Diana Mahoney

BOSTON – Although brain metastasis is a notoriously formidable foe in the battle against breast cancer, recent breakthroughs in some patient subgroups suggest a challenge to its reign of terror.

As the ranks of women living with advanced breast cancer have swelled, thanks to treatment advances that alter the natural history of the disease, so has the incidence of tumor progression in the brain, according to Dr. Nancy U. Lin. The brain is a particularly hospitable sanctuary for cancer cells because few of the current chemotherapy agents penetrate the blood-brain barrier.

Current strategies for managing brain metastases have not substantially altered patient outcomes, Dr. Lin told attendees at a breast cancer program sponsored by Harvard Medical School in Boston.

But improved understanding of the biology of primary tumors and the specific sensitivities of tumor subtypes to various therapies (along with the identification of mediators of CNS progression) promises to usher in a new era in the treatment – and possibly prevention – of brain metastases in breast cancer, predicted Dr. Lin of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston.

Most Common in HER2 and Triple-Negative Disease

A critical consideration in the development of treatment and prevention strategies is tumor subtype. The highest incidences of brain metastases in breast cancer occur in women with HER2-positive disease and those with triple-negative (estrogen receptor–, progesterone receptor–, and HER2-negative) disease, Dr. Lin said, noting that there is also significant variation in prognosis within these subtypes.

Although estimates for median survival after a diagnosis of brain metastasis from breast cancer have been 6 months on average in historical series, many recent series have reported a median survival of 1-2 years for metastatic breast cancer patients who are HER2-positive, she said. The median survival for patients with triple-negative disease is less than 6 months, however.

These survival differences have important management implications, Dr. Lin explained. Effective, targeted, extracranial therapies extend the survival of many HER2-positive patients relative to historical estimates, and ultimately, more than half of these patients die as a result of CNS progression. In contrast, the shorter survival of women with triple-negative disease is generally attributable to progression in both the brain and distant sites.

For this reason, she said, therapies targeting the central nervous system specifically are warranted in the HER2-positive setting, whereas improved systemic treatments that target all metastatic sites are needed for patients with triple-negative disease.

Despite advances in the understanding of brain metastasis in breast cancer, the currently available treatment options are limited; as yet, no guidelines have been published for the management of brain metastasis associated specifically with breast cancer, according to Dr. Lin.

Surgery, stereotactic radiosurgery, and whole-brain radiotherapy are potential local therapeutic options, depending on the number, size, and site of metastatic lesions, she said; conventional breast cancer chemotherapies also have demonstrated efficacy in the first-line setting.

Along with her Dana-Farber colleague, Dr. ElgeneLim, she recently published a review article outlining the range of local and systemic therapeutic considerations for this patient population (Oncology 2012 July 12 [Epub ahead of print]). First-line therapies "typically have better response rates than therapies in heavily pretreated disease, and there is a need to identify therapies that will work in CNS disease that progresses following local and systemic therapies," the authors observed.

Lapatinib Studied for CNS Penetration

Among HER2-directed therapies, the small-molecule TKI (tyrosine kinase inhibitor) lapatinib (Tykerb) continues to pique interest. Because of its micromolecular structure, the agent can achieve greater CNS penetration than can the macromolecular agents, including monoclonal antibodies.

To date, this theoretical advantage has been associated with modest clinical benefit in trials. For example, in a clinical trial of single agent lapatinib, Dr. Lin and colleagues demonstrated a 2.6% objective response and an approximately 20% clinical benefit (J. Clin. Oncol. 2008;26:1993-9).

In a trial comparing the drug in combination with capecitabine (Xeloda) or topotecan (Hycamtin) in patients with brain metastasis following radiotherapy (J. Neurooncol. 2011;105: 613-20), "the objective central nervous system response was 38%," in the lapatinib plus capecitabine arm, Dr. Lin said.

Although the study was closed early because of toxicity and lack of efficacy in the topotecan arm, the observation of CNS activity in the lapatinib-capecitabine arm was promising, as were updated results from the pivotal randomized registration trial of lapatinib, suggesting that lapatinib may delay the onset of brain metastases in breast cancer patients with HER2-positive metastatic disease (Oncologist 2010;15:924-34).

In an editorial accompanying the review article by Dr. Lim and Dr. Lin, Dr. Mark D. Pegram of Stanford (Calif.) University observed that the lapatinib data suggest that "an ‘adjuvant’ HER2-TKI immediately following primary neurosurgery and/or radiotherapy for newly diagnosed [breast cancer brain metastasis] might be a more compelling treatment strategy than waiting for measurable relapse to occur following primary local therapy for HER2-positive CNS metastasis"(Oncology 2012 July 12 [Epub ahead of print]).

The ongoing ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial, comparing adjuvant trastuzumab (Herceptin) with trastuzumab plus lapatinib, will offer important insight into the potential preventive value of lapatinib with respect to CNS relapse in early-stage HER2-positive disease, he wrote.

New Agents Also in Trials

Additional systemic and combination therapies representing a range of potential approaches are also under investigation, said Dr. Lin. These include the novel HER2-targeted therapies neratinib and afatinib, both of which are being evaluated in phase II trials, as well as cytotoxic agents targeting brain metastases specifically. The latter agents include the peptide-taxane conjugate GRN1005, the glutathione-pegylated liposomal doxorubicin 2B3-101, and the third-generation taxane TPI 287 – all three of which are being evaluated in phase I and II trials.

Also under investigation, she added, are PIK3CA inhibitors, mTOR (mammalian target of rapamycin) inhibitors, PARP (poly[ADP-ribose] polymerase) inhibitors, and VEGF (vascular endothelial growth factor)–targeting agents.

In order for research in this arena to bear fruit that translates into clinically effective strategies, the improvement of clinical trial availability and access should be a top priority, Dr. Lin stressed.

"Breast cancer patients with brain metastasis have been routinely excluded from clinical trials," which limits investigators’ ability to evaluate novel therapies, she said. "Our goal should be to increase and continue efforts to study novel agents in patients with brain metastases to establish better historical control data."

Dr. Lin disclosed financial relationships with GlaxoSmithKline, Genentech, Geron, Boehringer Ingelheim, Bayer, and Novartis.

BOSTON – Although brain metastasis is a notoriously formidable foe in the battle against breast cancer, recent breakthroughs in some patient subgroups suggest a challenge to its reign of terror.

As the ranks of women living with advanced breast cancer have swelled, thanks to treatment advances that alter the natural history of the disease, so has the incidence of tumor progression in the brain, according to Dr. Nancy U. Lin. The brain is a particularly hospitable sanctuary for cancer cells because few of the current chemotherapy agents penetrate the blood-brain barrier.

Current strategies for managing brain metastases have not substantially altered patient outcomes, Dr. Lin told attendees at a breast cancer program sponsored by Harvard Medical School in Boston.

But improved understanding of the biology of primary tumors and the specific sensitivities of tumor subtypes to various therapies (along with the identification of mediators of CNS progression) promises to usher in a new era in the treatment – and possibly prevention – of brain metastases in breast cancer, predicted Dr. Lin of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston.

Most Common in HER2 and Triple-Negative Disease

A critical consideration in the development of treatment and prevention strategies is tumor subtype. The highest incidences of brain metastases in breast cancer occur in women with HER2-positive disease and those with triple-negative (estrogen receptor–, progesterone receptor–, and HER2-negative) disease, Dr. Lin said, noting that there is also significant variation in prognosis within these subtypes.

Although estimates for median survival after a diagnosis of brain metastasis from breast cancer have been 6 months on average in historical series, many recent series have reported a median survival of 1-2 years for metastatic breast cancer patients who are HER2-positive, she said. The median survival for patients with triple-negative disease is less than 6 months, however.

These survival differences have important management implications, Dr. Lin explained. Effective, targeted, extracranial therapies extend the survival of many HER2-positive patients relative to historical estimates, and ultimately, more than half of these patients die as a result of CNS progression. In contrast, the shorter survival of women with triple-negative disease is generally attributable to progression in both the brain and distant sites.

For this reason, she said, therapies targeting the central nervous system specifically are warranted in the HER2-positive setting, whereas improved systemic treatments that target all metastatic sites are needed for patients with triple-negative disease.

Despite advances in the understanding of brain metastasis in breast cancer, the currently available treatment options are limited; as yet, no guidelines have been published for the management of brain metastasis associated specifically with breast cancer, according to Dr. Lin.

Surgery, stereotactic radiosurgery, and whole-brain radiotherapy are potential local therapeutic options, depending on the number, size, and site of metastatic lesions, she said; conventional breast cancer chemotherapies also have demonstrated efficacy in the first-line setting.

Along with her Dana-Farber colleague, Dr. ElgeneLim, she recently published a review article outlining the range of local and systemic therapeutic considerations for this patient population (Oncology 2012 July 12 [Epub ahead of print]). First-line therapies "typically have better response rates than therapies in heavily pretreated disease, and there is a need to identify therapies that will work in CNS disease that progresses following local and systemic therapies," the authors observed.

Lapatinib Studied for CNS Penetration

Among HER2-directed therapies, the small-molecule TKI (tyrosine kinase inhibitor) lapatinib (Tykerb) continues to pique interest. Because of its micromolecular structure, the agent can achieve greater CNS penetration than can the macromolecular agents, including monoclonal antibodies.

To date, this theoretical advantage has been associated with modest clinical benefit in trials. For example, in a clinical trial of single agent lapatinib, Dr. Lin and colleagues demonstrated a 2.6% objective response and an approximately 20% clinical benefit (J. Clin. Oncol. 2008;26:1993-9).

In a trial comparing the drug in combination with capecitabine (Xeloda) or topotecan (Hycamtin) in patients with brain metastasis following radiotherapy (J. Neurooncol. 2011;105: 613-20), "the objective central nervous system response was 38%," in the lapatinib plus capecitabine arm, Dr. Lin said.

Although the study was closed early because of toxicity and lack of efficacy in the topotecan arm, the observation of CNS activity in the lapatinib-capecitabine arm was promising, as were updated results from the pivotal randomized registration trial of lapatinib, suggesting that lapatinib may delay the onset of brain metastases in breast cancer patients with HER2-positive metastatic disease (Oncologist 2010;15:924-34).

In an editorial accompanying the review article by Dr. Lim and Dr. Lin, Dr. Mark D. Pegram of Stanford (Calif.) University observed that the lapatinib data suggest that "an ‘adjuvant’ HER2-TKI immediately following primary neurosurgery and/or radiotherapy for newly diagnosed [breast cancer brain metastasis] might be a more compelling treatment strategy than waiting for measurable relapse to occur following primary local therapy for HER2-positive CNS metastasis"(Oncology 2012 July 12 [Epub ahead of print]).

The ongoing ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial, comparing adjuvant trastuzumab (Herceptin) with trastuzumab plus lapatinib, will offer important insight into the potential preventive value of lapatinib with respect to CNS relapse in early-stage HER2-positive disease, he wrote.

New Agents Also in Trials

Additional systemic and combination therapies representing a range of potential approaches are also under investigation, said Dr. Lin. These include the novel HER2-targeted therapies neratinib and afatinib, both of which are being evaluated in phase II trials, as well as cytotoxic agents targeting brain metastases specifically. The latter agents include the peptide-taxane conjugate GRN1005, the glutathione-pegylated liposomal doxorubicin 2B3-101, and the third-generation taxane TPI 287 – all three of which are being evaluated in phase I and II trials.

Also under investigation, she added, are PIK3CA inhibitors, mTOR (mammalian target of rapamycin) inhibitors, PARP (poly[ADP-ribose] polymerase) inhibitors, and VEGF (vascular endothelial growth factor)–targeting agents.

In order for research in this arena to bear fruit that translates into clinically effective strategies, the improvement of clinical trial availability and access should be a top priority, Dr. Lin stressed.

"Breast cancer patients with brain metastasis have been routinely excluded from clinical trials," which limits investigators’ ability to evaluate novel therapies, she said. "Our goal should be to increase and continue efforts to study novel agents in patients with brain metastases to establish better historical control data."

Dr. Lin disclosed financial relationships with GlaxoSmithKline, Genentech, Geron, Boehringer Ingelheim, Bayer, and Novartis.

BOSTON – Although brain metastasis is a notoriously formidable foe in the battle against breast cancer, recent breakthroughs in some patient subgroups suggest a challenge to its reign of terror.

As the ranks of women living with advanced breast cancer have swelled, thanks to treatment advances that alter the natural history of the disease, so has the incidence of tumor progression in the brain, according to Dr. Nancy U. Lin. The brain is a particularly hospitable sanctuary for cancer cells because few of the current chemotherapy agents penetrate the blood-brain barrier.

Current strategies for managing brain metastases have not substantially altered patient outcomes, Dr. Lin told attendees at a breast cancer program sponsored by Harvard Medical School in Boston.

But improved understanding of the biology of primary tumors and the specific sensitivities of tumor subtypes to various therapies (along with the identification of mediators of CNS progression) promises to usher in a new era in the treatment – and possibly prevention – of brain metastases in breast cancer, predicted Dr. Lin of the Dana-Farber Cancer Institute and Harvard Medical School, both in Boston.

Most Common in HER2 and Triple-Negative Disease

A critical consideration in the development of treatment and prevention strategies is tumor subtype. The highest incidences of brain metastases in breast cancer occur in women with HER2-positive disease and those with triple-negative (estrogen receptor–, progesterone receptor–, and HER2-negative) disease, Dr. Lin said, noting that there is also significant variation in prognosis within these subtypes.

Although estimates for median survival after a diagnosis of brain metastasis from breast cancer have been 6 months on average in historical series, many recent series have reported a median survival of 1-2 years for metastatic breast cancer patients who are HER2-positive, she said. The median survival for patients with triple-negative disease is less than 6 months, however.

These survival differences have important management implications, Dr. Lin explained. Effective, targeted, extracranial therapies extend the survival of many HER2-positive patients relative to historical estimates, and ultimately, more than half of these patients die as a result of CNS progression. In contrast, the shorter survival of women with triple-negative disease is generally attributable to progression in both the brain and distant sites.

For this reason, she said, therapies targeting the central nervous system specifically are warranted in the HER2-positive setting, whereas improved systemic treatments that target all metastatic sites are needed for patients with triple-negative disease.

Despite advances in the understanding of brain metastasis in breast cancer, the currently available treatment options are limited; as yet, no guidelines have been published for the management of brain metastasis associated specifically with breast cancer, according to Dr. Lin.

Surgery, stereotactic radiosurgery, and whole-brain radiotherapy are potential local therapeutic options, depending on the number, size, and site of metastatic lesions, she said; conventional breast cancer chemotherapies also have demonstrated efficacy in the first-line setting.

Along with her Dana-Farber colleague, Dr. ElgeneLim, she recently published a review article outlining the range of local and systemic therapeutic considerations for this patient population (Oncology 2012 July 12 [Epub ahead of print]). First-line therapies "typically have better response rates than therapies in heavily pretreated disease, and there is a need to identify therapies that will work in CNS disease that progresses following local and systemic therapies," the authors observed.

Lapatinib Studied for CNS Penetration

Among HER2-directed therapies, the small-molecule TKI (tyrosine kinase inhibitor) lapatinib (Tykerb) continues to pique interest. Because of its micromolecular structure, the agent can achieve greater CNS penetration than can the macromolecular agents, including monoclonal antibodies.

To date, this theoretical advantage has been associated with modest clinical benefit in trials. For example, in a clinical trial of single agent lapatinib, Dr. Lin and colleagues demonstrated a 2.6% objective response and an approximately 20% clinical benefit (J. Clin. Oncol. 2008;26:1993-9).

In a trial comparing the drug in combination with capecitabine (Xeloda) or topotecan (Hycamtin) in patients with brain metastasis following radiotherapy (J. Neurooncol. 2011;105: 613-20), "the objective central nervous system response was 38%," in the lapatinib plus capecitabine arm, Dr. Lin said.

Although the study was closed early because of toxicity and lack of efficacy in the topotecan arm, the observation of CNS activity in the lapatinib-capecitabine arm was promising, as were updated results from the pivotal randomized registration trial of lapatinib, suggesting that lapatinib may delay the onset of brain metastases in breast cancer patients with HER2-positive metastatic disease (Oncologist 2010;15:924-34).

In an editorial accompanying the review article by Dr. Lim and Dr. Lin, Dr. Mark D. Pegram of Stanford (Calif.) University observed that the lapatinib data suggest that "an ‘adjuvant’ HER2-TKI immediately following primary neurosurgery and/or radiotherapy for newly diagnosed [breast cancer brain metastasis] might be a more compelling treatment strategy than waiting for measurable relapse to occur following primary local therapy for HER2-positive CNS metastasis"(Oncology 2012 July 12 [Epub ahead of print]).

The ongoing ALTTO (Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization) trial, comparing adjuvant trastuzumab (Herceptin) with trastuzumab plus lapatinib, will offer important insight into the potential preventive value of lapatinib with respect to CNS relapse in early-stage HER2-positive disease, he wrote.

New Agents Also in Trials

Additional systemic and combination therapies representing a range of potential approaches are also under investigation, said Dr. Lin. These include the novel HER2-targeted therapies neratinib and afatinib, both of which are being evaluated in phase II trials, as well as cytotoxic agents targeting brain metastases specifically. The latter agents include the peptide-taxane conjugate GRN1005, the glutathione-pegylated liposomal doxorubicin 2B3-101, and the third-generation taxane TPI 287 – all three of which are being evaluated in phase I and II trials.

Also under investigation, she added, are PIK3CA inhibitors, mTOR (mammalian target of rapamycin) inhibitors, PARP (poly[ADP-ribose] polymerase) inhibitors, and VEGF (vascular endothelial growth factor)–targeting agents.

In order for research in this arena to bear fruit that translates into clinically effective strategies, the improvement of clinical trial availability and access should be a top priority, Dr. Lin stressed.

"Breast cancer patients with brain metastasis have been routinely excluded from clinical trials," which limits investigators’ ability to evaluate novel therapies, she said. "Our goal should be to increase and continue efforts to study novel agents in patients with brain metastases to establish better historical control data."

Dr. Lin disclosed financial relationships with GlaxoSmithKline, Genentech, Geron, Boehringer Ingelheim, Bayer, and Novartis.

Pre-exposure HIV-1 prophylaxis with tenofovir alone or in combination with emtricitabine reduces the incidence of HIV-1 infection in healthy heterosexual partners of HIV-1-infected individuals, according to a large study published July 11 in the New England Journal of Medicine.

The findings provide proof of concept that pre-exposure prophylaxis can reduce HIV-1 acquisition in heterosexual populations, and suggest that the strategy may be a useful public health measure together with risk-reduction counseling and other prevention services, wrote Dr. Jared M. Baeten of the University of Washington in Seattle and his colleagues.

Of the 4,747 HIV-1 serodiscordant couples from nine sites in Kenya and Uganda enrolled in the Pre-exposure Prophylaxis (PrEP) study from July 2008 to November 2010, 1,584 and 1,579 of the seronegative partners were respectively randomized to a daily fixed dose of 300 mg of tenofovir (TDF) alone or 200 mg of tenofovir-emtricitabine (TDF-FTC), and 1,584 seronegative partners were randomized to placebo. More than half of the study’s seronegative partners in each study arm were male, including 62%, 64%, and 61% in the monotherapy, combination therapy, and placebo groups, respectively.

After 36 months, the incidence of HIV-1 was reduced by 67% and 75% in the monotherapy and combination groups, respectively, compared with placebo.

As per study protocol, all the seronegative partners had normal renal function, were not infected with the hepatitis B virus, and were not pregnant or breastfeeding. None of the HIV-1 seropositive partners were receiving antiretroviral therapy, nor did they meet Kenyan or Ugandan guidelines for initiation of antiretroviral therapy, the authors reported.

All the participants received a "comprehensive package" of HIV-1 prevention services, including HIV-1 testing and pre- and post-test counseling; screening and testing for sexually transmitted diseases; free condoms with training and counseling; referral for male circumcision; postexposure prophylaxis as per national standards; and the option of hepatitis B virus vaccination (N. Engl J. Med 2012 July 11 [doi: 10.1056/NEJMoa1108524]).

All the seronegative partners had monthly clinic visits during which they underwent HIV-1 and pregnancy testing, individualized adherence counseling, and standardized assessment of sexual behavior and side effects. Serum chemical and hematologic analyses were performed in the first month and then quarterly thereafter. CD4 counts were obtained at 6-month intervals, with referral to local clinics for those who became eligible for initiation of antiretroviral therapy.

During the course of the study, a total of 82 HIV-1 infections were documented in the previously seronegative participants, including 17 in the TDF group, 13 in the TDF-FTC group, and 52 in the placebo group, reflecting incidence rates per 100 person-years of 0.65, 0.50, and 1.99, respectively.

"The HIV-1 protective effects of TDF-FTC and TDF were not significantly different," the authors stated, noting that this finding contradicts those reported in previous studies of animal models. The rates of death, serious adverse events, and serum creatinine or phosphorus abnormalities were similar across the study groups.

When assessed by gender, the efficacy of TDF and TDF-FTC relative to placebo was 71% and 66%, respectively, in women, and 63% and 84% in men, with no statistical difference in the protective effects of either protocol according to sex, the authors observed.

In addition, "protection against HIV-1 was generally similar between subgroup categories for other prespecified subgroup analyses," including age, frequency of unprotected sex with study partner during past month, country, circumcision status of HIV-1 seronegative men, and plasma HIV-1 RNA levels and CD4 counts among the seropositive partner.

Of the participants receiving active treatment, eight were found to have been infected with HIV-1 at baseline, two of whom developed antiretroviral resistance during the study, the authors noted.

"Potential implementation of pre-exposure prophylaxis as a public health measure will require clinical monitoring, methods for encouraging adherence, and ensured access to antiretroviral therapy for HIV-1 infected persons," they wrote.

The trial was funded by the Bill and Melinda Gates Foundation. The authors disclosed no relevant financial conflicts of interest.

Pre-exposure HIV-1 prophylaxis with tenofovir alone or in combination with emtricitabine reduces the incidence of HIV-1 infection in healthy heterosexual partners of HIV-1-infected individuals, according to a large study published July 11 in the New England Journal of Medicine.

The findings provide proof of concept that pre-exposure prophylaxis can reduce HIV-1 acquisition in heterosexual populations, and suggest that the strategy may be a useful public health measure together with risk-reduction counseling and other prevention services, wrote Dr. Jared M. Baeten of the University of Washington in Seattle and his colleagues.

Of the 4,747 HIV-1 serodiscordant couples from nine sites in Kenya and Uganda enrolled in the Pre-exposure Prophylaxis (PrEP) study from July 2008 to November 2010, 1,584 and 1,579 of the seronegative partners were respectively randomized to a daily fixed dose of 300 mg of tenofovir (TDF) alone or 200 mg of tenofovir-emtricitabine (TDF-FTC), and 1,584 seronegative partners were randomized to placebo. More than half of the study’s seronegative partners in each study arm were male, including 62%, 64%, and 61% in the monotherapy, combination therapy, and placebo groups, respectively.

After 36 months, the incidence of HIV-1 was reduced by 67% and 75% in the monotherapy and combination groups, respectively, compared with placebo.

As per study protocol, all the seronegative partners had normal renal function, were not infected with the hepatitis B virus, and were not pregnant or breastfeeding. None of the HIV-1 seropositive partners were receiving antiretroviral therapy, nor did they meet Kenyan or Ugandan guidelines for initiation of antiretroviral therapy, the authors reported.

All the participants received a "comprehensive package" of HIV-1 prevention services, including HIV-1 testing and pre- and post-test counseling; screening and testing for sexually transmitted diseases; free condoms with training and counseling; referral for male circumcision; postexposure prophylaxis as per national standards; and the option of hepatitis B virus vaccination (N. Engl J. Med 2012 July 11 [doi: 10.1056/NEJMoa1108524]).

All the seronegative partners had monthly clinic visits during which they underwent HIV-1 and pregnancy testing, individualized adherence counseling, and standardized assessment of sexual behavior and side effects. Serum chemical and hematologic analyses were performed in the first month and then quarterly thereafter. CD4 counts were obtained at 6-month intervals, with referral to local clinics for those who became eligible for initiation of antiretroviral therapy.

During the course of the study, a total of 82 HIV-1 infections were documented in the previously seronegative participants, including 17 in the TDF group, 13 in the TDF-FTC group, and 52 in the placebo group, reflecting incidence rates per 100 person-years of 0.65, 0.50, and 1.99, respectively.

"The HIV-1 protective effects of TDF-FTC and TDF were not significantly different," the authors stated, noting that this finding contradicts those reported in previous studies of animal models. The rates of death, serious adverse events, and serum creatinine or phosphorus abnormalities were similar across the study groups.

When assessed by gender, the efficacy of TDF and TDF-FTC relative to placebo was 71% and 66%, respectively, in women, and 63% and 84% in men, with no statistical difference in the protective effects of either protocol according to sex, the authors observed.

In addition, "protection against HIV-1 was generally similar between subgroup categories for other prespecified subgroup analyses," including age, frequency of unprotected sex with study partner during past month, country, circumcision status of HIV-1 seronegative men, and plasma HIV-1 RNA levels and CD4 counts among the seropositive partner.

Of the participants receiving active treatment, eight were found to have been infected with HIV-1 at baseline, two of whom developed antiretroviral resistance during the study, the authors noted.

"Potential implementation of pre-exposure prophylaxis as a public health measure will require clinical monitoring, methods for encouraging adherence, and ensured access to antiretroviral therapy for HIV-1 infected persons," they wrote.

The trial was funded by the Bill and Melinda Gates Foundation. The authors disclosed no relevant financial conflicts of interest.

Pre-exposure HIV-1 prophylaxis with tenofovir alone or in combination with emtricitabine reduces the incidence of HIV-1 infection in healthy heterosexual partners of HIV-1-infected individuals, according to a large study published July 11 in the New England Journal of Medicine.

The findings provide proof of concept that pre-exposure prophylaxis can reduce HIV-1 acquisition in heterosexual populations, and suggest that the strategy may be a useful public health measure together with risk-reduction counseling and other prevention services, wrote Dr. Jared M. Baeten of the University of Washington in Seattle and his colleagues.

Of the 4,747 HIV-1 serodiscordant couples from nine sites in Kenya and Uganda enrolled in the Pre-exposure Prophylaxis (PrEP) study from July 2008 to November 2010, 1,584 and 1,579 of the seronegative partners were respectively randomized to a daily fixed dose of 300 mg of tenofovir (TDF) alone or 200 mg of tenofovir-emtricitabine (TDF-FTC), and 1,584 seronegative partners were randomized to placebo. More than half of the study’s seronegative partners in each study arm were male, including 62%, 64%, and 61% in the monotherapy, combination therapy, and placebo groups, respectively.

After 36 months, the incidence of HIV-1 was reduced by 67% and 75% in the monotherapy and combination groups, respectively, compared with placebo.

As per study protocol, all the seronegative partners had normal renal function, were not infected with the hepatitis B virus, and were not pregnant or breastfeeding. None of the HIV-1 seropositive partners were receiving antiretroviral therapy, nor did they meet Kenyan or Ugandan guidelines for initiation of antiretroviral therapy, the authors reported.

All the participants received a "comprehensive package" of HIV-1 prevention services, including HIV-1 testing and pre- and post-test counseling; screening and testing for sexually transmitted diseases; free condoms with training and counseling; referral for male circumcision; postexposure prophylaxis as per national standards; and the option of hepatitis B virus vaccination (N. Engl J. Med 2012 July 11 [doi: 10.1056/NEJMoa1108524]).

All the seronegative partners had monthly clinic visits during which they underwent HIV-1 and pregnancy testing, individualized adherence counseling, and standardized assessment of sexual behavior and side effects. Serum chemical and hematologic analyses were performed in the first month and then quarterly thereafter. CD4 counts were obtained at 6-month intervals, with referral to local clinics for those who became eligible for initiation of antiretroviral therapy.

During the course of the study, a total of 82 HIV-1 infections were documented in the previously seronegative participants, including 17 in the TDF group, 13 in the TDF-FTC group, and 52 in the placebo group, reflecting incidence rates per 100 person-years of 0.65, 0.50, and 1.99, respectively.

"The HIV-1 protective effects of TDF-FTC and TDF were not significantly different," the authors stated, noting that this finding contradicts those reported in previous studies of animal models. The rates of death, serious adverse events, and serum creatinine or phosphorus abnormalities were similar across the study groups.

When assessed by gender, the efficacy of TDF and TDF-FTC relative to placebo was 71% and 66%, respectively, in women, and 63% and 84% in men, with no statistical difference in the protective effects of either protocol according to sex, the authors observed.

In addition, "protection against HIV-1 was generally similar between subgroup categories for other prespecified subgroup analyses," including age, frequency of unprotected sex with study partner during past month, country, circumcision status of HIV-1 seronegative men, and plasma HIV-1 RNA levels and CD4 counts among the seropositive partner.

Of the participants receiving active treatment, eight were found to have been infected with HIV-1 at baseline, two of whom developed antiretroviral resistance during the study, the authors noted.

"Potential implementation of pre-exposure prophylaxis as a public health measure will require clinical monitoring, methods for encouraging adherence, and ensured access to antiretroviral therapy for HIV-1 infected persons," they wrote.

The trial was funded by the Bill and Melinda Gates Foundation. The authors disclosed no relevant financial conflicts of interest.

BOSTON – Treatment with continuous positive airway pressure does double duty in patients with obstructive sleep apnea by improving their mood while promoting restful sleep, Dr. Charles Bae reported at the annual meeting of the Associated Professional Sleep Societies.

In a retrospective study of 769 adults with OSA, the Cleveland Clinic neurologist and his colleagues observed a significant decrease in depressive symptoms as measured by the Patient Health Questionnaire 9 (PHQ-9) among patients who used a CPAP device.

"A number of studies have confirmed an association between obstructive sleep apnea and depressive symptoms, but until now none have looked specifically at the link between CPAP and symptom severity as measured by PHQ-9," Dr. Bae said in an interview. "Our goal was to assess the impact of CPAP therapy on patient mood by measuring the change in depressive symptoms following treatment."

Toward this end, the investigators reviewed data for all of the adult patients (18 years or older) with OSA seen at the Cleveland Clinic Sleep Disorders Center from January 2008 to July 2011. Patients who met study criteria had been treated with CPAP and had at least two outpatient visits (one before and one within 30 days after initiating CPAP), had completed the PHQ-9 questionnaire, and had a pre-CPAP score on the questionnaire of at least 5, Dr. Bae said.

Of the 769 study patients (mean age, 51.8 years), 654 were characterized as adherent to CPAP therapy based on self-reported use of the device 4 or more hours per night; the remaining 115 used the device either inconsistently or for fewer than 4 hours per night and were considered nonadherent. The baseline PHQ-9 scores for patients in the adherent and nonadherent groups were similar, at 11.2 and 11.8, respectively. Significant decreases from baseline in PHQ-9 scores were observed in both groups, but the difference was "significantly more robust" in the adherent group at 3.8, compared with 2.0 in the nonadherent group, Dr. Bae reported.

The results were even more robust among patients who had reported sleepiness at baseline, according to Dr. Bae. Specifically, in the patients who had a minimum score of 10 on the Epworth Sleepiness Scale prior to CPAP, ESS scores decreased by 4.0 in the adherent group vs. 2.8 in the nonadherent group, he said. In the CPAP-adherent group, there was a significant difference between sleepy vs. nonsleepy patients in their average decrease in PHQ-9 score. "The PHQ-9 score dropped 4.3 points among patients whose [ESS] score was at least 10 at baseline, compared with 3.1 points among those whose score was less than 10," he said.

Marital status was also examined as a covariate in the multiple regression model and appeared to have an effect. The mean PHQ-9 score decrease among the 475 married patients after CPAP was 4.0, compared with 3.0 among single patients and 2.3 among divorced patients, Dr. Bae said, noting that the difference between married and divorced patients was significant.

While the specific mechanisms contributing to the mood improvements associated with CPAP treatment in OSA patients can’t be ascertained from a retrospective study, the findings are fairly intuitive, according to Dr. Bae. When people sleep better, "a lot of things look better," he said.

Dr. Bae disclosed no relevant conflicts of interest.

BOSTON – Treatment with continuous positive airway pressure does double duty in patients with obstructive sleep apnea by improving their mood while promoting restful sleep, Dr. Charles Bae reported at the annual meeting of the Associated Professional Sleep Societies.

In a retrospective study of 769 adults with OSA, the Cleveland Clinic neurologist and his colleagues observed a significant decrease in depressive symptoms as measured by the Patient Health Questionnaire 9 (PHQ-9) among patients who used a CPAP device.

"A number of studies have confirmed an association between obstructive sleep apnea and depressive symptoms, but until now none have looked specifically at the link between CPAP and symptom severity as measured by PHQ-9," Dr. Bae said in an interview. "Our goal was to assess the impact of CPAP therapy on patient mood by measuring the change in depressive symptoms following treatment."

Toward this end, the investigators reviewed data for all of the adult patients (18 years or older) with OSA seen at the Cleveland Clinic Sleep Disorders Center from January 2008 to July 2011. Patients who met study criteria had been treated with CPAP and had at least two outpatient visits (one before and one within 30 days after initiating CPAP), had completed the PHQ-9 questionnaire, and had a pre-CPAP score on the questionnaire of at least 5, Dr. Bae said.

Of the 769 study patients (mean age, 51.8 years), 654 were characterized as adherent to CPAP therapy based on self-reported use of the device 4 or more hours per night; the remaining 115 used the device either inconsistently or for fewer than 4 hours per night and were considered nonadherent. The baseline PHQ-9 scores for patients in the adherent and nonadherent groups were similar, at 11.2 and 11.8, respectively. Significant decreases from baseline in PHQ-9 scores were observed in both groups, but the difference was "significantly more robust" in the adherent group at 3.8, compared with 2.0 in the nonadherent group, Dr. Bae reported.

The results were even more robust among patients who had reported sleepiness at baseline, according to Dr. Bae. Specifically, in the patients who had a minimum score of 10 on the Epworth Sleepiness Scale prior to CPAP, ESS scores decreased by 4.0 in the adherent group vs. 2.8 in the nonadherent group, he said. In the CPAP-adherent group, there was a significant difference between sleepy vs. nonsleepy patients in their average decrease in PHQ-9 score. "The PHQ-9 score dropped 4.3 points among patients whose [ESS] score was at least 10 at baseline, compared with 3.1 points among those whose score was less than 10," he said.

Marital status was also examined as a covariate in the multiple regression model and appeared to have an effect. The mean PHQ-9 score decrease among the 475 married patients after CPAP was 4.0, compared with 3.0 among single patients and 2.3 among divorced patients, Dr. Bae said, noting that the difference between married and divorced patients was significant.

While the specific mechanisms contributing to the mood improvements associated with CPAP treatment in OSA patients can’t be ascertained from a retrospective study, the findings are fairly intuitive, according to Dr. Bae. When people sleep better, "a lot of things look better," he said.

Dr. Bae disclosed no relevant conflicts of interest.

BOSTON – Treatment with continuous positive airway pressure does double duty in patients with obstructive sleep apnea by improving their mood while promoting restful sleep, Dr. Charles Bae reported at the annual meeting of the Associated Professional Sleep Societies.

In a retrospective study of 769 adults with OSA, the Cleveland Clinic neurologist and his colleagues observed a significant decrease in depressive symptoms as measured by the Patient Health Questionnaire 9 (PHQ-9) among patients who used a CPAP device.

"A number of studies have confirmed an association between obstructive sleep apnea and depressive symptoms, but until now none have looked specifically at the link between CPAP and symptom severity as measured by PHQ-9," Dr. Bae said in an interview. "Our goal was to assess the impact of CPAP therapy on patient mood by measuring the change in depressive symptoms following treatment."

Toward this end, the investigators reviewed data for all of the adult patients (18 years or older) with OSA seen at the Cleveland Clinic Sleep Disorders Center from January 2008 to July 2011. Patients who met study criteria had been treated with CPAP and had at least two outpatient visits (one before and one within 30 days after initiating CPAP), had completed the PHQ-9 questionnaire, and had a pre-CPAP score on the questionnaire of at least 5, Dr. Bae said.

Of the 769 study patients (mean age, 51.8 years), 654 were characterized as adherent to CPAP therapy based on self-reported use of the device 4 or more hours per night; the remaining 115 used the device either inconsistently or for fewer than 4 hours per night and were considered nonadherent. The baseline PHQ-9 scores for patients in the adherent and nonadherent groups were similar, at 11.2 and 11.8, respectively. Significant decreases from baseline in PHQ-9 scores were observed in both groups, but the difference was "significantly more robust" in the adherent group at 3.8, compared with 2.0 in the nonadherent group, Dr. Bae reported.

The results were even more robust among patients who had reported sleepiness at baseline, according to Dr. Bae. Specifically, in the patients who had a minimum score of 10 on the Epworth Sleepiness Scale prior to CPAP, ESS scores decreased by 4.0 in the adherent group vs. 2.8 in the nonadherent group, he said. In the CPAP-adherent group, there was a significant difference between sleepy vs. nonsleepy patients in their average decrease in PHQ-9 score. "The PHQ-9 score dropped 4.3 points among patients whose [ESS] score was at least 10 at baseline, compared with 3.1 points among those whose score was less than 10," he said.

Marital status was also examined as a covariate in the multiple regression model and appeared to have an effect. The mean PHQ-9 score decrease among the 475 married patients after CPAP was 4.0, compared with 3.0 among single patients and 2.3 among divorced patients, Dr. Bae said, noting that the difference between married and divorced patients was significant.

While the specific mechanisms contributing to the mood improvements associated with CPAP treatment in OSA patients can’t be ascertained from a retrospective study, the findings are fairly intuitive, according to Dr. Bae. When people sleep better, "a lot of things look better," he said.

Dr. Bae disclosed no relevant conflicts of interest.

A risk evaluation and mitigation strategy for extended-release and long-acting opioid medications has received Food and Drug Administration approval.

The move has been anticipated as an important element in an attempt to stem the swelling tide of abuse, misuse, and overdose of these prescription drugs while assuring continued access to the highly potent analgesics for patients with moderate to severe persistent pain, Dr. Margaret A. Hamburg said in a media briefing.

The new safety measures, which pertain to approximately 30 currently available medications, will require the manufacturers of the drugs to make FDA-approved education materials available to prescribers no later than March 1, 2013, via development grants to continuing education providers who will develop and deliver the training, said Dr. Hamburg, commissioner of the FDA. In addition, the risk evaluation and mitigation strategy (REMS) will include the distribution of a patient counseling leaflet to prescribers regarding the safe and effective use of the drugs; an updated, single-page medication guide for consumers, an implementation plan, and periodic assessments to evaluate the impact of the program on the safe use of these products, which the FDA will review and use to tweak the program as needed, she said.

"It is important to note that we are focusing on extended-release and long-acting opioid medications ... because these have very specific safety problems that have to be addressed very carefully," according to Dr. John Jenkins, director of the Office of New Drugs within the FDA’s Center for Drug Evaluation and Research. These drugs, including hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine, "can cause problems even when prescribed appropriately."

The prescriber education component of the REMS will include information regarding the risks and benefits of opioid therapy for individual patients, choosing patients appropriately, patient management and monitoring, and patient counseling, Dr. Jenkins explained. It will also include guidance on the potential for misuse, abuse, and addition, as well as recognizing evidence for these outcomes. The updated medication guide and patient counseling document will include information on how to safely use, store, and dispose of these analgesics, specific instructions for recognizing the signs of potential overdose and advice for preventing accidental exposure to family and household visitors, he said.

With respect to the assessment and auditing component of the program, the FDA has established goals, which the manufacturers are expected to achieve, for the percentage of prescribers who complete the training and for assessing prescribers’ understanding of the risk information. Participation in the educational programs is not mandatory for prescribers, Dr. Hamburg stated. The assessments are also required to evaluate whether the [REMS] adversely affect patient access to these drugs, she said. "Patients in pain must have continued assess to medications they need," she added.

The new REMS program is one component of a multiagency, national strategy unveiled by the White House in 2011 to address prescription drug abuse, "which is this country’s fastest-growing drug problem," said Dr. Hamburg, noting that opioid overdoses in particular were the cause of approximately 15,000 deaths among Americans in 2008 and nearly 16,000 in 2009. Called Epidemic: Responding to America's Prescription Drug Abuse Crisis, the national plan suggests expansion of state-based prescription drug-monitoring programs; seeks creation of recommendations for convenient and environmentally responsible ways to dispose of unused medications; and calls for legislative action to reduce "doctor shopping" and "pill mills."

In the absence of the legislative changes needed to fulfill the comprehensive White House plan, the REMS "is an important and timely step by FDA to supplement prescriber training and consumer information," R. Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said during the telebriefing.

A risk evaluation and mitigation strategy for extended-release and long-acting opioid medications has received Food and Drug Administration approval.

The move has been anticipated as an important element in an attempt to stem the swelling tide of abuse, misuse, and overdose of these prescription drugs while assuring continued access to the highly potent analgesics for patients with moderate to severe persistent pain, Dr. Margaret A. Hamburg said in a media briefing.

The new safety measures, which pertain to approximately 30 currently available medications, will require the manufacturers of the drugs to make FDA-approved education materials available to prescribers no later than March 1, 2013, via development grants to continuing education providers who will develop and deliver the training, said Dr. Hamburg, commissioner of the FDA. In addition, the risk evaluation and mitigation strategy (REMS) will include the distribution of a patient counseling leaflet to prescribers regarding the safe and effective use of the drugs; an updated, single-page medication guide for consumers, an implementation plan, and periodic assessments to evaluate the impact of the program on the safe use of these products, which the FDA will review and use to tweak the program as needed, she said.

"It is important to note that we are focusing on extended-release and long-acting opioid medications ... because these have very specific safety problems that have to be addressed very carefully," according to Dr. John Jenkins, director of the Office of New Drugs within the FDA’s Center for Drug Evaluation and Research. These drugs, including hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine, "can cause problems even when prescribed appropriately."

The prescriber education component of the REMS will include information regarding the risks and benefits of opioid therapy for individual patients, choosing patients appropriately, patient management and monitoring, and patient counseling, Dr. Jenkins explained. It will also include guidance on the potential for misuse, abuse, and addition, as well as recognizing evidence for these outcomes. The updated medication guide and patient counseling document will include information on how to safely use, store, and dispose of these analgesics, specific instructions for recognizing the signs of potential overdose and advice for preventing accidental exposure to family and household visitors, he said.

With respect to the assessment and auditing component of the program, the FDA has established goals, which the manufacturers are expected to achieve, for the percentage of prescribers who complete the training and for assessing prescribers’ understanding of the risk information. Participation in the educational programs is not mandatory for prescribers, Dr. Hamburg stated. The assessments are also required to evaluate whether the [REMS] adversely affect patient access to these drugs, she said. "Patients in pain must have continued assess to medications they need," she added.

The new REMS program is one component of a multiagency, national strategy unveiled by the White House in 2011 to address prescription drug abuse, "which is this country’s fastest-growing drug problem," said Dr. Hamburg, noting that opioid overdoses in particular were the cause of approximately 15,000 deaths among Americans in 2008 and nearly 16,000 in 2009. Called Epidemic: Responding to America's Prescription Drug Abuse Crisis, the national plan suggests expansion of state-based prescription drug-monitoring programs; seeks creation of recommendations for convenient and environmentally responsible ways to dispose of unused medications; and calls for legislative action to reduce "doctor shopping" and "pill mills."

In the absence of the legislative changes needed to fulfill the comprehensive White House plan, the REMS "is an important and timely step by FDA to supplement prescriber training and consumer information," R. Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said during the telebriefing.

A risk evaluation and mitigation strategy for extended-release and long-acting opioid medications has received Food and Drug Administration approval.

The move has been anticipated as an important element in an attempt to stem the swelling tide of abuse, misuse, and overdose of these prescription drugs while assuring continued access to the highly potent analgesics for patients with moderate to severe persistent pain, Dr. Margaret A. Hamburg said in a media briefing.

The new safety measures, which pertain to approximately 30 currently available medications, will require the manufacturers of the drugs to make FDA-approved education materials available to prescribers no later than March 1, 2013, via development grants to continuing education providers who will develop and deliver the training, said Dr. Hamburg, commissioner of the FDA. In addition, the risk evaluation and mitigation strategy (REMS) will include the distribution of a patient counseling leaflet to prescribers regarding the safe and effective use of the drugs; an updated, single-page medication guide for consumers, an implementation plan, and periodic assessments to evaluate the impact of the program on the safe use of these products, which the FDA will review and use to tweak the program as needed, she said.

"It is important to note that we are focusing on extended-release and long-acting opioid medications ... because these have very specific safety problems that have to be addressed very carefully," according to Dr. John Jenkins, director of the Office of New Drugs within the FDA’s Center for Drug Evaluation and Research. These drugs, including hydromorphone, oxycodone, morphine, oxymorphone, methadone, transdermal fentanyl, and transdermal buprenorphine, "can cause problems even when prescribed appropriately."

The prescriber education component of the REMS will include information regarding the risks and benefits of opioid therapy for individual patients, choosing patients appropriately, patient management and monitoring, and patient counseling, Dr. Jenkins explained. It will also include guidance on the potential for misuse, abuse, and addition, as well as recognizing evidence for these outcomes. The updated medication guide and patient counseling document will include information on how to safely use, store, and dispose of these analgesics, specific instructions for recognizing the signs of potential overdose and advice for preventing accidental exposure to family and household visitors, he said.

With respect to the assessment and auditing component of the program, the FDA has established goals, which the manufacturers are expected to achieve, for the percentage of prescribers who complete the training and for assessing prescribers’ understanding of the risk information. Participation in the educational programs is not mandatory for prescribers, Dr. Hamburg stated. The assessments are also required to evaluate whether the [REMS] adversely affect patient access to these drugs, she said. "Patients in pain must have continued assess to medications they need," she added.

The new REMS program is one component of a multiagency, national strategy unveiled by the White House in 2011 to address prescription drug abuse, "which is this country’s fastest-growing drug problem," said Dr. Hamburg, noting that opioid overdoses in particular were the cause of approximately 15,000 deaths among Americans in 2008 and nearly 16,000 in 2009. Called Epidemic: Responding to America's Prescription Drug Abuse Crisis, the national plan suggests expansion of state-based prescription drug-monitoring programs; seeks creation of recommendations for convenient and environmentally responsible ways to dispose of unused medications; and calls for legislative action to reduce "doctor shopping" and "pill mills."

In the absence of the legislative changes needed to fulfill the comprehensive White House plan, the REMS "is an important and timely step by FDA to supplement prescriber training and consumer information," R. Gil Kerlikowske, director of the White House Office of National Drug Control Policy, said during the telebriefing.

Real-time continuous glucose monitoring devices and insulin pumps more effectively optimize blood sugar control in some individuals with type 1 diabetes who use the devices as prescribed compared with conventional blood sugar monitoring and insulin delivery methods, a study has shown.

The newer, more expensive technologies are also associated with improvements in treatment satisfaction and quality-of-life measures, although they may be limited to highly motivated patients in expert settings, Hsin-Chieh Yeh, Ph.D., of Johns Hopkins University in Baltimore and her colleagues reported online July 10 in Annals of Internal Medicine (2012 July 10).

To determine whether the mode of intensive insulin therapy has a differential effect on outcomes in individuals with type 1 or type 2 diabetes, and whether outcomes differ by monitoring strategy, the investigators conducted a systematic review to evaluate the effectiveness of blood sugar sensors that constantly monitor glucose levels and pumps that deliver insulin around the clock as needed relative to glucose self-monitoring via frequent finger sticks and multiple daily injections (MDI) of insulin.

Toward this end, they reviewed a total of 33 randomized controlled trials in children and adults, including 19 that compared continuous subcutaneous insulin infusion (CSII) with MDI, 10 that compared real-time continuous glucose monitoring (rt-CGM) with self-monitoring of blood glucose (SMBG), and 4 that compared a sensor-augmented insulin pump with MDI and SMBG. Their analysis showed that CSII had a favorable effect relative to MDI on glycemic control in adults with type I diabetes, and that both methods worked equally well in preventing hypoglycemia.

Their results also suggest that rt-CGM and sensor-augmented pumps improve glycemic control relative to SMBG and MDI/SMBG, respectively, without increasing individuals’ risk of hypoglycemia.

For the analysis, the investigators included studies of adults, adolescents, or children with type 1 or type 2 diabetes that compared CSII with MDI consisting of at least three injections per day; rt-CGM with SMBG consisting of at least three finger sticks per day; and sensor-augmented pumps with MDI/SMBG. "We excluded studies where insulin was used in the CSII arm, because this is not the preferred clinical practice," the authors wrote, noting that they included studies using long- and rapid-acting analogues and/or neutral protamine Hagedorn and regular insulin in the MDI arms, because both regimens are used in current practice.

Those studies that evaluated process measures, intermediate outcomes, quality of life, or severe hypoglycemia were included in the analysis, as were randomized controlled trials and observational studies with a concurrent comparison group that evaluated microvascular or macrovascular outcomes or mortality. Study eligibility was reviewed independently by two investigators, the authors wrote.

With respect to the comparative effectiveness of CSII versus MDI in children and adolescents with type 1 diabetes, "our meta-analysis showed no difference between groups in the HbA_1c change from baseline after 16 or more weeks of follow-up," the authors reported. Similarly, the delivery methods appeared to have similar effects on glycemic control and the incidence of severe hypoglycemia in adults with type 2 diabetes. In contrast, CSII showed favorable effect on glycemic control in adults with type 1 diabetes, although the authors acknowledged that this result was influenced by a single study in which participants had higher hemoglobin A_1c values at enrollment, "allowing for greater HbA_1c lowering compared with other studies where participants were closer to the HbA_1c target at enrollment."

Evaluation of the comparative effectiveness of rt-CGM and SMBG showed that the former was associated with the achievement of a lower HbA_1c that reached statistical significance but was not clinically meaningful. The effect was slightly greater in studies where sensor compliance was at least 60% or greater, the authors wrote. "We also found that rt-CGM was associated with a lower HbA_1c level compared with MDI in individuals 18 years of age or younger," a finding that provides modest support for a recent recommendation in favor of rt-CGM use in children older than 8 years, they stated.

Finally, sensor-augmented pump use was associated with a statistically and clinically significant greater reduction in HbA_1c compared with MDI/SMBG use in individuals with type 1 diabetes, but there was not enough evidence to draw definitive conclusions about severe hypoglycemia or quality of life, they authors wrote.

The findings of the systematic review are limited by a number of considerations. The number of studies for each of the comparisons was small, and the authors may have missed unpublished studies, according to the authors. Further, the data are not generalizable to all diabetes patients, "as the management of CSII and rt-CGM are often limited to expert settings and highly motivated patients," and the study did not address the availability, costs, and insurance coverage of the various new technologies, which could be obstacles to their use, they acknowledged.

Although intensive insulin therapy delivered by MDI and rapid-acting analogue–based CSII were similarly effective in lowering HbA_1c levels with similar rates of hypoglycemia in patients with type 1 diabetes, the finding that rt-CGM was superior to SMBG in lowering HbA_1c levels without increasing the risk of severe hypoglycemia in type 1 diabetes patients – particularly those who are compliant with using the device – suggests "the addition of this monitoring method to SMBG and intensive insulin therapy can assist in achieving glycemic targets" in this patient population, the authors wrote.

The authors disclosed no relevant conflicts of interest. The research was supported by the Agency for Healthcare Research and Quality (AHRQ).

Real-time continuous glucose monitoring devices and insulin pumps more effectively optimize blood sugar control in some individuals with type 1 diabetes who use the devices as prescribed compared with conventional blood sugar monitoring and insulin delivery methods, a study has shown.

The newer, more expensive technologies are also associated with improvements in treatment satisfaction and quality-of-life measures, although they may be limited to highly motivated patients in expert settings, Hsin-Chieh Yeh, Ph.D., of Johns Hopkins University in Baltimore and her colleagues reported online July 10 in Annals of Internal Medicine (2012 July 10).

To determine whether the mode of intensive insulin therapy has a differential effect on outcomes in individuals with type 1 or type 2 diabetes, and whether outcomes differ by monitoring strategy, the investigators conducted a systematic review to evaluate the effectiveness of blood sugar sensors that constantly monitor glucose levels and pumps that deliver insulin around the clock as needed relative to glucose self-monitoring via frequent finger sticks and multiple daily injections (MDI) of insulin.

Toward this end, they reviewed a total of 33 randomized controlled trials in children and adults, including 19 that compared continuous subcutaneous insulin infusion (CSII) with MDI, 10 that compared real-time continuous glucose monitoring (rt-CGM) with self-monitoring of blood glucose (SMBG), and 4 that compared a sensor-augmented insulin pump with MDI and SMBG. Their analysis showed that CSII had a favorable effect relative to MDI on glycemic control in adults with type I diabetes, and that both methods worked equally well in preventing hypoglycemia.

Their results also suggest that rt-CGM and sensor-augmented pumps improve glycemic control relative to SMBG and MDI/SMBG, respectively, without increasing individuals’ risk of hypoglycemia.

For the analysis, the investigators included studies of adults, adolescents, or children with type 1 or type 2 diabetes that compared CSII with MDI consisting of at least three injections per day; rt-CGM with SMBG consisting of at least three finger sticks per day; and sensor-augmented pumps with MDI/SMBG. "We excluded studies where insulin was used in the CSII arm, because this is not the preferred clinical practice," the authors wrote, noting that they included studies using long- and rapid-acting analogues and/or neutral protamine Hagedorn and regular insulin in the MDI arms, because both regimens are used in current practice.

Those studies that evaluated process measures, intermediate outcomes, quality of life, or severe hypoglycemia were included in the analysis, as were randomized controlled trials and observational studies with a concurrent comparison group that evaluated microvascular or macrovascular outcomes or mortality. Study eligibility was reviewed independently by two investigators, the authors wrote.

With respect to the comparative effectiveness of CSII versus MDI in children and adolescents with type 1 diabetes, "our meta-analysis showed no difference between groups in the HbA_1c change from baseline after 16 or more weeks of follow-up," the authors reported. Similarly, the delivery methods appeared to have similar effects on glycemic control and the incidence of severe hypoglycemia in adults with type 2 diabetes. In contrast, CSII showed favorable effect on glycemic control in adults with type 1 diabetes, although the authors acknowledged that this result was influenced by a single study in which participants had higher hemoglobin A_1c values at enrollment, "allowing for greater HbA_1c lowering compared with other studies where participants were closer to the HbA_1c target at enrollment."

Evaluation of the comparative effectiveness of rt-CGM and SMBG showed that the former was associated with the achievement of a lower HbA_1c that reached statistical significance but was not clinically meaningful. The effect was slightly greater in studies where sensor compliance was at least 60% or greater, the authors wrote. "We also found that rt-CGM was associated with a lower HbA_1c level compared with MDI in individuals 18 years of age or younger," a finding that provides modest support for a recent recommendation in favor of rt-CGM use in children older than 8 years, they stated.

Finally, sensor-augmented pump use was associated with a statistically and clinically significant greater reduction in HbA_1c compared with MDI/SMBG use in individuals with type 1 diabetes, but there was not enough evidence to draw definitive conclusions about severe hypoglycemia or quality of life, they authors wrote.

The findings of the systematic review are limited by a number of considerations. The number of studies for each of the comparisons was small, and the authors may have missed unpublished studies, according to the authors. Further, the data are not generalizable to all diabetes patients, "as the management of CSII and rt-CGM are often limited to expert settings and highly motivated patients," and the study did not address the availability, costs, and insurance coverage of the various new technologies, which could be obstacles to their use, they acknowledged.

Although intensive insulin therapy delivered by MDI and rapid-acting analogue–based CSII were similarly effective in lowering HbA_1c levels with similar rates of hypoglycemia in patients with type 1 diabetes, the finding that rt-CGM was superior to SMBG in lowering HbA_1c levels without increasing the risk of severe hypoglycemia in type 1 diabetes patients – particularly those who are compliant with using the device – suggests "the addition of this monitoring method to SMBG and intensive insulin therapy can assist in achieving glycemic targets" in this patient population, the authors wrote.

The authors disclosed no relevant conflicts of interest. The research was supported by the Agency for Healthcare Research and Quality (AHRQ).

Real-time continuous glucose monitoring devices and insulin pumps more effectively optimize blood sugar control in some individuals with type 1 diabetes who use the devices as prescribed compared with conventional blood sugar monitoring and insulin delivery methods, a study has shown.

The newer, more expensive technologies are also associated with improvements in treatment satisfaction and quality-of-life measures, although they may be limited to highly motivated patients in expert settings, Hsin-Chieh Yeh, Ph.D., of Johns Hopkins University in Baltimore and her colleagues reported online July 10 in Annals of Internal Medicine (2012 July 10).

To determine whether the mode of intensive insulin therapy has a differential effect on outcomes in individuals with type 1 or type 2 diabetes, and whether outcomes differ by monitoring strategy, the investigators conducted a systematic review to evaluate the effectiveness of blood sugar sensors that constantly monitor glucose levels and pumps that deliver insulin around the clock as needed relative to glucose self-monitoring via frequent finger sticks and multiple daily injections (MDI) of insulin.

Toward this end, they reviewed a total of 33 randomized controlled trials in children and adults, including 19 that compared continuous subcutaneous insulin infusion (CSII) with MDI, 10 that compared real-time continuous glucose monitoring (rt-CGM) with self-monitoring of blood glucose (SMBG), and 4 that compared a sensor-augmented insulin pump with MDI and SMBG. Their analysis showed that CSII had a favorable effect relative to MDI on glycemic control in adults with type I diabetes, and that both methods worked equally well in preventing hypoglycemia.

Their results also suggest that rt-CGM and sensor-augmented pumps improve glycemic control relative to SMBG and MDI/SMBG, respectively, without increasing individuals’ risk of hypoglycemia.

For the analysis, the investigators included studies of adults, adolescents, or children with type 1 or type 2 diabetes that compared CSII with MDI consisting of at least three injections per day; rt-CGM with SMBG consisting of at least three finger sticks per day; and sensor-augmented pumps with MDI/SMBG. "We excluded studies where insulin was used in the CSII arm, because this is not the preferred clinical practice," the authors wrote, noting that they included studies using long- and rapid-acting analogues and/or neutral protamine Hagedorn and regular insulin in the MDI arms, because both regimens are used in current practice.

Those studies that evaluated process measures, intermediate outcomes, quality of life, or severe hypoglycemia were included in the analysis, as were randomized controlled trials and observational studies with a concurrent comparison group that evaluated microvascular or macrovascular outcomes or mortality. Study eligibility was reviewed independently by two investigators, the authors wrote.

With respect to the comparative effectiveness of CSII versus MDI in children and adolescents with type 1 diabetes, "our meta-analysis showed no difference between groups in the HbA_1c change from baseline after 16 or more weeks of follow-up," the authors reported. Similarly, the delivery methods appeared to have similar effects on glycemic control and the incidence of severe hypoglycemia in adults with type 2 diabetes. In contrast, CSII showed favorable effect on glycemic control in adults with type 1 diabetes, although the authors acknowledged that this result was influenced by a single study in which participants had higher hemoglobin A_1c values at enrollment, "allowing for greater HbA_1c lowering compared with other studies where participants were closer to the HbA_1c target at enrollment."

Evaluation of the comparative effectiveness of rt-CGM and SMBG showed that the former was associated with the achievement of a lower HbA_1c that reached statistical significance but was not clinically meaningful. The effect was slightly greater in studies where sensor compliance was at least 60% or greater, the authors wrote. "We also found that rt-CGM was associated with a lower HbA_1c level compared with MDI in individuals 18 years of age or younger," a finding that provides modest support for a recent recommendation in favor of rt-CGM use in children older than 8 years, they stated.

Finally, sensor-augmented pump use was associated with a statistically and clinically significant greater reduction in HbA_1c compared with MDI/SMBG use in individuals with type 1 diabetes, but there was not enough evidence to draw definitive conclusions about severe hypoglycemia or quality of life, they authors wrote.

The findings of the systematic review are limited by a number of considerations. The number of studies for each of the comparisons was small, and the authors may have missed unpublished studies, according to the authors. Further, the data are not generalizable to all diabetes patients, "as the management of CSII and rt-CGM are often limited to expert settings and highly motivated patients," and the study did not address the availability, costs, and insurance coverage of the various new technologies, which could be obstacles to their use, they acknowledged.

Although intensive insulin therapy delivered by MDI and rapid-acting analogue–based CSII were similarly effective in lowering HbA_1c levels with similar rates of hypoglycemia in patients with type 1 diabetes, the finding that rt-CGM was superior to SMBG in lowering HbA_1c levels without increasing the risk of severe hypoglycemia in type 1 diabetes patients – particularly those who are compliant with using the device – suggests "the addition of this monitoring method to SMBG and intensive insulin therapy can assist in achieving glycemic targets" in this patient population, the authors wrote.

The authors disclosed no relevant conflicts of interest. The research was supported by the Agency for Healthcare Research and Quality (AHRQ).

Neoadjuvant chemoradiation followed by liver transplantation is an effective and appropriate strategy for treating unresectable perihilar cholangiocarcinoma, according to a multicenter, retrospective study reported by Dr. Sarwa Darwish Murad and her colleagues in the July issue of Gastroenterology.

Historically, treatment options for the highly aggressive malignancy have been limited because many patients present with unresectable disease, and even among those in whom resection is possible, 5-year survival rates have been low. Further, the efficacy of orthotopic liver transplantation in these patients has been compromised by a high rate of tumor recurrence, and thus the disease has been considered a contraindication to the procedure, the authors wrote (Gastroenterology 2012 July [doi: 10.1053/j.gastro.2012.04.008]).

In 2006, based on reports of excellent single-center outcomes of the chemoradiation/transplantation protocol, the United Network of Organ Sharing (UNOS) developed a standardized Model of End-stage Liver Disease (MELD) exception for perihilar cholangiocarcinoma (Liver Transpl. 2006;12:S95-7).

In the current study, Dr. Murad of the Mayo Clinic in Rochester, Minn., and her coinvestigators analyzed data from 12 large-volume transplant centers in the United States that had treated three or more perihilar cholangiocarcinoma patients with neoadjuvant therapy and liver transplantation during 1993-2010.

A total of 287 patients met the study criteria. External radiation, brachytherapy, radiosensitizing therapy, and maintenance chemotherapy were completed by 99%, 75%, 98%, and 65%, respectively. Prior to liver transplantation, 71 patients (24.7%) dropped out after a median of 4.6 months. In the first 3.5 months of therapy, 11.5% dropped out, demonstrating the appropriateness of the MELD exception.

The median follow-up from the time of listing for transplantation was 2.5 years. During this period, 122 patients died after a median of 1.2 years from presentation. Of these deaths, 60 (49%) occurred prior to transplant, and resulted from tumor progression (52), liver failure (3), cardiovascular causes (2), multiorgan failure (2), and sepsis (1). Post transplant, 43 (20%) patients developed recurrence and 62 (22%) patients died, including those whose death was attributed to recurrence (40), sepsis (8), multiorgan failure (3), liver failure (3), post-transplant lymphoproliferative disease (2), and other causes (6).

Post transplant, the 2-, 5-, and 10-year recurrence-free survival rates were 78%, 65%, and 59%, respectively, "demonstrating this therapy to be highly effective," the authors said. No significant differences in recurrence-free survival were observed between patients who underwent deceased vs. living donor transplantation, or in patients with underlying primary sclerosing cholangitis compared with those without.

But survival times were significantly shorter for patients who did not meet the UNOS criteria, including those with a tumor greater than 3 cm, transperitoneal tumor biopsy, or metastatic disease. Specifically, the hazard ratio for patients transplanted outside of the current MELD exception criteria was 2.98 relative to those within the criteria. "Mass size caused the greatest disparity, with 5-year recurrence-free survival of 32% for those larger than 3 cm compared to 69% for smaller tumors," they wrote.

No significant differences were observed between patients who underwent operative staging and those who did not, nor was the timing of staging significantly associated with survival, the authors wrote. Similarly, recurrence-free survival for patients who had received brachytherapy did not differ from that of those who did not.

In an analysis of possible center effects, the investigators determined that there were no significant differences in recurrence-free survival despite the fact that one center contributed the largest number of patients (193). In a multivariate Cox regression model, "selection remained the only significant determinant of recurrence-free survival," according to the authors. In fact, they added, not only is selection the only variable that acts as an independent predictor of outcome and is modifiable at the same time, but "by adjusting selection alone, 5-year recurrence-free survival can be maximized to 72%."

The unadjusted 5-year disease-free survival rate of 65% "is not only similar to results from earlier single-center series but also similar to outcomes of liver transplantation for other malignant and nonmalignant indications," the authors wrote. In addition, the average 3-month dropout rate of 11.5% approximates the expected 10% (as per the standardized MELD exception score equivalent), and as such justifies "using scarce liver allografts for this otherwise lethal disease," they said.

The study is limited by its retrospective design and the fact that a large number of patients (193) came from one center, the authors acknowledged. Also, "due to heterogeneity in duration, type, and dose of maintenance chemotherapy administered at different centers, we were unable to determine the independent impact of maintenance chemotherapy," they wrote.

Although the findings confirm the excellent outcomes of neoadjuvant chemoradiation followed by liver transplantation in patients with perihilar cholangiocarcinoma, an important challenge for the future will be to "gain a greater understanding of the tumor biology in order to reduce wait-list dropout and post-transplant recurrence, either by further refinements in patient selection or, ideally, by more effective chemoradiotherapy," the authors concluded.

The authors had no financial conflicts of interest to disclose.

Neoadjuvant chemoradiation followed by liver transplantation is an effective and appropriate strategy for treating unresectable perihilar cholangiocarcinoma, according to a multicenter, retrospective study reported by Dr. Sarwa Darwish Murad and her colleagues in the July issue of Gastroenterology.

Historically, treatment options for the highly aggressive malignancy have been limited because many patients present with unresectable disease, and even among those in whom resection is possible, 5-year survival rates have been low. Further, the efficacy of orthotopic liver transplantation in these patients has been compromised by a high rate of tumor recurrence, and thus the disease has been considered a contraindication to the procedure, the authors wrote (Gastroenterology 2012 July [doi: 10.1053/j.gastro.2012.04.008]).

In 2006, based on reports of excellent single-center outcomes of the chemoradiation/transplantation protocol, the United Network of Organ Sharing (UNOS) developed a standardized Model of End-stage Liver Disease (MELD) exception for perihilar cholangiocarcinoma (Liver Transpl. 2006;12:S95-7).

In the current study, Dr. Murad of the Mayo Clinic in Rochester, Minn., and her coinvestigators analyzed data from 12 large-volume transplant centers in the United States that had treated three or more perihilar cholangiocarcinoma patients with neoadjuvant therapy and liver transplantation during 1993-2010.

A total of 287 patients met the study criteria. External radiation, brachytherapy, radiosensitizing therapy, and maintenance chemotherapy were completed by 99%, 75%, 98%, and 65%, respectively. Prior to liver transplantation, 71 patients (24.7%) dropped out after a median of 4.6 months. In the first 3.5 months of therapy, 11.5% dropped out, demonstrating the appropriateness of the MELD exception.

The median follow-up from the time of listing for transplantation was 2.5 years. During this period, 122 patients died after a median of 1.2 years from presentation. Of these deaths, 60 (49%) occurred prior to transplant, and resulted from tumor progression (52), liver failure (3), cardiovascular causes (2), multiorgan failure (2), and sepsis (1). Post transplant, 43 (20%) patients developed recurrence and 62 (22%) patients died, including those whose death was attributed to recurrence (40), sepsis (8), multiorgan failure (3), liver failure (3), post-transplant lymphoproliferative disease (2), and other causes (6).

Post transplant, the 2-, 5-, and 10-year recurrence-free survival rates were 78%, 65%, and 59%, respectively, "demonstrating this therapy to be highly effective," the authors said. No significant differences in recurrence-free survival were observed between patients who underwent deceased vs. living donor transplantation, or in patients with underlying primary sclerosing cholangitis compared with those without.

But survival times were significantly shorter for patients who did not meet the UNOS criteria, including those with a tumor greater than 3 cm, transperitoneal tumor biopsy, or metastatic disease. Specifically, the hazard ratio for patients transplanted outside of the current MELD exception criteria was 2.98 relative to those within the criteria. "Mass size caused the greatest disparity, with 5-year recurrence-free survival of 32% for those larger than 3 cm compared to 69% for smaller tumors," they wrote.

No significant differences were observed between patients who underwent operative staging and those who did not, nor was the timing of staging significantly associated with survival, the authors wrote. Similarly, recurrence-free survival for patients who had received brachytherapy did not differ from that of those who did not.

In an analysis of possible center effects, the investigators determined that there were no significant differences in recurrence-free survival despite the fact that one center contributed the largest number of patients (193). In a multivariate Cox regression model, "selection remained the only significant determinant of recurrence-free survival," according to the authors. In fact, they added, not only is selection the only variable that acts as an independent predictor of outcome and is modifiable at the same time, but "by adjusting selection alone, 5-year recurrence-free survival can be maximized to 72%."

The unadjusted 5-year disease-free survival rate of 65% "is not only similar to results from earlier single-center series but also similar to outcomes of liver transplantation for other malignant and nonmalignant indications," the authors wrote. In addition, the average 3-month dropout rate of 11.5% approximates the expected 10% (as per the standardized MELD exception score equivalent), and as such justifies "using scarce liver allografts for this otherwise lethal disease," they said.

The study is limited by its retrospective design and the fact that a large number of patients (193) came from one center, the authors acknowledged. Also, "due to heterogeneity in duration, type, and dose of maintenance chemotherapy administered at different centers, we were unable to determine the independent impact of maintenance chemotherapy," they wrote.

Although the findings confirm the excellent outcomes of neoadjuvant chemoradiation followed by liver transplantation in patients with perihilar cholangiocarcinoma, an important challenge for the future will be to "gain a greater understanding of the tumor biology in order to reduce wait-list dropout and post-transplant recurrence, either by further refinements in patient selection or, ideally, by more effective chemoradiotherapy," the authors concluded.

The authors had no financial conflicts of interest to disclose.

Neoadjuvant chemoradiation followed by liver transplantation is an effective and appropriate strategy for treating unresectable perihilar cholangiocarcinoma, according to a multicenter, retrospective study reported by Dr. Sarwa Darwish Murad and her colleagues in the July issue of Gastroenterology.

Historically, treatment options for the highly aggressive malignancy have been limited because many patients present with unresectable disease, and even among those in whom resection is possible, 5-year survival rates have been low. Further, the efficacy of orthotopic liver transplantation in these patients has been compromised by a high rate of tumor recurrence, and thus the disease has been considered a contraindication to the procedure, the authors wrote (Gastroenterology 2012 July [doi: 10.1053/j.gastro.2012.04.008]).

In 2006, based on reports of excellent single-center outcomes of the chemoradiation/transplantation protocol, the United Network of Organ Sharing (UNOS) developed a standardized Model of End-stage Liver Disease (MELD) exception for perihilar cholangiocarcinoma (Liver Transpl. 2006;12:S95-7).

In the current study, Dr. Murad of the Mayo Clinic in Rochester, Minn., and her coinvestigators analyzed data from 12 large-volume transplant centers in the United States that had treated three or more perihilar cholangiocarcinoma patients with neoadjuvant therapy and liver transplantation during 1993-2010.

A total of 287 patients met the study criteria. External radiation, brachytherapy, radiosensitizing therapy, and maintenance chemotherapy were completed by 99%, 75%, 98%, and 65%, respectively. Prior to liver transplantation, 71 patients (24.7%) dropped out after a median of 4.6 months. In the first 3.5 months of therapy, 11.5% dropped out, demonstrating the appropriateness of the MELD exception.

The median follow-up from the time of listing for transplantation was 2.5 years. During this period, 122 patients died after a median of 1.2 years from presentation. Of these deaths, 60 (49%) occurred prior to transplant, and resulted from tumor progression (52), liver failure (3), cardiovascular causes (2), multiorgan failure (2), and sepsis (1). Post transplant, 43 (20%) patients developed recurrence and 62 (22%) patients died, including those whose death was attributed to recurrence (40), sepsis (8), multiorgan failure (3), liver failure (3), post-transplant lymphoproliferative disease (2), and other causes (6).

Post transplant, the 2-, 5-, and 10-year recurrence-free survival rates were 78%, 65%, and 59%, respectively, "demonstrating this therapy to be highly effective," the authors said. No significant differences in recurrence-free survival were observed between patients who underwent deceased vs. living donor transplantation, or in patients with underlying primary sclerosing cholangitis compared with those without.

But survival times were significantly shorter for patients who did not meet the UNOS criteria, including those with a tumor greater than 3 cm, transperitoneal tumor biopsy, or metastatic disease. Specifically, the hazard ratio for patients transplanted outside of the current MELD exception criteria was 2.98 relative to those within the criteria. "Mass size caused the greatest disparity, with 5-year recurrence-free survival of 32% for those larger than 3 cm compared to 69% for smaller tumors," they wrote.

No significant differences were observed between patients who underwent operative staging and those who did not, nor was the timing of staging significantly associated with survival, the authors wrote. Similarly, recurrence-free survival for patients who had received brachytherapy did not differ from that of those who did not.

In an analysis of possible center effects, the investigators determined that there were no significant differences in recurrence-free survival despite the fact that one center contributed the largest number of patients (193). In a multivariate Cox regression model, "selection remained the only significant determinant of recurrence-free survival," according to the authors. In fact, they added, not only is selection the only variable that acts as an independent predictor of outcome and is modifiable at the same time, but "by adjusting selection alone, 5-year recurrence-free survival can be maximized to 72%."

The unadjusted 5-year disease-free survival rate of 65% "is not only similar to results from earlier single-center series but also similar to outcomes of liver transplantation for other malignant and nonmalignant indications," the authors wrote. In addition, the average 3-month dropout rate of 11.5% approximates the expected 10% (as per the standardized MELD exception score equivalent), and as such justifies "using scarce liver allografts for this otherwise lethal disease," they said.

The study is limited by its retrospective design and the fact that a large number of patients (193) came from one center, the authors acknowledged. Also, "due to heterogeneity in duration, type, and dose of maintenance chemotherapy administered at different centers, we were unable to determine the independent impact of maintenance chemotherapy," they wrote.

Although the findings confirm the excellent outcomes of neoadjuvant chemoradiation followed by liver transplantation in patients with perihilar cholangiocarcinoma, an important challenge for the future will be to "gain a greater understanding of the tumor biology in order to reduce wait-list dropout and post-transplant recurrence, either by further refinements in patient selection or, ideally, by more effective chemoradiotherapy," the authors concluded.

The authors had no financial conflicts of interest to disclose.

School’s out and the living is easy for teens come summertime, but a new government study suggests it’s also dangerous, as the rates of first-time substance use among 12- to 17-year-olds peak in June and July.

On an average day in these two summer months, approximately 11,000 adolescents use alcohol for the first time, 5,000 try their first cigarette, and 4,500 begin using marijuana, according to a report released June 3 by the Substance Abuse and Mental Health Services Administration (SAMHSA). The report is based on interviews with 231,500 adolescents in the National Survey on Drug Use and Health (NSDUH) during 2002-2010.

Copyright Stockphoto4U/iStockphoto.com

The daily average rates for first-time alcohol, cigarette, and marijuana use during the rest of the year are 5,000-8,000 for first-time alcohol use and 3,000-4,000 each for first-time cigarette and marijuana use, according to the report, titled "Monthly Variation in Substance Use Initiation among Adolescents."

First-time hallucinogen use also peaked in June and July, with a daily average rate of 1,500 new users per day, compared with 1,100-1,400 in other months. Inhalant initiation peaked in July specifically, with a daily average rate of 1,800 new users in that month, compared with 1,100-1,700 during the rest of the year, according to the report. No similar summer-month increases were observed in the use of cocaine or nonmedical prescription drugs.

The summer peaks of first-time use of many of the substances are likely associated with the increased idle time and decreased responsibilities and adult supervision during breaks from school, "although initiation of substance use can occur at any time," the authors wrote, noting that multiple implications can be drawn from the findings. For example, intensifying public service announcements and media campaigns targeting adolescents during the summer months may amplify their impact. "Messages focusing on preventing initiation may be particularly important during these months," they wrote.

Additionally, "the findings may point toward critical opportunities during the summer to implement activities and events that are attractive alternatives to drug use initiation or continued use," particularly in communities with limited prevention resources, according to the authors. From a law-enforcement perspective, targeted efforts toward preventing tobacco and alcohol sales to minors may be more effective during the peak initiation months.

The NSDUH is an annual nationwide survey involving interviews with approximately 70,000 randomly selected individuals aged 12 years and older. Respondents who report using various substances are asked to indicate the year and month of first use of each substance. The current report focused specifically on individuals who reported initiation in the use of substances within the year prior to the survey and who were 12-17 years old at the time of initiation, according to the authors.

The annual first-time substance use averages among adolescents surveyed from 2002 to 2010 were 2.9 million for alcohol (7,800 new users per day); 1.4 million for cigarettes (3,800 new users per day); 1.3 million for cigars (3,600 new users per day); 600,000 for smokeless tobacco (1,700 new users per day); 1.4 million for marijuana (3,700 new users per day); 900,000 for nonmedical prescription-type drugs (2,500 new pain reliever users per day, 900 new tranquilizer users per day, 800 new stimulant users per day, 200 new sedative users per day); 600,000 for inhalants (1,500 new users per day); 500,000 for hallucinogens (1,400 new users per day); and 300,000 for cocaine (800 new users per day).

No conflicts of interest were disclosed.

School’s out and the living is easy for teens come summertime, but a new government study suggests it’s also dangerous, as the rates of first-time substance use among 12- to 17-year-olds peak in June and July.

On an average day in these two summer months, approximately 11,000 adolescents use alcohol for the first time, 5,000 try their first cigarette, and 4,500 begin using marijuana, according to a report released June 3 by the Substance Abuse and Mental Health Services Administration (SAMHSA). The report is based on interviews with 231,500 adolescents in the National Survey on Drug Use and Health (NSDUH) during 2002-2010.

Copyright Stockphoto4U/iStockphoto.com

The daily average rates for first-time alcohol, cigarette, and marijuana use during the rest of the year are 5,000-8,000 for first-time alcohol use and 3,000-4,000 each for first-time cigarette and marijuana use, according to the report, titled "Monthly Variation in Substance Use Initiation among Adolescents."

First-time hallucinogen use also peaked in June and July, with a daily average rate of 1,500 new users per day, compared with 1,100-1,400 in other months. Inhalant initiation peaked in July specifically, with a daily average rate of 1,800 new users in that month, compared with 1,100-1,700 during the rest of the year, according to the report. No similar summer-month increases were observed in the use of cocaine or nonmedical prescription drugs.

The summer peaks of first-time use of many of the substances are likely associated with the increased idle time and decreased responsibilities and adult supervision during breaks from school, "although initiation of substance use can occur at any time," the authors wrote, noting that multiple implications can be drawn from the findings. For example, intensifying public service announcements and media campaigns targeting adolescents during the summer months may amplify their impact. "Messages focusing on preventing initiation may be particularly important during these months," they wrote.

Additionally, "the findings may point toward critical opportunities during the summer to implement activities and events that are attractive alternatives to drug use initiation or continued use," particularly in communities with limited prevention resources, according to the authors. From a law-enforcement perspective, targeted efforts toward preventing tobacco and alcohol sales to minors may be more effective during the peak initiation months.

The NSDUH is an annual nationwide survey involving interviews with approximately 70,000 randomly selected individuals aged 12 years and older. Respondents who report using various substances are asked to indicate the year and month of first use of each substance. The current report focused specifically on individuals who reported initiation in the use of substances within the year prior to the survey and who were 12-17 years old at the time of initiation, according to the authors.

The annual first-time substance use averages among adolescents surveyed from 2002 to 2010 were 2.9 million for alcohol (7,800 new users per day); 1.4 million for cigarettes (3,800 new users per day); 1.3 million for cigars (3,600 new users per day); 600,000 for smokeless tobacco (1,700 new users per day); 1.4 million for marijuana (3,700 new users per day); 900,000 for nonmedical prescription-type drugs (2,500 new pain reliever users per day, 900 new tranquilizer users per day, 800 new stimulant users per day, 200 new sedative users per day); 600,000 for inhalants (1,500 new users per day); 500,000 for hallucinogens (1,400 new users per day); and 300,000 for cocaine (800 new users per day).

No conflicts of interest were disclosed.

School’s out and the living is easy for teens come summertime, but a new government study suggests it’s also dangerous, as the rates of first-time substance use among 12- to 17-year-olds peak in June and July.

On an average day in these two summer months, approximately 11,000 adolescents use alcohol for the first time, 5,000 try their first cigarette, and 4,500 begin using marijuana, according to a report released June 3 by the Substance Abuse and Mental Health Services Administration (SAMHSA). The report is based on interviews with 231,500 adolescents in the National Survey on Drug Use and Health (NSDUH) during 2002-2010.

Copyright Stockphoto4U/iStockphoto.com

The daily average rates for first-time alcohol, cigarette, and marijuana use during the rest of the year are 5,000-8,000 for first-time alcohol use and 3,000-4,000 each for first-time cigarette and marijuana use, according to the report, titled "Monthly Variation in Substance Use Initiation among Adolescents."

First-time hallucinogen use also peaked in June and July, with a daily average rate of 1,500 new users per day, compared with 1,100-1,400 in other months. Inhalant initiation peaked in July specifically, with a daily average rate of 1,800 new users in that month, compared with 1,100-1,700 during the rest of the year, according to the report. No similar summer-month increases were observed in the use of cocaine or nonmedical prescription drugs.

The summer peaks of first-time use of many of the substances are likely associated with the increased idle time and decreased responsibilities and adult supervision during breaks from school, "although initiation of substance use can occur at any time," the authors wrote, noting that multiple implications can be drawn from the findings. For example, intensifying public service announcements and media campaigns targeting adolescents during the summer months may amplify their impact. "Messages focusing on preventing initiation may be particularly important during these months," they wrote.

Additionally, "the findings may point toward critical opportunities during the summer to implement activities and events that are attractive alternatives to drug use initiation or continued use," particularly in communities with limited prevention resources, according to the authors. From a law-enforcement perspective, targeted efforts toward preventing tobacco and alcohol sales to minors may be more effective during the peak initiation months.

The NSDUH is an annual nationwide survey involving interviews with approximately 70,000 randomly selected individuals aged 12 years and older. Respondents who report using various substances are asked to indicate the year and month of first use of each substance. The current report focused specifically on individuals who reported initiation in the use of substances within the year prior to the survey and who were 12-17 years old at the time of initiation, according to the authors.

The annual first-time substance use averages among adolescents surveyed from 2002 to 2010 were 2.9 million for alcohol (7,800 new users per day); 1.4 million for cigarettes (3,800 new users per day); 1.3 million for cigars (3,600 new users per day); 600,000 for smokeless tobacco (1,700 new users per day); 1.4 million for marijuana (3,700 new users per day); 900,000 for nonmedical prescription-type drugs (2,500 new pain reliever users per day, 900 new tranquilizer users per day, 800 new stimulant users per day, 200 new sedative users per day); 600,000 for inhalants (1,500 new users per day); 500,000 for hallucinogens (1,400 new users per day); and 300,000 for cocaine (800 new users per day).

No conflicts of interest were disclosed.

Aerosolized fluticasone decreases esophageal eosinophilia in adults with eosinophilic esophagitis but does not relieve the symptomatic dysphagia caused by the allergic inflammatory disease, Dr. Jeffrey A. Alexander and his colleagues reported in the July issue of Clinical Gastroenterology and Hepatology.

In a double-blind, placebo-controlled trial conducted by Dr. Alexander of the Mayo Clinic, Rochester, Minn., and his coauthors, 42 adults with eosinophilic esophagitis (EoE) were randomly assigned to receive 880 mcg of aerosolized fluticasone twice daily (21) or to use a placebo inhaler twice daily (21) for 6 weeks.

The study’s primary end point was complete symptom response, and secondary end points were partial symptom response, partial and complete histologic response, and eosinophil-derived neurotoxin response to treatment using Fisher’s exact test (Clin. Gastroenterol. Hepatol. 2012 July [doi:10.1016/j.cgh.2012.03.018]).

The study subjects were recruited from the Esophageal Clinic at Mayo Clinic Rochester during 2005-2009 for management of newly diagnosed EoE. Subjects had symptomatic dysphagia, had a peak eosinophil count of at least 20 eosinophils per high-power field on esophageal biopsy, and demonstrated at least 90% compliance with the study requirement that they keep symptom logs for review by phone interview after weeks 2 and 4, and at study completion.

For symptom assessment, a complete response was defined as an answer of "no" to the question: "In the past 2 weeks, have you had trouble swallowing, not associated with other cold symptoms?" on the Mayo Dysphagia Questionnaire–2 week, while an answer of "yes" along with a two-level or one-level decrease in frequency was considered a partial response. An answer of "yes" and a one-level decrease in one variable (either frequency or severity), plus an increase in the other variable, was classified as no response, the authors wrote.

A structured phone interview to assess side effects was conducted at weeks 2 and 4, and again at study completion, along with a physical exam, endoscopy, and 24-hour urine cortisol.

Six patients in the placebo group and two in the treatment group dropped out for reasons unrelated to the treatment. Of the 15 subjects who received 6 weeks of fluticasone, 11 had a complete histologic response, defined as a greater than 90% decrease in mean eosinophil count, compared with none of the 15 placebo subjects based on intention-to-treat analysis. By per-protocol analysis, "the histologic response was observed in 68% of subjects that received fluticasone [13/19], compared to none of those that received placebo," the authors wrote.

Analysis of symptom data in the treatment group showed that a complete dysphagia response occurred in 42.9% by intent-to-treat and 47.4% per protocol, neither of which was better than the respective placebo responses of 28.6% and 40.0%, according to the authors. Similarly, "the per-protocol analysis for a complete or partial response rate for fluticasone was 63.2%, versus a 46.7% response rate for placebo," representing a nonsignificant difference, they said.

The authors hypothesized that the factors contributing to the discrepancy between symptomatic and histologic responses include a possible underappreciation at endoscopy of esophageal stricture and small-caliber esophagus, and the possibility that esophageal narrowing may require dilation to relieve symptomatic dysphagia despite a histologic response.

In addition, "changes in esophageal compliance related to fibrosis may be important," they wrote, as a decrease in esophageal distensibility and compliance has been shown in EoE, which could well be a cause of dysphagia. Candida infections, which developed in 31.6% of the treatment group and none of the placebo group, could potentially lead to persistent dysphagia despite a histologic response, they said. Most likely, however, the discrepancy "reflects a waxing and waning of dysphagia in this disease," they concluded.

The study findings are limited by the relatively small sample size and the unexpectedly high dropout rate in the placebo group, which "left us somewhat underpowered for our primary end point," the authors wrote. Also, gastroesophageal reflux disease was not categorically excluded in all of the patients prior to enrollment. "While we would have liked to adjust for baseline differences in erosive esophagitis and PPI [protein pump inhibitor] use between treatment and placebo groups, this is beyond the limits of a dataset this size," they said.

The treatment was safe and well tolerated, but further study is needed to evaluate the optimal dose of therapy, length of therapy, and long-term safety of topical fluticasone, as well as other steroid medications. "Furthermore," the authors wrote, "delivery systems need to be developed that are easier to use and provide more direct drug delivery to the esophagus."

Dr. Alexander disclosed a financial relationship with Meritage Pharmacia.

Aerosolized fluticasone decreases esophageal eosinophilia in adults with eosinophilic esophagitis but does not relieve the symptomatic dysphagia caused by the allergic inflammatory disease, Dr. Jeffrey A. Alexander and his colleagues reported in the July issue of Clinical Gastroenterology and Hepatology.

In a double-blind, placebo-controlled trial conducted by Dr. Alexander of the Mayo Clinic, Rochester, Minn., and his coauthors, 42 adults with eosinophilic esophagitis (EoE) were randomly assigned to receive 880 mcg of aerosolized fluticasone twice daily (21) or to use a placebo inhaler twice daily (21) for 6 weeks.

The study’s primary end point was complete symptom response, and secondary end points were partial symptom response, partial and complete histologic response, and eosinophil-derived neurotoxin response to treatment using Fisher’s exact test (Clin. Gastroenterol. Hepatol. 2012 July [doi:10.1016/j.cgh.2012.03.018]).

The study subjects were recruited from the Esophageal Clinic at Mayo Clinic Rochester during 2005-2009 for management of newly diagnosed EoE. Subjects had symptomatic dysphagia, had a peak eosinophil count of at least 20 eosinophils per high-power field on esophageal biopsy, and demonstrated at least 90% compliance with the study requirement that they keep symptom logs for review by phone interview after weeks 2 and 4, and at study completion.

For symptom assessment, a complete response was defined as an answer of "no" to the question: "In the past 2 weeks, have you had trouble swallowing, not associated with other cold symptoms?" on the Mayo Dysphagia Questionnaire–2 week, while an answer of "yes" along with a two-level or one-level decrease in frequency was considered a partial response. An answer of "yes" and a one-level decrease in one variable (either frequency or severity), plus an increase in the other variable, was classified as no response, the authors wrote.

A structured phone interview to assess side effects was conducted at weeks 2 and 4, and again at study completion, along with a physical exam, endoscopy, and 24-hour urine cortisol.

Six patients in the placebo group and two in the treatment group dropped out for reasons unrelated to the treatment. Of the 15 subjects who received 6 weeks of fluticasone, 11 had a complete histologic response, defined as a greater than 90% decrease in mean eosinophil count, compared with none of the 15 placebo subjects based on intention-to-treat analysis. By per-protocol analysis, "the histologic response was observed in 68% of subjects that received fluticasone [13/19], compared to none of those that received placebo," the authors wrote.

Analysis of symptom data in the treatment group showed that a complete dysphagia response occurred in 42.9% by intent-to-treat and 47.4% per protocol, neither of which was better than the respective placebo responses of 28.6% and 40.0%, according to the authors. Similarly, "the per-protocol analysis for a complete or partial response rate for fluticasone was 63.2%, versus a 46.7% response rate for placebo," representing a nonsignificant difference, they said.

The authors hypothesized that the factors contributing to the discrepancy between symptomatic and histologic responses include a possible underappreciation at endoscopy of esophageal stricture and small-caliber esophagus, and the possibility that esophageal narrowing may require dilation to relieve symptomatic dysphagia despite a histologic response.

In addition, "changes in esophageal compliance related to fibrosis may be important," they wrote, as a decrease in esophageal distensibility and compliance has been shown in EoE, which could well be a cause of dysphagia. Candida infections, which developed in 31.6% of the treatment group and none of the placebo group, could potentially lead to persistent dysphagia despite a histologic response, they said. Most likely, however, the discrepancy "reflects a waxing and waning of dysphagia in this disease," they concluded.

The study findings are limited by the relatively small sample size and the unexpectedly high dropout rate in the placebo group, which "left us somewhat underpowered for our primary end point," the authors wrote. Also, gastroesophageal reflux disease was not categorically excluded in all of the patients prior to enrollment. "While we would have liked to adjust for baseline differences in erosive esophagitis and PPI [protein pump inhibitor] use between treatment and placebo groups, this is beyond the limits of a dataset this size," they said.

The treatment was safe and well tolerated, but further study is needed to evaluate the optimal dose of therapy, length of therapy, and long-term safety of topical fluticasone, as well as other steroid medications. "Furthermore," the authors wrote, "delivery systems need to be developed that are easier to use and provide more direct drug delivery to the esophagus."

Dr. Alexander disclosed a financial relationship with Meritage Pharmacia.

Aerosolized fluticasone decreases esophageal eosinophilia in adults with eosinophilic esophagitis but does not relieve the symptomatic dysphagia caused by the allergic inflammatory disease, Dr. Jeffrey A. Alexander and his colleagues reported in the July issue of Clinical Gastroenterology and Hepatology.

In a double-blind, placebo-controlled trial conducted by Dr. Alexander of the Mayo Clinic, Rochester, Minn., and his coauthors, 42 adults with eosinophilic esophagitis (EoE) were randomly assigned to receive 880 mcg of aerosolized fluticasone twice daily (21) or to use a placebo inhaler twice daily (21) for 6 weeks.

The study’s primary end point was complete symptom response, and secondary end points were partial symptom response, partial and complete histologic response, and eosinophil-derived neurotoxin response to treatment using Fisher’s exact test (Clin. Gastroenterol. Hepatol. 2012 July [doi:10.1016/j.cgh.2012.03.018]).

The study subjects were recruited from the Esophageal Clinic at Mayo Clinic Rochester during 2005-2009 for management of newly diagnosed EoE. Subjects had symptomatic dysphagia, had a peak eosinophil count of at least 20 eosinophils per high-power field on esophageal biopsy, and demonstrated at least 90% compliance with the study requirement that they keep symptom logs for review by phone interview after weeks 2 and 4, and at study completion.

For symptom assessment, a complete response was defined as an answer of "no" to the question: "In the past 2 weeks, have you had trouble swallowing, not associated with other cold symptoms?" on the Mayo Dysphagia Questionnaire–2 week, while an answer of "yes" along with a two-level or one-level decrease in frequency was considered a partial response. An answer of "yes" and a one-level decrease in one variable (either frequency or severity), plus an increase in the other variable, was classified as no response, the authors wrote.

A structured phone interview to assess side effects was conducted at weeks 2 and 4, and again at study completion, along with a physical exam, endoscopy, and 24-hour urine cortisol.

Six patients in the placebo group and two in the treatment group dropped out for reasons unrelated to the treatment. Of the 15 subjects who received 6 weeks of fluticasone, 11 had a complete histologic response, defined as a greater than 90% decrease in mean eosinophil count, compared with none of the 15 placebo subjects based on intention-to-treat analysis. By per-protocol analysis, "the histologic response was observed in 68% of subjects that received fluticasone [13/19], compared to none of those that received placebo," the authors wrote.

Analysis of symptom data in the treatment group showed that a complete dysphagia response occurred in 42.9% by intent-to-treat and 47.4% per protocol, neither of which was better than the respective placebo responses of 28.6% and 40.0%, according to the authors. Similarly, "the per-protocol analysis for a complete or partial response rate for fluticasone was 63.2%, versus a 46.7% response rate for placebo," representing a nonsignificant difference, they said.

The authors hypothesized that the factors contributing to the discrepancy between symptomatic and histologic responses include a possible underappreciation at endoscopy of esophageal stricture and small-caliber esophagus, and the possibility that esophageal narrowing may require dilation to relieve symptomatic dysphagia despite a histologic response.

In addition, "changes in esophageal compliance related to fibrosis may be important," they wrote, as a decrease in esophageal distensibility and compliance has been shown in EoE, which could well be a cause of dysphagia. Candida infections, which developed in 31.6% of the treatment group and none of the placebo group, could potentially lead to persistent dysphagia despite a histologic response, they said. Most likely, however, the discrepancy "reflects a waxing and waning of dysphagia in this disease," they concluded.

The study findings are limited by the relatively small sample size and the unexpectedly high dropout rate in the placebo group, which "left us somewhat underpowered for our primary end point," the authors wrote. Also, gastroesophageal reflux disease was not categorically excluded in all of the patients prior to enrollment. "While we would have liked to adjust for baseline differences in erosive esophagitis and PPI [protein pump inhibitor] use between treatment and placebo groups, this is beyond the limits of a dataset this size," they said.

The treatment was safe and well tolerated, but further study is needed to evaluate the optimal dose of therapy, length of therapy, and long-term safety of topical fluticasone, as well as other steroid medications. "Furthermore," the authors wrote, "delivery systems need to be developed that are easier to use and provide more direct drug delivery to the esophagus."

Dr. Alexander disclosed a financial relationship with Meritage Pharmacia.

BOSTON – Adaptive servoventilation is more reliably effective than continuous positive airway pressure is for the prolonged treatment of complex sleep apnea, a study has shown.

Prior studies have shown that the adaptive ventilatory support method, which continuously monitors and analyzes a patient’s breathing pattern and adds variable amounts of inspiratory pressure support to low levels of background expiratory positive airway pressure as needed, is initially more effective than is continuous positive airway pressure (CPAP) in complex sleep apnea patients. But sustained efficacy over time has not been established, according to Dr. Timothy I. Morgenthaler of the Center for Sleep Medicine at the Mayo Clinic in Rochester, Minn.

"The concern is that residual central breathing events may resolve over time with CPAP therapy, which is less expensive than adaptive servoventilation [ASV] and therefore may be a better option," he said at the annual meeting of the Associated Professional Sleep Societies.

To evaluate the longer-term efficacy of ASV relative to CPAP in individuals with complex sleep apnea syndrome (CSAS), Dr. Morgenthaler and his colleagues conducted a multicenter, prospective trial of 66 patients with CSAS, defined as those meeting the criteria for obstructive sleep apnea on diagnostic polysomnography who also had a central apnea index (CAI) score of 10 or higher while on optimal CPAP. The participants were randomized to treatment with either CPAP (n = 33) or ASV (n = 33), both titrated to optimal settings. Clinical and polysomnographic measures were collected at baseline and after 90 days of therapy, he said.

In addition to having a diagnosis of CSAS, eligible patients were older than 18 years and were naive to positive airway pressure treatment. The mean age of the study participants was 59.2 years, and the mean body mass index was 35.0 kg/m², with no between-group differences. Additionally, about 9% of the patients had congestive heart failure and 13.6% reported chronic opiate use, Dr. Morgenthaler reported.

At baseline, the mean apnea-hypopnea index (AHI) and CAI scores were 37.7 and 3.2, respectively. After second-night treatment titration, the AHI scores were 4.7 in the ASV group vs. 14.1 in the CPAP group, and the respective CAI scores were 1.1 and 8.8, said Dr. Morgenthaler. At 90 days, the AHI for the ASV group was 4.4, compared with 9.9 for CPAP, and the respective CAI scores were 0.7 and 4.8, he said.

"In the intention-to-treat analysis, treatment was successful [defined as an AHI of less than 10] in 89.7% of the adaptive servoventilation group," while only 64.5% of the CPAP patients attained similar success, Dr. Morgenthaler stated, noting that there were no significant differences between the groups with respect to compliance, Epworth Sleepiness Scale (ESS) changes, or sleep apnea quality of life index (SAQLI) scores.

Although significantly more ASV patients showed evidence of treatment efficacy based on polysomnographic measures than did CPAP patients, "there were no similar symptomatic differences between the groups," Dr. Morgenthaler acknowledged. It is possible, but yet to be determined, that ASV-induced improvements on polysomnography will translate into other positive health outcomes, such as maximal suppression of Cheyne-Stokes respiration and central sleep apnea (CSR-CSA), as well as improvement in brain natriuretic peptide, in patients with heart failure, he said.

Dr. Morgenthaler disclosed that this study was supported by a grant from ResMed, the manufacturer of the ASV device used in the investigation.

BOSTON – Adaptive servoventilation is more reliably effective than continuous positive airway pressure is for the prolonged treatment of complex sleep apnea, a study has shown.

Prior studies have shown that the adaptive ventilatory support method, which continuously monitors and analyzes a patient’s breathing pattern and adds variable amounts of inspiratory pressure support to low levels of background expiratory positive airway pressure as needed, is initially more effective than is continuous positive airway pressure (CPAP) in complex sleep apnea patients. But sustained efficacy over time has not been established, according to Dr. Timothy I. Morgenthaler of the Center for Sleep Medicine at the Mayo Clinic in Rochester, Minn.

"The concern is that residual central breathing events may resolve over time with CPAP therapy, which is less expensive than adaptive servoventilation [ASV] and therefore may be a better option," he said at the annual meeting of the Associated Professional Sleep Societies.

To evaluate the longer-term efficacy of ASV relative to CPAP in individuals with complex sleep apnea syndrome (CSAS), Dr. Morgenthaler and his colleagues conducted a multicenter, prospective trial of 66 patients with CSAS, defined as those meeting the criteria for obstructive sleep apnea on diagnostic polysomnography who also had a central apnea index (CAI) score of 10 or higher while on optimal CPAP. The participants were randomized to treatment with either CPAP (n = 33) or ASV (n = 33), both titrated to optimal settings. Clinical and polysomnographic measures were collected at baseline and after 90 days of therapy, he said.

In addition to having a diagnosis of CSAS, eligible patients were older than 18 years and were naive to positive airway pressure treatment. The mean age of the study participants was 59.2 years, and the mean body mass index was 35.0 kg/m², with no between-group differences. Additionally, about 9% of the patients had congestive heart failure and 13.6% reported chronic opiate use, Dr. Morgenthaler reported.

At baseline, the mean apnea-hypopnea index (AHI) and CAI scores were 37.7 and 3.2, respectively. After second-night treatment titration, the AHI scores were 4.7 in the ASV group vs. 14.1 in the CPAP group, and the respective CAI scores were 1.1 and 8.8, said Dr. Morgenthaler. At 90 days, the AHI for the ASV group was 4.4, compared with 9.9 for CPAP, and the respective CAI scores were 0.7 and 4.8, he said.

"In the intention-to-treat analysis, treatment was successful [defined as an AHI of less than 10] in 89.7% of the adaptive servoventilation group," while only 64.5% of the CPAP patients attained similar success, Dr. Morgenthaler stated, noting that there were no significant differences between the groups with respect to compliance, Epworth Sleepiness Scale (ESS) changes, or sleep apnea quality of life index (SAQLI) scores.

Although significantly more ASV patients showed evidence of treatment efficacy based on polysomnographic measures than did CPAP patients, "there were no similar symptomatic differences between the groups," Dr. Morgenthaler acknowledged. It is possible, but yet to be determined, that ASV-induced improvements on polysomnography will translate into other positive health outcomes, such as maximal suppression of Cheyne-Stokes respiration and central sleep apnea (CSR-CSA), as well as improvement in brain natriuretic peptide, in patients with heart failure, he said.

Dr. Morgenthaler disclosed that this study was supported by a grant from ResMed, the manufacturer of the ASV device used in the investigation.

BOSTON – Adaptive servoventilation is more reliably effective than continuous positive airway pressure is for the prolonged treatment of complex sleep apnea, a study has shown.

Prior studies have shown that the adaptive ventilatory support method, which continuously monitors and analyzes a patient’s breathing pattern and adds variable amounts of inspiratory pressure support to low levels of background expiratory positive airway pressure as needed, is initially more effective than is continuous positive airway pressure (CPAP) in complex sleep apnea patients. But sustained efficacy over time has not been established, according to Dr. Timothy I. Morgenthaler of the Center for Sleep Medicine at the Mayo Clinic in Rochester, Minn.

"The concern is that residual central breathing events may resolve over time with CPAP therapy, which is less expensive than adaptive servoventilation [ASV] and therefore may be a better option," he said at the annual meeting of the Associated Professional Sleep Societies.

To evaluate the longer-term efficacy of ASV relative to CPAP in individuals with complex sleep apnea syndrome (CSAS), Dr. Morgenthaler and his colleagues conducted a multicenter, prospective trial of 66 patients with CSAS, defined as those meeting the criteria for obstructive sleep apnea on diagnostic polysomnography who also had a central apnea index (CAI) score of 10 or higher while on optimal CPAP. The participants were randomized to treatment with either CPAP (n = 33) or ASV (n = 33), both titrated to optimal settings. Clinical and polysomnographic measures were collected at baseline and after 90 days of therapy, he said.

In addition to having a diagnosis of CSAS, eligible patients were older than 18 years and were naive to positive airway pressure treatment. The mean age of the study participants was 59.2 years, and the mean body mass index was 35.0 kg/m², with no between-group differences. Additionally, about 9% of the patients had congestive heart failure and 13.6% reported chronic opiate use, Dr. Morgenthaler reported.

At baseline, the mean apnea-hypopnea index (AHI) and CAI scores were 37.7 and 3.2, respectively. After second-night treatment titration, the AHI scores were 4.7 in the ASV group vs. 14.1 in the CPAP group, and the respective CAI scores were 1.1 and 8.8, said Dr. Morgenthaler. At 90 days, the AHI for the ASV group was 4.4, compared with 9.9 for CPAP, and the respective CAI scores were 0.7 and 4.8, he said.

"In the intention-to-treat analysis, treatment was successful [defined as an AHI of less than 10] in 89.7% of the adaptive servoventilation group," while only 64.5% of the CPAP patients attained similar success, Dr. Morgenthaler stated, noting that there were no significant differences between the groups with respect to compliance, Epworth Sleepiness Scale (ESS) changes, or sleep apnea quality of life index (SAQLI) scores.

Although significantly more ASV patients showed evidence of treatment efficacy based on polysomnographic measures than did CPAP patients, "there were no similar symptomatic differences between the groups," Dr. Morgenthaler acknowledged. It is possible, but yet to be determined, that ASV-induced improvements on polysomnography will translate into other positive health outcomes, such as maximal suppression of Cheyne-Stokes respiration and central sleep apnea (CSR-CSA), as well as improvement in brain natriuretic peptide, in patients with heart failure, he said.

Dr. Morgenthaler disclosed that this study was supported by a grant from ResMed, the manufacturer of the ASV device used in the investigation.