Diana Mahoney

Major Finding: Based on a decision-support tool, nearly 21% of 2,646 clinical scenarios created from different combinations of patient-level factors were considered appropriate for evaluation for epilepsy surgery; 17% were considered uncertain for appropriateness.

Data Source: An expert panel's use of a decision-support tool.

Disclosures: Dr. Jetté reported no conflicts of interest relevant to her presentation.

BOSTON — An online decision-support tool may help to close the protracted gap between seizure onset and referral for surgery in patients with medically intractable epilepsy, based on results obtained by an expert panel.

The user-friendly tool is designed for use by all clinicians who treat epilepsy patients but who may not be epilepsy specialists, said Dr. Nathalie Jett, who developed the tool with her colleagues at the University of Calgary (Alta.).

The tool rates the appropriateness and necessity of referring individual patients for a surgery evaluation based on factors such as age, epilepsy duration, seizure type, frequency and severity of seizures, the number of adequate epilepsy drug trials, and EEG and MRI findings, said Dr. Jetté of the department of neurology at the university.

“The goal is to help neurologists and other clinicians identify which patients should be referred for epilepsy surgery evaluation, and ultimately [to facilitate] earlier surgical treatment when appropriate,” Dr. Jetté said at the annual meeting of the American Epilepsy Society.

Despite surgical success rates as high as 90% and 60%, respectively, for patients with medically intractable temporal lobe epilepsy and other partial epilepsies, the average time between seizure onset and surgery for these patients is 9 years for children and 19 years for adults, according to Dr. Jetté, who attributed the underutilization of surgery to misconceptions about the associated risks. “Epilepsy surgery is often perceived as a last resort, rather than a reasonable option early on.”

To develop the rating tool, Dr. Jetté and her colleagues used the RAND/UCLA appropriateness method, in which they performed systematic literature reviews on the epidemiology and natural history of drug-resistant epilepsy, the cost and utilization of surgery, and outcomes of surgery for partial epilepsy.

Based on the literature review and on discussion during a face-to-face meeting, an expert panel comprising adult and pediatric neurologists, epileptologists, and epilepsy surgeons rated clinical scenarios (created from the possible combinations of the aforementioned patient factors) for their appropriateness for an epilepsy surgery evaluation, Dr. Jetté said.

“The scenarios were rated on a scale from 1 to 9, where 1 was the most inappropriate and 9 was the most appropriate. After extensive discussion, all of the scenarios were re-rated, and those that were appropriate for referral [rated a 7 or higher] were re-rated for necessity.”

For the rating purposes, surgical referral was considered a necessity if the presumed benefits of referral exceeded the risks by a sufficient margin, if failing to refer the patient would be improper care, if there was a reasonable chance the referral would benefit the patient, and if the magnitude of the expected benefit “was not small,” Dr. Jetté said.

Of 2,646 clinical scenarios, nearly 21% received a rating of at least 7 and as such were considered appropriate for a surgical evaluation. About 17% were considered uncertain for appropriateness because they were rated between 4 and 6, and nearly 62% were deemed inappropriate because they were rated between 1 and 3. Fewer than 1% of the scenarios could not be classified due to lack of consensus, she reported.

In practice, a patient who has failed one antiepileptic drug (AED) would be considered inappropriate for referral, whereas a patient who has failed two AEDs and has an abnormal MRI and EEG would typically be an appropriate candidate for surgical evaluation, Dr. Jetté explained.

With respect to necessity, “none of the appropriate cases were rated as unnecessary,” although four cases were not rated due to lack of consensus. Of the remaining appropriate cases, 56% were rated as most necessary, 42% as moderately necessary, and 2% as minimally necessary, she said.

The decision support tool, which is currently being tested and refined in Canadian clinics, is expected to be available online in mid-2010.

Major Finding: Based on a decision-support tool, nearly 21% of 2,646 clinical scenarios created from different combinations of patient-level factors were considered appropriate for evaluation for epilepsy surgery; 17% were considered uncertain for appropriateness.

Data Source: An expert panel's use of a decision-support tool.

Disclosures: Dr. Jetté reported no conflicts of interest relevant to her presentation.

BOSTON — An online decision-support tool may help to close the protracted gap between seizure onset and referral for surgery in patients with medically intractable epilepsy, based on results obtained by an expert panel.

The user-friendly tool is designed for use by all clinicians who treat epilepsy patients but who may not be epilepsy specialists, said Dr. Nathalie Jett, who developed the tool with her colleagues at the University of Calgary (Alta.).

The tool rates the appropriateness and necessity of referring individual patients for a surgery evaluation based on factors such as age, epilepsy duration, seizure type, frequency and severity of seizures, the number of adequate epilepsy drug trials, and EEG and MRI findings, said Dr. Jetté of the department of neurology at the university.

“The goal is to help neurologists and other clinicians identify which patients should be referred for epilepsy surgery evaluation, and ultimately [to facilitate] earlier surgical treatment when appropriate,” Dr. Jetté said at the annual meeting of the American Epilepsy Society.

Despite surgical success rates as high as 90% and 60%, respectively, for patients with medically intractable temporal lobe epilepsy and other partial epilepsies, the average time between seizure onset and surgery for these patients is 9 years for children and 19 years for adults, according to Dr. Jetté, who attributed the underutilization of surgery to misconceptions about the associated risks. “Epilepsy surgery is often perceived as a last resort, rather than a reasonable option early on.”

To develop the rating tool, Dr. Jetté and her colleagues used the RAND/UCLA appropriateness method, in which they performed systematic literature reviews on the epidemiology and natural history of drug-resistant epilepsy, the cost and utilization of surgery, and outcomes of surgery for partial epilepsy.

Based on the literature review and on discussion during a face-to-face meeting, an expert panel comprising adult and pediatric neurologists, epileptologists, and epilepsy surgeons rated clinical scenarios (created from the possible combinations of the aforementioned patient factors) for their appropriateness for an epilepsy surgery evaluation, Dr. Jetté said.

“The scenarios were rated on a scale from 1 to 9, where 1 was the most inappropriate and 9 was the most appropriate. After extensive discussion, all of the scenarios were re-rated, and those that were appropriate for referral [rated a 7 or higher] were re-rated for necessity.”

For the rating purposes, surgical referral was considered a necessity if the presumed benefits of referral exceeded the risks by a sufficient margin, if failing to refer the patient would be improper care, if there was a reasonable chance the referral would benefit the patient, and if the magnitude of the expected benefit “was not small,” Dr. Jetté said.

Of 2,646 clinical scenarios, nearly 21% received a rating of at least 7 and as such were considered appropriate for a surgical evaluation. About 17% were considered uncertain for appropriateness because they were rated between 4 and 6, and nearly 62% were deemed inappropriate because they were rated between 1 and 3. Fewer than 1% of the scenarios could not be classified due to lack of consensus, she reported.

In practice, a patient who has failed one antiepileptic drug (AED) would be considered inappropriate for referral, whereas a patient who has failed two AEDs and has an abnormal MRI and EEG would typically be an appropriate candidate for surgical evaluation, Dr. Jetté explained.

With respect to necessity, “none of the appropriate cases were rated as unnecessary,” although four cases were not rated due to lack of consensus. Of the remaining appropriate cases, 56% were rated as most necessary, 42% as moderately necessary, and 2% as minimally necessary, she said.

The decision support tool, which is currently being tested and refined in Canadian clinics, is expected to be available online in mid-2010.

Major Finding: Based on a decision-support tool, nearly 21% of 2,646 clinical scenarios created from different combinations of patient-level factors were considered appropriate for evaluation for epilepsy surgery; 17% were considered uncertain for appropriateness.

Data Source: An expert panel's use of a decision-support tool.

Disclosures: Dr. Jetté reported no conflicts of interest relevant to her presentation.

BOSTON — An online decision-support tool may help to close the protracted gap between seizure onset and referral for surgery in patients with medically intractable epilepsy, based on results obtained by an expert panel.

The user-friendly tool is designed for use by all clinicians who treat epilepsy patients but who may not be epilepsy specialists, said Dr. Nathalie Jett, who developed the tool with her colleagues at the University of Calgary (Alta.).

The tool rates the appropriateness and necessity of referring individual patients for a surgery evaluation based on factors such as age, epilepsy duration, seizure type, frequency and severity of seizures, the number of adequate epilepsy drug trials, and EEG and MRI findings, said Dr. Jetté of the department of neurology at the university.

“The goal is to help neurologists and other clinicians identify which patients should be referred for epilepsy surgery evaluation, and ultimately [to facilitate] earlier surgical treatment when appropriate,” Dr. Jetté said at the annual meeting of the American Epilepsy Society.

Despite surgical success rates as high as 90% and 60%, respectively, for patients with medically intractable temporal lobe epilepsy and other partial epilepsies, the average time between seizure onset and surgery for these patients is 9 years for children and 19 years for adults, according to Dr. Jetté, who attributed the underutilization of surgery to misconceptions about the associated risks. “Epilepsy surgery is often perceived as a last resort, rather than a reasonable option early on.”

To develop the rating tool, Dr. Jetté and her colleagues used the RAND/UCLA appropriateness method, in which they performed systematic literature reviews on the epidemiology and natural history of drug-resistant epilepsy, the cost and utilization of surgery, and outcomes of surgery for partial epilepsy.

Based on the literature review and on discussion during a face-to-face meeting, an expert panel comprising adult and pediatric neurologists, epileptologists, and epilepsy surgeons rated clinical scenarios (created from the possible combinations of the aforementioned patient factors) for their appropriateness for an epilepsy surgery evaluation, Dr. Jetté said.

“The scenarios were rated on a scale from 1 to 9, where 1 was the most inappropriate and 9 was the most appropriate. After extensive discussion, all of the scenarios were re-rated, and those that were appropriate for referral [rated a 7 or higher] were re-rated for necessity.”

For the rating purposes, surgical referral was considered a necessity if the presumed benefits of referral exceeded the risks by a sufficient margin, if failing to refer the patient would be improper care, if there was a reasonable chance the referral would benefit the patient, and if the magnitude of the expected benefit “was not small,” Dr. Jetté said.

Of 2,646 clinical scenarios, nearly 21% received a rating of at least 7 and as such were considered appropriate for a surgical evaluation. About 17% were considered uncertain for appropriateness because they were rated between 4 and 6, and nearly 62% were deemed inappropriate because they were rated between 1 and 3. Fewer than 1% of the scenarios could not be classified due to lack of consensus, she reported.

In practice, a patient who has failed one antiepileptic drug (AED) would be considered inappropriate for referral, whereas a patient who has failed two AEDs and has an abnormal MRI and EEG would typically be an appropriate candidate for surgical evaluation, Dr. Jetté explained.

With respect to necessity, “none of the appropriate cases were rated as unnecessary,” although four cases were not rated due to lack of consensus. Of the remaining appropriate cases, 56% were rated as most necessary, 42% as moderately necessary, and 2% as minimally necessary, she said.

The decision support tool, which is currently being tested and refined in Canadian clinics, is expected to be available online in mid-2010.

BOSTON — A new consensus definition of drug-resistant epilepsy promises to improve patient care and facilitate clinical research, according to the chair of a task force appointed by the International League Against Epilepsy Commission on Therapeutic Strategies.

According to the definition, epilepsy patients who have failed adequate trials of two tolerated, appropriately chosen and used antiepileptic drug regimens, whether as single or combination therapies, should be considered drug-resistant and referred for specialty evaluation.

The identification of drug-resistant, or refractory, epilepsy substantially influences clinical decision making as well as treatment research and development. Appropriately labeling a patient as drug resistant, for example, might lead to more timely consideration of surgical or other nonpharmacologic treatment, such as vagal nerve stimulation, he said. In addition, recognizing drug resistance in patients may provide insight into the neurobiology of the disease, which in turn can inform the development of new treatment, Dr. Patrick Kwan said at the annual meeting of the American Epilepsy Society.

The lack of a precise definition for refractory epilepsy until this time has meant the reliance on diverse criteria by clinicians and researchers, “which makes it difficult to compare findings across studies and to develop evidence-based practice recommendations,” said Dr. Kwan of the Chinese University of Hong Kong, Prince of Wales Hospital.

In an effort to level the playing field, the new definition is built on a framework that comprises a general scheme for categorizing patients' responses to each therapy and determining trial adequacy, he said.

For example, if a patient stops taking a given drug, it's important to know the circumstances of the withdrawal, according to Dr. Jacqueline French, professor of neurology at New York University and cochair of the therapeutic strategies commission.

“Was the drug ineffective after being titrated to its clinically effective dose range or was it withdrawn because of an adverse effect?” The former scenario will have some bearing on the presumed efficacy of other antiepileptic drugs, she stressed in a press briefing. The latter scenario, on the other hand, does not indicate a clinical failure of the drug with respect to its efficacy for seizure control, and as such should not be placed under the “drug-resistant” umbrella, she said.

The definition also requires that therapeutic interventions be appropriate for patients' epilepsy and seizure type and have been proven effective previously, preferably in randomized, controlled studies, Dr. French said.

With respect to trial adequacy, the task force deemed the following information necessary for assessing whether a drug intervention study is appropriate and informative for evaluating efficacy:

▸ The nature of the intervention, such as the type of drug.

▸ The mode of application, including the formulation, dose, dosing interval, and patient compliance.

▸ The duration of exposure.

▸ The occurrence of seizures and adverse effects during the trial period.

▸ The nature of the intervention, such as the type of drug.

▸ Whether there was an effort to optimize dose.

▸ The reasons for drug discontinuation, if applicable.

The outcomes of trials that do not fulfill these criteria should be considered “undetermined,” and as such should not be included in the drug failure count, Dr. Kwan stressed. Practically, this means that some patients may “fail,” in some manner, multiple antiepileptic drugs before they fail two appropriate, informative trials, he said.

Following two adequate, therapeutic trials, patients who do not achieve seizure freedom, defined by the task force as being seizure free for at least 1 year or three times the longest interseizure interval, should be referred from primary care or general neurology care to specialist centers for further evaluation, Dr. Kwan said.

Although it is expected that the definition will be adopted by clinicians at all health care levels, primary care physicians in particular will have a major role in applying the definition, as they are the most likely to have long-term relationships with these patients, he said.

Importantly, “by applying the definition, practitioners [and patients] can be alerted to the type of information that should be collected during clinical consultation,” Dr. Kwan and his task force colleagues wrote online in Epilepsia. “The proposed definition also has implications for the design of randomized drug trials and should prove useful in the selection of patients for such trials in which the criteria for considering a patient drug resistant are often poorly described,” they wrote, noting that a “standard definition of drug resistance can help ensure comparable results across trials” (Epilepsia 2009 Nov. 3 [doi:10.1111/j1528-11672009.02397.x]).

The definition is intended to be applicable to all patients, regardless of age of onset, type of epilepsy, seizure frequency, or seizure etiology, according to task force member Dr. Alexis Arzimanoglou of University Hospitals of Lyon (France). “The early detection of [drug-resistant] epilepsy should lead to early referral to a specialty center for evaluation and treatment,” he said. The definition “offers a new path for the early identification of those patients who may be cured from their epilepsy.”

Dr. Kwan stressed that the proposed definition is not the last word on drug-resistant epilepsy, but rather it represents “a testable hypothesis and a common starting point. Revision may be needed as more high-quality data become available.”

Disclosures: Members of the task force, whose work was funded by the ILAE, disclosed no relevant financial conflicts.

Recognizing drug resistance may provide insight into the neurobiology of epilepsy, Dr. Patrick Kwan said.

Source Courtesy American Epilepsy Society

BOSTON — A new consensus definition of drug-resistant epilepsy promises to improve patient care and facilitate clinical research, according to the chair of a task force appointed by the International League Against Epilepsy Commission on Therapeutic Strategies.

According to the definition, epilepsy patients who have failed adequate trials of two tolerated, appropriately chosen and used antiepileptic drug regimens, whether as single or combination therapies, should be considered drug-resistant and referred for specialty evaluation.

The identification of drug-resistant, or refractory, epilepsy substantially influences clinical decision making as well as treatment research and development. Appropriately labeling a patient as drug resistant, for example, might lead to more timely consideration of surgical or other nonpharmacologic treatment, such as vagal nerve stimulation, he said. In addition, recognizing drug resistance in patients may provide insight into the neurobiology of the disease, which in turn can inform the development of new treatment, Dr. Patrick Kwan said at the annual meeting of the American Epilepsy Society.

The lack of a precise definition for refractory epilepsy until this time has meant the reliance on diverse criteria by clinicians and researchers, “which makes it difficult to compare findings across studies and to develop evidence-based practice recommendations,” said Dr. Kwan of the Chinese University of Hong Kong, Prince of Wales Hospital.

In an effort to level the playing field, the new definition is built on a framework that comprises a general scheme for categorizing patients' responses to each therapy and determining trial adequacy, he said.

For example, if a patient stops taking a given drug, it's important to know the circumstances of the withdrawal, according to Dr. Jacqueline French, professor of neurology at New York University and cochair of the therapeutic strategies commission.

“Was the drug ineffective after being titrated to its clinically effective dose range or was it withdrawn because of an adverse effect?” The former scenario will have some bearing on the presumed efficacy of other antiepileptic drugs, she stressed in a press briefing. The latter scenario, on the other hand, does not indicate a clinical failure of the drug with respect to its efficacy for seizure control, and as such should not be placed under the “drug-resistant” umbrella, she said.

The definition also requires that therapeutic interventions be appropriate for patients' epilepsy and seizure type and have been proven effective previously, preferably in randomized, controlled studies, Dr. French said.

With respect to trial adequacy, the task force deemed the following information necessary for assessing whether a drug intervention study is appropriate and informative for evaluating efficacy:

▸ The nature of the intervention, such as the type of drug.

▸ The mode of application, including the formulation, dose, dosing interval, and patient compliance.

▸ The duration of exposure.

▸ The occurrence of seizures and adverse effects during the trial period.

▸ The nature of the intervention, such as the type of drug.

▸ Whether there was an effort to optimize dose.

▸ The reasons for drug discontinuation, if applicable.

The outcomes of trials that do not fulfill these criteria should be considered “undetermined,” and as such should not be included in the drug failure count, Dr. Kwan stressed. Practically, this means that some patients may “fail,” in some manner, multiple antiepileptic drugs before they fail two appropriate, informative trials, he said.

Following two adequate, therapeutic trials, patients who do not achieve seizure freedom, defined by the task force as being seizure free for at least 1 year or three times the longest interseizure interval, should be referred from primary care or general neurology care to specialist centers for further evaluation, Dr. Kwan said.

Although it is expected that the definition will be adopted by clinicians at all health care levels, primary care physicians in particular will have a major role in applying the definition, as they are the most likely to have long-term relationships with these patients, he said.

Importantly, “by applying the definition, practitioners [and patients] can be alerted to the type of information that should be collected during clinical consultation,” Dr. Kwan and his task force colleagues wrote online in Epilepsia. “The proposed definition also has implications for the design of randomized drug trials and should prove useful in the selection of patients for such trials in which the criteria for considering a patient drug resistant are often poorly described,” they wrote, noting that a “standard definition of drug resistance can help ensure comparable results across trials” (Epilepsia 2009 Nov. 3 [doi:10.1111/j1528-11672009.02397.x]).

The definition is intended to be applicable to all patients, regardless of age of onset, type of epilepsy, seizure frequency, or seizure etiology, according to task force member Dr. Alexis Arzimanoglou of University Hospitals of Lyon (France). “The early detection of [drug-resistant] epilepsy should lead to early referral to a specialty center for evaluation and treatment,” he said. The definition “offers a new path for the early identification of those patients who may be cured from their epilepsy.”

Dr. Kwan stressed that the proposed definition is not the last word on drug-resistant epilepsy, but rather it represents “a testable hypothesis and a common starting point. Revision may be needed as more high-quality data become available.”

Disclosures: Members of the task force, whose work was funded by the ILAE, disclosed no relevant financial conflicts.

Recognizing drug resistance may provide insight into the neurobiology of epilepsy, Dr. Patrick Kwan said.

Source Courtesy American Epilepsy Society

BOSTON — A new consensus definition of drug-resistant epilepsy promises to improve patient care and facilitate clinical research, according to the chair of a task force appointed by the International League Against Epilepsy Commission on Therapeutic Strategies.

According to the definition, epilepsy patients who have failed adequate trials of two tolerated, appropriately chosen and used antiepileptic drug regimens, whether as single or combination therapies, should be considered drug-resistant and referred for specialty evaluation.

The identification of drug-resistant, or refractory, epilepsy substantially influences clinical decision making as well as treatment research and development. Appropriately labeling a patient as drug resistant, for example, might lead to more timely consideration of surgical or other nonpharmacologic treatment, such as vagal nerve stimulation, he said. In addition, recognizing drug resistance in patients may provide insight into the neurobiology of the disease, which in turn can inform the development of new treatment, Dr. Patrick Kwan said at the annual meeting of the American Epilepsy Society.

The lack of a precise definition for refractory epilepsy until this time has meant the reliance on diverse criteria by clinicians and researchers, “which makes it difficult to compare findings across studies and to develop evidence-based practice recommendations,” said Dr. Kwan of the Chinese University of Hong Kong, Prince of Wales Hospital.

In an effort to level the playing field, the new definition is built on a framework that comprises a general scheme for categorizing patients' responses to each therapy and determining trial adequacy, he said.

For example, if a patient stops taking a given drug, it's important to know the circumstances of the withdrawal, according to Dr. Jacqueline French, professor of neurology at New York University and cochair of the therapeutic strategies commission.

“Was the drug ineffective after being titrated to its clinically effective dose range or was it withdrawn because of an adverse effect?” The former scenario will have some bearing on the presumed efficacy of other antiepileptic drugs, she stressed in a press briefing. The latter scenario, on the other hand, does not indicate a clinical failure of the drug with respect to its efficacy for seizure control, and as such should not be placed under the “drug-resistant” umbrella, she said.

The definition also requires that therapeutic interventions be appropriate for patients' epilepsy and seizure type and have been proven effective previously, preferably in randomized, controlled studies, Dr. French said.

With respect to trial adequacy, the task force deemed the following information necessary for assessing whether a drug intervention study is appropriate and informative for evaluating efficacy:

▸ The nature of the intervention, such as the type of drug.

▸ The mode of application, including the formulation, dose, dosing interval, and patient compliance.

▸ The duration of exposure.

▸ The occurrence of seizures and adverse effects during the trial period.

▸ The nature of the intervention, such as the type of drug.

▸ Whether there was an effort to optimize dose.

▸ The reasons for drug discontinuation, if applicable.

The outcomes of trials that do not fulfill these criteria should be considered “undetermined,” and as such should not be included in the drug failure count, Dr. Kwan stressed. Practically, this means that some patients may “fail,” in some manner, multiple antiepileptic drugs before they fail two appropriate, informative trials, he said.

Following two adequate, therapeutic trials, patients who do not achieve seizure freedom, defined by the task force as being seizure free for at least 1 year or three times the longest interseizure interval, should be referred from primary care or general neurology care to specialist centers for further evaluation, Dr. Kwan said.

Although it is expected that the definition will be adopted by clinicians at all health care levels, primary care physicians in particular will have a major role in applying the definition, as they are the most likely to have long-term relationships with these patients, he said.

Importantly, “by applying the definition, practitioners [and patients] can be alerted to the type of information that should be collected during clinical consultation,” Dr. Kwan and his task force colleagues wrote online in Epilepsia. “The proposed definition also has implications for the design of randomized drug trials and should prove useful in the selection of patients for such trials in which the criteria for considering a patient drug resistant are often poorly described,” they wrote, noting that a “standard definition of drug resistance can help ensure comparable results across trials” (Epilepsia 2009 Nov. 3 [doi:10.1111/j1528-11672009.02397.x]).

The definition is intended to be applicable to all patients, regardless of age of onset, type of epilepsy, seizure frequency, or seizure etiology, according to task force member Dr. Alexis Arzimanoglou of University Hospitals of Lyon (France). “The early detection of [drug-resistant] epilepsy should lead to early referral to a specialty center for evaluation and treatment,” he said. The definition “offers a new path for the early identification of those patients who may be cured from their epilepsy.”

Dr. Kwan stressed that the proposed definition is not the last word on drug-resistant epilepsy, but rather it represents “a testable hypothesis and a common starting point. Revision may be needed as more high-quality data become available.”

Disclosures: Members of the task force, whose work was funded by the ILAE, disclosed no relevant financial conflicts.

Recognizing drug resistance may provide insight into the neurobiology of epilepsy, Dr. Patrick Kwan said.

Source Courtesy American Epilepsy Society

BOSTON — The addition of the protease inhibitor telaprevir to antiviral therapy with pegylated interferon and ribavirin produced sustained virologic response in more than half of hepatitis C patients in a randomized trial who had previously failed the standard interferon/ribavirin protocol, Dr. John G. McHutchison reported at the annual meeting of the American Association for the Study of Liver Diseases.

The 453 patients with hepatitis C virus (HCV) genotype 1 enrolled in the multicenter PROVE3 trial—designed to assess the safety and efficacy of telaprevir plus pegylated interferon with or without ribavirin—were randomized to one of four tegimens.: telaprevir for 12 weeks and pegylated interferonanlus ribavirin for 24 weeks (T12/PR24);, telaprevir for 24 weeks and pegylated interferon plus ribavirin for 48 weeks (T24/PR48);, telaprevir and pegylated interferon only for 24 weeks (T24/P24);, or placebo and pegylated interferonaplus ribavirin for 24 weeks followed by pegylated interferon and ribavirin for 24 weeks (PR48), exid Dr. McHutchison of Duke University Medical Center, Durham, N.C.

The patients received the standard, subcutaneous 180 mcg/week of pegylated interferon, 1,000-1,200 mg of ribavirin according to body weight, and 1,250 mg of telaprevir on day 1 with 750 mg every 8 hours thereafter, he said.

Failure to respond to prior combination pegylated interferon/ribavirin treatment was defined as less than a 2-log decline in the serum HCV RNA level from baseline at 12 weeks;. Virologic breakthroughs, was defined as the development of viremia during treatment of a patient whose HCV RNA had previously become undetectable during ongoing therapy. Relapse, was defined as the reappearance of serum HCV RNA after the discontinuation of antiviral therapy and undetectable HCV RNA at the completion of therapy.

About 92% of the patients included in the intent-to-treat analysis had baseline HCV RNA levels of 800,000 IU/mL or higher, and 43% had cirrhosis or bridging fibrosis, The assigned treatment was completed by 235 of the patients, with discontinuation from protocol-defined stopping rules observed in 15% of the T12/PR 24 group, 23% of the T24/PR48 group, 37% in the T24/P24 group, and 59% in the PR48 group, Dr. McHutchison reported.

At 48 weeks after treatment completion, the sustained virologic response (SVR) rates across all three of the telaprevir-based regimens were significantly higher than in the interferon/ribavirin control arm, In the T12/PR24, the T24/PR48, and the T24/P24 groups, 51%, 53%, and 24% of the patients, respectively, achieved SVR, compared with 14% of the patients in the control group, he said.

Viral breakthrough rates during treatment were highest in the telaprevir/interferon-only group, at 21%, compared with 11%, 10%, and 3% in the T12/PR24, T24/PR48, and PR48 groups. Similarly, Dr. McHutchison noted, relapse rates 24 weeks after treatment were highest in the telaprevir/interferon-only group, at 53%, compared with 28%, 4%, and 52% in the T12/PR24, T24/PR48, and PR48 groups. “No late relapses occurred 48 weeks after treatment in the telaprevir groups,” he said.

The telaprevir-based therapy was most successful in patients who had relapsed after the initial dual combination therapy, In the T12/PR24, T24/PR48, and T24/P24 groups, respectively, SVR was achieved by 69%, 76%, and 42% of patients who had previously relapsed, compared with 39%, 38%, and 11% of patients who had not responded to the initial treatment, Dr. McHutchison said.

“The general safety profile of all of the telaprevir regimens was similar to that seen in treatment-naive patients,” Dr. McHutchison said. Grade 3 rash was observed in 5%, 4%, 3%, and 0% of the T12/PR24, T24/PR48, T24/P24, and PR48 groups, respectively, and grade 3 anemia was observed in 0%, 6%, 1%, and 1% of patients. And while 21 patients in the telaprevir groups discontinued treatment because of rash (18) or anemia (3), he said, “the number of withdrawals is not unusually high and is similar to the rates reported in prior phase II studies.”

The findings of this phase IIb study have important clinical implications, Dr. McHutchison said. “The high rate of cure among previous treatment failures gives hope to a large segment of hepatitis C infected patients who do not respond to the current standard of care,” he said, noting that the results still have to be confirmed in larger phase III clinical trials, that are ongoing.

Disclosures: This study was funded by Vertex Pharmaceuticals and Tibotec, manufacturers of telaprevir. Dr. McHutchison disclosed relationships with multiple pharmaceutical firms, including Vertex.

BOSTON — The addition of the protease inhibitor telaprevir to antiviral therapy with pegylated interferon and ribavirin produced sustained virologic response in more than half of hepatitis C patients in a randomized trial who had previously failed the standard interferon/ribavirin protocol, Dr. John G. McHutchison reported at the annual meeting of the American Association for the Study of Liver Diseases.

The 453 patients with hepatitis C virus (HCV) genotype 1 enrolled in the multicenter PROVE3 trial—designed to assess the safety and efficacy of telaprevir plus pegylated interferon with or without ribavirin—were randomized to one of four tegimens.: telaprevir for 12 weeks and pegylated interferonanlus ribavirin for 24 weeks (T12/PR24);, telaprevir for 24 weeks and pegylated interferon plus ribavirin for 48 weeks (T24/PR48);, telaprevir and pegylated interferon only for 24 weeks (T24/P24);, or placebo and pegylated interferonaplus ribavirin for 24 weeks followed by pegylated interferon and ribavirin for 24 weeks (PR48), exid Dr. McHutchison of Duke University Medical Center, Durham, N.C.

The patients received the standard, subcutaneous 180 mcg/week of pegylated interferon, 1,000-1,200 mg of ribavirin according to body weight, and 1,250 mg of telaprevir on day 1 with 750 mg every 8 hours thereafter, he said.

Failure to respond to prior combination pegylated interferon/ribavirin treatment was defined as less than a 2-log decline in the serum HCV RNA level from baseline at 12 weeks;. Virologic breakthroughs, was defined as the development of viremia during treatment of a patient whose HCV RNA had previously become undetectable during ongoing therapy. Relapse, was defined as the reappearance of serum HCV RNA after the discontinuation of antiviral therapy and undetectable HCV RNA at the completion of therapy.

About 92% of the patients included in the intent-to-treat analysis had baseline HCV RNA levels of 800,000 IU/mL or higher, and 43% had cirrhosis or bridging fibrosis, The assigned treatment was completed by 235 of the patients, with discontinuation from protocol-defined stopping rules observed in 15% of the T12/PR 24 group, 23% of the T24/PR48 group, 37% in the T24/P24 group, and 59% in the PR48 group, Dr. McHutchison reported.

At 48 weeks after treatment completion, the sustained virologic response (SVR) rates across all three of the telaprevir-based regimens were significantly higher than in the interferon/ribavirin control arm, In the T12/PR24, the T24/PR48, and the T24/P24 groups, 51%, 53%, and 24% of the patients, respectively, achieved SVR, compared with 14% of the patients in the control group, he said.

Viral breakthrough rates during treatment were highest in the telaprevir/interferon-only group, at 21%, compared with 11%, 10%, and 3% in the T12/PR24, T24/PR48, and PR48 groups. Similarly, Dr. McHutchison noted, relapse rates 24 weeks after treatment were highest in the telaprevir/interferon-only group, at 53%, compared with 28%, 4%, and 52% in the T12/PR24, T24/PR48, and PR48 groups. “No late relapses occurred 48 weeks after treatment in the telaprevir groups,” he said.

The telaprevir-based therapy was most successful in patients who had relapsed after the initial dual combination therapy, In the T12/PR24, T24/PR48, and T24/P24 groups, respectively, SVR was achieved by 69%, 76%, and 42% of patients who had previously relapsed, compared with 39%, 38%, and 11% of patients who had not responded to the initial treatment, Dr. McHutchison said.

“The general safety profile of all of the telaprevir regimens was similar to that seen in treatment-naive patients,” Dr. McHutchison said. Grade 3 rash was observed in 5%, 4%, 3%, and 0% of the T12/PR24, T24/PR48, T24/P24, and PR48 groups, respectively, and grade 3 anemia was observed in 0%, 6%, 1%, and 1% of patients. And while 21 patients in the telaprevir groups discontinued treatment because of rash (18) or anemia (3), he said, “the number of withdrawals is not unusually high and is similar to the rates reported in prior phase II studies.”

The findings of this phase IIb study have important clinical implications, Dr. McHutchison said. “The high rate of cure among previous treatment failures gives hope to a large segment of hepatitis C infected patients who do not respond to the current standard of care,” he said, noting that the results still have to be confirmed in larger phase III clinical trials, that are ongoing.

Disclosures: This study was funded by Vertex Pharmaceuticals and Tibotec, manufacturers of telaprevir. Dr. McHutchison disclosed relationships with multiple pharmaceutical firms, including Vertex.

BOSTON — The addition of the protease inhibitor telaprevir to antiviral therapy with pegylated interferon and ribavirin produced sustained virologic response in more than half of hepatitis C patients in a randomized trial who had previously failed the standard interferon/ribavirin protocol, Dr. John G. McHutchison reported at the annual meeting of the American Association for the Study of Liver Diseases.

The 453 patients with hepatitis C virus (HCV) genotype 1 enrolled in the multicenter PROVE3 trial—designed to assess the safety and efficacy of telaprevir plus pegylated interferon with or without ribavirin—were randomized to one of four tegimens.: telaprevir for 12 weeks and pegylated interferonanlus ribavirin for 24 weeks (T12/PR24);, telaprevir for 24 weeks and pegylated interferon plus ribavirin for 48 weeks (T24/PR48);, telaprevir and pegylated interferon only for 24 weeks (T24/P24);, or placebo and pegylated interferonaplus ribavirin for 24 weeks followed by pegylated interferon and ribavirin for 24 weeks (PR48), exid Dr. McHutchison of Duke University Medical Center, Durham, N.C.

The patients received the standard, subcutaneous 180 mcg/week of pegylated interferon, 1,000-1,200 mg of ribavirin according to body weight, and 1,250 mg of telaprevir on day 1 with 750 mg every 8 hours thereafter, he said.

Failure to respond to prior combination pegylated interferon/ribavirin treatment was defined as less than a 2-log decline in the serum HCV RNA level from baseline at 12 weeks;. Virologic breakthroughs, was defined as the development of viremia during treatment of a patient whose HCV RNA had previously become undetectable during ongoing therapy. Relapse, was defined as the reappearance of serum HCV RNA after the discontinuation of antiviral therapy and undetectable HCV RNA at the completion of therapy.

About 92% of the patients included in the intent-to-treat analysis had baseline HCV RNA levels of 800,000 IU/mL or higher, and 43% had cirrhosis or bridging fibrosis, The assigned treatment was completed by 235 of the patients, with discontinuation from protocol-defined stopping rules observed in 15% of the T12/PR 24 group, 23% of the T24/PR48 group, 37% in the T24/P24 group, and 59% in the PR48 group, Dr. McHutchison reported.

At 48 weeks after treatment completion, the sustained virologic response (SVR) rates across all three of the telaprevir-based regimens were significantly higher than in the interferon/ribavirin control arm, In the T12/PR24, the T24/PR48, and the T24/P24 groups, 51%, 53%, and 24% of the patients, respectively, achieved SVR, compared with 14% of the patients in the control group, he said.

Viral breakthrough rates during treatment were highest in the telaprevir/interferon-only group, at 21%, compared with 11%, 10%, and 3% in the T12/PR24, T24/PR48, and PR48 groups. Similarly, Dr. McHutchison noted, relapse rates 24 weeks after treatment were highest in the telaprevir/interferon-only group, at 53%, compared with 28%, 4%, and 52% in the T12/PR24, T24/PR48, and PR48 groups. “No late relapses occurred 48 weeks after treatment in the telaprevir groups,” he said.

The telaprevir-based therapy was most successful in patients who had relapsed after the initial dual combination therapy, In the T12/PR24, T24/PR48, and T24/P24 groups, respectively, SVR was achieved by 69%, 76%, and 42% of patients who had previously relapsed, compared with 39%, 38%, and 11% of patients who had not responded to the initial treatment, Dr. McHutchison said.

“The general safety profile of all of the telaprevir regimens was similar to that seen in treatment-naive patients,” Dr. McHutchison said. Grade 3 rash was observed in 5%, 4%, 3%, and 0% of the T12/PR24, T24/PR48, T24/P24, and PR48 groups, respectively, and grade 3 anemia was observed in 0%, 6%, 1%, and 1% of patients. And while 21 patients in the telaprevir groups discontinued treatment because of rash (18) or anemia (3), he said, “the number of withdrawals is not unusually high and is similar to the rates reported in prior phase II studies.”

The findings of this phase IIb study have important clinical implications, Dr. McHutchison said. “The high rate of cure among previous treatment failures gives hope to a large segment of hepatitis C infected patients who do not respond to the current standard of care,” he said, noting that the results still have to be confirmed in larger phase III clinical trials, that are ongoing.

Disclosures: This study was funded by Vertex Pharmaceuticals and Tibotec, manufacturers of telaprevir. Dr. McHutchison disclosed relationships with multiple pharmaceutical firms, including Vertex.

BOSTON — A gene signature that predicts survival after surgery for hepatocellular carcinoma also predicts the outcome of liver cirrhosis, a study has shown.

Compensated cirrhotic patients at risk of poor prognosis can be identified via the 186-gene signature of nontumor liver tissue, Dr. Yujin Hoshida reported at the annual meeting of the American Association for the Study of Liver Diseases.

The investigators performed whole-genome gene expression analysis of liver biopsy specimens obtained from 276 patients with compensated cirrhosis who were included in a prospective surveillance study for hepatocellular carcinoma, said Dr. Hoshida of the Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge Boston.

“The findings suggest that we might be able to identify patients who need preventive treatment for advanced cirrhosis and possibly hepatocellular carcinoma,” Dr. Hoshida said.

He and his colleagues previously developed and reported (N. Engl. J. Med. 2008;359:1995-2004) a technique for globally profiling gene expression from formalin-fixed, paraffin-embedded (FFPE) tissues. The method enabled the researchers to profile both nontumor and cancerous tissue obtained from 307 liver cancer patients participating in prospective surveillance studies.

The technique involved a modified cDNA-mediated annealing, selection, extension, and ligation assay to interrogate about 6,000 genes expressed in the tumor and nontumor tissue. By partitioning samples into training and validation sets, the researchers were able to develop a 186-gene signature of nontumor tissues to predict hepatocellular carcinoma survival.

In the current study, the investigators used Cox regression modeling to evaluate the potential associations between the 186-gene signature and overall survival, hepatocellular carcinoma, and hepatic decompensation in patients with compensated cirrhosis.

Almost all (98%, or 270) of the 276 patients from whom biopsy specimens were obtained were classified as Child-Pugh A with respect to cirrhosis severity, Dr. Hoshida said. About 90% of the participants had hepatitis C infection, and the median baseline serum alpha-fetoprotein level was 6 mg/dL. Most patients (62%) were male.

During the prospective surveillance period (median follow-up of 9.8 years), 90 patients (33%) died, 81 (29%) developed hepatocellular carcinoma, and 88 (32%) developed hepatic decompensation.

In multivariate analyses, the 186-gene signature was associated with overall survival, with a hazard ratio (HR) of 2.2. It also was associated with hepatocellular carcinoma development (HR 1.6) and hepatic decompensation (HR, 2.1). The association between the gene signature and each of the three outcomes remained significant after adjustment for bilirubin greater than 1.0 mg/dL and platelet count, Dr. Hoshida said.

Subsequent gene set enrichment analysis revealed enrichment of metabolic-related pathways in patients with a good prognosis and enrichment of pathways associated with inflammation (including those related to interferon and tumor necrosis factor–alpha signaling) in patients with a poorer prognosis, he noted.

Although additional clinical validation is required before the genetic signature is introduced into clinical practice, the findings are promising, said Dr. Hoshida, who noted that the prognostic prediction of early-stage cirrhosis will increase the opportunity for early medical intervention, including chemoprevention of advanced cirrhosis and hepatocellular carcinoma.

Disclosures: Dr. Hoshida reported having no relevant conflicts of interest.

My Take

Clinical Implications Not Yet Clear

This study, largely involving hepatitis C patients, adds to our knowledge of factors that influence the course of hepatic cirrhosis. The ability to predict which patients with cirrhosis are likely to decompensate or develop hepatocellular carcinoma (HCC) should be helpful in clinical management.

The study shows that gene enrichment for metabolic-related pathways predicts a better outcome for patients with cirrhosis, compared with gene enrichment for inflammatory pathways—a finding that intuitively fits with existing clinical information related to prognosis. It also seems that a greater emphasis on following those patients at greatest risk for HCC could reduce the costs of screening, if we could reduce screening of patients with less risk. This genetic risk information also might permit earlier intervention for patients suspected of having an HCC, or those at risk of decompensation.

But would this information change how we deal with an individual patient? Would it benefit patients to know that they are in the group with a worse prognosis? We need further studies to see if this can truly change how we manage the individual patient with cirrhosis.

ROWEN K. ZETTERMAN, M.D., a gastroenterologist, is dean of the school of medicine at Creighton University, Omaha, Neb. He reports no relevant conflicts of interest.

BOSTON — A gene signature that predicts survival after surgery for hepatocellular carcinoma also predicts the outcome of liver cirrhosis, a study has shown.

Compensated cirrhotic patients at risk of poor prognosis can be identified via the 186-gene signature of nontumor liver tissue, Dr. Yujin Hoshida reported at the annual meeting of the American Association for the Study of Liver Diseases.

The investigators performed whole-genome gene expression analysis of liver biopsy specimens obtained from 276 patients with compensated cirrhosis who were included in a prospective surveillance study for hepatocellular carcinoma, said Dr. Hoshida of the Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge Boston.

“The findings suggest that we might be able to identify patients who need preventive treatment for advanced cirrhosis and possibly hepatocellular carcinoma,” Dr. Hoshida said.

He and his colleagues previously developed and reported (N. Engl. J. Med. 2008;359:1995-2004) a technique for globally profiling gene expression from formalin-fixed, paraffin-embedded (FFPE) tissues. The method enabled the researchers to profile both nontumor and cancerous tissue obtained from 307 liver cancer patients participating in prospective surveillance studies.

The technique involved a modified cDNA-mediated annealing, selection, extension, and ligation assay to interrogate about 6,000 genes expressed in the tumor and nontumor tissue. By partitioning samples into training and validation sets, the researchers were able to develop a 186-gene signature of nontumor tissues to predict hepatocellular carcinoma survival.

In the current study, the investigators used Cox regression modeling to evaluate the potential associations between the 186-gene signature and overall survival, hepatocellular carcinoma, and hepatic decompensation in patients with compensated cirrhosis.

Almost all (98%, or 270) of the 276 patients from whom biopsy specimens were obtained were classified as Child-Pugh A with respect to cirrhosis severity, Dr. Hoshida said. About 90% of the participants had hepatitis C infection, and the median baseline serum alpha-fetoprotein level was 6 mg/dL. Most patients (62%) were male.

During the prospective surveillance period (median follow-up of 9.8 years), 90 patients (33%) died, 81 (29%) developed hepatocellular carcinoma, and 88 (32%) developed hepatic decompensation.

In multivariate analyses, the 186-gene signature was associated with overall survival, with a hazard ratio (HR) of 2.2. It also was associated with hepatocellular carcinoma development (HR 1.6) and hepatic decompensation (HR, 2.1). The association between the gene signature and each of the three outcomes remained significant after adjustment for bilirubin greater than 1.0 mg/dL and platelet count, Dr. Hoshida said.

Subsequent gene set enrichment analysis revealed enrichment of metabolic-related pathways in patients with a good prognosis and enrichment of pathways associated with inflammation (including those related to interferon and tumor necrosis factor–alpha signaling) in patients with a poorer prognosis, he noted.

Although additional clinical validation is required before the genetic signature is introduced into clinical practice, the findings are promising, said Dr. Hoshida, who noted that the prognostic prediction of early-stage cirrhosis will increase the opportunity for early medical intervention, including chemoprevention of advanced cirrhosis and hepatocellular carcinoma.

Disclosures: Dr. Hoshida reported having no relevant conflicts of interest.

My Take

Clinical Implications Not Yet Clear

This study, largely involving hepatitis C patients, adds to our knowledge of factors that influence the course of hepatic cirrhosis. The ability to predict which patients with cirrhosis are likely to decompensate or develop hepatocellular carcinoma (HCC) should be helpful in clinical management.

The study shows that gene enrichment for metabolic-related pathways predicts a better outcome for patients with cirrhosis, compared with gene enrichment for inflammatory pathways—a finding that intuitively fits with existing clinical information related to prognosis. It also seems that a greater emphasis on following those patients at greatest risk for HCC could reduce the costs of screening, if we could reduce screening of patients with less risk. This genetic risk information also might permit earlier intervention for patients suspected of having an HCC, or those at risk of decompensation.

But would this information change how we deal with an individual patient? Would it benefit patients to know that they are in the group with a worse prognosis? We need further studies to see if this can truly change how we manage the individual patient with cirrhosis.

ROWEN K. ZETTERMAN, M.D., a gastroenterologist, is dean of the school of medicine at Creighton University, Omaha, Neb. He reports no relevant conflicts of interest.

BOSTON — A gene signature that predicts survival after surgery for hepatocellular carcinoma also predicts the outcome of liver cirrhosis, a study has shown.

Compensated cirrhotic patients at risk of poor prognosis can be identified via the 186-gene signature of nontumor liver tissue, Dr. Yujin Hoshida reported at the annual meeting of the American Association for the Study of Liver Diseases.

The investigators performed whole-genome gene expression analysis of liver biopsy specimens obtained from 276 patients with compensated cirrhosis who were included in a prospective surveillance study for hepatocellular carcinoma, said Dr. Hoshida of the Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge Boston.

“The findings suggest that we might be able to identify patients who need preventive treatment for advanced cirrhosis and possibly hepatocellular carcinoma,” Dr. Hoshida said.

He and his colleagues previously developed and reported (N. Engl. J. Med. 2008;359:1995-2004) a technique for globally profiling gene expression from formalin-fixed, paraffin-embedded (FFPE) tissues. The method enabled the researchers to profile both nontumor and cancerous tissue obtained from 307 liver cancer patients participating in prospective surveillance studies.

The technique involved a modified cDNA-mediated annealing, selection, extension, and ligation assay to interrogate about 6,000 genes expressed in the tumor and nontumor tissue. By partitioning samples into training and validation sets, the researchers were able to develop a 186-gene signature of nontumor tissues to predict hepatocellular carcinoma survival.

In the current study, the investigators used Cox regression modeling to evaluate the potential associations between the 186-gene signature and overall survival, hepatocellular carcinoma, and hepatic decompensation in patients with compensated cirrhosis.

Almost all (98%, or 270) of the 276 patients from whom biopsy specimens were obtained were classified as Child-Pugh A with respect to cirrhosis severity, Dr. Hoshida said. About 90% of the participants had hepatitis C infection, and the median baseline serum alpha-fetoprotein level was 6 mg/dL. Most patients (62%) were male.

During the prospective surveillance period (median follow-up of 9.8 years), 90 patients (33%) died, 81 (29%) developed hepatocellular carcinoma, and 88 (32%) developed hepatic decompensation.

In multivariate analyses, the 186-gene signature was associated with overall survival, with a hazard ratio (HR) of 2.2. It also was associated with hepatocellular carcinoma development (HR 1.6) and hepatic decompensation (HR, 2.1). The association between the gene signature and each of the three outcomes remained significant after adjustment for bilirubin greater than 1.0 mg/dL and platelet count, Dr. Hoshida said.

Subsequent gene set enrichment analysis revealed enrichment of metabolic-related pathways in patients with a good prognosis and enrichment of pathways associated with inflammation (including those related to interferon and tumor necrosis factor–alpha signaling) in patients with a poorer prognosis, he noted.

Although additional clinical validation is required before the genetic signature is introduced into clinical practice, the findings are promising, said Dr. Hoshida, who noted that the prognostic prediction of early-stage cirrhosis will increase the opportunity for early medical intervention, including chemoprevention of advanced cirrhosis and hepatocellular carcinoma.

Disclosures: Dr. Hoshida reported having no relevant conflicts of interest.

My Take

Clinical Implications Not Yet Clear

This study, largely involving hepatitis C patients, adds to our knowledge of factors that influence the course of hepatic cirrhosis. The ability to predict which patients with cirrhosis are likely to decompensate or develop hepatocellular carcinoma (HCC) should be helpful in clinical management.

The study shows that gene enrichment for metabolic-related pathways predicts a better outcome for patients with cirrhosis, compared with gene enrichment for inflammatory pathways—a finding that intuitively fits with existing clinical information related to prognosis. It also seems that a greater emphasis on following those patients at greatest risk for HCC could reduce the costs of screening, if we could reduce screening of patients with less risk. This genetic risk information also might permit earlier intervention for patients suspected of having an HCC, or those at risk of decompensation.

But would this information change how we deal with an individual patient? Would it benefit patients to know that they are in the group with a worse prognosis? We need further studies to see if this can truly change how we manage the individual patient with cirrhosis.

ROWEN K. ZETTERMAN, M.D., a gastroenterologist, is dean of the school of medicine at Creighton University, Omaha, Neb. He reports no relevant conflicts of interest.

NEW YORK — A systems-level collaborative care model for the screening, referral, and treatment of depression and posttraumatic stress disorder in U.S. soldiers has led to an increase in the number of soldiers receiving mental health care, Col. Charles C. Engel, MC, USA, said at the American Psychiatric Association's Institute on Psychiatric Services.

A feasibility study of the Re-Engineering Systems for the Primary Care Treatment of Depression and PTSD in the Military (RESPECT-Mil) model shows that the intervention often leads to clinical improvements, Dr. Engel reported.

Since its 2007 rollout, the model has been implemented in 35 of a planned 43 primary care clinics on 15 military bases in the United States, Germany, and Italy. Preliminary data from the participating clinics indicate that screening for depression and PTSD has occurred in two-thirds of primary care visits, with a positive screen rate of 14%, said Dr. Engel, director of the Department of Defense Deployment Health Clinical Center at Walter Reed Army Medical Center, Washington, and associate professor in the department of psychiatry at the Uniformed Services University of the Health Sciences.

Of the 14% who screened positive, 60% received a diagnosis of depression or PTSD and started treatment, noted Dr. Engel, a psychiatric epidemiologist who has been instrumental in helping the departments of Veterans Affairs and Defense develop guidelines for depression, PTSD, and medically unexplained symptoms.

The RESPECT-Mil program, based on a three-component model that has been used extensively in civilian populations, addresses some of the challenges that have kept soldiers from receiving needed mental health services, including reluctance to seek behavioral health services, insufficient mental health workforce, lack of competency in evidence-based mental health practice, and inadequate access to care, Dr. Engel said.

It achieves those goals by integrating the efforts of primary care physicians, nurse care facilitators, and psychiatrists, starting with a mandate for universal screening for depression and PTSD for soldiers during routine primary care visits, he said.

Patients who screen positive on the two-question depression screen (PHQ-2) or the four-item PTSD screen undergo a diagnosis and severity assessment using the Patient Health Questionnaire-9 (PHQ-9) and the 17-item PTSD Check List, as well as a suicide and violence risk assessment, Dr. Engel said. “We've modified the assessment tools so that it's easy for clinicians to look at and determine whether patients are high or low probability for suffering from a trauma reaction or suicidal ideation.”

When there is a presumptive diagnosis of depression or PTSD, the primary care clinician will initiate treatment and offer follow-up monitoring with a psychiatrist-supervised care facilitator and, when necessary, a behavioral health specialist.

“The care facilitators are the single most important ingredient in the [RESPECT-Mil] model,” Dr. Engel said. After the initial primary care visit, the care facilitators serve as the liaisons between the primary care providers and the consulting psychiatrists. The care facilitators provide follow-up via telephone and consult weekly with the supervising psychiatrist to evaluate patient progress. Patients with significant mental health issues may be referred from primary care to specialty care. Patients' initial treatment response is evaluated at 6-8 weeks for those on antidepressants and 4-6 weeks for those undergoing psychological counseling, and the treatment plan is adjusted if necessary, he said.

The early data are promising, but “the real challenge is going to come during the course of [2010], because we're going to be doubling the size of the program by getting it into almost all of the Army's approximately 100 primary care clinics,” Dr. Engel said. As this happens, “it's going to be a great platform for studying systems solutions approaches.

Disclosures: Dr. Engel has no relevant conflicts of interest.

NEW YORK — A systems-level collaborative care model for the screening, referral, and treatment of depression and posttraumatic stress disorder in U.S. soldiers has led to an increase in the number of soldiers receiving mental health care, Col. Charles C. Engel, MC, USA, said at the American Psychiatric Association's Institute on Psychiatric Services.

A feasibility study of the Re-Engineering Systems for the Primary Care Treatment of Depression and PTSD in the Military (RESPECT-Mil) model shows that the intervention often leads to clinical improvements, Dr. Engel reported.

Since its 2007 rollout, the model has been implemented in 35 of a planned 43 primary care clinics on 15 military bases in the United States, Germany, and Italy. Preliminary data from the participating clinics indicate that screening for depression and PTSD has occurred in two-thirds of primary care visits, with a positive screen rate of 14%, said Dr. Engel, director of the Department of Defense Deployment Health Clinical Center at Walter Reed Army Medical Center, Washington, and associate professor in the department of psychiatry at the Uniformed Services University of the Health Sciences.

Of the 14% who screened positive, 60% received a diagnosis of depression or PTSD and started treatment, noted Dr. Engel, a psychiatric epidemiologist who has been instrumental in helping the departments of Veterans Affairs and Defense develop guidelines for depression, PTSD, and medically unexplained symptoms.

The RESPECT-Mil program, based on a three-component model that has been used extensively in civilian populations, addresses some of the challenges that have kept soldiers from receiving needed mental health services, including reluctance to seek behavioral health services, insufficient mental health workforce, lack of competency in evidence-based mental health practice, and inadequate access to care, Dr. Engel said.

It achieves those goals by integrating the efforts of primary care physicians, nurse care facilitators, and psychiatrists, starting with a mandate for universal screening for depression and PTSD for soldiers during routine primary care visits, he said.

Patients who screen positive on the two-question depression screen (PHQ-2) or the four-item PTSD screen undergo a diagnosis and severity assessment using the Patient Health Questionnaire-9 (PHQ-9) and the 17-item PTSD Check List, as well as a suicide and violence risk assessment, Dr. Engel said. “We've modified the assessment tools so that it's easy for clinicians to look at and determine whether patients are high or low probability for suffering from a trauma reaction or suicidal ideation.”

When there is a presumptive diagnosis of depression or PTSD, the primary care clinician will initiate treatment and offer follow-up monitoring with a psychiatrist-supervised care facilitator and, when necessary, a behavioral health specialist.

“The care facilitators are the single most important ingredient in the [RESPECT-Mil] model,” Dr. Engel said. After the initial primary care visit, the care facilitators serve as the liaisons between the primary care providers and the consulting psychiatrists. The care facilitators provide follow-up via telephone and consult weekly with the supervising psychiatrist to evaluate patient progress. Patients with significant mental health issues may be referred from primary care to specialty care. Patients' initial treatment response is evaluated at 6-8 weeks for those on antidepressants and 4-6 weeks for those undergoing psychological counseling, and the treatment plan is adjusted if necessary, he said.

The early data are promising, but “the real challenge is going to come during the course of [2010], because we're going to be doubling the size of the program by getting it into almost all of the Army's approximately 100 primary care clinics,” Dr. Engel said. As this happens, “it's going to be a great platform for studying systems solutions approaches.

Disclosures: Dr. Engel has no relevant conflicts of interest.

NEW YORK — A systems-level collaborative care model for the screening, referral, and treatment of depression and posttraumatic stress disorder in U.S. soldiers has led to an increase in the number of soldiers receiving mental health care, Col. Charles C. Engel, MC, USA, said at the American Psychiatric Association's Institute on Psychiatric Services.

A feasibility study of the Re-Engineering Systems for the Primary Care Treatment of Depression and PTSD in the Military (RESPECT-Mil) model shows that the intervention often leads to clinical improvements, Dr. Engel reported.

Since its 2007 rollout, the model has been implemented in 35 of a planned 43 primary care clinics on 15 military bases in the United States, Germany, and Italy. Preliminary data from the participating clinics indicate that screening for depression and PTSD has occurred in two-thirds of primary care visits, with a positive screen rate of 14%, said Dr. Engel, director of the Department of Defense Deployment Health Clinical Center at Walter Reed Army Medical Center, Washington, and associate professor in the department of psychiatry at the Uniformed Services University of the Health Sciences.

Of the 14% who screened positive, 60% received a diagnosis of depression or PTSD and started treatment, noted Dr. Engel, a psychiatric epidemiologist who has been instrumental in helping the departments of Veterans Affairs and Defense develop guidelines for depression, PTSD, and medically unexplained symptoms.

The RESPECT-Mil program, based on a three-component model that has been used extensively in civilian populations, addresses some of the challenges that have kept soldiers from receiving needed mental health services, including reluctance to seek behavioral health services, insufficient mental health workforce, lack of competency in evidence-based mental health practice, and inadequate access to care, Dr. Engel said.

It achieves those goals by integrating the efforts of primary care physicians, nurse care facilitators, and psychiatrists, starting with a mandate for universal screening for depression and PTSD for soldiers during routine primary care visits, he said.

Patients who screen positive on the two-question depression screen (PHQ-2) or the four-item PTSD screen undergo a diagnosis and severity assessment using the Patient Health Questionnaire-9 (PHQ-9) and the 17-item PTSD Check List, as well as a suicide and violence risk assessment, Dr. Engel said. “We've modified the assessment tools so that it's easy for clinicians to look at and determine whether patients are high or low probability for suffering from a trauma reaction or suicidal ideation.”

When there is a presumptive diagnosis of depression or PTSD, the primary care clinician will initiate treatment and offer follow-up monitoring with a psychiatrist-supervised care facilitator and, when necessary, a behavioral health specialist.

“The care facilitators are the single most important ingredient in the [RESPECT-Mil] model,” Dr. Engel said. After the initial primary care visit, the care facilitators serve as the liaisons between the primary care providers and the consulting psychiatrists. The care facilitators provide follow-up via telephone and consult weekly with the supervising psychiatrist to evaluate patient progress. Patients with significant mental health issues may be referred from primary care to specialty care. Patients' initial treatment response is evaluated at 6-8 weeks for those on antidepressants and 4-6 weeks for those undergoing psychological counseling, and the treatment plan is adjusted if necessary, he said.

The early data are promising, but “the real challenge is going to come during the course of [2010], because we're going to be doubling the size of the program by getting it into almost all of the Army's approximately 100 primary care clinics,” Dr. Engel said. As this happens, “it's going to be a great platform for studying systems solutions approaches.

Disclosures: Dr. Engel has no relevant conflicts of interest.

Revised recommendations for human papillomavirus vaccination—including a permissive recommendation for young men—and for measles, mumps, rubella immunization are part of the newly issued 2010 immunization schedule from the Advisory Committee on Immunization Practices at the Centers for Disease Control and Prevention.

The new schedule also includes updated indications and schedule information for hepatitis A and B vaccination, as well as clarifications about meningococcal and Haemophilus influenzae type B vaccination.

The 2010 Recommended Adult Immunization Schedule, which earned ACIP approval in October 2009, reflects current recommendations for the licensed vaccines, according to the schedule's accompanying report (Ann. Intern. Med. 2010;152:36-9). The schedule is approved by the American College of Physicians, as well as the American Academy of Family Physicians and the American College of Obstetricians and Gynecologists.

The revised schedule includes these changes:

▸ For human papillomavirus (HPV), a bivalent vaccine (HPV2) has been licensed for use in females. Therefore, either the bivalent or quadrivalent (HPV4) vaccination can be used for women between 19 and 26 years. In addition, HPV4 may be given to males aged 9-25 years “to reduce their likelihood of acquiring genital warts,” according to the revised schedule.

▸ For influenza vaccination, the term “seasonal” has been added to distinguish between seasonal and pandemic influenza vaccines.

▸ For measles, mumps, rubella (MMR) vaccination, most adults born after 1957 do not require repeat vaccination if they have documentation of having received at least one dose of the vaccine. Women without documentation of rubella vaccination should receive a dose of the MMR vaccine. Health care workers, college students, international travelers, and individuals who have been exposed to measles or mumps in an outbreak setting should receive two doses of MMR. When a second MMR dose is indicated, it should be administered 4 weeks after the first dose.

Health care facilities should “consider” MMR vaccination for unvaccinated health care workers born before 1957 who do not have evidence of immunity or disease, and should “recommend” vaccination of this group during an outbreak.

▸ For hepatitis A, vaccination is recommended for unvaccinated individuals who anticipate close personal contact with an international adoptee from a country with intermediate or high endemicity to hepatitis A. The first dose should be given at least 2 weeks before the arrival of the adoptee.

▸ For the three-dose hepatitis B vaccine, the second dose should be administered 1 month after the first dose, and the third dose should be administered at least 2 months after the second. If using the combined hepatitis A and B vaccine, three doses should be administered at 0, 1, and 6 months. Alternatively, a four-dose schedule, administered on days 0, 7, 21, and 30, followed by a 12-month booster, may be used.

▸ For meningococcal vaccination, the conjugate vaccine (MCV4) is preferred for adults aged 55 years or younger, while the polysaccharide vaccine (MPSV4) is recommended for adults older than 55 years. Revaccination with MCV4 after 5 years is recommended for individuals who continue to be at risk for infection, such as adults with anatomic or functional asplenia. However, it is not recommended for individuals whose only risk factor is continued on-campus residence.

▸ For Haemophilus influenzae type B (Hib) vaccination, there is no recommendation for individuals older than age 5 years. One dose of the vaccine is not contraindicated in certain high-risk patients who have not received the vaccine previously, including those patients with sickle cell disease, leukemia, HIV infection, or splenectomy.

Although vaccines are among the most effective strategies for preventing individual illness and protecting public health, “deaths from vaccine-preventable illnesses still occur in the United States,” noted Dr. Robert H. Hopkins Jr. and Dr. Keyur S. Vyas of the University of Arkansas, Little Rock, in an accompanying editorial.

Clinicians must overcome patients' perception of vaccines as necessary only for children and travelers, Dr. Hopkins and Dr. Vyas added. “Our challenge is to change this perception and to make immunizations integral to each encounter for physicians who care for adults in primary and specialty care settings.”

In addition, the importance of immunization “should be imparted directly to our patients, as well as to students and residents early in their training, as an essential component of the comprehensive care of adults in ambulatory and inpatient settings,” they said (Ann. Intern. Med. 2010;152:59-60).

The complete 2010 Adult Immunization Schedule will be available in English and Spanish at www.cdc.gov/vaccines/recs/schedules/adult-schedule.htm

Disclosures: Members of ACIP disclosed relationships with MedImmune, Sanofi Pasteur, Novartis, and Wyeth. According to the report, members with conflicts are not permitted to vote if the conflict involves the vaccine or agent being considered. Dr. Hopkins and Dr. Vyas reported no potential conflicts of interest.

Revised recommendations for human papillomavirus vaccination—including a permissive recommendation for young men—and for measles, mumps, rubella immunization are part of the newly issued 2010 immunization schedule from the Advisory Committee on Immunization Practices at the Centers for Disease Control and Prevention.

The new schedule also includes updated indications and schedule information for hepatitis A and B vaccination, as well as clarifications about meningococcal and Haemophilus influenzae type B vaccination.

The 2010 Recommended Adult Immunization Schedule, which earned ACIP approval in October 2009, reflects current recommendations for the licensed vaccines, according to the schedule's accompanying report (Ann. Intern. Med. 2010;152:36-9). The schedule is approved by the American College of Physicians, as well as the American Academy of Family Physicians and the American College of Obstetricians and Gynecologists.

The revised schedule includes these changes:

▸ For human papillomavirus (HPV), a bivalent vaccine (HPV2) has been licensed for use in females. Therefore, either the bivalent or quadrivalent (HPV4) vaccination can be used for women between 19 and 26 years. In addition, HPV4 may be given to males aged 9-25 years “to reduce their likelihood of acquiring genital warts,” according to the revised schedule.

▸ For influenza vaccination, the term “seasonal” has been added to distinguish between seasonal and pandemic influenza vaccines.

▸ For measles, mumps, rubella (MMR) vaccination, most adults born after 1957 do not require repeat vaccination if they have documentation of having received at least one dose of the vaccine. Women without documentation of rubella vaccination should receive a dose of the MMR vaccine. Health care workers, college students, international travelers, and individuals who have been exposed to measles or mumps in an outbreak setting should receive two doses of MMR. When a second MMR dose is indicated, it should be administered 4 weeks after the first dose.

Health care facilities should “consider” MMR vaccination for unvaccinated health care workers born before 1957 who do not have evidence of immunity or disease, and should “recommend” vaccination of this group during an outbreak.

▸ For hepatitis A, vaccination is recommended for unvaccinated individuals who anticipate close personal contact with an international adoptee from a country with intermediate or high endemicity to hepatitis A. The first dose should be given at least 2 weeks before the arrival of the adoptee.

▸ For the three-dose hepatitis B vaccine, the second dose should be administered 1 month after the first dose, and the third dose should be administered at least 2 months after the second. If using the combined hepatitis A and B vaccine, three doses should be administered at 0, 1, and 6 months. Alternatively, a four-dose schedule, administered on days 0, 7, 21, and 30, followed by a 12-month booster, may be used.

▸ For meningococcal vaccination, the conjugate vaccine (MCV4) is preferred for adults aged 55 years or younger, while the polysaccharide vaccine (MPSV4) is recommended for adults older than 55 years. Revaccination with MCV4 after 5 years is recommended for individuals who continue to be at risk for infection, such as adults with anatomic or functional asplenia. However, it is not recommended for individuals whose only risk factor is continued on-campus residence.

▸ For Haemophilus influenzae type B (Hib) vaccination, there is no recommendation for individuals older than age 5 years. One dose of the vaccine is not contraindicated in certain high-risk patients who have not received the vaccine previously, including those patients with sickle cell disease, leukemia, HIV infection, or splenectomy.

Although vaccines are among the most effective strategies for preventing individual illness and protecting public health, “deaths from vaccine-preventable illnesses still occur in the United States,” noted Dr. Robert H. Hopkins Jr. and Dr. Keyur S. Vyas of the University of Arkansas, Little Rock, in an accompanying editorial.

Clinicians must overcome patients' perception of vaccines as necessary only for children and travelers, Dr. Hopkins and Dr. Vyas added. “Our challenge is to change this perception and to make immunizations integral to each encounter for physicians who care for adults in primary and specialty care settings.”

In addition, the importance of immunization “should be imparted directly to our patients, as well as to students and residents early in their training, as an essential component of the comprehensive care of adults in ambulatory and inpatient settings,” they said (Ann. Intern. Med. 2010;152:59-60).

The complete 2010 Adult Immunization Schedule will be available in English and Spanish at www.cdc.gov/vaccines/recs/schedules/adult-schedule.htm

Disclosures: Members of ACIP disclosed relationships with MedImmune, Sanofi Pasteur, Novartis, and Wyeth. According to the report, members with conflicts are not permitted to vote if the conflict involves the vaccine or agent being considered. Dr. Hopkins and Dr. Vyas reported no potential conflicts of interest.

Revised recommendations for human papillomavirus vaccination—including a permissive recommendation for young men—and for measles, mumps, rubella immunization are part of the newly issued 2010 immunization schedule from the Advisory Committee on Immunization Practices at the Centers for Disease Control and Prevention.

The new schedule also includes updated indications and schedule information for hepatitis A and B vaccination, as well as clarifications about meningococcal and Haemophilus influenzae type B vaccination.

The 2010 Recommended Adult Immunization Schedule, which earned ACIP approval in October 2009, reflects current recommendations for the licensed vaccines, according to the schedule's accompanying report (Ann. Intern. Med. 2010;152:36-9). The schedule is approved by the American College of Physicians, as well as the American Academy of Family Physicians and the American College of Obstetricians and Gynecologists.

The revised schedule includes these changes:

▸ For human papillomavirus (HPV), a bivalent vaccine (HPV2) has been licensed for use in females. Therefore, either the bivalent or quadrivalent (HPV4) vaccination can be used for women between 19 and 26 years. In addition, HPV4 may be given to males aged 9-25 years “to reduce their likelihood of acquiring genital warts,” according to the revised schedule.

▸ For influenza vaccination, the term “seasonal” has been added to distinguish between seasonal and pandemic influenza vaccines.

▸ For measles, mumps, rubella (MMR) vaccination, most adults born after 1957 do not require repeat vaccination if they have documentation of having received at least one dose of the vaccine. Women without documentation of rubella vaccination should receive a dose of the MMR vaccine. Health care workers, college students, international travelers, and individuals who have been exposed to measles or mumps in an outbreak setting should receive two doses of MMR. When a second MMR dose is indicated, it should be administered 4 weeks after the first dose.

Health care facilities should “consider” MMR vaccination for unvaccinated health care workers born before 1957 who do not have evidence of immunity or disease, and should “recommend” vaccination of this group during an outbreak.

▸ For hepatitis A, vaccination is recommended for unvaccinated individuals who anticipate close personal contact with an international adoptee from a country with intermediate or high endemicity to hepatitis A. The first dose should be given at least 2 weeks before the arrival of the adoptee.

▸ For the three-dose hepatitis B vaccine, the second dose should be administered 1 month after the first dose, and the third dose should be administered at least 2 months after the second. If using the combined hepatitis A and B vaccine, three doses should be administered at 0, 1, and 6 months. Alternatively, a four-dose schedule, administered on days 0, 7, 21, and 30, followed by a 12-month booster, may be used.

▸ For meningococcal vaccination, the conjugate vaccine (MCV4) is preferred for adults aged 55 years or younger, while the polysaccharide vaccine (MPSV4) is recommended for adults older than 55 years. Revaccination with MCV4 after 5 years is recommended for individuals who continue to be at risk for infection, such as adults with anatomic or functional asplenia. However, it is not recommended for individuals whose only risk factor is continued on-campus residence.

▸ For Haemophilus influenzae type B (Hib) vaccination, there is no recommendation for individuals older than age 5 years. One dose of the vaccine is not contraindicated in certain high-risk patients who have not received the vaccine previously, including those patients with sickle cell disease, leukemia, HIV infection, or splenectomy.

Although vaccines are among the most effective strategies for preventing individual illness and protecting public health, “deaths from vaccine-preventable illnesses still occur in the United States,” noted Dr. Robert H. Hopkins Jr. and Dr. Keyur S. Vyas of the University of Arkansas, Little Rock, in an accompanying editorial.

Clinicians must overcome patients' perception of vaccines as necessary only for children and travelers, Dr. Hopkins and Dr. Vyas added. “Our challenge is to change this perception and to make immunizations integral to each encounter for physicians who care for adults in primary and specialty care settings.”

In addition, the importance of immunization “should be imparted directly to our patients, as well as to students and residents early in their training, as an essential component of the comprehensive care of adults in ambulatory and inpatient settings,” they said (Ann. Intern. Med. 2010;152:59-60).

The complete 2010 Adult Immunization Schedule will be available in English and Spanish at www.cdc.gov/vaccines/recs/schedules/adult-schedule.htm

Disclosures: Members of ACIP disclosed relationships with MedImmune, Sanofi Pasteur, Novartis, and Wyeth. According to the report, members with conflicts are not permitted to vote if the conflict involves the vaccine or agent being considered. Dr. Hopkins and Dr. Vyas reported no potential conflicts of interest.

Major Findings: Using a decision-support tool, nearly 21% of 2,646 clinical scenarios created from different combinations of patient-level factors were considered appropriate for evaluation for epilepsy surgery. None of the surgeries was rated as unnecessary.

Data Source: An expert panel's use of a decision-support tool.

Disclosures: The investigator had no relevant disclosures or conflicts of interest.

BOSTON — An online decision-support tool may help to close the protracted gap between seizure onset and referral for surgery in patients with medically intractable epilepsy, based on results obtained by an expert panel.

The user-friendly tool is designed for use by clinicians who treat epilepsy patients but may not be epilepsy specialists, according to Dr. Nathalie Jetté, who developed the tool with her colleagues at the University of Calgary (Alta.)

The tool rates the appropriateness and necessity of referring individual patients for a surgery evaluation based on factors such as age, epilepsy duration, seizure type, frequency and severity of seizures, the number of adequate epilepsy drug trials, and EEG and MRI findings, Dr. Jetté said at the annual meeting of the American Epilepsy Society.

Despite surgical success rates as high as 90% for patients with medically intractable temporal lobe epilepsy, the average time between seizure onset and surgery for these patients is 9 years for children and 19 years for adults, according to Dr. Jetté.

Based on a literature review and on discussion during a face-to-face meeting, an expert panel rated clinical scenarios for their appropriateness for an epilepsy surgery evaluation, Dr. Jetté said.

“The scenarios were rated on a scale from 1 to 9, where 1 was the most inappropriate and 9 was the most appropriate. After extensive discussion, all of the scenarios were re-rated, and those that were appropriate for referral [rated a 7 or higher] were re-rated for necessity,” she said.

For rating purposes, referral was considered a necessity if the presumed benefits exceeded the risks by a sufficient margin; if failing to refer the patient would be improper care; if there was a reasonable chance the referral would benefit the patient; and if the magnitude of the expected benefit “was not small,” she said.

Of 2,646 clinical scenarios, nearly 21% received a rating of at least 7 and were considered appropriate for surgical referral. About 17% were considered uncertain for appropriateness because they were rated 4–6, and nearly 62% were deemed inappropriate because they were rated 1–3, Dr. Jetté said.

In practice, a patient who failed one antiepileptic drug (AED) would be inappropriate for referral, but a patient who failed two AEDs and had an abnormal MRI and EEG would typically be an appropriate candidate for surgical evaluation, she explained. With respect to necessity, “none of the appropriate cases were rated as unnecessary,” she said.

Major Findings: Using a decision-support tool, nearly 21% of 2,646 clinical scenarios created from different combinations of patient-level factors were considered appropriate for evaluation for epilepsy surgery. None of the surgeries was rated as unnecessary.

Data Source: An expert panel's use of a decision-support tool.

Disclosures: The investigator had no relevant disclosures or conflicts of interest.

BOSTON — An online decision-support tool may help to close the protracted gap between seizure onset and referral for surgery in patients with medically intractable epilepsy, based on results obtained by an expert panel.

The user-friendly tool is designed for use by clinicians who treat epilepsy patients but may not be epilepsy specialists, according to Dr. Nathalie Jetté, who developed the tool with her colleagues at the University of Calgary (Alta.)

The tool rates the appropriateness and necessity of referring individual patients for a surgery evaluation based on factors such as age, epilepsy duration, seizure type, frequency and severity of seizures, the number of adequate epilepsy drug trials, and EEG and MRI findings, Dr. Jetté said at the annual meeting of the American Epilepsy Society.

Despite surgical success rates as high as 90% for patients with medically intractable temporal lobe epilepsy, the average time between seizure onset and surgery for these patients is 9 years for children and 19 years for adults, according to Dr. Jetté.

Based on a literature review and on discussion during a face-to-face meeting, an expert panel rated clinical scenarios for their appropriateness for an epilepsy surgery evaluation, Dr. Jetté said.

“The scenarios were rated on a scale from 1 to 9, where 1 was the most inappropriate and 9 was the most appropriate. After extensive discussion, all of the scenarios were re-rated, and those that were appropriate for referral [rated a 7 or higher] were re-rated for necessity,” she said.

For rating purposes, referral was considered a necessity if the presumed benefits exceeded the risks by a sufficient margin; if failing to refer the patient would be improper care; if there was a reasonable chance the referral would benefit the patient; and if the magnitude of the expected benefit “was not small,” she said.

Of 2,646 clinical scenarios, nearly 21% received a rating of at least 7 and were considered appropriate for surgical referral. About 17% were considered uncertain for appropriateness because they were rated 4–6, and nearly 62% were deemed inappropriate because they were rated 1–3, Dr. Jetté said.

In practice, a patient who failed one antiepileptic drug (AED) would be inappropriate for referral, but a patient who failed two AEDs and had an abnormal MRI and EEG would typically be an appropriate candidate for surgical evaluation, she explained. With respect to necessity, “none of the appropriate cases were rated as unnecessary,” she said.

Major Findings: Using a decision-support tool, nearly 21% of 2,646 clinical scenarios created from different combinations of patient-level factors were considered appropriate for evaluation for epilepsy surgery. None of the surgeries was rated as unnecessary.

Data Source: An expert panel's use of a decision-support tool.

Disclosures: The investigator had no relevant disclosures or conflicts of interest.

BOSTON — An online decision-support tool may help to close the protracted gap between seizure onset and referral for surgery in patients with medically intractable epilepsy, based on results obtained by an expert panel.

The user-friendly tool is designed for use by clinicians who treat epilepsy patients but may not be epilepsy specialists, according to Dr. Nathalie Jetté, who developed the tool with her colleagues at the University of Calgary (Alta.)

The tool rates the appropriateness and necessity of referring individual patients for a surgery evaluation based on factors such as age, epilepsy duration, seizure type, frequency and severity of seizures, the number of adequate epilepsy drug trials, and EEG and MRI findings, Dr. Jetté said at the annual meeting of the American Epilepsy Society.

Despite surgical success rates as high as 90% for patients with medically intractable temporal lobe epilepsy, the average time between seizure onset and surgery for these patients is 9 years for children and 19 years for adults, according to Dr. Jetté.

Based on a literature review and on discussion during a face-to-face meeting, an expert panel rated clinical scenarios for their appropriateness for an epilepsy surgery evaluation, Dr. Jetté said.

“The scenarios were rated on a scale from 1 to 9, where 1 was the most inappropriate and 9 was the most appropriate. After extensive discussion, all of the scenarios were re-rated, and those that were appropriate for referral [rated a 7 or higher] were re-rated for necessity,” she said.

For rating purposes, referral was considered a necessity if the presumed benefits exceeded the risks by a sufficient margin; if failing to refer the patient would be improper care; if there was a reasonable chance the referral would benefit the patient; and if the magnitude of the expected benefit “was not small,” she said.

Of 2,646 clinical scenarios, nearly 21% received a rating of at least 7 and were considered appropriate for surgical referral. About 17% were considered uncertain for appropriateness because they were rated 4–6, and nearly 62% were deemed inappropriate because they were rated 1–3, Dr. Jetté said.

In practice, a patient who failed one antiepileptic drug (AED) would be inappropriate for referral, but a patient who failed two AEDs and had an abnormal MRI and EEG would typically be an appropriate candidate for surgical evaluation, she explained. With respect to necessity, “none of the appropriate cases were rated as unnecessary,” she said.

Major Findings: Seizures declined by a mean of 29% during active stimulation with the device over the first 12 weeks, compared with a 14% reduction during sham activation.

Source of Data: Multicenter, randomized, sham-controlled clinical trial of 191 patients with medically intractable partial onset seizures.

Disclosures: Dr. Morrell is the chief medical officer of NeuroPace, which developed the system and funded the trial.

BOSTON — Patients with treatment-resistant epilepsy can significantly reduce their frequency of seizures with the use of an implantable device that detects pre-seizure electrical activity and preemptively aborts seizures, the results of a multicenter randomized controlled trial suggest.

In 191 patients with medically intractable partial onset seizures who were implanted with the neurostimulator, seizures declined by a mean of 29% during active stimulation with the device, compared with a 14% reduction during sham activation, Dr. Martha J. Morrell reported at the annual meeting of the American Epilepsy Society.

In the later, open-label phase of the study in which all of the patients received the active stimulation, nearly half of the 171 patients for whom 12 weeks of data were available experienced at least a 50% reduction in seizure frequency relative to baseline, said Dr. Morrell, clinical professor of neurology at Stanford (Calif.) University and chief medical officer of NeuroPace, developer of the Responsive Neurostimulator System (RNS).

The cranially implanted RNS device differs from conventional, “open loop” brain stimulation technologies that involve the scheduled delivery of electrical stimulation to specific brain regions independent of brain activity.

The responsive neurostimulation system comprises electrodes that are surgically implanted in epileptic regions of the brain and connected to the computerized, battery-powered neurostimulator, which is embedded in the patient's skull. The device is programmed to detect and disrupt significant electrical events.

“The programming is done wirelessly by the physician via a laptop computer,” Dr. Morrell said. “It's highly modifiable in that the physician can view the patient's electrocorticographic activity in real-time and change the [signal-detection] criteria at any time based on individual patient characteristics.”

Because the neurostimulation occurs in response to aberrant electrical activity in the patient's brain, fewer electrical impulses are being delivered to the brain than would occur with continuous stimulation. This in turn diminishes the possibility of treatment-related adverse events, Dr. Morrell explained.

In an initial feasibility study of 65 patients, the responsive neurostimulation system demonstrated excellent safety, tolerability, and preliminary evidence of efficacy, Dr. Morrell said.

The preliminary efficacy evidence from that study showed that a minimum 50% reduction in seizure frequency was experienced by 43% of the patients with complex partial seizures and 35% of those with total disabling seizures (Neurotherapeutics 2008;5:68–74).

In the double-blind pivotal trial, the 191 patients were randomized to active or sham therapy. All of the patients were 18–70 years of age (median age 35 years), and all had partial onset epilepsy localized to one or two foci and had failed at least two antiepileptic medications.

The patients were taking an average of three antiepileptic medications to attempt seizure control, and approximately 34% of the patients had been treated previously with vagus nerve stimulation, 33% had prior surgical resection, and 16% had been treated with both.

Of the 191 patients implanted with the responsive neurostimulator device, 50% had mesial temporal seizure onset, 42% had neocortical seizure onset, and 8% had both, Dr. Morrell said in a press briefing at the meeting.

The trial consisted of an initial 12-week period prior to system implantation during which baseline seizure activity was collected, followed by a 12-week blinded period when participants were randomly assigned to have the responsive stimulation activated or left inactive, she said.

At each of the 31 trial sites, the patients and one neurologist were blinded to the stimulation status, while a separate neurologist programmed the devices to maintain the study blinding. The responsive stimulation was optimized in the treatment over the next four weeks, followed by 84 days of data collection, Dr. Morrell said.

The responsive neurostimulation system has not yet received Food and Drug Administration approval, but NeuroPace plans to submit a premarket approval application early this year, she said.

My Take

Devices Likely to Improve Over Time

The development and use of stimulation devices for medically refractory epilepsy represents an altogether new approach when surgery is not possible and pharmacology is ineffective. Open loop devices that deliver electrical stimulation on a duty cycle include the vagal nerve stimulator (Cyberonics) and the thalamic deep brain stimulator (Medtronic).

The Responsive Neurostimulator device (NeuroPace), the first closed loop stimulator, is distinctly different than the other devices. Once it is permanently implanted using depth or surface leads, the RNS device detects and analyzes EEG/electrocorticography on a continuous basis. The device is programmed to “recognize” an individual's unique ictal onset through various algorithms. Once the abnormal signal is detected, the device responds quickly to deliver a small electrical potential in an attempt to abort the abnormal EEG activity before it can spread and become a clinical seizure.

Results for both the randomized, blinded portion and long-term, open-label portion of the pivotal RNS showed statistically significant reductions in seizure frequency with acceptably low rates of complications. With time, device technology is likely to be refined and improved, both through technical advances and additional clinical data.

DR. KATHERINE NOE and DR. JOSEPH DRAZKOWSKI are epilepsy specialists at the Mayo Clinic, Scottsdale, Ariz. They were both investigators in the RNS trial.

DR. NOE

DR. DRAZKOWSKI

Major Findings: Seizures declined by a mean of 29% during active stimulation with the device over the first 12 weeks, compared with a 14% reduction during sham activation.

Source of Data: Multicenter, randomized, sham-controlled clinical trial of 191 patients with medically intractable partial onset seizures.

Disclosures: Dr. Morrell is the chief medical officer of NeuroPace, which developed the system and funded the trial.

BOSTON — Patients with treatment-resistant epilepsy can significantly reduce their frequency of seizures with the use of an implantable device that detects pre-seizure electrical activity and preemptively aborts seizures, the results of a multicenter randomized controlled trial suggest.

In 191 patients with medically intractable partial onset seizures who were implanted with the neurostimulator, seizures declined by a mean of 29% during active stimulation with the device, compared with a 14% reduction during sham activation, Dr. Martha J. Morrell reported at the annual meeting of the American Epilepsy Society.

In the later, open-label phase of the study in which all of the patients received the active stimulation, nearly half of the 171 patients for whom 12 weeks of data were available experienced at least a 50% reduction in seizure frequency relative to baseline, said Dr. Morrell, clinical professor of neurology at Stanford (Calif.) University and chief medical officer of NeuroPace, developer of the Responsive Neurostimulator System (RNS).

The cranially implanted RNS device differs from conventional, “open loop” brain stimulation technologies that involve the scheduled delivery of electrical stimulation to specific brain regions independent of brain activity.

The responsive neurostimulation system comprises electrodes that are surgically implanted in epileptic regions of the brain and connected to the computerized, battery-powered neurostimulator, which is embedded in the patient's skull. The device is programmed to detect and disrupt significant electrical events.

“The programming is done wirelessly by the physician via a laptop computer,” Dr. Morrell said. “It's highly modifiable in that the physician can view the patient's electrocorticographic activity in real-time and change the [signal-detection] criteria at any time based on individual patient characteristics.”

Because the neurostimulation occurs in response to aberrant electrical activity in the patient's brain, fewer electrical impulses are being delivered to the brain than would occur with continuous stimulation. This in turn diminishes the possibility of treatment-related adverse events, Dr. Morrell explained.

In an initial feasibility study of 65 patients, the responsive neurostimulation system demonstrated excellent safety, tolerability, and preliminary evidence of efficacy, Dr. Morrell said.

The preliminary efficacy evidence from that study showed that a minimum 50% reduction in seizure frequency was experienced by 43% of the patients with complex partial seizures and 35% of those with total disabling seizures (Neurotherapeutics 2008;5:68–74).

In the double-blind pivotal trial, the 191 patients were randomized to active or sham therapy. All of the patients were 18–70 years of age (median age 35 years), and all had partial onset epilepsy localized to one or two foci and had failed at least two antiepileptic medications.

The patients were taking an average of three antiepileptic medications to attempt seizure control, and approximately 34% of the patients had been treated previously with vagus nerve stimulation, 33% had prior surgical resection, and 16% had been treated with both.

Of the 191 patients implanted with the responsive neurostimulator device, 50% had mesial temporal seizure onset, 42% had neocortical seizure onset, and 8% had both, Dr. Morrell said in a press briefing at the meeting.

The trial consisted of an initial 12-week period prior to system implantation during which baseline seizure activity was collected, followed by a 12-week blinded period when participants were randomly assigned to have the responsive stimulation activated or left inactive, she said.

At each of the 31 trial sites, the patients and one neurologist were blinded to the stimulation status, while a separate neurologist programmed the devices to maintain the study blinding. The responsive stimulation was optimized in the treatment over the next four weeks, followed by 84 days of data collection, Dr. Morrell said.

The responsive neurostimulation system has not yet received Food and Drug Administration approval, but NeuroPace plans to submit a premarket approval application early this year, she said.

My Take

Devices Likely to Improve Over Time

The development and use of stimulation devices for medically refractory epilepsy represents an altogether new approach when surgery is not possible and pharmacology is ineffective. Open loop devices that deliver electrical stimulation on a duty cycle include the vagal nerve stimulator (Cyberonics) and the thalamic deep brain stimulator (Medtronic).

The Responsive Neurostimulator device (NeuroPace), the first closed loop stimulator, is distinctly different than the other devices. Once it is permanently implanted using depth or surface leads, the RNS device detects and analyzes EEG/electrocorticography on a continuous basis. The device is programmed to “recognize” an individual's unique ictal onset through various algorithms. Once the abnormal signal is detected, the device responds quickly to deliver a small electrical potential in an attempt to abort the abnormal EEG activity before it can spread and become a clinical seizure.

Results for both the randomized, blinded portion and long-term, open-label portion of the pivotal RNS showed statistically significant reductions in seizure frequency with acceptably low rates of complications. With time, device technology is likely to be refined and improved, both through technical advances and additional clinical data.

DR. KATHERINE NOE and DR. JOSEPH DRAZKOWSKI are epilepsy specialists at the Mayo Clinic, Scottsdale, Ariz. They were both investigators in the RNS trial.

DR. NOE

DR. DRAZKOWSKI

Major Findings: Seizures declined by a mean of 29% during active stimulation with the device over the first 12 weeks, compared with a 14% reduction during sham activation.

Source of Data: Multicenter, randomized, sham-controlled clinical trial of 191 patients with medically intractable partial onset seizures.

Disclosures: Dr. Morrell is the chief medical officer of NeuroPace, which developed the system and funded the trial.

BOSTON — Patients with treatment-resistant epilepsy can significantly reduce their frequency of seizures with the use of an implantable device that detects pre-seizure electrical activity and preemptively aborts seizures, the results of a multicenter randomized controlled trial suggest.

In 191 patients with medically intractable partial onset seizures who were implanted with the neurostimulator, seizures declined by a mean of 29% during active stimulation with the device, compared with a 14% reduction during sham activation, Dr. Martha J. Morrell reported at the annual meeting of the American Epilepsy Society.

In the later, open-label phase of the study in which all of the patients received the active stimulation, nearly half of the 171 patients for whom 12 weeks of data were available experienced at least a 50% reduction in seizure frequency relative to baseline, said Dr. Morrell, clinical professor of neurology at Stanford (Calif.) University and chief medical officer of NeuroPace, developer of the Responsive Neurostimulator System (RNS).

The cranially implanted RNS device differs from conventional, “open loop” brain stimulation technologies that involve the scheduled delivery of electrical stimulation to specific brain regions independent of brain activity.

The responsive neurostimulation system comprises electrodes that are surgically implanted in epileptic regions of the brain and connected to the computerized, battery-powered neurostimulator, which is embedded in the patient's skull. The device is programmed to detect and disrupt significant electrical events.

“The programming is done wirelessly by the physician via a laptop computer,” Dr. Morrell said. “It's highly modifiable in that the physician can view the patient's electrocorticographic activity in real-time and change the [signal-detection] criteria at any time based on individual patient characteristics.”

Because the neurostimulation occurs in response to aberrant electrical activity in the patient's brain, fewer electrical impulses are being delivered to the brain than would occur with continuous stimulation. This in turn diminishes the possibility of treatment-related adverse events, Dr. Morrell explained.

In an initial feasibility study of 65 patients, the responsive neurostimulation system demonstrated excellent safety, tolerability, and preliminary evidence of efficacy, Dr. Morrell said.

The preliminary efficacy evidence from that study showed that a minimum 50% reduction in seizure frequency was experienced by 43% of the patients with complex partial seizures and 35% of those with total disabling seizures (Neurotherapeutics 2008;5:68–74).

In the double-blind pivotal trial, the 191 patients were randomized to active or sham therapy. All of the patients were 18–70 years of age (median age 35 years), and all had partial onset epilepsy localized to one or two foci and had failed at least two antiepileptic medications.

The patients were taking an average of three antiepileptic medications to attempt seizure control, and approximately 34% of the patients had been treated previously with vagus nerve stimulation, 33% had prior surgical resection, and 16% had been treated with both.

Of the 191 patients implanted with the responsive neurostimulator device, 50% had mesial temporal seizure onset, 42% had neocortical seizure onset, and 8% had both, Dr. Morrell said in a press briefing at the meeting.

The trial consisted of an initial 12-week period prior to system implantation during which baseline seizure activity was collected, followed by a 12-week blinded period when participants were randomly assigned to have the responsive stimulation activated or left inactive, she said.

At each of the 31 trial sites, the patients and one neurologist were blinded to the stimulation status, while a separate neurologist programmed the devices to maintain the study blinding. The responsive stimulation was optimized in the treatment over the next four weeks, followed by 84 days of data collection, Dr. Morrell said.

The responsive neurostimulation system has not yet received Food and Drug Administration approval, but NeuroPace plans to submit a premarket approval application early this year, she said.

My Take

Devices Likely to Improve Over Time

The development and use of stimulation devices for medically refractory epilepsy represents an altogether new approach when surgery is not possible and pharmacology is ineffective. Open loop devices that deliver electrical stimulation on a duty cycle include the vagal nerve stimulator (Cyberonics) and the thalamic deep brain stimulator (Medtronic).

The Responsive Neurostimulator device (NeuroPace), the first closed loop stimulator, is distinctly different than the other devices. Once it is permanently implanted using depth or surface leads, the RNS device detects and analyzes EEG/electrocorticography on a continuous basis. The device is programmed to “recognize” an individual's unique ictal onset through various algorithms. Once the abnormal signal is detected, the device responds quickly to deliver a small electrical potential in an attempt to abort the abnormal EEG activity before it can spread and become a clinical seizure.

Results for both the randomized, blinded portion and long-term, open-label portion of the pivotal RNS showed statistically significant reductions in seizure frequency with acceptably low rates of complications. With time, device technology is likely to be refined and improved, both through technical advances and additional clinical data.

DR. KATHERINE NOE and DR. JOSEPH DRAZKOWSKI are epilepsy specialists at the Mayo Clinic, Scottsdale, Ariz. They were both investigators in the RNS trial.

DR. NOE

DR. DRAZKOWSKI

BOSTON — A gene signature that predicts survival after surgery for hepatocellular carcinoma also predicts the outcome of liver cirrhosis, a study has shown.

“The findings suggest that we might be able to identify patients who need preventive treatment for advanced cirrhosis and possibly hepatocellular carcinoma,” Dr. Yujin Hoshida said at the annual meeting of the American Association for the Study of Liver Diseases.

Compensated cirrhotic patients at risk of poor prognosis can be identified via the 186-gene signature of nontumor liver tissue, Dr. Hoshida said.

The investigators performed whole-genome gene expression analysis of liver biopsy specimens obtained from 276 patients with compensated cirrhosis who were included in a prospective surveillance study for hepatocellular carcinoma, said Dr. Hoshida of the Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.

Dr. Hoshida and his colleagues previously developed and reported (N. Engl. J. Med. 2008;359:1995–2004) a technique for globally profiling gene expression from formalin-fixed, paraffin-embedded (FFPE) tissues. The method enabled them to profile both nontumor and cancerous tissue obtained from 307 liver cancer patients participating in prospective surveillance studies.

The technique involved the use of a modified cDNA-mediated annealing, selection, extension, and ligation assay to interrogate approximately 6,000 genes expressed in the tumor and nontumor tissue. By partitioning samples into training and validation sets, the investigators were able to develop a 186-gene signature of nontumor tissues to predict hepatocellular carcinoma survival.

In the current study, the investigators used Cox regression modeling to evaluate the potential associations between the 186-gene signature and overall survival, hepatocellular carcinoma, and hepatic decompensation in patients with compensated cirrhosis.

Almost all (98%, or 270) of the 276 patients from whom biopsy specimens were obtained were classified as Child-Pugh A with respect to cirrhosis severity, Dr. Hoshida said. Approximately 90% of the participants had hepatitis C infection, and the median baseline serum alpha-fetoprotein level was 6 mg/dL. Most patients (62%) were male.

During the prospective surveillance period (median follow-up of 9.8 years), 90 patients (33%) died, 81 (29%) developed hepatocellular carcinoma, and 88 (32%) developed hepatic decompensation, he reported.

In multivariate analyses, the 186-gene signature was associated with overall survival, with a hazard ratio (HR) of 2.2. It also was associated with hepatocellular carcinoma development (HR, 1.6) and hepatic decompensation (HR, 2.1). The association between the gene signature and each of the three outcomes remained significant after adjustment for bilirubin greater than 1.0 mg/dL and platelet count, Dr. Hoshida said.

Subsequent gene set enrichment analysis revealed enrichment of metabolic related pathways in patients with a good prognosis and enrichment of pathways associated with inflammation (including those related to interferon and tumor necrosis factor-alpha signaling) in patients with a poorer prognosis, he noted.

Dr. Hoshida reported having no conflicts of interest.

BOSTON — A gene signature that predicts survival after surgery for hepatocellular carcinoma also predicts the outcome of liver cirrhosis, a study has shown.

“The findings suggest that we might be able to identify patients who need preventive treatment for advanced cirrhosis and possibly hepatocellular carcinoma,” Dr. Yujin Hoshida said at the annual meeting of the American Association for the Study of Liver Diseases.

Compensated cirrhotic patients at risk of poor prognosis can be identified via the 186-gene signature of nontumor liver tissue, Dr. Hoshida said.

The investigators performed whole-genome gene expression analysis of liver biopsy specimens obtained from 276 patients with compensated cirrhosis who were included in a prospective surveillance study for hepatocellular carcinoma, said Dr. Hoshida of the Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.

Dr. Hoshida and his colleagues previously developed and reported (N. Engl. J. Med. 2008;359:1995–2004) a technique for globally profiling gene expression from formalin-fixed, paraffin-embedded (FFPE) tissues. The method enabled them to profile both nontumor and cancerous tissue obtained from 307 liver cancer patients participating in prospective surveillance studies.

The technique involved the use of a modified cDNA-mediated annealing, selection, extension, and ligation assay to interrogate approximately 6,000 genes expressed in the tumor and nontumor tissue. By partitioning samples into training and validation sets, the investigators were able to develop a 186-gene signature of nontumor tissues to predict hepatocellular carcinoma survival.

In the current study, the investigators used Cox regression modeling to evaluate the potential associations between the 186-gene signature and overall survival, hepatocellular carcinoma, and hepatic decompensation in patients with compensated cirrhosis.

Almost all (98%, or 270) of the 276 patients from whom biopsy specimens were obtained were classified as Child-Pugh A with respect to cirrhosis severity, Dr. Hoshida said. Approximately 90% of the participants had hepatitis C infection, and the median baseline serum alpha-fetoprotein level was 6 mg/dL. Most patients (62%) were male.

During the prospective surveillance period (median follow-up of 9.8 years), 90 patients (33%) died, 81 (29%) developed hepatocellular carcinoma, and 88 (32%) developed hepatic decompensation, he reported.

In multivariate analyses, the 186-gene signature was associated with overall survival, with a hazard ratio (HR) of 2.2. It also was associated with hepatocellular carcinoma development (HR, 1.6) and hepatic decompensation (HR, 2.1). The association between the gene signature and each of the three outcomes remained significant after adjustment for bilirubin greater than 1.0 mg/dL and platelet count, Dr. Hoshida said.

Subsequent gene set enrichment analysis revealed enrichment of metabolic related pathways in patients with a good prognosis and enrichment of pathways associated with inflammation (including those related to interferon and tumor necrosis factor-alpha signaling) in patients with a poorer prognosis, he noted.

Dr. Hoshida reported having no conflicts of interest.

BOSTON — A gene signature that predicts survival after surgery for hepatocellular carcinoma also predicts the outcome of liver cirrhosis, a study has shown.

“The findings suggest that we might be able to identify patients who need preventive treatment for advanced cirrhosis and possibly hepatocellular carcinoma,” Dr. Yujin Hoshida said at the annual meeting of the American Association for the Study of Liver Diseases.

Compensated cirrhotic patients at risk of poor prognosis can be identified via the 186-gene signature of nontumor liver tissue, Dr. Hoshida said.

The investigators performed whole-genome gene expression analysis of liver biopsy specimens obtained from 276 patients with compensated cirrhosis who were included in a prospective surveillance study for hepatocellular carcinoma, said Dr. Hoshida of the Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge.

Dr. Hoshida and his colleagues previously developed and reported (N. Engl. J. Med. 2008;359:1995–2004) a technique for globally profiling gene expression from formalin-fixed, paraffin-embedded (FFPE) tissues. The method enabled them to profile both nontumor and cancerous tissue obtained from 307 liver cancer patients participating in prospective surveillance studies.

The technique involved the use of a modified cDNA-mediated annealing, selection, extension, and ligation assay to interrogate approximately 6,000 genes expressed in the tumor and nontumor tissue. By partitioning samples into training and validation sets, the investigators were able to develop a 186-gene signature of nontumor tissues to predict hepatocellular carcinoma survival.

In the current study, the investigators used Cox regression modeling to evaluate the potential associations between the 186-gene signature and overall survival, hepatocellular carcinoma, and hepatic decompensation in patients with compensated cirrhosis.

Almost all (98%, or 270) of the 276 patients from whom biopsy specimens were obtained were classified as Child-Pugh A with respect to cirrhosis severity, Dr. Hoshida said. Approximately 90% of the participants had hepatitis C infection, and the median baseline serum alpha-fetoprotein level was 6 mg/dL. Most patients (62%) were male.

During the prospective surveillance period (median follow-up of 9.8 years), 90 patients (33%) died, 81 (29%) developed hepatocellular carcinoma, and 88 (32%) developed hepatic decompensation, he reported.

In multivariate analyses, the 186-gene signature was associated with overall survival, with a hazard ratio (HR) of 2.2. It also was associated with hepatocellular carcinoma development (HR, 1.6) and hepatic decompensation (HR, 2.1). The association between the gene signature and each of the three outcomes remained significant after adjustment for bilirubin greater than 1.0 mg/dL and platelet count, Dr. Hoshida said.

Subsequent gene set enrichment analysis revealed enrichment of metabolic related pathways in patients with a good prognosis and enrichment of pathways associated with inflammation (including those related to interferon and tumor necrosis factor-alpha signaling) in patients with a poorer prognosis, he noted.

Dr. Hoshida reported having no conflicts of interest.

BOSTON — The use of vitamin E supplements by patients with nonalcoholic steatohepatitis was associated with a greater improvement in nonalcoholic fatty liver disease activity scores and cytologic ballooning, compared with the use of pioglitazone or placebo, results from a randomized controlled trial showed.

The investigation was spurred by findings suggesting that oxidative damage and insulin resistance both play a role in the chronic liver disease, Dr. Arun J. Sanyal said at the American Association for the Study of Liver Diseases. He and his colleagues at Virginia Commonwealth University, Richmond, sought to evaluate the role of vitamin E, an antioxidant, and pioglitazone, an insulin-sensitizing agent, in the treatment of nonalcoholic steatohepatitis (NASH).

The 247 patients were randomized to receive 800 IU of vitamin E once daily, 30 mg of pioglitazone once daily, or placebo for 96 weeks. All of the patients had biopsy-proven steatohepatitis with a nonalcoholic fatty liver disease (NAFLD) activity score of 4 or higher within 6 months prior to randomization, Dr. Sanyal said.

The study's primary end point was improvement—defined as a decrease in NAFLD activity score of 2 points or more and a decrease of at least 1 point in cytologic ballooning—and no worsening of fibrosis. Secondary end points included changes in histologic features, liver enzymes, insulin resistance, anthropometric measures, and quality of life, Dr. Sanyal explained.

Because the study encompassed two primary comparisons (vitamin E vs. placebo and pioglitazone vs. placebo) “we prespecified a significance value for the primary end point,” he said, noting that a P value less than .025 relative to placebo was considered significant.

Compared with placebo, both vitamin E and pioglitazone were associated with liver function improvement, decreased ballooning, and better fibrosis stabilization at 96 weeks, although only vitamin E met the prespecified level of significance for the preliminary end point, Dr, Sanyal said.

Of the 84 patients randomized to vitamin E, 43% demonstrated the predefined composite improvement, compared with 34% of the pioglitazone group and 19% of the placebo group, he said.

The failure of pioglitazone to meet the end point criteria can likely be attributed to the fact that substantially fewer patients in that group had ballooning at baseline “and therefore couldn't demonstrate a reduction with treatment,” he said.

Improvement in steatosis as measured by poststudy biopsy, lobular inflammation, ballooning scores, and serum alanine aminotransferase levels were observed in both treatment groups compared with placebo, Dr. Sanyal reported.

Regarding other secondary end points, patients on pioglitazone had greater weight gain (mean 4.7 kg) than did those on vitamin E (0.4 kg) or placebo (0.8 kg), but they also were the only group to demonstrate an improvement in insulin resistance, said Dr. Sanyal, who described that outcome as expected, as previous studies have produced similar results. Neither treatment produced significant changes in quality of life, he said.

Although the study suggests that both vitamin E and pioglitazone can lead to biochemical and histologic improvement in NASH, studies are needed not only to determine the sustainability of the observed histological and clinical outcomes, but also the long-term safety.

With respect to the vitamin E findings in particular, “this should resurrect our efforts to use antioxidants [for NASH] and, more importantly, to develop very potent antioxidants that are well tolerated in these patients,” Dr. Scott Friedman, of the Mount Sinai School of Medicine, New York.

The study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases.

Dr. Sanyal disclosed financial relationships with Amylin Pharmaceuticals, Astellas Pharma Inc., Bayer AG, Exalenz Bioscience Ltd., Gilead, Ikaria Holdings Inc., Intercept, Onyx Pharmaceuticals, Pfizer Inc., Salix Pharmaceuticals, Sanofi-Aventis, Takeda Pharmaceuticals Co., and Vertex Pharmaceuticals. Dr. Friedman disclosed relationships with Angion Biomedica Corp., Axcan Pharma Inc., Celera Corp., Exalenz, Intercept, Sanofi-Aventis, Stromedix Inc., and 7TM Pharma.

Only vitamin E met the prespecified level of significance for the preliminary end point.

Source DR. SANYAL

BOSTON — The use of vitamin E supplements by patients with nonalcoholic steatohepatitis was associated with a greater improvement in nonalcoholic fatty liver disease activity scores and cytologic ballooning, compared with the use of pioglitazone or placebo, results from a randomized controlled trial showed.

The investigation was spurred by findings suggesting that oxidative damage and insulin resistance both play a role in the chronic liver disease, Dr. Arun J. Sanyal said at the American Association for the Study of Liver Diseases. He and his colleagues at Virginia Commonwealth University, Richmond, sought to evaluate the role of vitamin E, an antioxidant, and pioglitazone, an insulin-sensitizing agent, in the treatment of nonalcoholic steatohepatitis (NASH).

The 247 patients were randomized to receive 800 IU of vitamin E once daily, 30 mg of pioglitazone once daily, or placebo for 96 weeks. All of the patients had biopsy-proven steatohepatitis with a nonalcoholic fatty liver disease (NAFLD) activity score of 4 or higher within 6 months prior to randomization, Dr. Sanyal said.

The study's primary end point was improvement—defined as a decrease in NAFLD activity score of 2 points or more and a decrease of at least 1 point in cytologic ballooning—and no worsening of fibrosis. Secondary end points included changes in histologic features, liver enzymes, insulin resistance, anthropometric measures, and quality of life, Dr. Sanyal explained.

Because the study encompassed two primary comparisons (vitamin E vs. placebo and pioglitazone vs. placebo) “we prespecified a significance value for the primary end point,” he said, noting that a P value less than .025 relative to placebo was considered significant.

Compared with placebo, both vitamin E and pioglitazone were associated with liver function improvement, decreased ballooning, and better fibrosis stabilization at 96 weeks, although only vitamin E met the prespecified level of significance for the preliminary end point, Dr, Sanyal said.

Of the 84 patients randomized to vitamin E, 43% demonstrated the predefined composite improvement, compared with 34% of the pioglitazone group and 19% of the placebo group, he said.

The failure of pioglitazone to meet the end point criteria can likely be attributed to the fact that substantially fewer patients in that group had ballooning at baseline “and therefore couldn't demonstrate a reduction with treatment,” he said.

Improvement in steatosis as measured by poststudy biopsy, lobular inflammation, ballooning scores, and serum alanine aminotransferase levels were observed in both treatment groups compared with placebo, Dr. Sanyal reported.

Regarding other secondary end points, patients on pioglitazone had greater weight gain (mean 4.7 kg) than did those on vitamin E (0.4 kg) or placebo (0.8 kg), but they also were the only group to demonstrate an improvement in insulin resistance, said Dr. Sanyal, who described that outcome as expected, as previous studies have produced similar results. Neither treatment produced significant changes in quality of life, he said.

Although the study suggests that both vitamin E and pioglitazone can lead to biochemical and histologic improvement in NASH, studies are needed not only to determine the sustainability of the observed histological and clinical outcomes, but also the long-term safety.

With respect to the vitamin E findings in particular, “this should resurrect our efforts to use antioxidants [for NASH] and, more importantly, to develop very potent antioxidants that are well tolerated in these patients,” Dr. Scott Friedman, of the Mount Sinai School of Medicine, New York.

The study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases.

Dr. Sanyal disclosed financial relationships with Amylin Pharmaceuticals, Astellas Pharma Inc., Bayer AG, Exalenz Bioscience Ltd., Gilead, Ikaria Holdings Inc., Intercept, Onyx Pharmaceuticals, Pfizer Inc., Salix Pharmaceuticals, Sanofi-Aventis, Takeda Pharmaceuticals Co., and Vertex Pharmaceuticals. Dr. Friedman disclosed relationships with Angion Biomedica Corp., Axcan Pharma Inc., Celera Corp., Exalenz, Intercept, Sanofi-Aventis, Stromedix Inc., and 7TM Pharma.

Only vitamin E met the prespecified level of significance for the preliminary end point.

Source DR. SANYAL

BOSTON — The use of vitamin E supplements by patients with nonalcoholic steatohepatitis was associated with a greater improvement in nonalcoholic fatty liver disease activity scores and cytologic ballooning, compared with the use of pioglitazone or placebo, results from a randomized controlled trial showed.

The investigation was spurred by findings suggesting that oxidative damage and insulin resistance both play a role in the chronic liver disease, Dr. Arun J. Sanyal said at the American Association for the Study of Liver Diseases. He and his colleagues at Virginia Commonwealth University, Richmond, sought to evaluate the role of vitamin E, an antioxidant, and pioglitazone, an insulin-sensitizing agent, in the treatment of nonalcoholic steatohepatitis (NASH).

The 247 patients were randomized to receive 800 IU of vitamin E once daily, 30 mg of pioglitazone once daily, or placebo for 96 weeks. All of the patients had biopsy-proven steatohepatitis with a nonalcoholic fatty liver disease (NAFLD) activity score of 4 or higher within 6 months prior to randomization, Dr. Sanyal said.

The study's primary end point was improvement—defined as a decrease in NAFLD activity score of 2 points or more and a decrease of at least 1 point in cytologic ballooning—and no worsening of fibrosis. Secondary end points included changes in histologic features, liver enzymes, insulin resistance, anthropometric measures, and quality of life, Dr. Sanyal explained.

Because the study encompassed two primary comparisons (vitamin E vs. placebo and pioglitazone vs. placebo) “we prespecified a significance value for the primary end point,” he said, noting that a P value less than .025 relative to placebo was considered significant.

Compared with placebo, both vitamin E and pioglitazone were associated with liver function improvement, decreased ballooning, and better fibrosis stabilization at 96 weeks, although only vitamin E met the prespecified level of significance for the preliminary end point, Dr, Sanyal said.

Of the 84 patients randomized to vitamin E, 43% demonstrated the predefined composite improvement, compared with 34% of the pioglitazone group and 19% of the placebo group, he said.

The failure of pioglitazone to meet the end point criteria can likely be attributed to the fact that substantially fewer patients in that group had ballooning at baseline “and therefore couldn't demonstrate a reduction with treatment,” he said.

Improvement in steatosis as measured by poststudy biopsy, lobular inflammation, ballooning scores, and serum alanine aminotransferase levels were observed in both treatment groups compared with placebo, Dr. Sanyal reported.

Regarding other secondary end points, patients on pioglitazone had greater weight gain (mean 4.7 kg) than did those on vitamin E (0.4 kg) or placebo (0.8 kg), but they also were the only group to demonstrate an improvement in insulin resistance, said Dr. Sanyal, who described that outcome as expected, as previous studies have produced similar results. Neither treatment produced significant changes in quality of life, he said.

Although the study suggests that both vitamin E and pioglitazone can lead to biochemical and histologic improvement in NASH, studies are needed not only to determine the sustainability of the observed histological and clinical outcomes, but also the long-term safety.

With respect to the vitamin E findings in particular, “this should resurrect our efforts to use antioxidants [for NASH] and, more importantly, to develop very potent antioxidants that are well tolerated in these patients,” Dr. Scott Friedman, of the Mount Sinai School of Medicine, New York.

The study was sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases.

Dr. Sanyal disclosed financial relationships with Amylin Pharmaceuticals, Astellas Pharma Inc., Bayer AG, Exalenz Bioscience Ltd., Gilead, Ikaria Holdings Inc., Intercept, Onyx Pharmaceuticals, Pfizer Inc., Salix Pharmaceuticals, Sanofi-Aventis, Takeda Pharmaceuticals Co., and Vertex Pharmaceuticals. Dr. Friedman disclosed relationships with Angion Biomedica Corp., Axcan Pharma Inc., Celera Corp., Exalenz, Intercept, Sanofi-Aventis, Stromedix Inc., and 7TM Pharma.

Only vitamin E met the prespecified level of significance for the preliminary end point.

Source DR. SANYAL