number of patients will have local tenderness, ecchymosis, and edema that can persist for more than a month. Although there may be targeted applications for the technology, it is not likely to be as effective or as well tolerated as some other options, he said.

New areas of inquiry include adding massage to treatment, encouraging speedier and more uniform results. New flat applicators show promise for more effective treatment. Physicians are seeing more patients who have concerns about male breast tissue, submental fat, and acne, for whom these technologies hold promise.

“If we had been having this discussion 5 years ago,” he said, “I would have been rather jaundiced about the outlook in this field. These days, the future is quite bright.”

Dr. Zachary reports that he has financial disclosures related to Solta Medical, Zeltiq, Zimmer, Cutera, and Alma.

[email protected]

On Twitter @karioakes

Physicians seeking optimal body contouring results for their aesthetic medicine patients are increasingly turning to a variety of energy-based options. Newer technologies for body shaping deliver energy to heat or cool tissue, and each has its own side effect and tolerability profile. Finding the right technology fit for a practice and for a particular patient requires that clinicians understand how these technologies work and who is most likely to benefit.

Dr. Christopher Zachary, professor and chair of dermatology at the University of California, Irvine, reviewed current options for energy-based body sculpting at this year’s Summit in Aesthetic Medicine held in Dana Point, Calif. Current energy-based technologies, he said, either heat or cool tissue to achieve a deliberate panniculitis, followed by gradual apoptosis of fat cells. As adipocytes undergo apoptosis, intracellular contents are metabolized, so intact adipose tissue is not excreted as it is in liposuction, for example.

Dr. Zachary explained that fat destruction caused by cold was first noticed by physicians treating young children with cheek dimples after prolonged exposure to icy treats, a phenomenon they termed “Popsicle panniculitis.” However, heating fat tissue can have the same effect. Whether the technology uses heating or cooling to achieve body contouring, he said, is not as important as the volume and duration of treatment.

Ideally, energy-based contouring technologies should be able to achieve bulk treatment of a relatively large area for a significant amount of time, from 10 to 60 minutes. These criteria allow for the larger-scale controlled loss of cell viability critical for successful contouring, he said.

Zeltiq’s CoolSculpting has been a leader in body contouring using cold technologies, he continued. By achieving bulk cooling of adipose tissue, CoolSculpting can achieve both sculpting and debulking of abdominal, thigh, and flank problem areas. The procedure is generally well tolerated, and achieves gradual recontouring over the weeks following treatment.

Radiofrequency body contouring, said Dr. Zachary, has been led by Cutera. “Cutera has really done the best studies in this area,” he said. The technology uses large electrodes that heat tissue to 45-47° C for 3-6 minutes, “achieving some nice results.” This level of heating achieves significant apoptosis of adipose tissue but is well tolerated.

Near-infrared technology has been pioneered by Cynosure, which can be used to treat bulk areas of tissue. Again, said Dr. Zachary, “The company has done the right studies, using ultrasound and histology to measure results. They’re using the right parameters.”

Another technique is microfocused ultrasound, as pioneered by companies such as Liposonix. This technology creates a well-defined, focused injury and creates a painful acute necrosis. “This doesn’t fit my criteria for effective bulk heating or cooling,” he noted. Additionally, a significant number of patients will have local tenderness, ecchymosis, and edema that can persist for more than a month. Although there may be targeted applications for the technology, it is not likely to be as effective or as well tolerated as some other options, he said.

New areas of inquiry include adding massage to treatment, encouraging speedier and more uniform results. New flat applicators show promise for more effective treatment. Physicians are seeing more patients who have concerns about male breast tissue, submental fat, and acne, for whom these technologies hold promise.

“If we had been having this discussion 5 years ago,” he said, “I would have been rather jaundiced about the outlook in this field. These days, the future is quite bright.”

Dr. Zachary reports that he has financial disclosures related to Solta Medical, Zeltiq, Zimmer, Cutera, and Alma.

[email protected]

On Twitter @karioakes

Physicians seeking optimal body contouring results for their aesthetic medicine patients are increasingly turning to a variety of energy-based options. Newer technologies for body shaping deliver energy to heat or cool tissue, and each has its own side effect and tolerability profile. Finding the right technology fit for a practice and for a particular patient requires that clinicians understand how these technologies work and who is most likely to benefit.

Dr. Christopher Zachary, professor and chair of dermatology at the University of California, Irvine, reviewed current options for energy-based body sculpting at this year’s Summit in Aesthetic Medicine held in Dana Point, Calif. Current energy-based technologies, he said, either heat or cool tissue to achieve a deliberate panniculitis, followed by gradual apoptosis of fat cells. As adipocytes undergo apoptosis, intracellular contents are metabolized, so intact adipose tissue is not excreted as it is in liposuction, for example.

Dr. Zachary explained that fat destruction caused by cold was first noticed by physicians treating young children with cheek dimples after prolonged exposure to icy treats, a phenomenon they termed “Popsicle panniculitis.” However, heating fat tissue can have the same effect. Whether the technology uses heating or cooling to achieve body contouring, he said, is not as important as the volume and duration of treatment.

Ideally, energy-based contouring technologies should be able to achieve bulk treatment of a relatively large area for a significant amount of time, from 10 to 60 minutes. These criteria allow for the larger-scale controlled loss of cell viability critical for successful contouring, he said.

Zeltiq’s CoolSculpting has been a leader in body contouring using cold technologies, he continued. By achieving bulk cooling of adipose tissue, CoolSculpting can achieve both sculpting and debulking of abdominal, thigh, and flank problem areas. The procedure is generally well tolerated, and achieves gradual recontouring over the weeks following treatment.

Radiofrequency body contouring, said Dr. Zachary, has been led by Cutera. “Cutera has really done the best studies in this area,” he said. The technology uses large electrodes that heat tissue to 45-47° C for 3-6 minutes, “achieving some nice results.” This level of heating achieves significant apoptosis of adipose tissue but is well tolerated.

Near-infrared technology has been pioneered by Cynosure, which can be used to treat bulk areas of tissue. Again, said Dr. Zachary, “The company has done the right studies, using ultrasound and histology to measure results. They’re using the right parameters.”

Another technique is microfocused ultrasound, as pioneered by companies such as Liposonix. This technology creates a well-defined, focused injury and creates a painful acute necrosis. “This doesn’t fit my criteria for effective bulk heating or cooling,” he noted. Additionally, a significant number of patients will have local tenderness, ecchymosis, and edema that can persist for more than a month. Although there may be targeted applications for the technology, it is not likely to be as effective or as well tolerated as some other options, he said.

New areas of inquiry include adding massage to treatment, encouraging speedier and more uniform results. New flat applicators show promise for more effective treatment. Physicians are seeing more patients who have concerns about male breast tissue, submental fat, and acne, for whom these technologies hold promise.

“If we had been having this discussion 5 years ago,” he said, “I would have been rather jaundiced about the outlook in this field. These days, the future is quite bright.”

Dr. Zachary reports that he has financial disclosures related to Solta Medical, Zeltiq, Zimmer, Cutera, and Alma.

[email protected]

On Twitter @karioakes

Hyaluronic acid fillers are a safe and effective aesthetic medicine modality, but some patients experience significant pain and bruising from dermal filler injections. Adding lidocaine may help with pain, and many clinicians also will add epinephrine to filler injections, believing they’ll achieve even less pain and mitigate bruising because of epinephrine’s vasoconstrictive effects.

However, quality evidence is lacking to support the addition of epinephrine, according to Dr. Amir Moradi, a facial plastic and reconstructive surgeon in private practice in San Diego. He conducted a split-face study that found no benefit from adding epinephrine to hyaluronic acid injections, and presented his results at the Summit in Aesthetic Medicine in Dana Point, Calif.

The study enrolled 30 patients in a double-blind, split-face comparison study of the hyaluronic acid filler Belotero (BEL) alone to Belotero with lidocaine (BEL-L), and to Belotero with lidocaine and epinephrine (BEL-LE). Patients received superficial to mid-dermal injections for perioral lines, and investigators obtained pretreatment photos and assessed wrinkle severity on the 5-point Merz scale.

Patients were allocated randomly and equally to treatment arms, so that 10 received BEL and BEL-L, 10 received BEL and BEL-LE, and 10 received BEL-L and BEL-LE. Each patient received a maximum of 1 mL of filler on each side of the face. An assistant prepared syringes in a manner that made them indistinguishable, so the operator and patient were blinded to treatment arm. All patients received massage and ice to the perioral area immediately after treatment.

Investigators asked patients to report the pain they experienced during injections on a 10-point Likert scale immediately after their injections were complete. Bruising was assessed by the physician investigator, by another blinded evaluator, and by the patients themselves pretreatment, and on days 1, 7, and 14 after injections. Because no validated standardized bruising scale exists, the investigators devised a scale of 0-3 to describe mild, moderate, and severe bruising according to the visibility and size of the discolored areas.

Contrary to anecdotal reports and against the investigators’ expectations, patients saw no significant difference in either pain or bruising with the addition of lidocaine, with or without epinephrine, to the hyaluronic acid dermal filler. Patients in all treatment arms generally had the worst bruising at day 1, with a resolution by about half at day 7, and bruising gone or nearly gone by day 14.

Calling for more and larger studies in this field, Dr. Moradi noted that the “limited benefit of lidocaine could be due to not waiting long enough for lidocaine to fully take effect.”

For pain, Dr. Moradi said in an interview, “How and when you ask the question really makes a difference. Because if you wait even 30 seconds afterward, it can change the answer.” He noted that his results showed no improvement in pain with lidocaine compared with hyaluronic acid alone. He plans further investigation using an assessment method that will allow patients to report pain during injections.

Planning more study into whether lidocaine, alone or with epinephrine, helps pain and bruising, Dr. Moradi expects to see some benefit for the adjuncts when a physician needs to go back and reinject an area. However, the field needs more well-designed studies with standardized assessments, he said. “We need to look at what the evidence says,”

Dr. Moradi reports that he has financial disclosures related to Allergan, Galderma, and Merz.

[email protected]

On Twitter @karioakes

Hyaluronic acid fillers are a safe and effective aesthetic medicine modality, but some patients experience significant pain and bruising from dermal filler injections. Adding lidocaine may help with pain, and many clinicians also will add epinephrine to filler injections, believing they’ll achieve even less pain and mitigate bruising because of epinephrine’s vasoconstrictive effects.

However, quality evidence is lacking to support the addition of epinephrine, according to Dr. Amir Moradi, a facial plastic and reconstructive surgeon in private practice in San Diego. He conducted a split-face study that found no benefit from adding epinephrine to hyaluronic acid injections, and presented his results at the Summit in Aesthetic Medicine in Dana Point, Calif.

The study enrolled 30 patients in a double-blind, split-face comparison study of the hyaluronic acid filler Belotero (BEL) alone to Belotero with lidocaine (BEL-L), and to Belotero with lidocaine and epinephrine (BEL-LE). Patients received superficial to mid-dermal injections for perioral lines, and investigators obtained pretreatment photos and assessed wrinkle severity on the 5-point Merz scale.

Patients were allocated randomly and equally to treatment arms, so that 10 received BEL and BEL-L, 10 received BEL and BEL-LE, and 10 received BEL-L and BEL-LE. Each patient received a maximum of 1 mL of filler on each side of the face. An assistant prepared syringes in a manner that made them indistinguishable, so the operator and patient were blinded to treatment arm. All patients received massage and ice to the perioral area immediately after treatment.

Investigators asked patients to report the pain they experienced during injections on a 10-point Likert scale immediately after their injections were complete. Bruising was assessed by the physician investigator, by another blinded evaluator, and by the patients themselves pretreatment, and on days 1, 7, and 14 after injections. Because no validated standardized bruising scale exists, the investigators devised a scale of 0-3 to describe mild, moderate, and severe bruising according to the visibility and size of the discolored areas.

Contrary to anecdotal reports and against the investigators’ expectations, patients saw no significant difference in either pain or bruising with the addition of lidocaine, with or without epinephrine, to the hyaluronic acid dermal filler. Patients in all treatment arms generally had the worst bruising at day 1, with a resolution by about half at day 7, and bruising gone or nearly gone by day 14.

Calling for more and larger studies in this field, Dr. Moradi noted that the “limited benefit of lidocaine could be due to not waiting long enough for lidocaine to fully take effect.”

For pain, Dr. Moradi said in an interview, “How and when you ask the question really makes a difference. Because if you wait even 30 seconds afterward, it can change the answer.” He noted that his results showed no improvement in pain with lidocaine compared with hyaluronic acid alone. He plans further investigation using an assessment method that will allow patients to report pain during injections.

Planning more study into whether lidocaine, alone or with epinephrine, helps pain and bruising, Dr. Moradi expects to see some benefit for the adjuncts when a physician needs to go back and reinject an area. However, the field needs more well-designed studies with standardized assessments, he said. “We need to look at what the evidence says,”

Dr. Moradi reports that he has financial disclosures related to Allergan, Galderma, and Merz.

[email protected]

On Twitter @karioakes

Hyaluronic acid fillers are a safe and effective aesthetic medicine modality, but some patients experience significant pain and bruising from dermal filler injections. Adding lidocaine may help with pain, and many clinicians also will add epinephrine to filler injections, believing they’ll achieve even less pain and mitigate bruising because of epinephrine’s vasoconstrictive effects.

However, quality evidence is lacking to support the addition of epinephrine, according to Dr. Amir Moradi, a facial plastic and reconstructive surgeon in private practice in San Diego. He conducted a split-face study that found no benefit from adding epinephrine to hyaluronic acid injections, and presented his results at the Summit in Aesthetic Medicine in Dana Point, Calif.

The study enrolled 30 patients in a double-blind, split-face comparison study of the hyaluronic acid filler Belotero (BEL) alone to Belotero with lidocaine (BEL-L), and to Belotero with lidocaine and epinephrine (BEL-LE). Patients received superficial to mid-dermal injections for perioral lines, and investigators obtained pretreatment photos and assessed wrinkle severity on the 5-point Merz scale.

Patients were allocated randomly and equally to treatment arms, so that 10 received BEL and BEL-L, 10 received BEL and BEL-LE, and 10 received BEL-L and BEL-LE. Each patient received a maximum of 1 mL of filler on each side of the face. An assistant prepared syringes in a manner that made them indistinguishable, so the operator and patient were blinded to treatment arm. All patients received massage and ice to the perioral area immediately after treatment.

Investigators asked patients to report the pain they experienced during injections on a 10-point Likert scale immediately after their injections were complete. Bruising was assessed by the physician investigator, by another blinded evaluator, and by the patients themselves pretreatment, and on days 1, 7, and 14 after injections. Because no validated standardized bruising scale exists, the investigators devised a scale of 0-3 to describe mild, moderate, and severe bruising according to the visibility and size of the discolored areas.

Contrary to anecdotal reports and against the investigators’ expectations, patients saw no significant difference in either pain or bruising with the addition of lidocaine, with or without epinephrine, to the hyaluronic acid dermal filler. Patients in all treatment arms generally had the worst bruising at day 1, with a resolution by about half at day 7, and bruising gone or nearly gone by day 14.

Calling for more and larger studies in this field, Dr. Moradi noted that the “limited benefit of lidocaine could be due to not waiting long enough for lidocaine to fully take effect.”

For pain, Dr. Moradi said in an interview, “How and when you ask the question really makes a difference. Because if you wait even 30 seconds afterward, it can change the answer.” He noted that his results showed no improvement in pain with lidocaine compared with hyaluronic acid alone. He plans further investigation using an assessment method that will allow patients to report pain during injections.

Planning more study into whether lidocaine, alone or with epinephrine, helps pain and bruising, Dr. Moradi expects to see some benefit for the adjuncts when a physician needs to go back and reinject an area. However, the field needs more well-designed studies with standardized assessments, he said. “We need to look at what the evidence says,”

Dr. Moradi reports that he has financial disclosures related to Allergan, Galderma, and Merz.

[email protected]

On Twitter @karioakes

GAITHERSBURG, MD. – The biologic agent mepolizumab was unanimously recommended for approval as a treatment for severe asthma in adults at a June 4 meeting of the Food and Drug Administration’s Pulmonary-Allergy Drugs Advisory Committee.

All 14 members of the advisory panel agreed that the efficacy data provide substantial evidence of a clinically meaningful benefit of mepolizumab for the treatment of severe asthma in adults; 13 of the 14 members agreed that the data adequately demonstrated safety in adults. However, only four panel members recommended approval for adolescents aged 12-17 years, with the majority of panel members citing concerns that the low number of adolescents studied to date did not allow safety to be adequately evaluated in a younger population, especially for a medication that would be taken for many years – perhaps for a lifetime.

If approved by the FDA, the biologic agent would be available as a once-monthly treatment that is injected subcutaneously by a health care professional. Mepolizumab would be marketed by Glaxo Smith Kline under the trade name Nucala. Mepolizumab is a first-in-class humanized monoclonal antibody that targets interleukin-5, a glycoprotein cytokine that mediates production of eosinophils. Elevation of eosinophils in blood and tissue is associated with an increase in cytokines and other inflammatory molecules that can trigger or exacerbate airway inflammation in asthma. One other monoclonal antibody, the anti-IgE biologic omulizimab (Xolair), has been approved to treat asthma. Glaxo Smith Kline brought mepolizumab to the FDA for use as an add-on therapy for the small subset of asthma patients whose disease remains uncontrolled despite the optimal use of inhaled corticosteroids and additional therapies such as leukotriene inhibitors or theophylline. This population experiences more frequent asthma exacerbations, has more emergency department visits and hospitalizations, and uses higher doses of oral corticosteroids. Approximately 60% of those with severe asthma have marked eosinophilia.Panel members uniformly cited the efficacy data for adults with severe asthma; several panelists also remarked on the importance of developing more steroid-sparing alternatives for this population.

The panel endorsed neither efficacy nor safety for those aged 12-17 years, with 9 of the 14 panelists voting not to endorse efficacy and 13 members voting not to endorse safety findings. Mepolizumab’s efficacy, many panelists said, was not clearly established from the data presented, which drew from small numbers of adolescents enrolled in the studies.

Dr. David Au, acting director of Health Services Research and Development at Seattle’s VA Puget Sound Health Care system, observed that “adolescents are not small adults – their lungs continue to mature over time.” Many panelists, however, also called for ongoing study, noting the significant unmet need for steroid alternatives in the adolescent population.

Several panelists advocated postmarketing surveillance for long-term use, with particular attention to those with parasitic disease, to monitoring any sign of malignancy, and to tracking opportunistic diseases such as herpes zoster.

An early clinical trial of mepolizumab, conducted in 1999, failed to show benefit for an undifferentiated population of patients with moderate to severe asthma. However, independent research later identified marked eosinophilia as a factor associated with more frequent asthma exacerbations and a series of clinical trials begun in 2011 targeted patients with severe asthma and eosinophilic inflammation. A global program was initiated, with 12% of patients overall coming from the United States.

Pivotal phase 2b/3, double blind, placebo-controlled clinical trials included a dose-ranging study tracking asthma exacerbations enrolling 616 patients for 52 weeks.

The recommended dose of 100 mg subcutaneously every 4 weeks, as well as a 75-mg IV dose, was used for an additional 576 patients for 32 weeks, with the primary outcome measure being the number of asthma exacerbations. A final 24-week study of 135 patients with severe asthma measured the reduction in oral corticosteroid use, compared with placebo, as well as the number of asthma exacerbations. In all of the studies, patients’ asthma treatment was optimized according to standard of care before adding mepolizumab.

In each study and in pooled data, mepolizumab approximately halved the number of asthma exacerbations for study participants when compared with those using placebo. A 24-week corticosteroid-sparing study showed significant reduction in oral corticosteroid use, without loss of asthma control, for the mepolizumab group. Prespecified subgroup analyses were hampered because of low participation numbers for African Americans and adolescents, and because confidence intervals for these subgroups often ranged over 1, limiting interpretation of benefit results for these groups. The overall safety profile was good, with adverse event rates similar in the treatment and placebo arms. Headache and injection-site reactions were the most commonly reported adverse events but were similar between treatment and placebo arms. No episodes of anaphylaxis were reported, and neutralizing antibodies developed in one patient total across all studies. Ongoing open-label studies continue.The FDA’s independent biostatistical analysis showed clear evidence of efficacy for mepolizumab, with demonstrated consistent, statistically significant decreases of about one exacerbation per year, according to the agency.In its analysis, the agency observed a positive association between higher eosinophil count and mepolizumab treatment effect, meaning that those with higher eosinophil counts saw a greater benefit from mepolizumab, as measured by a reduction in exacerbations.

The number of deaths was balanced across treatment arms, though a larger number of respiratory-related deaths than expected was seen overall. This higher number of deaths may reflect the severity of asthma in the study population. The respiratory-related serious adverse events, according to the FDA, favor treatment over placebo.

No treatment-related cardiovascular risks were identified.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists reported no relevant conflicts of interest.

GAITHERSBURG, MD. – The biologic agent mepolizumab was unanimously recommended for approval as a treatment for severe asthma in adults at a June 4 meeting of the Food and Drug Administration’s Pulmonary-Allergy Drugs Advisory Committee.

All 14 members of the advisory panel agreed that the efficacy data provide substantial evidence of a clinically meaningful benefit of mepolizumab for the treatment of severe asthma in adults; 13 of the 14 members agreed that the data adequately demonstrated safety in adults. However, only four panel members recommended approval for adolescents aged 12-17 years, with the majority of panel members citing concerns that the low number of adolescents studied to date did not allow safety to be adequately evaluated in a younger population, especially for a medication that would be taken for many years – perhaps for a lifetime.

If approved by the FDA, the biologic agent would be available as a once-monthly treatment that is injected subcutaneously by a health care professional. Mepolizumab would be marketed by Glaxo Smith Kline under the trade name Nucala. Mepolizumab is a first-in-class humanized monoclonal antibody that targets interleukin-5, a glycoprotein cytokine that mediates production of eosinophils. Elevation of eosinophils in blood and tissue is associated with an increase in cytokines and other inflammatory molecules that can trigger or exacerbate airway inflammation in asthma. One other monoclonal antibody, the anti-IgE biologic omulizimab (Xolair), has been approved to treat asthma. Glaxo Smith Kline brought mepolizumab to the FDA for use as an add-on therapy for the small subset of asthma patients whose disease remains uncontrolled despite the optimal use of inhaled corticosteroids and additional therapies such as leukotriene inhibitors or theophylline. This population experiences more frequent asthma exacerbations, has more emergency department visits and hospitalizations, and uses higher doses of oral corticosteroids. Approximately 60% of those with severe asthma have marked eosinophilia.Panel members uniformly cited the efficacy data for adults with severe asthma; several panelists also remarked on the importance of developing more steroid-sparing alternatives for this population.

The panel endorsed neither efficacy nor safety for those aged 12-17 years, with 9 of the 14 panelists voting not to endorse efficacy and 13 members voting not to endorse safety findings. Mepolizumab’s efficacy, many panelists said, was not clearly established from the data presented, which drew from small numbers of adolescents enrolled in the studies.

Dr. David Au, acting director of Health Services Research and Development at Seattle’s VA Puget Sound Health Care system, observed that “adolescents are not small adults – their lungs continue to mature over time.” Many panelists, however, also called for ongoing study, noting the significant unmet need for steroid alternatives in the adolescent population.

Several panelists advocated postmarketing surveillance for long-term use, with particular attention to those with parasitic disease, to monitoring any sign of malignancy, and to tracking opportunistic diseases such as herpes zoster.

An early clinical trial of mepolizumab, conducted in 1999, failed to show benefit for an undifferentiated population of patients with moderate to severe asthma. However, independent research later identified marked eosinophilia as a factor associated with more frequent asthma exacerbations and a series of clinical trials begun in 2011 targeted patients with severe asthma and eosinophilic inflammation. A global program was initiated, with 12% of patients overall coming from the United States.

Pivotal phase 2b/3, double blind, placebo-controlled clinical trials included a dose-ranging study tracking asthma exacerbations enrolling 616 patients for 52 weeks.

The recommended dose of 100 mg subcutaneously every 4 weeks, as well as a 75-mg IV dose, was used for an additional 576 patients for 32 weeks, with the primary outcome measure being the number of asthma exacerbations. A final 24-week study of 135 patients with severe asthma measured the reduction in oral corticosteroid use, compared with placebo, as well as the number of asthma exacerbations. In all of the studies, patients’ asthma treatment was optimized according to standard of care before adding mepolizumab.

In each study and in pooled data, mepolizumab approximately halved the number of asthma exacerbations for study participants when compared with those using placebo. A 24-week corticosteroid-sparing study showed significant reduction in oral corticosteroid use, without loss of asthma control, for the mepolizumab group. Prespecified subgroup analyses were hampered because of low participation numbers for African Americans and adolescents, and because confidence intervals for these subgroups often ranged over 1, limiting interpretation of benefit results for these groups. The overall safety profile was good, with adverse event rates similar in the treatment and placebo arms. Headache and injection-site reactions were the most commonly reported adverse events but were similar between treatment and placebo arms. No episodes of anaphylaxis were reported, and neutralizing antibodies developed in one patient total across all studies. Ongoing open-label studies continue.The FDA’s independent biostatistical analysis showed clear evidence of efficacy for mepolizumab, with demonstrated consistent, statistically significant decreases of about one exacerbation per year, according to the agency.In its analysis, the agency observed a positive association between higher eosinophil count and mepolizumab treatment effect, meaning that those with higher eosinophil counts saw a greater benefit from mepolizumab, as measured by a reduction in exacerbations.

The number of deaths was balanced across treatment arms, though a larger number of respiratory-related deaths than expected was seen overall. This higher number of deaths may reflect the severity of asthma in the study population. The respiratory-related serious adverse events, according to the FDA, favor treatment over placebo.

No treatment-related cardiovascular risks were identified.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists reported no relevant conflicts of interest.

GAITHERSBURG, MD. – The biologic agent mepolizumab was unanimously recommended for approval as a treatment for severe asthma in adults at a June 4 meeting of the Food and Drug Administration’s Pulmonary-Allergy Drugs Advisory Committee.

All 14 members of the advisory panel agreed that the efficacy data provide substantial evidence of a clinically meaningful benefit of mepolizumab for the treatment of severe asthma in adults; 13 of the 14 members agreed that the data adequately demonstrated safety in adults. However, only four panel members recommended approval for adolescents aged 12-17 years, with the majority of panel members citing concerns that the low number of adolescents studied to date did not allow safety to be adequately evaluated in a younger population, especially for a medication that would be taken for many years – perhaps for a lifetime.

If approved by the FDA, the biologic agent would be available as a once-monthly treatment that is injected subcutaneously by a health care professional. Mepolizumab would be marketed by Glaxo Smith Kline under the trade name Nucala. Mepolizumab is a first-in-class humanized monoclonal antibody that targets interleukin-5, a glycoprotein cytokine that mediates production of eosinophils. Elevation of eosinophils in blood and tissue is associated with an increase in cytokines and other inflammatory molecules that can trigger or exacerbate airway inflammation in asthma. One other monoclonal antibody, the anti-IgE biologic omulizimab (Xolair), has been approved to treat asthma. Glaxo Smith Kline brought mepolizumab to the FDA for use as an add-on therapy for the small subset of asthma patients whose disease remains uncontrolled despite the optimal use of inhaled corticosteroids and additional therapies such as leukotriene inhibitors or theophylline. This population experiences more frequent asthma exacerbations, has more emergency department visits and hospitalizations, and uses higher doses of oral corticosteroids. Approximately 60% of those with severe asthma have marked eosinophilia.Panel members uniformly cited the efficacy data for adults with severe asthma; several panelists also remarked on the importance of developing more steroid-sparing alternatives for this population.

The panel endorsed neither efficacy nor safety for those aged 12-17 years, with 9 of the 14 panelists voting not to endorse efficacy and 13 members voting not to endorse safety findings. Mepolizumab’s efficacy, many panelists said, was not clearly established from the data presented, which drew from small numbers of adolescents enrolled in the studies.

Dr. David Au, acting director of Health Services Research and Development at Seattle’s VA Puget Sound Health Care system, observed that “adolescents are not small adults – their lungs continue to mature over time.” Many panelists, however, also called for ongoing study, noting the significant unmet need for steroid alternatives in the adolescent population.

Several panelists advocated postmarketing surveillance for long-term use, with particular attention to those with parasitic disease, to monitoring any sign of malignancy, and to tracking opportunistic diseases such as herpes zoster.

An early clinical trial of mepolizumab, conducted in 1999, failed to show benefit for an undifferentiated population of patients with moderate to severe asthma. However, independent research later identified marked eosinophilia as a factor associated with more frequent asthma exacerbations and a series of clinical trials begun in 2011 targeted patients with severe asthma and eosinophilic inflammation. A global program was initiated, with 12% of patients overall coming from the United States.

Pivotal phase 2b/3, double blind, placebo-controlled clinical trials included a dose-ranging study tracking asthma exacerbations enrolling 616 patients for 52 weeks.

The recommended dose of 100 mg subcutaneously every 4 weeks, as well as a 75-mg IV dose, was used for an additional 576 patients for 32 weeks, with the primary outcome measure being the number of asthma exacerbations. A final 24-week study of 135 patients with severe asthma measured the reduction in oral corticosteroid use, compared with placebo, as well as the number of asthma exacerbations. In all of the studies, patients’ asthma treatment was optimized according to standard of care before adding mepolizumab.

In each study and in pooled data, mepolizumab approximately halved the number of asthma exacerbations for study participants when compared with those using placebo. A 24-week corticosteroid-sparing study showed significant reduction in oral corticosteroid use, without loss of asthma control, for the mepolizumab group. Prespecified subgroup analyses were hampered because of low participation numbers for African Americans and adolescents, and because confidence intervals for these subgroups often ranged over 1, limiting interpretation of benefit results for these groups. The overall safety profile was good, with adverse event rates similar in the treatment and placebo arms. Headache and injection-site reactions were the most commonly reported adverse events but were similar between treatment and placebo arms. No episodes of anaphylaxis were reported, and neutralizing antibodies developed in one patient total across all studies. Ongoing open-label studies continue.The FDA’s independent biostatistical analysis showed clear evidence of efficacy for mepolizumab, with demonstrated consistent, statistically significant decreases of about one exacerbation per year, according to the agency.In its analysis, the agency observed a positive association between higher eosinophil count and mepolizumab treatment effect, meaning that those with higher eosinophil counts saw a greater benefit from mepolizumab, as measured by a reduction in exacerbations.

The number of deaths was balanced across treatment arms, though a larger number of respiratory-related deaths than expected was seen overall. This higher number of deaths may reflect the severity of asthma in the study population. The respiratory-related serious adverse events, according to the FDA, favor treatment over placebo.

No treatment-related cardiovascular risks were identified.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists reported no relevant conflicts of interest.

GAITHERSBURG, MD. – The biologic agent mepolizumab was unanimously recommended for approval as a treatment for severe asthma in adults at a June 4 meeting of the Food and Drug Administration’s Pulmonary-Allergy Drugs Advisory Committee.

All 14 members of the advisory panel agreed that the efficacy data provide substantial evidence of a clinically meaningful benefit of mepolizumab for the treatment of severe asthma in adults; 13 of the 14 members agreed that the data adequately demonstrated safety in adults. However, only four panel members recommended approval for adolescents aged 12-17 years, with the majority of panel members citing concerns that the low number of adolescents studied to date did not allow safety to be adequately evaluated in a younger population, especially for a medication that would be taken for many years – perhaps for a lifetime.

If approved by the FDA, the biologic agent would be available as a once-monthly treatment that is injected subcutaneously by a health care professional. Mepolizumab would be marketed by Glaxo Smith Kline under the trade name Nucala. Mepolizumab is a first-in-class humanized monoclonal antibody that targets interleukin-5, a glycoprotein cytokine that mediates production of eosinophils. Elevation of eosinophils in blood and tissue is associated with an increase in cytokines and other inflammatory molecules that can trigger or exacerbate airway inflammation in asthma. One other monoclonal antibody, the anti-IgE biologic omulizimab (Xolair), has been approved to treat asthma. Glaxo Smith Kline brought mepolizumab to the FDA for use as an add-on therapy for the small subset of asthma patients whose disease remains uncontrolled despite the optimal use of inhaled corticosteroids and additional therapies such as leukotriene inhibitors or theophylline. This population experiences more frequent asthma exacerbations, has more emergency department visits and hospitalizations, and uses higher doses of oral corticosteroids. Approximately 60% of those with severe asthma have marked eosinophilia.Panel members uniformly cited the efficacy data for adults with severe asthma; several panelists also remarked on the importance of developing more steroid-sparing alternatives for this population.

The panel endorsed neither efficacy nor safety for those aged 12-17 years, with 9 of the 14 panelists voting not to endorse efficacy and 13 members voting not to endorse safety findings. Mepolizumab’s efficacy, many panelists said, was not clearly established from the data presented, which drew from small numbers of adolescents enrolled in the studies.

Dr. David Au, acting director of Health Services Research and Development at Seattle’s VA Puget Sound Health Care system, observed that “adolescents are not small adults – their lungs continue to mature over time.” Many panelists, however, also called for ongoing study, noting the significant unmet need for steroid alternatives in the adolescent population.

Several panelists advocated postmarketing surveillance for long-term use, with particular attention to those with parasitic disease, to monitoring any sign of malignancy, and to tracking opportunistic diseases such as herpes zoster.

An early clinical trial of mepolizumab, conducted in 1999, failed to show benefit for an undifferentiated population of patients with moderate to severe asthma. However, independent research later identified marked eosinophilia as a factor associated with more frequent asthma exacerbations and a series of clinical trials begun in 2011 targeted patients with severe asthma and eosinophilic inflammation. A global program was initiated, with 12% of patients overall coming from the United States.

Pivotal phase 2b/3, double blind, placebo-controlled clinical trials included a dose-ranging study tracking asthma exacerbations enrolling 616 patients for 52 weeks.

The recommended dose of 100 mg subcutaneously every 4 weeks, as well as a 75-mg IV dose, was used for an additional 576 patients for 32 weeks, with the primary outcome measure being the number of asthma exacerbations. A final 24-week study of 135 patients with severe asthma measured the reduction in oral corticosteroid use, compared with placebo, as well as the number of asthma exacerbations. In all of the studies, patients’ asthma treatment was optimized according to standard of care before adding mepolizumab.

In each study and in pooled data, mepolizumab approximately halved the number of asthma exacerbations for study participants when compared with those using placebo. A 24-week corticosteroid-sparing study showed significant reduction in oral corticosteroid use, without loss of asthma control, for the mepolizumab group. Prespecified subgroup analyses were hampered because of low participation numbers for African Americans and adolescents, and because confidence intervals for these subgroups often ranged over 1, limiting interpretation of benefit results for these groups. The overall safety profile was good, with adverse event rates similar in the treatment and placebo arms. Headache and injection-site reactions were the most commonly reported adverse events but were similar between treatment and placebo arms. No episodes of anaphylaxis were reported, and neutralizing antibodies developed in one patient total across all studies. Ongoing open-label studies continue.The FDA’s independent biostatistical analysis showed clear evidence of efficacy for mepolizumab, with demonstrated consistent, statistically significant decreases of about one exacerbation per year, according to the agency.In its analysis, the agency observed a positive association between higher eosinophil count and mepolizumab treatment effect, meaning that those with higher eosinophil counts saw a greater benefit from mepolizumab, as measured by a reduction in exacerbations.

The number of deaths was balanced across treatment arms, though a larger number of respiratory-related deaths than expected was seen overall. This higher number of deaths may reflect the severity of asthma in the study population. The respiratory-related serious adverse events, according to the FDA, favor treatment over placebo.

No treatment-related cardiovascular risks were identified.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists reported no relevant conflicts of interest.

GAITHERSBURG, MD. – The biologic agent mepolizumab was unanimously recommended for approval as a treatment for severe asthma in adults at a June 4 meeting of the Food and Drug Administration’s Pulmonary-Allergy Drugs Advisory Committee.

All 14 members of the advisory panel agreed that the efficacy data provide substantial evidence of a clinically meaningful benefit of mepolizumab for the treatment of severe asthma in adults; 13 of the 14 members agreed that the data adequately demonstrated safety in adults. However, only four panel members recommended approval for adolescents aged 12-17 years, with the majority of panel members citing concerns that the low number of adolescents studied to date did not allow safety to be adequately evaluated in a younger population, especially for a medication that would be taken for many years – perhaps for a lifetime.

If approved by the FDA, the biologic agent would be available as a once-monthly treatment that is injected subcutaneously by a health care professional. Mepolizumab would be marketed by Glaxo Smith Kline under the trade name Nucala. Mepolizumab is a first-in-class humanized monoclonal antibody that targets interleukin-5, a glycoprotein cytokine that mediates production of eosinophils. Elevation of eosinophils in blood and tissue is associated with an increase in cytokines and other inflammatory molecules that can trigger or exacerbate airway inflammation in asthma. One other monoclonal antibody, the anti-IgE biologic omulizimab (Xolair), has been approved to treat asthma. Glaxo Smith Kline brought mepolizumab to the FDA for use as an add-on therapy for the small subset of asthma patients whose disease remains uncontrolled despite the optimal use of inhaled corticosteroids and additional therapies such as leukotriene inhibitors or theophylline. This population experiences more frequent asthma exacerbations, has more emergency department visits and hospitalizations, and uses higher doses of oral corticosteroids. Approximately 60% of those with severe asthma have marked eosinophilia.Panel members uniformly cited the efficacy data for adults with severe asthma; several panelists also remarked on the importance of developing more steroid-sparing alternatives for this population.

The panel endorsed neither efficacy nor safety for those aged 12-17 years, with 9 of the 14 panelists voting not to endorse efficacy and 13 members voting not to endorse safety findings. Mepolizumab’s efficacy, many panelists said, was not clearly established from the data presented, which drew from small numbers of adolescents enrolled in the studies.

Dr. David Au, acting director of Health Services Research and Development at Seattle’s VA Puget Sound Health Care system, observed that “adolescents are not small adults – their lungs continue to mature over time.” Many panelists, however, also called for ongoing study, noting the significant unmet need for steroid alternatives in the adolescent population.

Several panelists advocated postmarketing surveillance for long-term use, with particular attention to those with parasitic disease, to monitoring any sign of malignancy, and to tracking opportunistic diseases such as herpes zoster.

An early clinical trial of mepolizumab, conducted in 1999, failed to show benefit for an undifferentiated population of patients with moderate to severe asthma. However, independent research later identified marked eosinophilia as a factor associated with more frequent asthma exacerbations and a series of clinical trials begun in 2011 targeted patients with severe asthma and eosinophilic inflammation. A global program was initiated, with 12% of patients overall coming from the United States.

Pivotal phase 2b/3, double blind, placebo-controlled clinical trials included a dose-ranging study tracking asthma exacerbations enrolling 616 patients for 52 weeks.

The recommended dose of 100 mg subcutaneously every 4 weeks, as well as a 75-mg IV dose, was used for an additional 576 patients for 32 weeks, with the primary outcome measure being the number of asthma exacerbations. A final 24-week study of 135 patients with severe asthma measured the reduction in oral corticosteroid use, compared with placebo, as well as the number of asthma exacerbations. In all of the studies, patients’ asthma treatment was optimized according to standard of care before adding mepolizumab.

In each study and in pooled data, mepolizumab approximately halved the number of asthma exacerbations for study participants when compared with those using placebo. A 24-week corticosteroid-sparing study showed significant reduction in oral corticosteroid use, without loss of asthma control, for the mepolizumab group. Prespecified subgroup analyses were hampered because of low participation numbers for African Americans and adolescents, and because confidence intervals for these subgroups often ranged over 1, limiting interpretation of benefit results for these groups. The overall safety profile was good, with adverse event rates similar in the treatment and placebo arms. Headache and injection-site reactions were the most commonly reported adverse events but were similar between treatment and placebo arms. No episodes of anaphylaxis were reported, and neutralizing antibodies developed in one patient total across all studies. Ongoing open-label studies continue.The FDA’s independent biostatistical analysis showed clear evidence of efficacy for mepolizumab, with demonstrated consistent, statistically significant decreases of about one exacerbation per year, according to the agency.In its analysis, the agency observed a positive association between higher eosinophil count and mepolizumab treatment effect, meaning that those with higher eosinophil counts saw a greater benefit from mepolizumab, as measured by a reduction in exacerbations.

The number of deaths was balanced across treatment arms, though a larger number of respiratory-related deaths than expected was seen overall. This higher number of deaths may reflect the severity of asthma in the study population. The respiratory-related serious adverse events, according to the FDA, favor treatment over placebo.

No treatment-related cardiovascular risks were identified.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists reported no relevant conflicts of interest.

GAITHERSBURG, MD. – The biologic agent mepolizumab was unanimously recommended for approval as a treatment for severe asthma in adults at a June 4 meeting of the Food and Drug Administration’s Pulmonary-Allergy Drugs Advisory Committee.

All 14 members of the advisory panel agreed that the efficacy data provide substantial evidence of a clinically meaningful benefit of mepolizumab for the treatment of severe asthma in adults; 13 of the 14 members agreed that the data adequately demonstrated safety in adults. However, only four panel members recommended approval for adolescents aged 12-17 years, with the majority of panel members citing concerns that the low number of adolescents studied to date did not allow safety to be adequately evaluated in a younger population, especially for a medication that would be taken for many years – perhaps for a lifetime.

If approved by the FDA, the biologic agent would be available as a once-monthly treatment that is injected subcutaneously by a health care professional. Mepolizumab would be marketed by Glaxo Smith Kline under the trade name Nucala. Mepolizumab is a first-in-class humanized monoclonal antibody that targets interleukin-5, a glycoprotein cytokine that mediates production of eosinophils. Elevation of eosinophils in blood and tissue is associated with an increase in cytokines and other inflammatory molecules that can trigger or exacerbate airway inflammation in asthma. One other monoclonal antibody, the anti-IgE biologic omulizimab (Xolair), has been approved to treat asthma. Glaxo Smith Kline brought mepolizumab to the FDA for use as an add-on therapy for the small subset of asthma patients whose disease remains uncontrolled despite the optimal use of inhaled corticosteroids and additional therapies such as leukotriene inhibitors or theophylline. This population experiences more frequent asthma exacerbations, has more emergency department visits and hospitalizations, and uses higher doses of oral corticosteroids. Approximately 60% of those with severe asthma have marked eosinophilia.Panel members uniformly cited the efficacy data for adults with severe asthma; several panelists also remarked on the importance of developing more steroid-sparing alternatives for this population.

The panel endorsed neither efficacy nor safety for those aged 12-17 years, with 9 of the 14 panelists voting not to endorse efficacy and 13 members voting not to endorse safety findings. Mepolizumab’s efficacy, many panelists said, was not clearly established from the data presented, which drew from small numbers of adolescents enrolled in the studies.

Dr. David Au, acting director of Health Services Research and Development at Seattle’s VA Puget Sound Health Care system, observed that “adolescents are not small adults – their lungs continue to mature over time.” Many panelists, however, also called for ongoing study, noting the significant unmet need for steroid alternatives in the adolescent population.

Several panelists advocated postmarketing surveillance for long-term use, with particular attention to those with parasitic disease, to monitoring any sign of malignancy, and to tracking opportunistic diseases such as herpes zoster.

An early clinical trial of mepolizumab, conducted in 1999, failed to show benefit for an undifferentiated population of patients with moderate to severe asthma. However, independent research later identified marked eosinophilia as a factor associated with more frequent asthma exacerbations and a series of clinical trials begun in 2011 targeted patients with severe asthma and eosinophilic inflammation. A global program was initiated, with 12% of patients overall coming from the United States.

Pivotal phase 2b/3, double blind, placebo-controlled clinical trials included a dose-ranging study tracking asthma exacerbations enrolling 616 patients for 52 weeks.

The recommended dose of 100 mg subcutaneously every 4 weeks, as well as a 75-mg IV dose, was used for an additional 576 patients for 32 weeks, with the primary outcome measure being the number of asthma exacerbations. A final 24-week study of 135 patients with severe asthma measured the reduction in oral corticosteroid use, compared with placebo, as well as the number of asthma exacerbations. In all of the studies, patients’ asthma treatment was optimized according to standard of care before adding mepolizumab.

In each study and in pooled data, mepolizumab approximately halved the number of asthma exacerbations for study participants when compared with those using placebo. A 24-week corticosteroid-sparing study showed significant reduction in oral corticosteroid use, without loss of asthma control, for the mepolizumab group. Prespecified subgroup analyses were hampered because of low participation numbers for African Americans and adolescents, and because confidence intervals for these subgroups often ranged over 1, limiting interpretation of benefit results for these groups. The overall safety profile was good, with adverse event rates similar in the treatment and placebo arms. Headache and injection-site reactions were the most commonly reported adverse events but were similar between treatment and placebo arms. No episodes of anaphylaxis were reported, and neutralizing antibodies developed in one patient total across all studies. Ongoing open-label studies continue.The FDA’s independent biostatistical analysis showed clear evidence of efficacy for mepolizumab, with demonstrated consistent, statistically significant decreases of about one exacerbation per year, according to the agency.In its analysis, the agency observed a positive association between higher eosinophil count and mepolizumab treatment effect, meaning that those with higher eosinophil counts saw a greater benefit from mepolizumab, as measured by a reduction in exacerbations.

The number of deaths was balanced across treatment arms, though a larger number of respiratory-related deaths than expected was seen overall. This higher number of deaths may reflect the severity of asthma in the study population. The respiratory-related serious adverse events, according to the FDA, favor treatment over placebo.

No treatment-related cardiovascular risks were identified.

The FDA usually follows the recommendations of its advisory panels. The FDA panelists reported no relevant conflicts of interest.

Ketamine, in use as an anesthetic since the 1960s, shows promise for a new indication – rapid and durable improvement in treatment-resistant depression. Its effects on depression and anxiety might be attributable to activation of a brain region known as the infralimbic prefrontal cortex, a study published online June 8 suggested.

The precise mechanism by which ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, improves treatment-resistant depression has not been identified, though the prefrontal cortex is thought to play a role in modulating depression. Reporting their findings online in the Proceedings of the National Academy of Sciences, Dr. Manabu Fuchikami and his colleagues targeted the infralimbic prefrontal cortex (IL-PFC) for selective activation by ketamine and by optogenetic stimulation.

Dr. Fuchikami of the department of psychiatry at Yale University in New Haven, Conn., and his coinvestigators placed microinfusions of ketamine into several different areas of the prefrontal cortex of rat subjects. Control rats received infusions of muscimol, a chemical that inactivates neurons in these brain regions, before receiving ketamine (Proc. Natl. Acad. Sci. U.S.A. 2015 June 8 [doi:10.1073/pnas.1414728112]).

After ketamine microinfusion with or without muscimol, the rodents underwent behavioral testing to assess the degree of depression or anxiety they displayed in situations of stress. The rats whose IL-PFC regions were activated by ketamine showed significantly less depression and anxiety (P < 0.05) as measured by the behavioral testing.

Confirmation that IL-PFC activation is responsible for ketamine’s antidepressant effects in the rat subjects was provided by optogenetic testing. In optogenetics, a molecule that causes neuronal activation in response to light of a particular wavelength is inserted into specific cells, in this case, by means of a customized virus. These neurons can then be activated selectively with pulsating light. “We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects,” said Dr. Fuchikami and colleagues.

The IL-PFC optogenetic stimulation group was compared with a control group receiving light without optogenetic stimulation. A separate group of rats received optogenetic stimulation of a different brain region, the prelimbic prefrontal cortex (PrL-PFC). The IL-PFC stimulation group saw significant anxiolytic and antidepressant effects, compared with the control group (range, P = 0.037; P < 0.01 for various behavioral tests). No significant changes were seen in the PrL-PFC treatment group, compared with controls.

The synaptic responses seen with optogenetic stimulation of the IL-PFC also were similar to those seen when ketamine was systemically administered. “IL-PFC stimulation is necessary and sufficient for the antidepressant behavioral actions of ketamine,” the researchers said.

The study was supported by the National Institute of Mental Health, Yale University, and the state of Connecticut. The authors reported no conflicts of interest.

Ketamine, in use as an anesthetic since the 1960s, shows promise for a new indication – rapid and durable improvement in treatment-resistant depression. Its effects on depression and anxiety might be attributable to activation of a brain region known as the infralimbic prefrontal cortex, a study published online June 8 suggested.

The precise mechanism by which ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, improves treatment-resistant depression has not been identified, though the prefrontal cortex is thought to play a role in modulating depression. Reporting their findings online in the Proceedings of the National Academy of Sciences, Dr. Manabu Fuchikami and his colleagues targeted the infralimbic prefrontal cortex (IL-PFC) for selective activation by ketamine and by optogenetic stimulation.

Dr. Fuchikami of the department of psychiatry at Yale University in New Haven, Conn., and his coinvestigators placed microinfusions of ketamine into several different areas of the prefrontal cortex of rat subjects. Control rats received infusions of muscimol, a chemical that inactivates neurons in these brain regions, before receiving ketamine (Proc. Natl. Acad. Sci. U.S.A. 2015 June 8 [doi:10.1073/pnas.1414728112]).

After ketamine microinfusion with or without muscimol, the rodents underwent behavioral testing to assess the degree of depression or anxiety they displayed in situations of stress. The rats whose IL-PFC regions were activated by ketamine showed significantly less depression and anxiety (P < 0.05) as measured by the behavioral testing.

Confirmation that IL-PFC activation is responsible for ketamine’s antidepressant effects in the rat subjects was provided by optogenetic testing. In optogenetics, a molecule that causes neuronal activation in response to light of a particular wavelength is inserted into specific cells, in this case, by means of a customized virus. These neurons can then be activated selectively with pulsating light. “We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects,” said Dr. Fuchikami and colleagues.

The IL-PFC optogenetic stimulation group was compared with a control group receiving light without optogenetic stimulation. A separate group of rats received optogenetic stimulation of a different brain region, the prelimbic prefrontal cortex (PrL-PFC). The IL-PFC stimulation group saw significant anxiolytic and antidepressant effects, compared with the control group (range, P = 0.037; P < 0.01 for various behavioral tests). No significant changes were seen in the PrL-PFC treatment group, compared with controls.

The synaptic responses seen with optogenetic stimulation of the IL-PFC also were similar to those seen when ketamine was systemically administered. “IL-PFC stimulation is necessary and sufficient for the antidepressant behavioral actions of ketamine,” the researchers said.

The study was supported by the National Institute of Mental Health, Yale University, and the state of Connecticut. The authors reported no conflicts of interest.

Ketamine, in use as an anesthetic since the 1960s, shows promise for a new indication – rapid and durable improvement in treatment-resistant depression. Its effects on depression and anxiety might be attributable to activation of a brain region known as the infralimbic prefrontal cortex, a study published online June 8 suggested.

The precise mechanism by which ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, improves treatment-resistant depression has not been identified, though the prefrontal cortex is thought to play a role in modulating depression. Reporting their findings online in the Proceedings of the National Academy of Sciences, Dr. Manabu Fuchikami and his colleagues targeted the infralimbic prefrontal cortex (IL-PFC) for selective activation by ketamine and by optogenetic stimulation.

Dr. Fuchikami of the department of psychiatry at Yale University in New Haven, Conn., and his coinvestigators placed microinfusions of ketamine into several different areas of the prefrontal cortex of rat subjects. Control rats received infusions of muscimol, a chemical that inactivates neurons in these brain regions, before receiving ketamine (Proc. Natl. Acad. Sci. U.S.A. 2015 June 8 [doi:10.1073/pnas.1414728112]).

After ketamine microinfusion with or without muscimol, the rodents underwent behavioral testing to assess the degree of depression or anxiety they displayed in situations of stress. The rats whose IL-PFC regions were activated by ketamine showed significantly less depression and anxiety (P < 0.05) as measured by the behavioral testing.

Confirmation that IL-PFC activation is responsible for ketamine’s antidepressant effects in the rat subjects was provided by optogenetic testing. In optogenetics, a molecule that causes neuronal activation in response to light of a particular wavelength is inserted into specific cells, in this case, by means of a customized virus. These neurons can then be activated selectively with pulsating light. “We also found that optogenetic stimulation of the IL-PFC produced rapid and long-lasting antidepressant and anxiolytic effects,” said Dr. Fuchikami and colleagues.

The IL-PFC optogenetic stimulation group was compared with a control group receiving light without optogenetic stimulation. A separate group of rats received optogenetic stimulation of a different brain region, the prelimbic prefrontal cortex (PrL-PFC). The IL-PFC stimulation group saw significant anxiolytic and antidepressant effects, compared with the control group (range, P = 0.037; P < 0.01 for various behavioral tests). No significant changes were seen in the PrL-PFC treatment group, compared with controls.

The synaptic responses seen with optogenetic stimulation of the IL-PFC also were similar to those seen when ketamine was systemically administered. “IL-PFC stimulation is necessary and sufficient for the antidepressant behavioral actions of ketamine,” the researchers said.

The study was supported by the National Institute of Mental Health, Yale University, and the state of Connecticut. The authors reported no conflicts of interest.

SAN DIEGO – Routine preoperative use of genetic testing to detect mutations implicated in thyroid carcinogenesis can help guide perioperative decision making, though risks associated with mutations are not always clear-cut.

For individuals with thyroid cancer (TC), the presence of certain mutations was associated with higher risk of early recurrence of cancer as well as distant metastases, according to a recent study presented by Dr. Linwah Yip at the annual meeting of the American Surgical Association. She and her colleagues at the University of Pittsburgh built on their previous work to characterize how thyroid cancer genotype relates both to cancer histology and to disease-related outcomes.

Using data from the electronic medical record of a single institution, Dr. Yip and her colleagues examined data from consecutive patients who had initial surgery for histologically confirmed TC. Of the 1,510 patients in the study cohort, 77% were women, and patients had a mean age of 49 years. All of the cancers in the study were tested for mutations in seven genes known to be associated with thyroid carcinogenesis. Mutation testing was a routine part of preoperative care for thyroid cancer patients, often performed on preoperative fine needle aspiration (FNA) biopsy.

Outcomes tracked in the study, Dr. Yip said, included the type and stage of thyroid cancer identified and whether the cancer recurred.

Mutations were found in 1,039 patients (69%), and no more than one mutation was found in any one tumor. No tumor genotype was specifically associated with tumor size or whether the tumor was multifocal.

Overall, BRAF V600E was the most common mutation associated with TC, and patients with this mutation were the ones most likely to have a recurrence (P = .001). However, Dr. Yip noted that there is phenotypic heterogeneity in how the recurrences present. More distant metastatic disease and lateral lymph node metastases were most likely with RET/PTC1 and three mutations (P = .02).

By contrast, about 25% of thyroid cancers in the study showed mutations in RAS, PAX8/PPARG, or BRAF K601E. These mutations were associated with a more indolent disease course, with more encapsulated tumors and an overall disease-free survival of nearly 100% at 5 years after diagnosis. Dr. Yip said, “However, RAS variations can be associated with any histologic type of thyroid cancer, including anaplastic.”

Dr. Yip said that clinicians should consider conducting perioperative neck ultrasound with lymph node mapping if BRAF V600E or RET/PTC mutations are found. Her recommendation for these patients was a total thyroidectomy, with consideration of a central compartment neck dissection performed prophylactically, in light of the > 50% chance for lymph node involvement. Additionally, surveillance for distant metastases in the form of a chest CT should be considered when tumors are REC/PTC positive.

Study limitations include its retrospective nature and the fact that the treating physicians were not blinded to mutation testing results. Additionally, Dr. Yip noted, in patients with multifocal disease, only the most aggressive tumor was included.

Dr. Chris McHenry of Case Western Reserve University, Cleveland, noted in discussion that disease-specific survival was not related to mutation testing in this study. For patients with advanced thyroid cancer who have limited treatment options, however, mutation testing may help direct specific adjuvant therapies based on risk.

Dr. Nikiforov is a consultant for Quest Diagnostics. The others reported no disclosures.

The complete manuscript of this study and its presentation at the American Surgical Association’s 135th Annual Meeting, April 2015, in San Diego, California, are anticipated to be published in the Annals of Surgery pending editorial review.

SAN DIEGO – Routine preoperative use of genetic testing to detect mutations implicated in thyroid carcinogenesis can help guide perioperative decision making, though risks associated with mutations are not always clear-cut.

For individuals with thyroid cancer (TC), the presence of certain mutations was associated with higher risk of early recurrence of cancer as well as distant metastases, according to a recent study presented by Dr. Linwah Yip at the annual meeting of the American Surgical Association. She and her colleagues at the University of Pittsburgh built on their previous work to characterize how thyroid cancer genotype relates both to cancer histology and to disease-related outcomes.

Using data from the electronic medical record of a single institution, Dr. Yip and her colleagues examined data from consecutive patients who had initial surgery for histologically confirmed TC. Of the 1,510 patients in the study cohort, 77% were women, and patients had a mean age of 49 years. All of the cancers in the study were tested for mutations in seven genes known to be associated with thyroid carcinogenesis. Mutation testing was a routine part of preoperative care for thyroid cancer patients, often performed on preoperative fine needle aspiration (FNA) biopsy.

Outcomes tracked in the study, Dr. Yip said, included the type and stage of thyroid cancer identified and whether the cancer recurred.

Mutations were found in 1,039 patients (69%), and no more than one mutation was found in any one tumor. No tumor genotype was specifically associated with tumor size or whether the tumor was multifocal.

Overall, BRAF V600E was the most common mutation associated with TC, and patients with this mutation were the ones most likely to have a recurrence (P = .001). However, Dr. Yip noted that there is phenotypic heterogeneity in how the recurrences present. More distant metastatic disease and lateral lymph node metastases were most likely with RET/PTC1 and three mutations (P = .02).

By contrast, about 25% of thyroid cancers in the study showed mutations in RAS, PAX8/PPARG, or BRAF K601E. These mutations were associated with a more indolent disease course, with more encapsulated tumors and an overall disease-free survival of nearly 100% at 5 years after diagnosis. Dr. Yip said, “However, RAS variations can be associated with any histologic type of thyroid cancer, including anaplastic.”

Dr. Yip said that clinicians should consider conducting perioperative neck ultrasound with lymph node mapping if BRAF V600E or RET/PTC mutations are found. Her recommendation for these patients was a total thyroidectomy, with consideration of a central compartment neck dissection performed prophylactically, in light of the > 50% chance for lymph node involvement. Additionally, surveillance for distant metastases in the form of a chest CT should be considered when tumors are REC/PTC positive.

Study limitations include its retrospective nature and the fact that the treating physicians were not blinded to mutation testing results. Additionally, Dr. Yip noted, in patients with multifocal disease, only the most aggressive tumor was included.

Dr. Chris McHenry of Case Western Reserve University, Cleveland, noted in discussion that disease-specific survival was not related to mutation testing in this study. For patients with advanced thyroid cancer who have limited treatment options, however, mutation testing may help direct specific adjuvant therapies based on risk.

Dr. Nikiforov is a consultant for Quest Diagnostics. The others reported no disclosures.

The complete manuscript of this study and its presentation at the American Surgical Association’s 135th Annual Meeting, April 2015, in San Diego, California, are anticipated to be published in the Annals of Surgery pending editorial review.

SAN DIEGO – Routine preoperative use of genetic testing to detect mutations implicated in thyroid carcinogenesis can help guide perioperative decision making, though risks associated with mutations are not always clear-cut.

For individuals with thyroid cancer (TC), the presence of certain mutations was associated with higher risk of early recurrence of cancer as well as distant metastases, according to a recent study presented by Dr. Linwah Yip at the annual meeting of the American Surgical Association. She and her colleagues at the University of Pittsburgh built on their previous work to characterize how thyroid cancer genotype relates both to cancer histology and to disease-related outcomes.

Using data from the electronic medical record of a single institution, Dr. Yip and her colleagues examined data from consecutive patients who had initial surgery for histologically confirmed TC. Of the 1,510 patients in the study cohort, 77% were women, and patients had a mean age of 49 years. All of the cancers in the study were tested for mutations in seven genes known to be associated with thyroid carcinogenesis. Mutation testing was a routine part of preoperative care for thyroid cancer patients, often performed on preoperative fine needle aspiration (FNA) biopsy.

Outcomes tracked in the study, Dr. Yip said, included the type and stage of thyroid cancer identified and whether the cancer recurred.

Mutations were found in 1,039 patients (69%), and no more than one mutation was found in any one tumor. No tumor genotype was specifically associated with tumor size or whether the tumor was multifocal.

Overall, BRAF V600E was the most common mutation associated with TC, and patients with this mutation were the ones most likely to have a recurrence (P = .001). However, Dr. Yip noted that there is phenotypic heterogeneity in how the recurrences present. More distant metastatic disease and lateral lymph node metastases were most likely with RET/PTC1 and three mutations (P = .02).

By contrast, about 25% of thyroid cancers in the study showed mutations in RAS, PAX8/PPARG, or BRAF K601E. These mutations were associated with a more indolent disease course, with more encapsulated tumors and an overall disease-free survival of nearly 100% at 5 years after diagnosis. Dr. Yip said, “However, RAS variations can be associated with any histologic type of thyroid cancer, including anaplastic.”

Dr. Yip said that clinicians should consider conducting perioperative neck ultrasound with lymph node mapping if BRAF V600E or RET/PTC mutations are found. Her recommendation for these patients was a total thyroidectomy, with consideration of a central compartment neck dissection performed prophylactically, in light of the > 50% chance for lymph node involvement. Additionally, surveillance for distant metastases in the form of a chest CT should be considered when tumors are REC/PTC positive.

Study limitations include its retrospective nature and the fact that the treating physicians were not blinded to mutation testing results. Additionally, Dr. Yip noted, in patients with multifocal disease, only the most aggressive tumor was included.

Dr. Chris McHenry of Case Western Reserve University, Cleveland, noted in discussion that disease-specific survival was not related to mutation testing in this study. For patients with advanced thyroid cancer who have limited treatment options, however, mutation testing may help direct specific adjuvant therapies based on risk.

Dr. Nikiforov is a consultant for Quest Diagnostics. The others reported no disclosures.

The complete manuscript of this study and its presentation at the American Surgical Association’s 135th Annual Meeting, April 2015, in San Diego, California, are anticipated to be published in the Annals of Surgery pending editorial review.

For recently postmenopausal women, oral combined hormone therapy may help with symptoms of depression and anxiety. But hormone therapy did not produce any changes in cognition.

In a large, randomized controlled trial of oral and transdermal estrogens compared with each other and placebo, Carey Gleason, Ph.D., of the University of Wisconsin, Madison, and colleagues found that exogenous estrogen had no effect on cognitive performance in recently postmenopausal women over a 4-year study period. For women taking low-dose oral conjugated equine estrogens, a small to moderate improvement in some mood symptoms occurred; women receiving estrogen via a transdermal patch did not see this improvement in mood.

The results were published in PLOS Medicine (PLoS. Med. 2015;12:e1001833 [doi:10.1371/journal.pmed.1001833]).

Previous studies had shown mixed findings of the effects of menopausal hormone therapy on cognition, largely depending on whether treatment was initiated early on or later in menopause.

The 693 participants in the Kronos Early Estrogen Prevention Study - Cognitive and Affective Study (KEEPS-Cog) were a mean 52.6 years old, and the average time since the last menstrual period was 1.4 years. Enrollees were randomized to one of three study arms where they received either a 0.45 mg/day oral conjugated equine estrogen tablet, 200 mg/day cyclical progesterone capsule, and a placebo skin patch; or a 50 microgram/day transdermal estradiol patch, 200 mg/day cyclical progesterone capsule, and a placebo tablet; or a placebo tablet, capsule and patch. Treatment lasted for 4 years.

Cognitive status was measured over the 4 years using the Modified Mini-Mental State (3MS) exam and an additional battery of cognitive tests that assessed verbal learning, auditory attention and working memory, visual attention and executive function, and mental and linguistic flexibility. The Profile of Mood States (POMS) was used to evaluate mood. This test, designed to detect specific affective states in nondepressed individuals, assessed levels of tension-anxiety, depression-dejection, anger-hostility, fatigue, vigor, and confusion-bewilderment.

Dr. Gleason and her colleagues found no improvement in cognitive function with either formulation of menopausal hormone therapy.

“Contrary to our hypothesis, treatment with t-E2 [transdermal estrogen] did not improve cognition in recently postmenopausal women,” the researchers wrote.

For women taking oral estrogen, POMS subscores for tension-anxiety and depression-dejection showed significant improvement over time (for both, P < 0.001). The effect was not seen for transdermal estrogen; Dr. Gleason and her colleagues hypothesized that differences in the formulations of the two products, which resulted in different levels of estradiol versus estrone in participants, may have contributed to the result.

Most of the study’s enrollees were white women with low risk for cardiovascular disease, and most participants had at least a bachelor’s degree, so the generalizability of the KEEPS-Cog findings may be limited. Also, the study’s length and design did not permit assessment of dementia or other clinical diagnoses.

The KEEPS-Cog study, said Dr. Gleason and colleagues, can be incorporated into clinical decision making for women deciding whether to use menopausal hormone therapy. Using these results, a younger woman in good cardiovascular health “can weigh the known risks of [menopausal hormone therapy] against potential benefits for her unique symptom profile, and make an informed decision as to whether she would benefit from [menopausal hormone therapy] or whether she would prefer to manage symptoms through other means.”

The study was supported by the National Institutes of Health; the parent KEEPS trial was also supported by the Aurora Foundation. Dr. Cedars, Dr. Asthana, Dr. Santoro, and Dr. Taylor reported grant support and other financial relationships with pharmaceutical companies. The other authors reported no relevant financial disclosures.

For recently postmenopausal women, oral combined hormone therapy may help with symptoms of depression and anxiety. But hormone therapy did not produce any changes in cognition.

In a large, randomized controlled trial of oral and transdermal estrogens compared with each other and placebo, Carey Gleason, Ph.D., of the University of Wisconsin, Madison, and colleagues found that exogenous estrogen had no effect on cognitive performance in recently postmenopausal women over a 4-year study period. For women taking low-dose oral conjugated equine estrogens, a small to moderate improvement in some mood symptoms occurred; women receiving estrogen via a transdermal patch did not see this improvement in mood.

The results were published in PLOS Medicine (PLoS. Med. 2015;12:e1001833 [doi:10.1371/journal.pmed.1001833]).

Previous studies had shown mixed findings of the effects of menopausal hormone therapy on cognition, largely depending on whether treatment was initiated early on or later in menopause.

The 693 participants in the Kronos Early Estrogen Prevention Study - Cognitive and Affective Study (KEEPS-Cog) were a mean 52.6 years old, and the average time since the last menstrual period was 1.4 years. Enrollees were randomized to one of three study arms where they received either a 0.45 mg/day oral conjugated equine estrogen tablet, 200 mg/day cyclical progesterone capsule, and a placebo skin patch; or a 50 microgram/day transdermal estradiol patch, 200 mg/day cyclical progesterone capsule, and a placebo tablet; or a placebo tablet, capsule and patch. Treatment lasted for 4 years.

Cognitive status was measured over the 4 years using the Modified Mini-Mental State (3MS) exam and an additional battery of cognitive tests that assessed verbal learning, auditory attention and working memory, visual attention and executive function, and mental and linguistic flexibility. The Profile of Mood States (POMS) was used to evaluate mood. This test, designed to detect specific affective states in nondepressed individuals, assessed levels of tension-anxiety, depression-dejection, anger-hostility, fatigue, vigor, and confusion-bewilderment.

Dr. Gleason and her colleagues found no improvement in cognitive function with either formulation of menopausal hormone therapy.

“Contrary to our hypothesis, treatment with t-E2 [transdermal estrogen] did not improve cognition in recently postmenopausal women,” the researchers wrote.

For women taking oral estrogen, POMS subscores for tension-anxiety and depression-dejection showed significant improvement over time (for both, P < 0.001). The effect was not seen for transdermal estrogen; Dr. Gleason and her colleagues hypothesized that differences in the formulations of the two products, which resulted in different levels of estradiol versus estrone in participants, may have contributed to the result.

Most of the study’s enrollees were white women with low risk for cardiovascular disease, and most participants had at least a bachelor’s degree, so the generalizability of the KEEPS-Cog findings may be limited. Also, the study’s length and design did not permit assessment of dementia or other clinical diagnoses.

The KEEPS-Cog study, said Dr. Gleason and colleagues, can be incorporated into clinical decision making for women deciding whether to use menopausal hormone therapy. Using these results, a younger woman in good cardiovascular health “can weigh the known risks of [menopausal hormone therapy] against potential benefits for her unique symptom profile, and make an informed decision as to whether she would benefit from [menopausal hormone therapy] or whether she would prefer to manage symptoms through other means.”

The study was supported by the National Institutes of Health; the parent KEEPS trial was also supported by the Aurora Foundation. Dr. Cedars, Dr. Asthana, Dr. Santoro, and Dr. Taylor reported grant support and other financial relationships with pharmaceutical companies. The other authors reported no relevant financial disclosures.

For recently postmenopausal women, oral combined hormone therapy may help with symptoms of depression and anxiety. But hormone therapy did not produce any changes in cognition.

In a large, randomized controlled trial of oral and transdermal estrogens compared with each other and placebo, Carey Gleason, Ph.D., of the University of Wisconsin, Madison, and colleagues found that exogenous estrogen had no effect on cognitive performance in recently postmenopausal women over a 4-year study period. For women taking low-dose oral conjugated equine estrogens, a small to moderate improvement in some mood symptoms occurred; women receiving estrogen via a transdermal patch did not see this improvement in mood.

The results were published in PLOS Medicine (PLoS. Med. 2015;12:e1001833 [doi:10.1371/journal.pmed.1001833]).

Previous studies had shown mixed findings of the effects of menopausal hormone therapy on cognition, largely depending on whether treatment was initiated early on or later in menopause.

The 693 participants in the Kronos Early Estrogen Prevention Study - Cognitive and Affective Study (KEEPS-Cog) were a mean 52.6 years old, and the average time since the last menstrual period was 1.4 years. Enrollees were randomized to one of three study arms where they received either a 0.45 mg/day oral conjugated equine estrogen tablet, 200 mg/day cyclical progesterone capsule, and a placebo skin patch; or a 50 microgram/day transdermal estradiol patch, 200 mg/day cyclical progesterone capsule, and a placebo tablet; or a placebo tablet, capsule and patch. Treatment lasted for 4 years.

Cognitive status was measured over the 4 years using the Modified Mini-Mental State (3MS) exam and an additional battery of cognitive tests that assessed verbal learning, auditory attention and working memory, visual attention and executive function, and mental and linguistic flexibility. The Profile of Mood States (POMS) was used to evaluate mood. This test, designed to detect specific affective states in nondepressed individuals, assessed levels of tension-anxiety, depression-dejection, anger-hostility, fatigue, vigor, and confusion-bewilderment.

Dr. Gleason and her colleagues found no improvement in cognitive function with either formulation of menopausal hormone therapy.

“Contrary to our hypothesis, treatment with t-E2 [transdermal estrogen] did not improve cognition in recently postmenopausal women,” the researchers wrote.

For women taking oral estrogen, POMS subscores for tension-anxiety and depression-dejection showed significant improvement over time (for both, P < 0.001). The effect was not seen for transdermal estrogen; Dr. Gleason and her colleagues hypothesized that differences in the formulations of the two products, which resulted in different levels of estradiol versus estrone in participants, may have contributed to the result.

Most of the study’s enrollees were white women with low risk for cardiovascular disease, and most participants had at least a bachelor’s degree, so the generalizability of the KEEPS-Cog findings may be limited. Also, the study’s length and design did not permit assessment of dementia or other clinical diagnoses.

The KEEPS-Cog study, said Dr. Gleason and colleagues, can be incorporated into clinical decision making for women deciding whether to use menopausal hormone therapy. Using these results, a younger woman in good cardiovascular health “can weigh the known risks of [menopausal hormone therapy] against potential benefits for her unique symptom profile, and make an informed decision as to whether she would benefit from [menopausal hormone therapy] or whether she would prefer to manage symptoms through other means.”

The study was supported by the National Institutes of Health; the parent KEEPS trial was also supported by the Aurora Foundation. Dr. Cedars, Dr. Asthana, Dr. Santoro, and Dr. Taylor reported grant support and other financial relationships with pharmaceutical companies. The other authors reported no relevant financial disclosures.