Sharon Worcester

Cobas human papillomavirus testing with individual human papillomavirus types 16 and 18 detection could serve as a more sensitive and more efficient approach to cervical cancer screening than traditional liquid-based cytology methods alone, according to a subanalysis of data from the ATHENA study.

The findings of the current analysis have implications for the development of strategies – including triage to colposcopy – for managing HPV-positive women, Philip E. Castle, Ph.D., of the American Society for Clinical Pathology Institute, Washington, D.C., and his colleagues reported in the Aug. 23 issue of Lancet Oncology.

The investigators analyzed data from 41,955 women aged 25 years and older who were part of the ATHENA (Addressing the Need for Advanced HPV Diagnostics) study, which was designed to assess the performance of HPV testing and HPV-16 and HPV-18 genotyping, compared with liquid-based cytology for cervical cancer screening. Of 40,901 women who had valid cobas HPV and liquid-based cytology test results available, 10% (4,275) tested HPV positive and 6% (2,617) had abnormal cytology; of these, 1.1 % (431) were diagnosed with cervical intraepithelial neoplasia grade 2 (CIN 2) or worse, and 0.7% (274) were diagnosed with CIN 3 or worse.

An analysis of the results of colposcopy, which was performed in 2,609 women found to have atypical squamous cells of undetermined significance (ASCUS) or worse cytology, 5,726 women with a positive HPV test by either of the first-generation HPV DNA assays used in the study (Amplicor HPV test and Linear Array HPG genotyping), and 1,041 women who were HPV negative and who had negative for intraepithelial or malignant (NILM) cervical cytology, showed that the cobas HPV test was significantly more sensitive for detecting CIN 3 or worse than was liquid-based cytology at a threshold of ASCUS or worse (92% vs. 53.3%), the investigators found (Lancet Oncol. 2011;12:880-90).

Adding cytology to HPV testing increased the sensitivity for detection of CIN 3 or worse by less than 5% (from 92% to 96.7%), but increased the number of screen positives by more than 35%, Dr. Castle and his associates said.

When used as a triage test for identifying high-grade CIN (grade 3 or higher), the detection of HPV-16, HPV-18, or both alone was statistically equivalent to the detection of ASCUS or worse alone in terms of both sensitivity (59.5% and 52.8%, respectively) and positive predictive value (15.5% and 14.1%), they noted.

Sensitivity was further increased – and the positive predictive value (PPV) decreased – by use of HPV-16, HPV-18, or both as an additional or complementary triage strategy to ASCUS or worse, they said, adding: "Notably, testing positive for HPV-16, HPV-18, or both had a sensitivity of 53.8% ... and [a] PPV of 10.2% ... for CIN 3 or worse in women aged 25 years or older who were HPV positive and had NILM cytology."

In addition, the use of a threshold of low-grade squamous intraepithelial lesion (LSIL) or worse with HPV-16, HPV-18, or both was more sensitive than detection of ASCUS or worse alone with similar PPV, and detection of high-grade squamous intraepithelial lesion (HSIL) or worse with HPV-16, HPV-18, or both had a higher sensitivity and PPV than ASCUS or worse alone.

HPV Testing for Cervical Disease Proven Rational

The findings suggest that that the use of HPV testing as the primary screening test to rule out cervical disease, along with a specific test like liquid-based cytology to help determine which women should be sent for immediate colposcopy, is a rational approach, and they support the premise that co-testing has little benefit over HPV testing alone, the investigators noted.

"However, until clinicians become comfortable with the use of HPV as a first-line test, they might initially favor co-testing, and so co-testing could have an underlying merit that is difficult to quantify," Dr. Castle and his associates wrote, adding that "the decision to switch from co-testing to HPV testing alone, and the intervals between screenings will ultimately depend on clinicians’ perceptions of acceptable risks."

"Nevertheless, on the basis of our findings, we suggest that detection of HPV-16, HPV-18, or both combined with a raised threshold of abnormal cervical cytology (LSIL or worse) might be preferable to the existing recommendations for management of HPV-positive women," the investigators wrote, noting that testing and genotyping for HPV-16, HPV-18, or both – with or without liquid-based cytology – can provide potentially cost-effective and safe screening.

"Because the HPV-16 and HPV-18 readouts for the cobas HPV test are provided concurrently with the pooled detection of other carcinogenic HPV genotypes," the use of this test to triage HPV-positive women for colposcopy could prove much more efficient than cytology, they added.

Also, a strategy of applying cytology reflexively to those who are HPV positive without HPV-16 or HPV-18 genotype, with referral to colposcopy only if they have LSIL or HSIL, or worse, would increase the sensitivity for detection of CIN 3 or worse in HPV-positive women to a level above that provided by HPV- 16 and HPV-18, or both, without sacrificing good PPV, they said. The comparative performance and cost effectiveness of various strategies will need to be assessed in future studies to identify best practices, they noted.

New Cervical Cancer Screening Strategies Preferable

In an accompanying editorial, Dr. Guglielmo Ronco and his colleagues said that a cervical cancer screening strategy that allows immediate identification of all women with lesions needing treatment would be preferable to the current approach of rescreening HPV-positive women with normal cytology at 1 year, with colposcopy performed if infection is still present or if cytology has become abnormal.

"Unfortunately, all combinations of genotyping and cytology in Castle and colleagues’ study had less than 80% sensitivity, leading the investigators to recommend test repetitions after 1 year," Dr. Ronco and his colleagues wrote (Lancet Oncol. 2011;12:831-2).

Still, the increased sensitivity provided by the combined triage tests would allow some CIN 3 or worse lesions to be detected earlier, noted Dr. Ronco of the Centre of Cancer Prevention in Turin, Italy, and his associates.

Furthermore, strategies using other biomarkers to triage HPV-positive women are currently being assessed; the cross-sectional sensitivity of immunochemistry for p16INK4a overexpression for CIN 3 or worse, for example, is 91%, which suggests that short-term retesting could be avoided in those who test negative for p16INK4a. Dr. Ronco and his colleagues warned, however, that since HPV-positive women are at increased risk for developing new lesions, premature reallocation to screening intervals as long as those recommended for HPV-negative women "might not be advisable."

"Additional longitudinal data are needed to define the safest time interval before retesting in women with HPV infection who were negative for p16INK4a or any other triage test," they wrote.

They also noted that the findings of this study, though designed for developed countries, can provide useful information about triage strategies for "countries where high-quality cytology has been difficult to implement and combinations of HPV tests might eventually offer a more sustainable option."

Dr. Ronco and his coauthors said they had no relevant financial disclosures.

The study was funded by Roche Molecular Systems. Dr. Castle said he has a nondisclosure agreement to work with Roche on the analysis of their clinical trial but receives no financial compensation. Other authors on the study disclosed that they are employed by Roche Molecular Systems and/or have stock or stock options in the company, or that they have received consulting fees, honoraria, and/or other compensation from Roche, BD Diagnostics, Qiagen, Gen-Probe, Ventana, and/or Merck.

Cobas human papillomavirus testing with individual human papillomavirus types 16 and 18 detection could serve as a more sensitive and more efficient approach to cervical cancer screening than traditional liquid-based cytology methods alone, according to a subanalysis of data from the ATHENA study.

The findings of the current analysis have implications for the development of strategies – including triage to colposcopy – for managing HPV-positive women, Philip E. Castle, Ph.D., of the American Society for Clinical Pathology Institute, Washington, D.C., and his colleagues reported in the Aug. 23 issue of Lancet Oncology.

The investigators analyzed data from 41,955 women aged 25 years and older who were part of the ATHENA (Addressing the Need for Advanced HPV Diagnostics) study, which was designed to assess the performance of HPV testing and HPV-16 and HPV-18 genotyping, compared with liquid-based cytology for cervical cancer screening. Of 40,901 women who had valid cobas HPV and liquid-based cytology test results available, 10% (4,275) tested HPV positive and 6% (2,617) had abnormal cytology; of these, 1.1 % (431) were diagnosed with cervical intraepithelial neoplasia grade 2 (CIN 2) or worse, and 0.7% (274) were diagnosed with CIN 3 or worse.

An analysis of the results of colposcopy, which was performed in 2,609 women found to have atypical squamous cells of undetermined significance (ASCUS) or worse cytology, 5,726 women with a positive HPV test by either of the first-generation HPV DNA assays used in the study (Amplicor HPV test and Linear Array HPG genotyping), and 1,041 women who were HPV negative and who had negative for intraepithelial or malignant (NILM) cervical cytology, showed that the cobas HPV test was significantly more sensitive for detecting CIN 3 or worse than was liquid-based cytology at a threshold of ASCUS or worse (92% vs. 53.3%), the investigators found (Lancet Oncol. 2011;12:880-90).

Adding cytology to HPV testing increased the sensitivity for detection of CIN 3 or worse by less than 5% (from 92% to 96.7%), but increased the number of screen positives by more than 35%, Dr. Castle and his associates said.

When used as a triage test for identifying high-grade CIN (grade 3 or higher), the detection of HPV-16, HPV-18, or both alone was statistically equivalent to the detection of ASCUS or worse alone in terms of both sensitivity (59.5% and 52.8%, respectively) and positive predictive value (15.5% and 14.1%), they noted.

Sensitivity was further increased – and the positive predictive value (PPV) decreased – by use of HPV-16, HPV-18, or both as an additional or complementary triage strategy to ASCUS or worse, they said, adding: "Notably, testing positive for HPV-16, HPV-18, or both had a sensitivity of 53.8% ... and [a] PPV of 10.2% ... for CIN 3 or worse in women aged 25 years or older who were HPV positive and had NILM cytology."

In addition, the use of a threshold of low-grade squamous intraepithelial lesion (LSIL) or worse with HPV-16, HPV-18, or both was more sensitive than detection of ASCUS or worse alone with similar PPV, and detection of high-grade squamous intraepithelial lesion (HSIL) or worse with HPV-16, HPV-18, or both had a higher sensitivity and PPV than ASCUS or worse alone.

HPV Testing for Cervical Disease Proven Rational

The findings suggest that that the use of HPV testing as the primary screening test to rule out cervical disease, along with a specific test like liquid-based cytology to help determine which women should be sent for immediate colposcopy, is a rational approach, and they support the premise that co-testing has little benefit over HPV testing alone, the investigators noted.

"However, until clinicians become comfortable with the use of HPV as a first-line test, they might initially favor co-testing, and so co-testing could have an underlying merit that is difficult to quantify," Dr. Castle and his associates wrote, adding that "the decision to switch from co-testing to HPV testing alone, and the intervals between screenings will ultimately depend on clinicians’ perceptions of acceptable risks."

"Nevertheless, on the basis of our findings, we suggest that detection of HPV-16, HPV-18, or both combined with a raised threshold of abnormal cervical cytology (LSIL or worse) might be preferable to the existing recommendations for management of HPV-positive women," the investigators wrote, noting that testing and genotyping for HPV-16, HPV-18, or both – with or without liquid-based cytology – can provide potentially cost-effective and safe screening.

"Because the HPV-16 and HPV-18 readouts for the cobas HPV test are provided concurrently with the pooled detection of other carcinogenic HPV genotypes," the use of this test to triage HPV-positive women for colposcopy could prove much more efficient than cytology, they added.

Also, a strategy of applying cytology reflexively to those who are HPV positive without HPV-16 or HPV-18 genotype, with referral to colposcopy only if they have LSIL or HSIL, or worse, would increase the sensitivity for detection of CIN 3 or worse in HPV-positive women to a level above that provided by HPV- 16 and HPV-18, or both, without sacrificing good PPV, they said. The comparative performance and cost effectiveness of various strategies will need to be assessed in future studies to identify best practices, they noted.

New Cervical Cancer Screening Strategies Preferable

In an accompanying editorial, Dr. Guglielmo Ronco and his colleagues said that a cervical cancer screening strategy that allows immediate identification of all women with lesions needing treatment would be preferable to the current approach of rescreening HPV-positive women with normal cytology at 1 year, with colposcopy performed if infection is still present or if cytology has become abnormal.

"Unfortunately, all combinations of genotyping and cytology in Castle and colleagues’ study had less than 80% sensitivity, leading the investigators to recommend test repetitions after 1 year," Dr. Ronco and his colleagues wrote (Lancet Oncol. 2011;12:831-2).

Still, the increased sensitivity provided by the combined triage tests would allow some CIN 3 or worse lesions to be detected earlier, noted Dr. Ronco of the Centre of Cancer Prevention in Turin, Italy, and his associates.

Furthermore, strategies using other biomarkers to triage HPV-positive women are currently being assessed; the cross-sectional sensitivity of immunochemistry for p16INK4a overexpression for CIN 3 or worse, for example, is 91%, which suggests that short-term retesting could be avoided in those who test negative for p16INK4a. Dr. Ronco and his colleagues warned, however, that since HPV-positive women are at increased risk for developing new lesions, premature reallocation to screening intervals as long as those recommended for HPV-negative women "might not be advisable."

"Additional longitudinal data are needed to define the safest time interval before retesting in women with HPV infection who were negative for p16INK4a or any other triage test," they wrote.

They also noted that the findings of this study, though designed for developed countries, can provide useful information about triage strategies for "countries where high-quality cytology has been difficult to implement and combinations of HPV tests might eventually offer a more sustainable option."

Dr. Ronco and his coauthors said they had no relevant financial disclosures.

The study was funded by Roche Molecular Systems. Dr. Castle said he has a nondisclosure agreement to work with Roche on the analysis of their clinical trial but receives no financial compensation. Other authors on the study disclosed that they are employed by Roche Molecular Systems and/or have stock or stock options in the company, or that they have received consulting fees, honoraria, and/or other compensation from Roche, BD Diagnostics, Qiagen, Gen-Probe, Ventana, and/or Merck.

Cobas human papillomavirus testing with individual human papillomavirus types 16 and 18 detection could serve as a more sensitive and more efficient approach to cervical cancer screening than traditional liquid-based cytology methods alone, according to a subanalysis of data from the ATHENA study.

The findings of the current analysis have implications for the development of strategies – including triage to colposcopy – for managing HPV-positive women, Philip E. Castle, Ph.D., of the American Society for Clinical Pathology Institute, Washington, D.C., and his colleagues reported in the Aug. 23 issue of Lancet Oncology.

The investigators analyzed data from 41,955 women aged 25 years and older who were part of the ATHENA (Addressing the Need for Advanced HPV Diagnostics) study, which was designed to assess the performance of HPV testing and HPV-16 and HPV-18 genotyping, compared with liquid-based cytology for cervical cancer screening. Of 40,901 women who had valid cobas HPV and liquid-based cytology test results available, 10% (4,275) tested HPV positive and 6% (2,617) had abnormal cytology; of these, 1.1 % (431) were diagnosed with cervical intraepithelial neoplasia grade 2 (CIN 2) or worse, and 0.7% (274) were diagnosed with CIN 3 or worse.

An analysis of the results of colposcopy, which was performed in 2,609 women found to have atypical squamous cells of undetermined significance (ASCUS) or worse cytology, 5,726 women with a positive HPV test by either of the first-generation HPV DNA assays used in the study (Amplicor HPV test and Linear Array HPG genotyping), and 1,041 women who were HPV negative and who had negative for intraepithelial or malignant (NILM) cervical cytology, showed that the cobas HPV test was significantly more sensitive for detecting CIN 3 or worse than was liquid-based cytology at a threshold of ASCUS or worse (92% vs. 53.3%), the investigators found (Lancet Oncol. 2011;12:880-90).

Adding cytology to HPV testing increased the sensitivity for detection of CIN 3 or worse by less than 5% (from 92% to 96.7%), but increased the number of screen positives by more than 35%, Dr. Castle and his associates said.

When used as a triage test for identifying high-grade CIN (grade 3 or higher), the detection of HPV-16, HPV-18, or both alone was statistically equivalent to the detection of ASCUS or worse alone in terms of both sensitivity (59.5% and 52.8%, respectively) and positive predictive value (15.5% and 14.1%), they noted.

Sensitivity was further increased – and the positive predictive value (PPV) decreased – by use of HPV-16, HPV-18, or both as an additional or complementary triage strategy to ASCUS or worse, they said, adding: "Notably, testing positive for HPV-16, HPV-18, or both had a sensitivity of 53.8% ... and [a] PPV of 10.2% ... for CIN 3 or worse in women aged 25 years or older who were HPV positive and had NILM cytology."

In addition, the use of a threshold of low-grade squamous intraepithelial lesion (LSIL) or worse with HPV-16, HPV-18, or both was more sensitive than detection of ASCUS or worse alone with similar PPV, and detection of high-grade squamous intraepithelial lesion (HSIL) or worse with HPV-16, HPV-18, or both had a higher sensitivity and PPV than ASCUS or worse alone.

HPV Testing for Cervical Disease Proven Rational

The findings suggest that that the use of HPV testing as the primary screening test to rule out cervical disease, along with a specific test like liquid-based cytology to help determine which women should be sent for immediate colposcopy, is a rational approach, and they support the premise that co-testing has little benefit over HPV testing alone, the investigators noted.

"However, until clinicians become comfortable with the use of HPV as a first-line test, they might initially favor co-testing, and so co-testing could have an underlying merit that is difficult to quantify," Dr. Castle and his associates wrote, adding that "the decision to switch from co-testing to HPV testing alone, and the intervals between screenings will ultimately depend on clinicians’ perceptions of acceptable risks."

"Nevertheless, on the basis of our findings, we suggest that detection of HPV-16, HPV-18, or both combined with a raised threshold of abnormal cervical cytology (LSIL or worse) might be preferable to the existing recommendations for management of HPV-positive women," the investigators wrote, noting that testing and genotyping for HPV-16, HPV-18, or both – with or without liquid-based cytology – can provide potentially cost-effective and safe screening.

"Because the HPV-16 and HPV-18 readouts for the cobas HPV test are provided concurrently with the pooled detection of other carcinogenic HPV genotypes," the use of this test to triage HPV-positive women for colposcopy could prove much more efficient than cytology, they added.

Also, a strategy of applying cytology reflexively to those who are HPV positive without HPV-16 or HPV-18 genotype, with referral to colposcopy only if they have LSIL or HSIL, or worse, would increase the sensitivity for detection of CIN 3 or worse in HPV-positive women to a level above that provided by HPV- 16 and HPV-18, or both, without sacrificing good PPV, they said. The comparative performance and cost effectiveness of various strategies will need to be assessed in future studies to identify best practices, they noted.

New Cervical Cancer Screening Strategies Preferable

In an accompanying editorial, Dr. Guglielmo Ronco and his colleagues said that a cervical cancer screening strategy that allows immediate identification of all women with lesions needing treatment would be preferable to the current approach of rescreening HPV-positive women with normal cytology at 1 year, with colposcopy performed if infection is still present or if cytology has become abnormal.

"Unfortunately, all combinations of genotyping and cytology in Castle and colleagues’ study had less than 80% sensitivity, leading the investigators to recommend test repetitions after 1 year," Dr. Ronco and his colleagues wrote (Lancet Oncol. 2011;12:831-2).

Still, the increased sensitivity provided by the combined triage tests would allow some CIN 3 or worse lesions to be detected earlier, noted Dr. Ronco of the Centre of Cancer Prevention in Turin, Italy, and his associates.

Furthermore, strategies using other biomarkers to triage HPV-positive women are currently being assessed; the cross-sectional sensitivity of immunochemistry for p16INK4a overexpression for CIN 3 or worse, for example, is 91%, which suggests that short-term retesting could be avoided in those who test negative for p16INK4a. Dr. Ronco and his colleagues warned, however, that since HPV-positive women are at increased risk for developing new lesions, premature reallocation to screening intervals as long as those recommended for HPV-negative women "might not be advisable."

"Additional longitudinal data are needed to define the safest time interval before retesting in women with HPV infection who were negative for p16INK4a or any other triage test," they wrote.

They also noted that the findings of this study, though designed for developed countries, can provide useful information about triage strategies for "countries where high-quality cytology has been difficult to implement and combinations of HPV tests might eventually offer a more sustainable option."

Dr. Ronco and his coauthors said they had no relevant financial disclosures.

The study was funded by Roche Molecular Systems. Dr. Castle said he has a nondisclosure agreement to work with Roche on the analysis of their clinical trial but receives no financial compensation. Other authors on the study disclosed that they are employed by Roche Molecular Systems and/or have stock or stock options in the company, or that they have received consulting fees, honoraria, and/or other compensation from Roche, BD Diagnostics, Qiagen, Gen-Probe, Ventana, and/or Merck.

Pegloticase, a unique, recently approved urate-lowering therapy, was superior to placebo for lowering uric acid levels and resolved some tophi in patients with refractory chronic gout in two replicate randomized, placebo-controlled trials.

Patients in both trials, including 109 patients in Trial C0405 and 116 in Trial C0406, were randomized to receive either biweekly infusions of pegloticase (biweekly treatment), biweekly infusions with alternating pegloticase and placebo (monthly treatment), or biweekly placebo. The primary end point of plasma uric acid levels less than 6 mg/dL in months 3 and 6 of treatment was achieved in 47% and 38% of those in the two trials, respectively, who were randomized to receive biweekly treatment, and in 20% and 39% of patients in the two trials, respectively, who were randomized to receive monthly treatment. None of the patients in the placebo group in either trial achieved the primary end point, Dr. John S. Sundy of Duke University, Durham, N.C., and his colleagues report in the Aug. 17 issue of JAMA.

When data from the two trials were pooled, 42% of patients receiving active treatment biweekly and 35% of patients receiving active treatment monthly achieved the primary end point, the investigators found (JAMA 2011;306:711-20).

Pegloticase is a mammalian recombinant uricase conjugated to monomethoxypoly. It serves as an enzymatic alternative to conventional urate-lowering therapy, which fails in about 3% of gout patients as a result of refractoriness, contraindications, or intolerance. Treatment in these 6-month, multicenter trials was given starting at week 1 as a 2-hour intravenous infusion of 250 ml 0.9% sodium chloride containing 8 mg pegloticase or placebo, depending on randomization.

In addition to the significantly greater effectiveness of active treatment versus placebo in regard to the primary end point, 40% and 21% of patients in the biweekly and monthly treatment groups, respectively, also experienced a complete response for one or more tophus by the final follow-up visit, compared with only 7% of those in the placebo groups, the investigators said.

Also, the treatment groups experienced reductions in tender joint count and swollen joint count, compared with placebo, although the differences were significant only for tender joint count.

Significant improvements in physical function and quality of life were also noted in the treatment groups, compared with the placebo groups, and biweekly treatment was associated with significant changes from baseline in the Health Assessment Questionnaire-Disability Index scores and Short Form-36 Physical Component Summary scores that met or exceeded the minimum clinically important differences established for the respective instrument in inflammatory arthritides, the investigators noted.

During the first 3 months of the studies, both the incidence of gout flares and the number of flares per patient were higher in the treatment versus placebo groups, but during months 4-6, continued biweekly treatment was associated with a significant reduction in the proportion of patients with gout flare, compared with placebo, and flares per patient also were reduced, although this difference was not statistically significant, they said.

Adverse events were common in the treatment groups, with one or more occurring in more than 90% of patients receiving active treatment. Serious adverse events occurred more often in the biweekly treatment groups and the monthly groups, compared with the placebo groups (24% and 23% vs. 12%). Gout flare and infusion-related reactions were the most common adverse events.

Serious infusion reactions occurred in 5% and 8% of the biweekly and monthly patient groups, respectively, and resolution of all infusion reactions begin within minutes of slowing or discontinuing the infusion or initiating supportive treatment; all resolved completely. The investigators stressed the importance of minimizing the risk of infusion reactions by using prophylaxis in clinical practice, as was done in these studies.

They also emphasized the importance of stabilizing cardiovascular comorbidities prior to initiating treatment, given the "relatively small number of mechanistically diverse albeit serious cardiovascular adverse events" that occurred during these studies (two deaths were attributed to cardiovascular adverse events in the biweekly treatment group, and one nonfatal myocardial infarction occurred in a patient receiving monthly treatment). All of the cardiovascular events occurred in patients with four or more cardiovascular risk factors at baseline, they noted.

"Despite the 4-fold greater number of patients receiving pegloticase vs. placebo, the elevated CV risk profile of this population and the absence of a compelling mechanism connecting pegloticase with CV AEs, the observed numerical imbalance in these events underlines the need for care in selecting patients for pegloticase treatment," they added.

These parallel trials "have documented sustained [uric acid] reductions and significant clinical improvement in a substantial proportion of patients with chronic gout and refractoriness to, or intolerance of, conventional urate-lowering therapy," the investigators wrote.

The significant disease-modifying benefits of biweekly treatment with pegloticase were evident within 6 months and, of note, the improvements in physical function and quality of life scores exceeding the minimal clinically important difference in pegloticase-treated patients, when considered in light of the deterioration in pain and quality of life seen in placebo patients in these studies, provide evidence that "chronic elevations in uric acid are associated with significant functional impairment as measured by several criteria," they said, explaining that this relationship has previously been difficult to distinguish from functional impairment associated with the serious comorbidities common in gout patients.

These studies were funded by Savient Pharmaceuticals, the maker of pegloticase. Dr. Sundy reported receiving fees for consulting and grants from Ardea Bioscience, Novartis, Nuon Therapeutics, Regeneron, and Savient Pharmaceuticals as well as payment for lectures, including service on the speakers bureau for Takeda Pharmaceuticals North America. Other authors also disclosed relationships with Savient Pharmaceuticals and other companies. Complete disclosures are included in the JAMA article.

Pegloticase, a unique, recently approved urate-lowering therapy, was superior to placebo for lowering uric acid levels and resolved some tophi in patients with refractory chronic gout in two replicate randomized, placebo-controlled trials.

Patients in both trials, including 109 patients in Trial C0405 and 116 in Trial C0406, were randomized to receive either biweekly infusions of pegloticase (biweekly treatment), biweekly infusions with alternating pegloticase and placebo (monthly treatment), or biweekly placebo. The primary end point of plasma uric acid levels less than 6 mg/dL in months 3 and 6 of treatment was achieved in 47% and 38% of those in the two trials, respectively, who were randomized to receive biweekly treatment, and in 20% and 39% of patients in the two trials, respectively, who were randomized to receive monthly treatment. None of the patients in the placebo group in either trial achieved the primary end point, Dr. John S. Sundy of Duke University, Durham, N.C., and his colleagues report in the Aug. 17 issue of JAMA.

When data from the two trials were pooled, 42% of patients receiving active treatment biweekly and 35% of patients receiving active treatment monthly achieved the primary end point, the investigators found (JAMA 2011;306:711-20).

Pegloticase is a mammalian recombinant uricase conjugated to monomethoxypoly. It serves as an enzymatic alternative to conventional urate-lowering therapy, which fails in about 3% of gout patients as a result of refractoriness, contraindications, or intolerance. Treatment in these 6-month, multicenter trials was given starting at week 1 as a 2-hour intravenous infusion of 250 ml 0.9% sodium chloride containing 8 mg pegloticase or placebo, depending on randomization.

In addition to the significantly greater effectiveness of active treatment versus placebo in regard to the primary end point, 40% and 21% of patients in the biweekly and monthly treatment groups, respectively, also experienced a complete response for one or more tophus by the final follow-up visit, compared with only 7% of those in the placebo groups, the investigators said.

Also, the treatment groups experienced reductions in tender joint count and swollen joint count, compared with placebo, although the differences were significant only for tender joint count.

Significant improvements in physical function and quality of life were also noted in the treatment groups, compared with the placebo groups, and biweekly treatment was associated with significant changes from baseline in the Health Assessment Questionnaire-Disability Index scores and Short Form-36 Physical Component Summary scores that met or exceeded the minimum clinically important differences established for the respective instrument in inflammatory arthritides, the investigators noted.

During the first 3 months of the studies, both the incidence of gout flares and the number of flares per patient were higher in the treatment versus placebo groups, but during months 4-6, continued biweekly treatment was associated with a significant reduction in the proportion of patients with gout flare, compared with placebo, and flares per patient also were reduced, although this difference was not statistically significant, they said.

Adverse events were common in the treatment groups, with one or more occurring in more than 90% of patients receiving active treatment. Serious adverse events occurred more often in the biweekly treatment groups and the monthly groups, compared with the placebo groups (24% and 23% vs. 12%). Gout flare and infusion-related reactions were the most common adverse events.

Serious infusion reactions occurred in 5% and 8% of the biweekly and monthly patient groups, respectively, and resolution of all infusion reactions begin within minutes of slowing or discontinuing the infusion or initiating supportive treatment; all resolved completely. The investigators stressed the importance of minimizing the risk of infusion reactions by using prophylaxis in clinical practice, as was done in these studies.

They also emphasized the importance of stabilizing cardiovascular comorbidities prior to initiating treatment, given the "relatively small number of mechanistically diverse albeit serious cardiovascular adverse events" that occurred during these studies (two deaths were attributed to cardiovascular adverse events in the biweekly treatment group, and one nonfatal myocardial infarction occurred in a patient receiving monthly treatment). All of the cardiovascular events occurred in patients with four or more cardiovascular risk factors at baseline, they noted.

"Despite the 4-fold greater number of patients receiving pegloticase vs. placebo, the elevated CV risk profile of this population and the absence of a compelling mechanism connecting pegloticase with CV AEs, the observed numerical imbalance in these events underlines the need for care in selecting patients for pegloticase treatment," they added.

These parallel trials "have documented sustained [uric acid] reductions and significant clinical improvement in a substantial proportion of patients with chronic gout and refractoriness to, or intolerance of, conventional urate-lowering therapy," the investigators wrote.

The significant disease-modifying benefits of biweekly treatment with pegloticase were evident within 6 months and, of note, the improvements in physical function and quality of life scores exceeding the minimal clinically important difference in pegloticase-treated patients, when considered in light of the deterioration in pain and quality of life seen in placebo patients in these studies, provide evidence that "chronic elevations in uric acid are associated with significant functional impairment as measured by several criteria," they said, explaining that this relationship has previously been difficult to distinguish from functional impairment associated with the serious comorbidities common in gout patients.

These studies were funded by Savient Pharmaceuticals, the maker of pegloticase. Dr. Sundy reported receiving fees for consulting and grants from Ardea Bioscience, Novartis, Nuon Therapeutics, Regeneron, and Savient Pharmaceuticals as well as payment for lectures, including service on the speakers bureau for Takeda Pharmaceuticals North America. Other authors also disclosed relationships with Savient Pharmaceuticals and other companies. Complete disclosures are included in the JAMA article.

Pegloticase, a unique, recently approved urate-lowering therapy, was superior to placebo for lowering uric acid levels and resolved some tophi in patients with refractory chronic gout in two replicate randomized, placebo-controlled trials.

Patients in both trials, including 109 patients in Trial C0405 and 116 in Trial C0406, were randomized to receive either biweekly infusions of pegloticase (biweekly treatment), biweekly infusions with alternating pegloticase and placebo (monthly treatment), or biweekly placebo. The primary end point of plasma uric acid levels less than 6 mg/dL in months 3 and 6 of treatment was achieved in 47% and 38% of those in the two trials, respectively, who were randomized to receive biweekly treatment, and in 20% and 39% of patients in the two trials, respectively, who were randomized to receive monthly treatment. None of the patients in the placebo group in either trial achieved the primary end point, Dr. John S. Sundy of Duke University, Durham, N.C., and his colleagues report in the Aug. 17 issue of JAMA.

When data from the two trials were pooled, 42% of patients receiving active treatment biweekly and 35% of patients receiving active treatment monthly achieved the primary end point, the investigators found (JAMA 2011;306:711-20).

Pegloticase is a mammalian recombinant uricase conjugated to monomethoxypoly. It serves as an enzymatic alternative to conventional urate-lowering therapy, which fails in about 3% of gout patients as a result of refractoriness, contraindications, or intolerance. Treatment in these 6-month, multicenter trials was given starting at week 1 as a 2-hour intravenous infusion of 250 ml 0.9% sodium chloride containing 8 mg pegloticase or placebo, depending on randomization.

In addition to the significantly greater effectiveness of active treatment versus placebo in regard to the primary end point, 40% and 21% of patients in the biweekly and monthly treatment groups, respectively, also experienced a complete response for one or more tophus by the final follow-up visit, compared with only 7% of those in the placebo groups, the investigators said.

Also, the treatment groups experienced reductions in tender joint count and swollen joint count, compared with placebo, although the differences were significant only for tender joint count.

Significant improvements in physical function and quality of life were also noted in the treatment groups, compared with the placebo groups, and biweekly treatment was associated with significant changes from baseline in the Health Assessment Questionnaire-Disability Index scores and Short Form-36 Physical Component Summary scores that met or exceeded the minimum clinically important differences established for the respective instrument in inflammatory arthritides, the investigators noted.

During the first 3 months of the studies, both the incidence of gout flares and the number of flares per patient were higher in the treatment versus placebo groups, but during months 4-6, continued biweekly treatment was associated with a significant reduction in the proportion of patients with gout flare, compared with placebo, and flares per patient also were reduced, although this difference was not statistically significant, they said.

Adverse events were common in the treatment groups, with one or more occurring in more than 90% of patients receiving active treatment. Serious adverse events occurred more often in the biweekly treatment groups and the monthly groups, compared with the placebo groups (24% and 23% vs. 12%). Gout flare and infusion-related reactions were the most common adverse events.

Serious infusion reactions occurred in 5% and 8% of the biweekly and monthly patient groups, respectively, and resolution of all infusion reactions begin within minutes of slowing or discontinuing the infusion or initiating supportive treatment; all resolved completely. The investigators stressed the importance of minimizing the risk of infusion reactions by using prophylaxis in clinical practice, as was done in these studies.

They also emphasized the importance of stabilizing cardiovascular comorbidities prior to initiating treatment, given the "relatively small number of mechanistically diverse albeit serious cardiovascular adverse events" that occurred during these studies (two deaths were attributed to cardiovascular adverse events in the biweekly treatment group, and one nonfatal myocardial infarction occurred in a patient receiving monthly treatment). All of the cardiovascular events occurred in patients with four or more cardiovascular risk factors at baseline, they noted.

"Despite the 4-fold greater number of patients receiving pegloticase vs. placebo, the elevated CV risk profile of this population and the absence of a compelling mechanism connecting pegloticase with CV AEs, the observed numerical imbalance in these events underlines the need for care in selecting patients for pegloticase treatment," they added.

These parallel trials "have documented sustained [uric acid] reductions and significant clinical improvement in a substantial proportion of patients with chronic gout and refractoriness to, or intolerance of, conventional urate-lowering therapy," the investigators wrote.

The significant disease-modifying benefits of biweekly treatment with pegloticase were evident within 6 months and, of note, the improvements in physical function and quality of life scores exceeding the minimal clinically important difference in pegloticase-treated patients, when considered in light of the deterioration in pain and quality of life seen in placebo patients in these studies, provide evidence that "chronic elevations in uric acid are associated with significant functional impairment as measured by several criteria," they said, explaining that this relationship has previously been difficult to distinguish from functional impairment associated with the serious comorbidities common in gout patients.

These studies were funded by Savient Pharmaceuticals, the maker of pegloticase. Dr. Sundy reported receiving fees for consulting and grants from Ardea Bioscience, Novartis, Nuon Therapeutics, Regeneron, and Savient Pharmaceuticals as well as payment for lectures, including service on the speakers bureau for Takeda Pharmaceuticals North America. Other authors also disclosed relationships with Savient Pharmaceuticals and other companies. Complete disclosures are included in the JAMA article.

LAKE BUENA VISTA, FLA. (EGMN) – Serial computed tomography scans commonly used to monitor patients following endovascular aneurysm repair may be unnecessary after 6 years, according to the findings of a retrospective study of 2,965 scans in 608 EVAR patients.

Furthermore, such scans are more likely to detect a clinically significant incidental finding that warrants further workup than to find a problem with the endograft, Dr. Elizabeth L. Detschelt said in a presentation at the annual meeting of the Society for Clinical Vascular Surgery .

The average annual rate of detection of EVAR-related findings was 4% (range 2%-5%), which remained constant over the first 6 years of follow-up, and the rate after 6 years was 0%. However, the annual detection rate for new clinically significant incidental findings on these scans was 25% (range 14%-32%), which remained constant for more than 10 years, said Dr. Detschelt of Allegheny General Hospital, Pittsburgh.

On multivariate analysis, predictors of detection of new clinically significant findings included age over 65 years, glomerular filtration rate less than 60 mL/min per 1.73 m², and tobacco use. No predictors were identified for EVAR-related findings, she noted.

The patients underwent EVAR for infrarenal aneurysm at a single institution between Dec. 1, 1999, and Nov. 30, 2009, and were followed for a mean of 32 months. These results are particularly relevant, Dr. Detschelt said, because risks from repeated scans, which are commonly used for serial imaging in EVAR patients to monitor for endoleak and other problems, are currently a topic of intense debate.

"Recently, the literature has really been inundated with concerns about the cumulative effects of such radiation exposure by these CT scan protocols, and in addition there’s a fair amount of literature to cite a very high rate of incidental findings that we detect on this follow-up with CT protocol," said Dr. Detschelt. Although such findings require follow-up, the literature suggests that this often falls through the cracks, she added.

In this study, EVAR-related findings included endoleak, limb occlusion, and endograft migration. Clinically significant incidental findings were varied, with the most common occurring in the broad categories of genitourinary findings, hepatobiliary findings, hernias, pulmonary neoplasms, and other vascular and cardiac lesions.

Not only do the findings suggest that serial imaging is not needed for EVAR-related concerns after 6 years, but they also underscore the importance of carefully evaluating post-EVAR CT scans for clinically significant incidental findings.

"As the ordering physicians of these CT scans, it is our legal responsibility to ensure that they have appropriate workup, so this is going to mean that not only do we have to look at the scans to assess the status of our aneurysm repair, but we also have to read the radiologist’s report to make sure we’re not missing something," she said.

That’s particularly true for patients who are older, who smoke, and who have a degree of renal insufficiency, she added.

The findings also raise the question of whether post-EVAR patients should undergo monitoring using other imaging techniques such as ultrasound, or whether a less frequent CT scan protocol can be used to reduce patient exposure to radiation and reduce patient costs.

These questions – along with the bigger question of whether it is more prudent to not use CT scans in order to reduce radiation exposure or to continue with CT monitoring to pick up findings that potentially could save or improve lives – require better data to inform decision making, she concluded.

During a discussion period after Dr. Detschelt’s talk, one audience member cautioned against suggesting that CT monitoring be considered for the purpose of detecting incidental nonvascular issues, saying that raises the argument of whether the general population aged 65-75 years should also undergo serial CT scans to find incidental nonvascular issues. He also noted that at his institution, the concerns about serial CT monitoring post EVAR are addressed in part by using duplex ultrasound in the immediate postoperative period, with follow-up by duplex ultrasound in those patients with no problems detected on the initial ultrasound.

He said findings from his experience and others have been published, and show that this is approach is "probably safe and effective." Dr. Detschelt responded that while duplex ultrasound is not used immediately postoperatively at her institution, there has been a move toward using it for long-term follow-up there. At many institutions, however, workforce issues come into play, because the duplex studies are more time intensive and require specially trained vascular staff, she said.

Dr. Detschelt had no disclosures.

LAKE BUENA VISTA, FLA. (EGMN) – Serial computed tomography scans commonly used to monitor patients following endovascular aneurysm repair may be unnecessary after 6 years, according to the findings of a retrospective study of 2,965 scans in 608 EVAR patients.

Furthermore, such scans are more likely to detect a clinically significant incidental finding that warrants further workup than to find a problem with the endograft, Dr. Elizabeth L. Detschelt said in a presentation at the annual meeting of the Society for Clinical Vascular Surgery .

The average annual rate of detection of EVAR-related findings was 4% (range 2%-5%), which remained constant over the first 6 years of follow-up, and the rate after 6 years was 0%. However, the annual detection rate for new clinically significant incidental findings on these scans was 25% (range 14%-32%), which remained constant for more than 10 years, said Dr. Detschelt of Allegheny General Hospital, Pittsburgh.

On multivariate analysis, predictors of detection of new clinically significant findings included age over 65 years, glomerular filtration rate less than 60 mL/min per 1.73 m², and tobacco use. No predictors were identified for EVAR-related findings, she noted.

The patients underwent EVAR for infrarenal aneurysm at a single institution between Dec. 1, 1999, and Nov. 30, 2009, and were followed for a mean of 32 months. These results are particularly relevant, Dr. Detschelt said, because risks from repeated scans, which are commonly used for serial imaging in EVAR patients to monitor for endoleak and other problems, are currently a topic of intense debate.

"Recently, the literature has really been inundated with concerns about the cumulative effects of such radiation exposure by these CT scan protocols, and in addition there’s a fair amount of literature to cite a very high rate of incidental findings that we detect on this follow-up with CT protocol," said Dr. Detschelt. Although such findings require follow-up, the literature suggests that this often falls through the cracks, she added.

In this study, EVAR-related findings included endoleak, limb occlusion, and endograft migration. Clinically significant incidental findings were varied, with the most common occurring in the broad categories of genitourinary findings, hepatobiliary findings, hernias, pulmonary neoplasms, and other vascular and cardiac lesions.

Not only do the findings suggest that serial imaging is not needed for EVAR-related concerns after 6 years, but they also underscore the importance of carefully evaluating post-EVAR CT scans for clinically significant incidental findings.

"As the ordering physicians of these CT scans, it is our legal responsibility to ensure that they have appropriate workup, so this is going to mean that not only do we have to look at the scans to assess the status of our aneurysm repair, but we also have to read the radiologist’s report to make sure we’re not missing something," she said.

That’s particularly true for patients who are older, who smoke, and who have a degree of renal insufficiency, she added.

The findings also raise the question of whether post-EVAR patients should undergo monitoring using other imaging techniques such as ultrasound, or whether a less frequent CT scan protocol can be used to reduce patient exposure to radiation and reduce patient costs.

These questions – along with the bigger question of whether it is more prudent to not use CT scans in order to reduce radiation exposure or to continue with CT monitoring to pick up findings that potentially could save or improve lives – require better data to inform decision making, she concluded.

During a discussion period after Dr. Detschelt’s talk, one audience member cautioned against suggesting that CT monitoring be considered for the purpose of detecting incidental nonvascular issues, saying that raises the argument of whether the general population aged 65-75 years should also undergo serial CT scans to find incidental nonvascular issues. He also noted that at his institution, the concerns about serial CT monitoring post EVAR are addressed in part by using duplex ultrasound in the immediate postoperative period, with follow-up by duplex ultrasound in those patients with no problems detected on the initial ultrasound.

He said findings from his experience and others have been published, and show that this is approach is "probably safe and effective." Dr. Detschelt responded that while duplex ultrasound is not used immediately postoperatively at her institution, there has been a move toward using it for long-term follow-up there. At many institutions, however, workforce issues come into play, because the duplex studies are more time intensive and require specially trained vascular staff, she said.

Dr. Detschelt had no disclosures.

LAKE BUENA VISTA, FLA. (EGMN) – Serial computed tomography scans commonly used to monitor patients following endovascular aneurysm repair may be unnecessary after 6 years, according to the findings of a retrospective study of 2,965 scans in 608 EVAR patients.

Furthermore, such scans are more likely to detect a clinically significant incidental finding that warrants further workup than to find a problem with the endograft, Dr. Elizabeth L. Detschelt said in a presentation at the annual meeting of the Society for Clinical Vascular Surgery .

The average annual rate of detection of EVAR-related findings was 4% (range 2%-5%), which remained constant over the first 6 years of follow-up, and the rate after 6 years was 0%. However, the annual detection rate for new clinically significant incidental findings on these scans was 25% (range 14%-32%), which remained constant for more than 10 years, said Dr. Detschelt of Allegheny General Hospital, Pittsburgh.

On multivariate analysis, predictors of detection of new clinically significant findings included age over 65 years, glomerular filtration rate less than 60 mL/min per 1.73 m², and tobacco use. No predictors were identified for EVAR-related findings, she noted.

The patients underwent EVAR for infrarenal aneurysm at a single institution between Dec. 1, 1999, and Nov. 30, 2009, and were followed for a mean of 32 months. These results are particularly relevant, Dr. Detschelt said, because risks from repeated scans, which are commonly used for serial imaging in EVAR patients to monitor for endoleak and other problems, are currently a topic of intense debate.

"Recently, the literature has really been inundated with concerns about the cumulative effects of such radiation exposure by these CT scan protocols, and in addition there’s a fair amount of literature to cite a very high rate of incidental findings that we detect on this follow-up with CT protocol," said Dr. Detschelt. Although such findings require follow-up, the literature suggests that this often falls through the cracks, she added.

In this study, EVAR-related findings included endoleak, limb occlusion, and endograft migration. Clinically significant incidental findings were varied, with the most common occurring in the broad categories of genitourinary findings, hepatobiliary findings, hernias, pulmonary neoplasms, and other vascular and cardiac lesions.

Not only do the findings suggest that serial imaging is not needed for EVAR-related concerns after 6 years, but they also underscore the importance of carefully evaluating post-EVAR CT scans for clinically significant incidental findings.

"As the ordering physicians of these CT scans, it is our legal responsibility to ensure that they have appropriate workup, so this is going to mean that not only do we have to look at the scans to assess the status of our aneurysm repair, but we also have to read the radiologist’s report to make sure we’re not missing something," she said.

That’s particularly true for patients who are older, who smoke, and who have a degree of renal insufficiency, she added.

The findings also raise the question of whether post-EVAR patients should undergo monitoring using other imaging techniques such as ultrasound, or whether a less frequent CT scan protocol can be used to reduce patient exposure to radiation and reduce patient costs.

These questions – along with the bigger question of whether it is more prudent to not use CT scans in order to reduce radiation exposure or to continue with CT monitoring to pick up findings that potentially could save or improve lives – require better data to inform decision making, she concluded.

During a discussion period after Dr. Detschelt’s talk, one audience member cautioned against suggesting that CT monitoring be considered for the purpose of detecting incidental nonvascular issues, saying that raises the argument of whether the general population aged 65-75 years should also undergo serial CT scans to find incidental nonvascular issues. He also noted that at his institution, the concerns about serial CT monitoring post EVAR are addressed in part by using duplex ultrasound in the immediate postoperative period, with follow-up by duplex ultrasound in those patients with no problems detected on the initial ultrasound.

He said findings from his experience and others have been published, and show that this is approach is "probably safe and effective." Dr. Detschelt responded that while duplex ultrasound is not used immediately postoperatively at her institution, there has been a move toward using it for long-term follow-up there. At many institutions, however, workforce issues come into play, because the duplex studies are more time intensive and require specially trained vascular staff, she said.

Dr. Detschelt had no disclosures.

Linaclotide, an investigational drug, significantly improved symptoms of chronic constipation in two studies involving 1,276 patients.

"In addition to improving stool frequency, linaclotide significantly improved stool consistency, reduced straining, and reduced abdominal symptoms (bloating and discomfort), which are often reported to be bothersome to patients with chronic constipation," Dr. Anthony J. Lembo of Harvard Medical School, Boston, and his colleagues reported in the Aug. 11 issue of The New England Journal of Medicine.

In patients randomized to active therapy, effects were observed within the first day of treatment and were sustained throughout the 12-week trial.

Linaclotide is a novel synthetic peptide agonist of the guanylate cyclase C receptor on the luminal surface of the intestinal epithelium. The drug’s effects are likely a result of increased luminal fluid with an acceleration of intestinal transit. Additional mechanisms such as reduced visceral hypersensitivity may also contribute to the improvement of abdominal symptoms, the researchers said.

In both trials, patients were randomized to receive once-daily placebo or once-daily treatment with 145 mcg or 290 mcg of linaclotide. Both active treatment doses were associated with significantly greater improvements in bowel and abdominal symptoms, compared with placebo. In the first trial, 21.2% and 19.4% of patients on the 145-mcg and 290-mcg doses, respectively, achieved the study’s primary end point of three or more complete spontaneous bowel movements (CSBMs) per week plus an increase of one or more CSBMs per week over baseline during at least 9 of the 12 study weeks. In the placebo group, 3.3% reached the end point.

During a randomized withdrawal phase following completion of the treatment period, the linaclotide-treated patients were randomized to continue receiving linaclotide at the same dose or to receive placebo. Patients who initially received placebo began receiving 290 mcg of linaclotide. Those who continued on linaclotide or were switched to the active treatment had sustained increases in the rate of CSBMs that were similar to the levels seen during the treatment phase of the study. Those who switched from treatment to placebo experienced a decreased rate of CSBMs similar to the rates in the placebo group during the treatment phase, the investigators said (N. Engl. J. Med. 2011;365:527-36).

The second trial (Trial 01) was identical to the first, but it did not include a randomized withdrawal phase. The primary end point was met by 16% and 21.3% of patients in the 145-mcg and 290-mcg linaclotide groups, compared with 6.0% in the placebo group.

During each week of treatment in both trials, the proportion of patients meeting the primary end point was significantly greater for both doses of linaclotide compared with placebo. Also in both trials, overall response did not significantly differ based on the linaclotide dose.

In both trials and at both doses, linaclotide-treated patients also had significantly greater improvements than did the placebo patients on all secondary end points, including changes in bowel symptoms (the number of weekly CSBMs and spontaneous bowel movements, stool consistency, and straining severity), abdominal symptoms (discomfort and bloating), and constipation severity. However, linaclotide patients had an increased incidence of diarrhea, which prompted 4.2% of treated patients to discontinue. Otherwise, the incidence of adverse events was similar among all study groups, the researchers said.

Quality of life scores improved significantly in the linaclotide patients, compared with the placebo patients. At 12 weeks in Trial 303, 44.9% and 35.5% of those in the 145-mcg and 290-mcg groups, respectively, had an improvement of 1 or more point from baseline on overall Patient Assessment of Constipation Quality of Life (PAC-QOL) scores. In the placebo group, PAC-QOL scores improved in 18.7%. At 12 weeks in Trial 01, improved scores were seen in 42.2% and 46.8% in the 145-mcg and 290-mcg groups, respectively, and in 27.8% on placebo.

"Improvements in the overall and component PAC-QOL scores were significantly greater with both linaclotide doses in each trial, as compared with placebo (with the exception of psychosocial discomfort in Trial 303 for patients given the 290-mcg dose)," the investigators wrote.

Patients in both trials were adults aged 18 and older with chronic constipation who were enrolled into the study at one of 212 participating clinical centers in the United States or Canada from August 20, 2008, through August 12, 2009. Participants were randomized in equal portions to one of the three study groups, and all three groups were well balanced in terms of demographics and baseline bowel and abdominal symptoms.

Linaclotide has the potential to offer multisymptom relief to patients with chronic constipation, but long-term studies are needed to evaluate the safety of long-term treatment, the researchers concluded.

This study was supported by Ironwood Pharmaceuticals and Forest Research Institute, the developers of linaclotide. Dr. Lembo reported receiving consulting and/or honorarium and other fees from both companies, as well as grant funding from Novartis, and serving as a consultant for numerous other companies. The other authors reported being employed by, and owning stock or stock options in, either Ironwood Pharmaceuticals or Forest Research Institute.

Linaclotide, an investigational drug, significantly improved symptoms of chronic constipation in two studies involving 1,276 patients.

"In addition to improving stool frequency, linaclotide significantly improved stool consistency, reduced straining, and reduced abdominal symptoms (bloating and discomfort), which are often reported to be bothersome to patients with chronic constipation," Dr. Anthony J. Lembo of Harvard Medical School, Boston, and his colleagues reported in the Aug. 11 issue of The New England Journal of Medicine.

In patients randomized to active therapy, effects were observed within the first day of treatment and were sustained throughout the 12-week trial.

Linaclotide is a novel synthetic peptide agonist of the guanylate cyclase C receptor on the luminal surface of the intestinal epithelium. The drug’s effects are likely a result of increased luminal fluid with an acceleration of intestinal transit. Additional mechanisms such as reduced visceral hypersensitivity may also contribute to the improvement of abdominal symptoms, the researchers said.

In both trials, patients were randomized to receive once-daily placebo or once-daily treatment with 145 mcg or 290 mcg of linaclotide. Both active treatment doses were associated with significantly greater improvements in bowel and abdominal symptoms, compared with placebo. In the first trial, 21.2% and 19.4% of patients on the 145-mcg and 290-mcg doses, respectively, achieved the study’s primary end point of three or more complete spontaneous bowel movements (CSBMs) per week plus an increase of one or more CSBMs per week over baseline during at least 9 of the 12 study weeks. In the placebo group, 3.3% reached the end point.

During a randomized withdrawal phase following completion of the treatment period, the linaclotide-treated patients were randomized to continue receiving linaclotide at the same dose or to receive placebo. Patients who initially received placebo began receiving 290 mcg of linaclotide. Those who continued on linaclotide or were switched to the active treatment had sustained increases in the rate of CSBMs that were similar to the levels seen during the treatment phase of the study. Those who switched from treatment to placebo experienced a decreased rate of CSBMs similar to the rates in the placebo group during the treatment phase, the investigators said (N. Engl. J. Med. 2011;365:527-36).

The second trial (Trial 01) was identical to the first, but it did not include a randomized withdrawal phase. The primary end point was met by 16% and 21.3% of patients in the 145-mcg and 290-mcg linaclotide groups, compared with 6.0% in the placebo group.

During each week of treatment in both trials, the proportion of patients meeting the primary end point was significantly greater for both doses of linaclotide compared with placebo. Also in both trials, overall response did not significantly differ based on the linaclotide dose.

In both trials and at both doses, linaclotide-treated patients also had significantly greater improvements than did the placebo patients on all secondary end points, including changes in bowel symptoms (the number of weekly CSBMs and spontaneous bowel movements, stool consistency, and straining severity), abdominal symptoms (discomfort and bloating), and constipation severity. However, linaclotide patients had an increased incidence of diarrhea, which prompted 4.2% of treated patients to discontinue. Otherwise, the incidence of adverse events was similar among all study groups, the researchers said.

Quality of life scores improved significantly in the linaclotide patients, compared with the placebo patients. At 12 weeks in Trial 303, 44.9% and 35.5% of those in the 145-mcg and 290-mcg groups, respectively, had an improvement of 1 or more point from baseline on overall Patient Assessment of Constipation Quality of Life (PAC-QOL) scores. In the placebo group, PAC-QOL scores improved in 18.7%. At 12 weeks in Trial 01, improved scores were seen in 42.2% and 46.8% in the 145-mcg and 290-mcg groups, respectively, and in 27.8% on placebo.

"Improvements in the overall and component PAC-QOL scores were significantly greater with both linaclotide doses in each trial, as compared with placebo (with the exception of psychosocial discomfort in Trial 303 for patients given the 290-mcg dose)," the investigators wrote.

Patients in both trials were adults aged 18 and older with chronic constipation who were enrolled into the study at one of 212 participating clinical centers in the United States or Canada from August 20, 2008, through August 12, 2009. Participants were randomized in equal portions to one of the three study groups, and all three groups were well balanced in terms of demographics and baseline bowel and abdominal symptoms.

Linaclotide has the potential to offer multisymptom relief to patients with chronic constipation, but long-term studies are needed to evaluate the safety of long-term treatment, the researchers concluded.

This study was supported by Ironwood Pharmaceuticals and Forest Research Institute, the developers of linaclotide. Dr. Lembo reported receiving consulting and/or honorarium and other fees from both companies, as well as grant funding from Novartis, and serving as a consultant for numerous other companies. The other authors reported being employed by, and owning stock or stock options in, either Ironwood Pharmaceuticals or Forest Research Institute.

Linaclotide, an investigational drug, significantly improved symptoms of chronic constipation in two studies involving 1,276 patients.

"In addition to improving stool frequency, linaclotide significantly improved stool consistency, reduced straining, and reduced abdominal symptoms (bloating and discomfort), which are often reported to be bothersome to patients with chronic constipation," Dr. Anthony J. Lembo of Harvard Medical School, Boston, and his colleagues reported in the Aug. 11 issue of The New England Journal of Medicine.

In patients randomized to active therapy, effects were observed within the first day of treatment and were sustained throughout the 12-week trial.

Linaclotide is a novel synthetic peptide agonist of the guanylate cyclase C receptor on the luminal surface of the intestinal epithelium. The drug’s effects are likely a result of increased luminal fluid with an acceleration of intestinal transit. Additional mechanisms such as reduced visceral hypersensitivity may also contribute to the improvement of abdominal symptoms, the researchers said.

In both trials, patients were randomized to receive once-daily placebo or once-daily treatment with 145 mcg or 290 mcg of linaclotide. Both active treatment doses were associated with significantly greater improvements in bowel and abdominal symptoms, compared with placebo. In the first trial, 21.2% and 19.4% of patients on the 145-mcg and 290-mcg doses, respectively, achieved the study’s primary end point of three or more complete spontaneous bowel movements (CSBMs) per week plus an increase of one or more CSBMs per week over baseline during at least 9 of the 12 study weeks. In the placebo group, 3.3% reached the end point.

During a randomized withdrawal phase following completion of the treatment period, the linaclotide-treated patients were randomized to continue receiving linaclotide at the same dose or to receive placebo. Patients who initially received placebo began receiving 290 mcg of linaclotide. Those who continued on linaclotide or were switched to the active treatment had sustained increases in the rate of CSBMs that were similar to the levels seen during the treatment phase of the study. Those who switched from treatment to placebo experienced a decreased rate of CSBMs similar to the rates in the placebo group during the treatment phase, the investigators said (N. Engl. J. Med. 2011;365:527-36).

The second trial (Trial 01) was identical to the first, but it did not include a randomized withdrawal phase. The primary end point was met by 16% and 21.3% of patients in the 145-mcg and 290-mcg linaclotide groups, compared with 6.0% in the placebo group.

During each week of treatment in both trials, the proportion of patients meeting the primary end point was significantly greater for both doses of linaclotide compared with placebo. Also in both trials, overall response did not significantly differ based on the linaclotide dose.

In both trials and at both doses, linaclotide-treated patients also had significantly greater improvements than did the placebo patients on all secondary end points, including changes in bowel symptoms (the number of weekly CSBMs and spontaneous bowel movements, stool consistency, and straining severity), abdominal symptoms (discomfort and bloating), and constipation severity. However, linaclotide patients had an increased incidence of diarrhea, which prompted 4.2% of treated patients to discontinue. Otherwise, the incidence of adverse events was similar among all study groups, the researchers said.

Quality of life scores improved significantly in the linaclotide patients, compared with the placebo patients. At 12 weeks in Trial 303, 44.9% and 35.5% of those in the 145-mcg and 290-mcg groups, respectively, had an improvement of 1 or more point from baseline on overall Patient Assessment of Constipation Quality of Life (PAC-QOL) scores. In the placebo group, PAC-QOL scores improved in 18.7%. At 12 weeks in Trial 01, improved scores were seen in 42.2% and 46.8% in the 145-mcg and 290-mcg groups, respectively, and in 27.8% on placebo.

"Improvements in the overall and component PAC-QOL scores were significantly greater with both linaclotide doses in each trial, as compared with placebo (with the exception of psychosocial discomfort in Trial 303 for patients given the 290-mcg dose)," the investigators wrote.

Patients in both trials were adults aged 18 and older with chronic constipation who were enrolled into the study at one of 212 participating clinical centers in the United States or Canada from August 20, 2008, through August 12, 2009. Participants were randomized in equal portions to one of the three study groups, and all three groups were well balanced in terms of demographics and baseline bowel and abdominal symptoms.

Linaclotide has the potential to offer multisymptom relief to patients with chronic constipation, but long-term studies are needed to evaluate the safety of long-term treatment, the researchers concluded.

This study was supported by Ironwood Pharmaceuticals and Forest Research Institute, the developers of linaclotide. Dr. Lembo reported receiving consulting and/or honorarium and other fees from both companies, as well as grant funding from Novartis, and serving as a consultant for numerous other companies. The other authors reported being employed by, and owning stock or stock options in, either Ironwood Pharmaceuticals or Forest Research Institute.

BOCA RATON, FLA. – Experience with various lasers for the treatment and prophylaxis of nonmelanoma skin cancers is increasing, and the outcomes are promising.

One setting where lasers have particular potential is in patients with multiple basal cell carcinomas, Dr. Keyvan Nouri said at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

BCCs tend to have telangiectasias, and by specifically targeting the tumor vasculature, the BCC burden can be decreased or eliminated by laser treatment with little damage to surrounding skin. An ablative approach can also eliminate premalignant cells, said Dr. Nouri, professor of dermatology and otolaryngology and director of Mohs, dermatologic, and laser surgery at the University of Miami.

Studies using this approach have been conducted over the past several years using CO₂, Er:YAG, pulsed-dye, and alexandrite lasers.

The 10,600-nm CO₂ laser achieves a depth of 15-200 mcm in a single pass, which is adequate for coagulating the epidermis and superficial dermis, and for eliminating squamous cells at risk for evolution to actinic keratosis or squamous cell carcinoma. It also is partially effective for eliminating cells en route to basal cell carcinoma, he said, noting that deeper treatment can be achieved with multiple passes or protocol modifications.

In one study using this CO₂ laser, 14 patients with diffuse facial AKs underwent resurfacing and experienced significant long-term reduction in AK burden (Dermatol. Surg. 1997;23:885-9). In another report of two patients with a history of multiple nonmelanoma skin cancer who were treated with two-pass CO₂ resurfacing, no new lesions developed in the treated area at 33 and 52 months (Dermatol. Surg. 1999;25:513-16).

In a randomized controlled study of 34 patients, no differences in outcomes were seen at 5 years regardless of whether patients were treated with the CO₂ laser, a 30% trichloroacetic acid peel, or 5% fluorouracil cream twice daily for 3 weeks. All of the treatments reduced AK counts by 83%-92%, and reduced the incidence of nonmelanoma skin cancers, compared with control groups (Dermatol. Surg. 1999;25:729-32), Dr. Nouri said.

In three of his patients with basal cell nevus syndrome, the Ultrapulse CO₂ laser also proved effective for treatment. Postoperative Mohs micrographic surgical sections verified complete histologic clearance, and the patients had minimal scarring at follow-up (Dermatol. Surg. 2002;28:287-90).

A high-energy pulsed CO₂ laser has also been used to treat a squamous cell carcinoma in situ on the nose with one pass (at 250 mJ, 8 W). In that case, no recurrence had occurred at 5 months’ follow-up, and the cosmetic result was excellent, Dr. Nouri said.

In a series of patients with nodular and superficial BCCs, a combination of curettage and one or two passes with the high-energy pulsed CO₂ laser was also effective, with no histologic evidence or residual tumor and no known recurrences.

In another study, the pulsed CO₂ laser was effective for treating 30 neoplasms, including 17 BCCs and 13 SCCs (Arch. Dermatol. 1998;134:1247-52). Two or three passes were used (at 500 mJ and 2-4 W). Treatment with a 4-mm margin and three passes is recommended for complete vaporization of neoplasms using this laser, Dr. Nouri said. Also, one SCC in situ in that study was incompletely ablated after three passes, so this modality alone is not recommended for thick or keratotic lesions, he said.

More recently, fractional laser resurfacing and pulsed-dye laser treatment have also shown promise for nonmelanoma skin cancers. In a pilot study of 28 patients with mild to moderate actinic damage who were treated with a fractional Er:YAG laser (2,940 nm) with one to four treatments at 4-week intervals, 75% had excellent results and the other 25% had good results. The effects were maintained at up to 9 months (Dermatol. Surg. 2008;34:1048-53).

And the 595-nm pulsed-dye laser has been used successfully to target tumor vasculature in glottal dysplasia and SCCs. Depending on fluence and spot size, the 595-nm pulsed-dye laser can penetrate skin to thicknesses ranging from 0.75 to 1.25 mm, which encompasses most BCCs, Dr. Nouri said.

In one study, a single treatment on seven BCCs resulted in histologic clearance of only one tumor (Lasers Med. Sci. 2003;18:125-6), but in two other studies of patients with superficial BCCs, this laser was associated with no clinical recurrences at a minimum follow-up of 1 year in 16 of 20 BCCs (Lasers Med. Sci. 2005;20:147-8; Dermatol. Ther. 2008; 21:402-5).

In another study, 20 BCCs treated with four 595-nm pulsed-dye laser treatments at 2-week intervals showed that nearly all BCCs less than 1.5 cm responded completely, compared with about 17% of controls. Larger BCCs had a complete response rate of 25% vs. 0% in controls.

Tumors with an incomplete response showed a significant reduction in tumor burden following treatment, with residual histologic tumor burden ranging from less than 1% to 29% of the original clinical tumor diameter, compared with 13%-68% residual tumor burden for the corresponding controls.

The investigators took the study one step further, treating 14 patients with a total of 20 BCCs on the trunk or extremities with four treatments at 3- to 4-week intervals; 19 of 20 BCCs had a complete clinical response, regardless of size and histological subtype (Lasers Surg. Med. 2009; 41:417-22). The investigators concluded that the 595-nm pulsed-dye laser is a "novel, quick, and relatively nonpainful treatment" for BCCs when used in the appropriate clinical setting, Dr. Nouri said.

As for the long-pulse alexandrite laser, it is selective like the pulsed-dye laser, but has deeper penetration, and may be helpful in significantly reducing tumor burden with a single treatment, he said.

In 15 of 18 patients with basal cell nevus syndrome who were treated in one study, a complete clinical response was seen at follow-ups of 2 and 7 months (Lasers Surg. Med. 2010;42:68-71).

No particular laser has emerged as the ideal tool for the treatment or prevention of skin cancer, but work is ongoing. More research is needed to confirm the observations made thus far, as well as to optimize treatment parameters, but the findings to date are encouraging, Dr. Nouri said, noting that he is confident that laser and light sources will eventually be used more for both medical and oncologic purposes.

Dr. Nouri disclosed that he has received grants or research support from Aesthera, CureLight, and Omnilux.

BOCA RATON, FLA. – Experience with various lasers for the treatment and prophylaxis of nonmelanoma skin cancers is increasing, and the outcomes are promising.

One setting where lasers have particular potential is in patients with multiple basal cell carcinomas, Dr. Keyvan Nouri said at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

BCCs tend to have telangiectasias, and by specifically targeting the tumor vasculature, the BCC burden can be decreased or eliminated by laser treatment with little damage to surrounding skin. An ablative approach can also eliminate premalignant cells, said Dr. Nouri, professor of dermatology and otolaryngology and director of Mohs, dermatologic, and laser surgery at the University of Miami.

Studies using this approach have been conducted over the past several years using CO₂, Er:YAG, pulsed-dye, and alexandrite lasers.

The 10,600-nm CO₂ laser achieves a depth of 15-200 mcm in a single pass, which is adequate for coagulating the epidermis and superficial dermis, and for eliminating squamous cells at risk for evolution to actinic keratosis or squamous cell carcinoma. It also is partially effective for eliminating cells en route to basal cell carcinoma, he said, noting that deeper treatment can be achieved with multiple passes or protocol modifications.

In one study using this CO₂ laser, 14 patients with diffuse facial AKs underwent resurfacing and experienced significant long-term reduction in AK burden (Dermatol. Surg. 1997;23:885-9). In another report of two patients with a history of multiple nonmelanoma skin cancer who were treated with two-pass CO₂ resurfacing, no new lesions developed in the treated area at 33 and 52 months (Dermatol. Surg. 1999;25:513-16).

In a randomized controlled study of 34 patients, no differences in outcomes were seen at 5 years regardless of whether patients were treated with the CO₂ laser, a 30% trichloroacetic acid peel, or 5% fluorouracil cream twice daily for 3 weeks. All of the treatments reduced AK counts by 83%-92%, and reduced the incidence of nonmelanoma skin cancers, compared with control groups (Dermatol. Surg. 1999;25:729-32), Dr. Nouri said.

In three of his patients with basal cell nevus syndrome, the Ultrapulse CO₂ laser also proved effective for treatment. Postoperative Mohs micrographic surgical sections verified complete histologic clearance, and the patients had minimal scarring at follow-up (Dermatol. Surg. 2002;28:287-90).

A high-energy pulsed CO₂ laser has also been used to treat a squamous cell carcinoma in situ on the nose with one pass (at 250 mJ, 8 W). In that case, no recurrence had occurred at 5 months’ follow-up, and the cosmetic result was excellent, Dr. Nouri said.

In a series of patients with nodular and superficial BCCs, a combination of curettage and one or two passes with the high-energy pulsed CO₂ laser was also effective, with no histologic evidence or residual tumor and no known recurrences.

In another study, the pulsed CO₂ laser was effective for treating 30 neoplasms, including 17 BCCs and 13 SCCs (Arch. Dermatol. 1998;134:1247-52). Two or three passes were used (at 500 mJ and 2-4 W). Treatment with a 4-mm margin and three passes is recommended for complete vaporization of neoplasms using this laser, Dr. Nouri said. Also, one SCC in situ in that study was incompletely ablated after three passes, so this modality alone is not recommended for thick or keratotic lesions, he said.

More recently, fractional laser resurfacing and pulsed-dye laser treatment have also shown promise for nonmelanoma skin cancers. In a pilot study of 28 patients with mild to moderate actinic damage who were treated with a fractional Er:YAG laser (2,940 nm) with one to four treatments at 4-week intervals, 75% had excellent results and the other 25% had good results. The effects were maintained at up to 9 months (Dermatol. Surg. 2008;34:1048-53).

And the 595-nm pulsed-dye laser has been used successfully to target tumor vasculature in glottal dysplasia and SCCs. Depending on fluence and spot size, the 595-nm pulsed-dye laser can penetrate skin to thicknesses ranging from 0.75 to 1.25 mm, which encompasses most BCCs, Dr. Nouri said.

In one study, a single treatment on seven BCCs resulted in histologic clearance of only one tumor (Lasers Med. Sci. 2003;18:125-6), but in two other studies of patients with superficial BCCs, this laser was associated with no clinical recurrences at a minimum follow-up of 1 year in 16 of 20 BCCs (Lasers Med. Sci. 2005;20:147-8; Dermatol. Ther. 2008; 21:402-5).

In another study, 20 BCCs treated with four 595-nm pulsed-dye laser treatments at 2-week intervals showed that nearly all BCCs less than 1.5 cm responded completely, compared with about 17% of controls. Larger BCCs had a complete response rate of 25% vs. 0% in controls.

Tumors with an incomplete response showed a significant reduction in tumor burden following treatment, with residual histologic tumor burden ranging from less than 1% to 29% of the original clinical tumor diameter, compared with 13%-68% residual tumor burden for the corresponding controls.

The investigators took the study one step further, treating 14 patients with a total of 20 BCCs on the trunk or extremities with four treatments at 3- to 4-week intervals; 19 of 20 BCCs had a complete clinical response, regardless of size and histological subtype (Lasers Surg. Med. 2009; 41:417-22). The investigators concluded that the 595-nm pulsed-dye laser is a "novel, quick, and relatively nonpainful treatment" for BCCs when used in the appropriate clinical setting, Dr. Nouri said.

As for the long-pulse alexandrite laser, it is selective like the pulsed-dye laser, but has deeper penetration, and may be helpful in significantly reducing tumor burden with a single treatment, he said.

In 15 of 18 patients with basal cell nevus syndrome who were treated in one study, a complete clinical response was seen at follow-ups of 2 and 7 months (Lasers Surg. Med. 2010;42:68-71).

No particular laser has emerged as the ideal tool for the treatment or prevention of skin cancer, but work is ongoing. More research is needed to confirm the observations made thus far, as well as to optimize treatment parameters, but the findings to date are encouraging, Dr. Nouri said, noting that he is confident that laser and light sources will eventually be used more for both medical and oncologic purposes.

Dr. Nouri disclosed that he has received grants or research support from Aesthera, CureLight, and Omnilux.

BOCA RATON, FLA. – Experience with various lasers for the treatment and prophylaxis of nonmelanoma skin cancers is increasing, and the outcomes are promising.

One setting where lasers have particular potential is in patients with multiple basal cell carcinomas, Dr. Keyvan Nouri said at the annual meeting of the Florida Society of Dermatology and Dermatologic Surgery.

BCCs tend to have telangiectasias, and by specifically targeting the tumor vasculature, the BCC burden can be decreased or eliminated by laser treatment with little damage to surrounding skin. An ablative approach can also eliminate premalignant cells, said Dr. Nouri, professor of dermatology and otolaryngology and director of Mohs, dermatologic, and laser surgery at the University of Miami.

Studies using this approach have been conducted over the past several years using CO₂, Er:YAG, pulsed-dye, and alexandrite lasers.

The 10,600-nm CO₂ laser achieves a depth of 15-200 mcm in a single pass, which is adequate for coagulating the epidermis and superficial dermis, and for eliminating squamous cells at risk for evolution to actinic keratosis or squamous cell carcinoma. It also is partially effective for eliminating cells en route to basal cell carcinoma, he said, noting that deeper treatment can be achieved with multiple passes or protocol modifications.

In one study using this CO₂ laser, 14 patients with diffuse facial AKs underwent resurfacing and experienced significant long-term reduction in AK burden (Dermatol. Surg. 1997;23:885-9). In another report of two patients with a history of multiple nonmelanoma skin cancer who were treated with two-pass CO₂ resurfacing, no new lesions developed in the treated area at 33 and 52 months (Dermatol. Surg. 1999;25:513-16).

In a randomized controlled study of 34 patients, no differences in outcomes were seen at 5 years regardless of whether patients were treated with the CO₂ laser, a 30% trichloroacetic acid peel, or 5% fluorouracil cream twice daily for 3 weeks. All of the treatments reduced AK counts by 83%-92%, and reduced the incidence of nonmelanoma skin cancers, compared with control groups (Dermatol. Surg. 1999;25:729-32), Dr. Nouri said.

In three of his patients with basal cell nevus syndrome, the Ultrapulse CO₂ laser also proved effective for treatment. Postoperative Mohs micrographic surgical sections verified complete histologic clearance, and the patients had minimal scarring at follow-up (Dermatol. Surg. 2002;28:287-90).

A high-energy pulsed CO₂ laser has also been used to treat a squamous cell carcinoma in situ on the nose with one pass (at 250 mJ, 8 W). In that case, no recurrence had occurred at 5 months’ follow-up, and the cosmetic result was excellent, Dr. Nouri said.

In a series of patients with nodular and superficial BCCs, a combination of curettage and one or two passes with the high-energy pulsed CO₂ laser was also effective, with no histologic evidence or residual tumor and no known recurrences.

In another study, the pulsed CO₂ laser was effective for treating 30 neoplasms, including 17 BCCs and 13 SCCs (Arch. Dermatol. 1998;134:1247-52). Two or three passes were used (at 500 mJ and 2-4 W). Treatment with a 4-mm margin and three passes is recommended for complete vaporization of neoplasms using this laser, Dr. Nouri said. Also, one SCC in situ in that study was incompletely ablated after three passes, so this modality alone is not recommended for thick or keratotic lesions, he said.

More recently, fractional laser resurfacing and pulsed-dye laser treatment have also shown promise for nonmelanoma skin cancers. In a pilot study of 28 patients with mild to moderate actinic damage who were treated with a fractional Er:YAG laser (2,940 nm) with one to four treatments at 4-week intervals, 75% had excellent results and the other 25% had good results. The effects were maintained at up to 9 months (Dermatol. Surg. 2008;34:1048-53).

And the 595-nm pulsed-dye laser has been used successfully to target tumor vasculature in glottal dysplasia and SCCs. Depending on fluence and spot size, the 595-nm pulsed-dye laser can penetrate skin to thicknesses ranging from 0.75 to 1.25 mm, which encompasses most BCCs, Dr. Nouri said.

In one study, a single treatment on seven BCCs resulted in histologic clearance of only one tumor (Lasers Med. Sci. 2003;18:125-6), but in two other studies of patients with superficial BCCs, this laser was associated with no clinical recurrences at a minimum follow-up of 1 year in 16 of 20 BCCs (Lasers Med. Sci. 2005;20:147-8; Dermatol. Ther. 2008; 21:402-5).

In another study, 20 BCCs treated with four 595-nm pulsed-dye laser treatments at 2-week intervals showed that nearly all BCCs less than 1.5 cm responded completely, compared with about 17% of controls. Larger BCCs had a complete response rate of 25% vs. 0% in controls.

Tumors with an incomplete response showed a significant reduction in tumor burden following treatment, with residual histologic tumor burden ranging from less than 1% to 29% of the original clinical tumor diameter, compared with 13%-68% residual tumor burden for the corresponding controls.

The investigators took the study one step further, treating 14 patients with a total of 20 BCCs on the trunk or extremities with four treatments at 3- to 4-week intervals; 19 of 20 BCCs had a complete clinical response, regardless of size and histological subtype (Lasers Surg. Med. 2009; 41:417-22). The investigators concluded that the 595-nm pulsed-dye laser is a "novel, quick, and relatively nonpainful treatment" for BCCs when used in the appropriate clinical setting, Dr. Nouri said.

As for the long-pulse alexandrite laser, it is selective like the pulsed-dye laser, but has deeper penetration, and may be helpful in significantly reducing tumor burden with a single treatment, he said.

In 15 of 18 patients with basal cell nevus syndrome who were treated in one study, a complete clinical response was seen at follow-ups of 2 and 7 months (Lasers Surg. Med. 2010;42:68-71).

No particular laser has emerged as the ideal tool for the treatment or prevention of skin cancer, but work is ongoing. More research is needed to confirm the observations made thus far, as well as to optimize treatment parameters, but the findings to date are encouraging, Dr. Nouri said, noting that he is confident that laser and light sources will eventually be used more for both medical and oncologic purposes.

Dr. Nouri disclosed that he has received grants or research support from Aesthera, CureLight, and Omnilux.

PARIS – Concerns that individuals with early symptoms of Alzheimer’s disease may avoid or delay seeking medical care because of a perceived lack of effective therapies or other worries may be largely unfounded.

In fact, expectations about just what can be done for those who receive an Alzheimer’s disease diagnosis may be too high, according to the findings of a recent five-country telephone survey presented at the Alzheimer’s Association International Conference.

In all, 85%-95% of the 2,678 adults aged 18 and older from France, Germany, Poland, Spain, and the United States said they would see a doctor if they were experiencing confusion or memory loss, 52%-71% said they believe that an effective treatment currently exists or will soon be available, and 38%-59% said they believe a reliable test for early Alzheimer’s disease currently exists, Robert Blendon, Sc.D., reported during a press briefing at the conference.

If anything, the findings suggest that clinicians will have to temper the expectations of those who come in seeking answers about their symptoms, said Dr. Blendon, professor of health policy and political analysis at the Harvard School of Public Health, Boston.

Alzheimer’s disease organizations in many countries, including the United States, are working to promote early diagnosis. One purpose of this random telephone survey, which was a joint project of the Harvard School of Public Health and Alzheimer Europe, was to determine if the public would respond to such campaigns. The investigators also wanted to elucidate cultural differences regarding views on Alzheimer’s disease, he said.

In addition to the somewhat surprising responses regarding whether or not they would seek a diagnosis, the majority (51%-78%) of respondents from each country also said that if an accurate preclinical diagnostic test existed, they would seek a diagnosis.

Respondents expressed deep overall concerns about developing Alzheimer’s disease. In four of the five countries, Alzheimer’s ranked second after cancer as the most feared disease. In Poland, it ranked third after cancer and heart disease.

More than half of the respondents from each of the countries (54%-77%) said they had known someone with the disease, and nearly 30% said they had personal experience with a family member who had Alzheimer’s disease.

The findings suggest that if educational campaigns were undertaken to persuade the public about seeking care for symptoms that might be associated with Alzheimer’s disease, a large proportion would do so, Dr. Blendon said.

It would be important, however, to address what appear to be unrealistic expectations about the availability of diagnostic testing and effective therapies at this time. A particular leadership challenge for any public education campaign would be to promote early diagnosis while providing positive reasons for seeking a diagnosis (such as allowing those with early Alzheimer’s disease to be involved in planning their long-term care), given the current absence of disease-modifying treatment, he said.

The level of fear about Alzheimer’s disease that is apparent from this survey is evidence of the urgency with which the public wants the matter addressed through research and government support, Dr. Blendon noted.

The majority of respondents (86% from France, 68% from Germany, 75% from Poland, 83% from Spain, and 67% from the United States) expressed strong support for increasing government spending for research on new treatments, he said.

The study was supported by a grant from Bayer Corp. to Alzheimer Europe. Dr. Blendon did not report any disclosures.

PARIS – Concerns that individuals with early symptoms of Alzheimer’s disease may avoid or delay seeking medical care because of a perceived lack of effective therapies or other worries may be largely unfounded.

In fact, expectations about just what can be done for those who receive an Alzheimer’s disease diagnosis may be too high, according to the findings of a recent five-country telephone survey presented at the Alzheimer’s Association International Conference.

In all, 85%-95% of the 2,678 adults aged 18 and older from France, Germany, Poland, Spain, and the United States said they would see a doctor if they were experiencing confusion or memory loss, 52%-71% said they believe that an effective treatment currently exists or will soon be available, and 38%-59% said they believe a reliable test for early Alzheimer’s disease currently exists, Robert Blendon, Sc.D., reported during a press briefing at the conference.

If anything, the findings suggest that clinicians will have to temper the expectations of those who come in seeking answers about their symptoms, said Dr. Blendon, professor of health policy and political analysis at the Harvard School of Public Health, Boston.

Alzheimer’s disease organizations in many countries, including the United States, are working to promote early diagnosis. One purpose of this random telephone survey, which was a joint project of the Harvard School of Public Health and Alzheimer Europe, was to determine if the public would respond to such campaigns. The investigators also wanted to elucidate cultural differences regarding views on Alzheimer’s disease, he said.

In addition to the somewhat surprising responses regarding whether or not they would seek a diagnosis, the majority (51%-78%) of respondents from each country also said that if an accurate preclinical diagnostic test existed, they would seek a diagnosis.

Respondents expressed deep overall concerns about developing Alzheimer’s disease. In four of the five countries, Alzheimer’s ranked second after cancer as the most feared disease. In Poland, it ranked third after cancer and heart disease.

More than half of the respondents from each of the countries (54%-77%) said they had known someone with the disease, and nearly 30% said they had personal experience with a family member who had Alzheimer’s disease.

The findings suggest that if educational campaigns were undertaken to persuade the public about seeking care for symptoms that might be associated with Alzheimer’s disease, a large proportion would do so, Dr. Blendon said.

It would be important, however, to address what appear to be unrealistic expectations about the availability of diagnostic testing and effective therapies at this time. A particular leadership challenge for any public education campaign would be to promote early diagnosis while providing positive reasons for seeking a diagnosis (such as allowing those with early Alzheimer’s disease to be involved in planning their long-term care), given the current absence of disease-modifying treatment, he said.

The level of fear about Alzheimer’s disease that is apparent from this survey is evidence of the urgency with which the public wants the matter addressed through research and government support, Dr. Blendon noted.

The majority of respondents (86% from France, 68% from Germany, 75% from Poland, 83% from Spain, and 67% from the United States) expressed strong support for increasing government spending for research on new treatments, he said.

The study was supported by a grant from Bayer Corp. to Alzheimer Europe. Dr. Blendon did not report any disclosures.

PARIS – Concerns that individuals with early symptoms of Alzheimer’s disease may avoid or delay seeking medical care because of a perceived lack of effective therapies or other worries may be largely unfounded.

In fact, expectations about just what can be done for those who receive an Alzheimer’s disease diagnosis may be too high, according to the findings of a recent five-country telephone survey presented at the Alzheimer’s Association International Conference.

In all, 85%-95% of the 2,678 adults aged 18 and older from France, Germany, Poland, Spain, and the United States said they would see a doctor if they were experiencing confusion or memory loss, 52%-71% said they believe that an effective treatment currently exists or will soon be available, and 38%-59% said they believe a reliable test for early Alzheimer’s disease currently exists, Robert Blendon, Sc.D., reported during a press briefing at the conference.

If anything, the findings suggest that clinicians will have to temper the expectations of those who come in seeking answers about their symptoms, said Dr. Blendon, professor of health policy and political analysis at the Harvard School of Public Health, Boston.

Alzheimer’s disease organizations in many countries, including the United States, are working to promote early diagnosis. One purpose of this random telephone survey, which was a joint project of the Harvard School of Public Health and Alzheimer Europe, was to determine if the public would respond to such campaigns. The investigators also wanted to elucidate cultural differences regarding views on Alzheimer’s disease, he said.

In addition to the somewhat surprising responses regarding whether or not they would seek a diagnosis, the majority (51%-78%) of respondents from each country also said that if an accurate preclinical diagnostic test existed, they would seek a diagnosis.

Respondents expressed deep overall concerns about developing Alzheimer’s disease. In four of the five countries, Alzheimer’s ranked second after cancer as the most feared disease. In Poland, it ranked third after cancer and heart disease.

More than half of the respondents from each of the countries (54%-77%) said they had known someone with the disease, and nearly 30% said they had personal experience with a family member who had Alzheimer’s disease.

The findings suggest that if educational campaigns were undertaken to persuade the public about seeking care for symptoms that might be associated with Alzheimer’s disease, a large proportion would do so, Dr. Blendon said.

It would be important, however, to address what appear to be unrealistic expectations about the availability of diagnostic testing and effective therapies at this time. A particular leadership challenge for any public education campaign would be to promote early diagnosis while providing positive reasons for seeking a diagnosis (such as allowing those with early Alzheimer’s disease to be involved in planning their long-term care), given the current absence of disease-modifying treatment, he said.

The level of fear about Alzheimer’s disease that is apparent from this survey is evidence of the urgency with which the public wants the matter addressed through research and government support, Dr. Blendon noted.

The majority of respondents (86% from France, 68% from Germany, 75% from Poland, 83% from Spain, and 67% from the United States) expressed strong support for increasing government spending for research on new treatments, he said.

The study was supported by a grant from Bayer Corp. to Alzheimer Europe. Dr. Blendon did not report any disclosures.

PARIS – Falls occur significantly more often among cognitively normal older adults with evidence of preclinical Alzheimer’s disease on positron emission tomography than among those with no signs of Alzheimer’s, according to findings from an ongoing prospective cohort study.

If the findings hold up, they suggest that falls could prove to be an early signal of the disease, Susan Stark, Ph.D., said at the Alzheimer’s Association International Conference.

Her study involved 119 adults from longitudinal studies of memory and aging at Washington University’s Knight Alzheimer's Disease Research Center in St. Louis who underwent amyloid imaging via Pittsburgh compound-B PET scanning (PIB PET). A total of 18 had a positive scan, indicating amyloid plaque burden in the brain consistent with preclinical Alzheimer’s disease, Dr. Stark reported in a poster.

Of those 18 subjects, 12 (67%) experienced at least one fall during the first 8 months of the study, compared with only 36 of 101 (36%) patients with a negative PIB PET, indicating low amyloid plaque burden. The rate of falls among those in the latter group is about what would be expected among healthy adults in this age group, said Dr. Stark of the occupational therapy program in the department of neurology at Washington University.

Participants had a mean age of 74.5 years, were mostly female (64%), and reported falls monthly by mail. All underwent clinical evaluation and a PET scan with PIB PET. They also provided cerebrospinal fluid for biomarker analysis.

The findings point to the importance of understanding not only the cognitive impairments associated with Alzheimer’s disease but also the motor changes that appear to precede cognitive changes, Dr. Stark noted.

In a written statement highlighting the research, Maria Carrillo, Ph.D., agreed that the findings "illustrate the significance of understanding that, in some people, changes in gait and balance may appear before cognitive impairment."

Evidence increasingly suggests that "silent" biological brain changes may be occurring a decade or more before outward symptoms of Alzheimer’s can be seen, said Dr. Carrillo, senior director of medical and scientific relations for the Alzheimer’s Association.

"According to this study, a fall by an older adult who otherwise has a low risk of falling may signal a need for diagnostic evaluation for Alzheimer’s," she said.

Dr. Stark added that while her study is the first she knows of that has identified a risk of increased falls related to a diagnosis of preclinical Alzheimer’s disease, the findings are consistent with those from previous studies of mobility problems in those with very early symptomatic disease or mild cognitive impairment.

Dr. Carrillo said additional research is urgently needed to further explore the connection between motor deficits and falls as an early sign of disease.

Not only will such research elucidate such connections, it might also help prevent falls and the multiple problems associated with them in older adults, Dr. Carrillo added.

"In the near future, with continued research, we will improve our ability to detect and intervene early in Alzheimer’s disease. With earlier detection, perhaps we can also lower the risk of falls, which can be disabling, expensive, and even deadly in older adults," she said.

This study was funded by the National Institute on Aging. Neither Dr. Stark nor Dr. Carrillo had disclosures to report.

PARIS – Falls occur significantly more often among cognitively normal older adults with evidence of preclinical Alzheimer’s disease on positron emission tomography than among those with no signs of Alzheimer’s, according to findings from an ongoing prospective cohort study.

If the findings hold up, they suggest that falls could prove to be an early signal of the disease, Susan Stark, Ph.D., said at the Alzheimer’s Association International Conference.

Her study involved 119 adults from longitudinal studies of memory and aging at Washington University’s Knight Alzheimer's Disease Research Center in St. Louis who underwent amyloid imaging via Pittsburgh compound-B PET scanning (PIB PET). A total of 18 had a positive scan, indicating amyloid plaque burden in the brain consistent with preclinical Alzheimer’s disease, Dr. Stark reported in a poster.

Of those 18 subjects, 12 (67%) experienced at least one fall during the first 8 months of the study, compared with only 36 of 101 (36%) patients with a negative PIB PET, indicating low amyloid plaque burden. The rate of falls among those in the latter group is about what would be expected among healthy adults in this age group, said Dr. Stark of the occupational therapy program in the department of neurology at Washington University.

Participants had a mean age of 74.5 years, were mostly female (64%), and reported falls monthly by mail. All underwent clinical evaluation and a PET scan with PIB PET. They also provided cerebrospinal fluid for biomarker analysis.

The findings point to the importance of understanding not only the cognitive impairments associated with Alzheimer’s disease but also the motor changes that appear to precede cognitive changes, Dr. Stark noted.

In a written statement highlighting the research, Maria Carrillo, Ph.D., agreed that the findings "illustrate the significance of understanding that, in some people, changes in gait and balance may appear before cognitive impairment."

Evidence increasingly suggests that "silent" biological brain changes may be occurring a decade or more before outward symptoms of Alzheimer’s can be seen, said Dr. Carrillo, senior director of medical and scientific relations for the Alzheimer’s Association.

"According to this study, a fall by an older adult who otherwise has a low risk of falling may signal a need for diagnostic evaluation for Alzheimer’s," she said.

Dr. Stark added that while her study is the first she knows of that has identified a risk of increased falls related to a diagnosis of preclinical Alzheimer’s disease, the findings are consistent with those from previous studies of mobility problems in those with very early symptomatic disease or mild cognitive impairment.

Dr. Carrillo said additional research is urgently needed to further explore the connection between motor deficits and falls as an early sign of disease.

Not only will such research elucidate such connections, it might also help prevent falls and the multiple problems associated with them in older adults, Dr. Carrillo added.

"In the near future, with continued research, we will improve our ability to detect and intervene early in Alzheimer’s disease. With earlier detection, perhaps we can also lower the risk of falls, which can be disabling, expensive, and even deadly in older adults," she said.

This study was funded by the National Institute on Aging. Neither Dr. Stark nor Dr. Carrillo had disclosures to report.

PARIS – Falls occur significantly more often among cognitively normal older adults with evidence of preclinical Alzheimer’s disease on positron emission tomography than among those with no signs of Alzheimer’s, according to findings from an ongoing prospective cohort study.

If the findings hold up, they suggest that falls could prove to be an early signal of the disease, Susan Stark, Ph.D., said at the Alzheimer’s Association International Conference.

Her study involved 119 adults from longitudinal studies of memory and aging at Washington University’s Knight Alzheimer's Disease Research Center in St. Louis who underwent amyloid imaging via Pittsburgh compound-B PET scanning (PIB PET). A total of 18 had a positive scan, indicating amyloid plaque burden in the brain consistent with preclinical Alzheimer’s disease, Dr. Stark reported in a poster.

Of those 18 subjects, 12 (67%) experienced at least one fall during the first 8 months of the study, compared with only 36 of 101 (36%) patients with a negative PIB PET, indicating low amyloid plaque burden. The rate of falls among those in the latter group is about what would be expected among healthy adults in this age group, said Dr. Stark of the occupational therapy program in the department of neurology at Washington University.

Participants had a mean age of 74.5 years, were mostly female (64%), and reported falls monthly by mail. All underwent clinical evaluation and a PET scan with PIB PET. They also provided cerebrospinal fluid for biomarker analysis.

The findings point to the importance of understanding not only the cognitive impairments associated with Alzheimer’s disease but also the motor changes that appear to precede cognitive changes, Dr. Stark noted.

In a written statement highlighting the research, Maria Carrillo, Ph.D., agreed that the findings "illustrate the significance of understanding that, in some people, changes in gait and balance may appear before cognitive impairment."

Evidence increasingly suggests that "silent" biological brain changes may be occurring a decade or more before outward symptoms of Alzheimer’s can be seen, said Dr. Carrillo, senior director of medical and scientific relations for the Alzheimer’s Association.

"According to this study, a fall by an older adult who otherwise has a low risk of falling may signal a need for diagnostic evaluation for Alzheimer’s," she said.

Dr. Stark added that while her study is the first she knows of that has identified a risk of increased falls related to a diagnosis of preclinical Alzheimer’s disease, the findings are consistent with those from previous studies of mobility problems in those with very early symptomatic disease or mild cognitive impairment.

Dr. Carrillo said additional research is urgently needed to further explore the connection between motor deficits and falls as an early sign of disease.

Not only will such research elucidate such connections, it might also help prevent falls and the multiple problems associated with them in older adults, Dr. Carrillo added.

"In the near future, with continued research, we will improve our ability to detect and intervene early in Alzheimer’s disease. With earlier detection, perhaps we can also lower the risk of falls, which can be disabling, expensive, and even deadly in older adults," she said.

This study was funded by the National Institute on Aging. Neither Dr. Stark nor Dr. Carrillo had disclosures to report.

PARIS – Interim findings from the Dominantly Inherited Alzheimer Network study provide encouraging insights about the potential for preclinical detection of Alzheimer’s disease and are setting the stage for prevention trials to begin as early as 2012.

Specifically, the findings from the Dominantly Inherited Alzheimer Network (DIAN) suggest that measurable changes in brain chemistry are apparent at up to 20 or more years before the onset of dementia in Alzheimer’s disease patients, DIAN investigators reported at the Alzheimer’s Association International Conference.

DIAN, an international collaboration involving 11 leading Alzheimer’s research centers in the United States, the United Kingdom, and Australia, was established in 2008 to investigate an autosomal dominant form of Alzheimer’s disease caused by rare genetic mutations in either amyloid precursor protein (APP), or presenilin 1 (PSEN1) or 2 (PSEN2) that virtually ensure a carrier will develop the disease before they reach their 50s – and perhaps as early as their 20s or 30s. The network aims to enroll 200 mutation carriers and 200 noncarrier siblings to evaluate the sequence and rate of biomarker abnormalities that develop prior to the onset of detectable cognitive changes associated with the disease.

The approximately 1% of Alzheimer’s disease patients who have the genetic form of the disease are believed to comprise an ideal study population for this purpose. The findings presented at the conference indicate that autosomal dominant Alzheimer’s disease is quite similar to the far more common later-onset, sporadic form of the disease, and that the two forms of the disease share pathophysiological mechanisms, according to Dr. Randall Bateman, assistant director of DIAN and professor of neurology at Washington University in St. Louis, which serves as the coordinating center for the network.

Findings from the initial 195 patients enrolled in DIAN for whom cerebrospinal fluid and plasma samples were available indicate that patterns of biomarker changes observed in prior studies of sporadic Alzheimer’s patients are also seen in the DIAN cohort. These changes include increased levels of amyloid-beta42 in the blood and decreased levels in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of amyloid plaques in the brain) and elevated levels of tau and phosphorylated tau in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of neurofibrillary tangles and/or brain cell death). The presence of both amyloid plaques and neurofibrillary tangles is characteristic of Alzheimer’s disease, said Anne M. Fagan, Ph.D., a research professor in the department of neurology at Washington University and the DIAN Biomarker Core director. 

"What’s really important is that we see these changes even before the onset of symptoms," Dr. Fagan said, adding that the levels of amyloid-beta42 in CSF decrease with increasing dementia severity.

The opposite is seen with tau, with levels in the CSF increasing with the progression of dementia symptoms, and this is also consistent with what is seen in sporadic Alzheimer’s disease, she said.

"Importantly, changes can be detected many years prior to the appearance of cognitive symptoms. We have some people who are 30 years prior to their estimated age of onset (based on family history, which is a reasonably accurate predictor of carrier age of onset) and we’re already starting to see some changes and some differences in these people that early," she said.

The findings suggest that these changes represent a potential target for treatments and preventive measures, Dr. Bateman said.

"This group provides several unique insights into the process of Alzheimer’s disease ... we think the DIAN network represents an ideal cohort to bring forth treatment trials and prevention trials," he said, explaining that the cohort is particularly well-suited for proof-of-concept studies of the effects of drugs on biomarkers, and for primary and secondary prevention studies in asymptomatic carriers.

Several factors provide the rationale for conducting such trials, he said.

For one thing, current therapeutic trials may be too late.

"We may be trying to treat the disease in its latest stage of development with treatments that may be ideally suited for some of the earlier stages of development," he said.

Since amyloid plaques can develop 15-20 years prior to symptom development, applying therapeutics that target the amyloid protein at the earlier signs of damage may prevent dementia, he explained.

Also, the risk-benefit ratio in this population is clear given that 100% of carriers are destined to develop Alzheimer’s – and the timing of that development can be estimated with reasonable certainty.

"If we can offer them treatment before they develop dementia, it offers them a chance of hope," he said.

Furthermore, since many of the agents currently in trials were developed based on information derived from the genetic mutations seen in the DIAN cohort, and since that information informed one of the major hypotheses (the amyloid hypothesis) about Alzheimer’s disease, it seems likely that these individuals are the most likely to respond to the treatments, he said, adding that if they are successful, these studies could bridge prevention trials between the genetic and sporadic forms of the disease.

Based on this rationale, DIAN is moving forward with the development of additional trials within the network, he said.

To date, a clinical trials committee has been formed and is charged with designing and managing the most effective trials through interactions with pharmaceutical sponsors, the National Institute on Aging, and the U.S. Food and Drug Administration. The committee has completed its scientific review and vetting of the rational for trials in this cohort, formed a "Pharma Consortium" with members from 12 pharmaceutical companies, and started the DIAN Therapeutic Trials Unit to implement the trials.

Multiple meetings have been held, and DIAN has obtained the support of regulatory agencies, including the FDA and the European Medicines Agency, Dr. Bateman noted.

Additionally, 11 therapeutic nomination packets have been received from pharmaceutical companies and are under consideration for use in the trials. He declined to identify the candidate drugs but said most are anti-amyloid agents.

The first trials should begin in early 2012, he said.

The hope is that these trials will lead to the same kind of success seen with statin drugs, which were initially tested in patients with an aggressive genetic form of hypercholesterolemia that struck people early in life, increasing their risk for heart attack and stroke.

The treatment was found to be effective in this population, and the findings translated into a highly effective therapy for the population at large, Dr. Bateman said, noting that millions of people around the world have benefited from treatment with those drugs.

The findings from DIAN, and the future directions of the network represent "a very exciting and new style of a collaborative type of multinational research, which is going to allow us to understand things in a way that couldn’t be done before by targeting populations at very high risk, and which allows us for the first time to really approach the problem of preventing Alzheimer’s rather than intervening after it’s developed, " said Dr. Ralph Nixon, professor of psychiatry and cell biology at New York University and moderator of a press briefing about the findings.

The approach is one that the Alzheimer’s Association has encouraged in recent years because "it cuts across a number of missions of the association, which are to underscore the importance of early detection so we can be in a position to treat these individuals when therapies are available for them," said Dr. Nixon, who also is vice chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Council.

"But I think the most important message really is that we now have from this study the validation that it really is possible to detect changes at such an early stage that we are going to enhance the chances of administering therapies that will be more effective, even retesting therapies that might have failed in interventional trials ... as well as testing new innovative therapies that come along," he said.

DIAN is supported by a National Institutes of Health grant, as well as by grants from an anonymous foundation. The presenters had no conflicts of interest to report. 

PARIS – Interim findings from the Dominantly Inherited Alzheimer Network study provide encouraging insights about the potential for preclinical detection of Alzheimer’s disease and are setting the stage for prevention trials to begin as early as 2012.

Specifically, the findings from the Dominantly Inherited Alzheimer Network (DIAN) suggest that measurable changes in brain chemistry are apparent at up to 20 or more years before the onset of dementia in Alzheimer’s disease patients, DIAN investigators reported at the Alzheimer’s Association International Conference.

DIAN, an international collaboration involving 11 leading Alzheimer’s research centers in the United States, the United Kingdom, and Australia, was established in 2008 to investigate an autosomal dominant form of Alzheimer’s disease caused by rare genetic mutations in either amyloid precursor protein (APP), or presenilin 1 (PSEN1) or 2 (PSEN2) that virtually ensure a carrier will develop the disease before they reach their 50s – and perhaps as early as their 20s or 30s. The network aims to enroll 200 mutation carriers and 200 noncarrier siblings to evaluate the sequence and rate of biomarker abnormalities that develop prior to the onset of detectable cognitive changes associated with the disease.

The approximately 1% of Alzheimer’s disease patients who have the genetic form of the disease are believed to comprise an ideal study population for this purpose. The findings presented at the conference indicate that autosomal dominant Alzheimer’s disease is quite similar to the far more common later-onset, sporadic form of the disease, and that the two forms of the disease share pathophysiological mechanisms, according to Dr. Randall Bateman, assistant director of DIAN and professor of neurology at Washington University in St. Louis, which serves as the coordinating center for the network.

Findings from the initial 195 patients enrolled in DIAN for whom cerebrospinal fluid and plasma samples were available indicate that patterns of biomarker changes observed in prior studies of sporadic Alzheimer’s patients are also seen in the DIAN cohort. These changes include increased levels of amyloid-beta42 in the blood and decreased levels in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of amyloid plaques in the brain) and elevated levels of tau and phosphorylated tau in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of neurofibrillary tangles and/or brain cell death). The presence of both amyloid plaques and neurofibrillary tangles is characteristic of Alzheimer’s disease, said Anne M. Fagan, Ph.D., a research professor in the department of neurology at Washington University and the DIAN Biomarker Core director. 

"What’s really important is that we see these changes even before the onset of symptoms," Dr. Fagan said, adding that the levels of amyloid-beta42 in CSF decrease with increasing dementia severity.

The opposite is seen with tau, with levels in the CSF increasing with the progression of dementia symptoms, and this is also consistent with what is seen in sporadic Alzheimer’s disease, she said.

"Importantly, changes can be detected many years prior to the appearance of cognitive symptoms. We have some people who are 30 years prior to their estimated age of onset (based on family history, which is a reasonably accurate predictor of carrier age of onset) and we’re already starting to see some changes and some differences in these people that early," she said.

The findings suggest that these changes represent a potential target for treatments and preventive measures, Dr. Bateman said.

"This group provides several unique insights into the process of Alzheimer’s disease ... we think the DIAN network represents an ideal cohort to bring forth treatment trials and prevention trials," he said, explaining that the cohort is particularly well-suited for proof-of-concept studies of the effects of drugs on biomarkers, and for primary and secondary prevention studies in asymptomatic carriers.

Several factors provide the rationale for conducting such trials, he said.

For one thing, current therapeutic trials may be too late.

"We may be trying to treat the disease in its latest stage of development with treatments that may be ideally suited for some of the earlier stages of development," he said.

Since amyloid plaques can develop 15-20 years prior to symptom development, applying therapeutics that target the amyloid protein at the earlier signs of damage may prevent dementia, he explained.

Also, the risk-benefit ratio in this population is clear given that 100% of carriers are destined to develop Alzheimer’s – and the timing of that development can be estimated with reasonable certainty.

"If we can offer them treatment before they develop dementia, it offers them a chance of hope," he said.

Furthermore, since many of the agents currently in trials were developed based on information derived from the genetic mutations seen in the DIAN cohort, and since that information informed one of the major hypotheses (the amyloid hypothesis) about Alzheimer’s disease, it seems likely that these individuals are the most likely to respond to the treatments, he said, adding that if they are successful, these studies could bridge prevention trials between the genetic and sporadic forms of the disease.

Based on this rationale, DIAN is moving forward with the development of additional trials within the network, he said.

To date, a clinical trials committee has been formed and is charged with designing and managing the most effective trials through interactions with pharmaceutical sponsors, the National Institute on Aging, and the U.S. Food and Drug Administration. The committee has completed its scientific review and vetting of the rational for trials in this cohort, formed a "Pharma Consortium" with members from 12 pharmaceutical companies, and started the DIAN Therapeutic Trials Unit to implement the trials.

Multiple meetings have been held, and DIAN has obtained the support of regulatory agencies, including the FDA and the European Medicines Agency, Dr. Bateman noted.

Additionally, 11 therapeutic nomination packets have been received from pharmaceutical companies and are under consideration for use in the trials. He declined to identify the candidate drugs but said most are anti-amyloid agents.

The first trials should begin in early 2012, he said.

The hope is that these trials will lead to the same kind of success seen with statin drugs, which were initially tested in patients with an aggressive genetic form of hypercholesterolemia that struck people early in life, increasing their risk for heart attack and stroke.

The treatment was found to be effective in this population, and the findings translated into a highly effective therapy for the population at large, Dr. Bateman said, noting that millions of people around the world have benefited from treatment with those drugs.

The findings from DIAN, and the future directions of the network represent "a very exciting and new style of a collaborative type of multinational research, which is going to allow us to understand things in a way that couldn’t be done before by targeting populations at very high risk, and which allows us for the first time to really approach the problem of preventing Alzheimer’s rather than intervening after it’s developed, " said Dr. Ralph Nixon, professor of psychiatry and cell biology at New York University and moderator of a press briefing about the findings.

The approach is one that the Alzheimer’s Association has encouraged in recent years because "it cuts across a number of missions of the association, which are to underscore the importance of early detection so we can be in a position to treat these individuals when therapies are available for them," said Dr. Nixon, who also is vice chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Council.

"But I think the most important message really is that we now have from this study the validation that it really is possible to detect changes at such an early stage that we are going to enhance the chances of administering therapies that will be more effective, even retesting therapies that might have failed in interventional trials ... as well as testing new innovative therapies that come along," he said.

DIAN is supported by a National Institutes of Health grant, as well as by grants from an anonymous foundation. The presenters had no conflicts of interest to report. 

PARIS – Interim findings from the Dominantly Inherited Alzheimer Network study provide encouraging insights about the potential for preclinical detection of Alzheimer’s disease and are setting the stage for prevention trials to begin as early as 2012.

Specifically, the findings from the Dominantly Inherited Alzheimer Network (DIAN) suggest that measurable changes in brain chemistry are apparent at up to 20 or more years before the onset of dementia in Alzheimer’s disease patients, DIAN investigators reported at the Alzheimer’s Association International Conference.

DIAN, an international collaboration involving 11 leading Alzheimer’s research centers in the United States, the United Kingdom, and Australia, was established in 2008 to investigate an autosomal dominant form of Alzheimer’s disease caused by rare genetic mutations in either amyloid precursor protein (APP), or presenilin 1 (PSEN1) or 2 (PSEN2) that virtually ensure a carrier will develop the disease before they reach their 50s – and perhaps as early as their 20s or 30s. The network aims to enroll 200 mutation carriers and 200 noncarrier siblings to evaluate the sequence and rate of biomarker abnormalities that develop prior to the onset of detectable cognitive changes associated with the disease.

The approximately 1% of Alzheimer’s disease patients who have the genetic form of the disease are believed to comprise an ideal study population for this purpose. The findings presented at the conference indicate that autosomal dominant Alzheimer’s disease is quite similar to the far more common later-onset, sporadic form of the disease, and that the two forms of the disease share pathophysiological mechanisms, according to Dr. Randall Bateman, assistant director of DIAN and professor of neurology at Washington University in St. Louis, which serves as the coordinating center for the network.

Findings from the initial 195 patients enrolled in DIAN for whom cerebrospinal fluid and plasma samples were available indicate that patterns of biomarker changes observed in prior studies of sporadic Alzheimer’s patients are also seen in the DIAN cohort. These changes include increased levels of amyloid-beta42 in the blood and decreased levels in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of amyloid plaques in the brain) and elevated levels of tau and phosphorylated tau in the cerebrospinal fluid, compared with noncarriers (reflecting the presence of neurofibrillary tangles and/or brain cell death). The presence of both amyloid plaques and neurofibrillary tangles is characteristic of Alzheimer’s disease, said Anne M. Fagan, Ph.D., a research professor in the department of neurology at Washington University and the DIAN Biomarker Core director. 

"What’s really important is that we see these changes even before the onset of symptoms," Dr. Fagan said, adding that the levels of amyloid-beta42 in CSF decrease with increasing dementia severity.

The opposite is seen with tau, with levels in the CSF increasing with the progression of dementia symptoms, and this is also consistent with what is seen in sporadic Alzheimer’s disease, she said.

"Importantly, changes can be detected many years prior to the appearance of cognitive symptoms. We have some people who are 30 years prior to their estimated age of onset (based on family history, which is a reasonably accurate predictor of carrier age of onset) and we’re already starting to see some changes and some differences in these people that early," she said.

The findings suggest that these changes represent a potential target for treatments and preventive measures, Dr. Bateman said.

"This group provides several unique insights into the process of Alzheimer’s disease ... we think the DIAN network represents an ideal cohort to bring forth treatment trials and prevention trials," he said, explaining that the cohort is particularly well-suited for proof-of-concept studies of the effects of drugs on biomarkers, and for primary and secondary prevention studies in asymptomatic carriers.

Several factors provide the rationale for conducting such trials, he said.

For one thing, current therapeutic trials may be too late.

"We may be trying to treat the disease in its latest stage of development with treatments that may be ideally suited for some of the earlier stages of development," he said.

Since amyloid plaques can develop 15-20 years prior to symptom development, applying therapeutics that target the amyloid protein at the earlier signs of damage may prevent dementia, he explained.

Also, the risk-benefit ratio in this population is clear given that 100% of carriers are destined to develop Alzheimer’s – and the timing of that development can be estimated with reasonable certainty.

"If we can offer them treatment before they develop dementia, it offers them a chance of hope," he said.

Furthermore, since many of the agents currently in trials were developed based on information derived from the genetic mutations seen in the DIAN cohort, and since that information informed one of the major hypotheses (the amyloid hypothesis) about Alzheimer’s disease, it seems likely that these individuals are the most likely to respond to the treatments, he said, adding that if they are successful, these studies could bridge prevention trials between the genetic and sporadic forms of the disease.

Based on this rationale, DIAN is moving forward with the development of additional trials within the network, he said.

To date, a clinical trials committee has been formed and is charged with designing and managing the most effective trials through interactions with pharmaceutical sponsors, the National Institute on Aging, and the U.S. Food and Drug Administration. The committee has completed its scientific review and vetting of the rational for trials in this cohort, formed a "Pharma Consortium" with members from 12 pharmaceutical companies, and started the DIAN Therapeutic Trials Unit to implement the trials.

Multiple meetings have been held, and DIAN has obtained the support of regulatory agencies, including the FDA and the European Medicines Agency, Dr. Bateman noted.

Additionally, 11 therapeutic nomination packets have been received from pharmaceutical companies and are under consideration for use in the trials. He declined to identify the candidate drugs but said most are anti-amyloid agents.

The first trials should begin in early 2012, he said.

The hope is that these trials will lead to the same kind of success seen with statin drugs, which were initially tested in patients with an aggressive genetic form of hypercholesterolemia that struck people early in life, increasing their risk for heart attack and stroke.

The treatment was found to be effective in this population, and the findings translated into a highly effective therapy for the population at large, Dr. Bateman said, noting that millions of people around the world have benefited from treatment with those drugs.

The findings from DIAN, and the future directions of the network represent "a very exciting and new style of a collaborative type of multinational research, which is going to allow us to understand things in a way that couldn’t be done before by targeting populations at very high risk, and which allows us for the first time to really approach the problem of preventing Alzheimer’s rather than intervening after it’s developed, " said Dr. Ralph Nixon, professor of psychiatry and cell biology at New York University and moderator of a press briefing about the findings.

The approach is one that the Alzheimer’s Association has encouraged in recent years because "it cuts across a number of missions of the association, which are to underscore the importance of early detection so we can be in a position to treat these individuals when therapies are available for them," said Dr. Nixon, who also is vice chairman of the Alzheimer’s Association’s Medical and Scientific Advisory Council.

"But I think the most important message really is that we now have from this study the validation that it really is possible to detect changes at such an early stage that we are going to enhance the chances of administering therapies that will be more effective, even retesting therapies that might have failed in interventional trials ... as well as testing new innovative therapies that come along," he said.

DIAN is supported by a National Institutes of Health grant, as well as by grants from an anonymous foundation. The presenters had no conflicts of interest to report. 

Researchers have identified a number of predictors of damage and/or death in patients with systemic lupus erythematosus.

Data from the inception cohort of 160 SLE patients show that predictors of new damage or death in this population include older age at diagnosis (odds ratio, 1.02), hypercholesterolemia (OR, 2.67), antiphospholipid syndrome (OR, 2.97), BILAG (British Isles Lupus Assessment Group)-2004 mucocutaneous grade A or B disease activity score (OR, 2.75), BILAG-2004 haematological grade A or B score (OR, 18.20), cumulative hydroxychloroquine (per gram) exposure (OR, 0.98), and cumulative mepacrine (per gram) exposure (OR, 1.96 × 10

Factors found not to be associated with damage or death were other BILAG-2004 system scores, sex, ethnicity, hypertension, smoking status, prior damage, and cumulative exposure to immunosuppressives/biologic therapies, Dr. Yee said at the annual European Congress of Rheumatology in London.

The investigators included only SLE patients from the multicenter study, which began in 2004, who achieved the fourth American College of Rheumatology criteria for an SLE diagnosis within 12 months at the time of recruitment. Patients had a mean age of 35 years, and the median follow-up was 39 months with a total follow-up of 497 patient years.

Two of the 160 patients died, and 35 instances of damage occurred in 30 patients.

Damage was musculoskeletal in 31% of cases; ophthalmic in 23% of cases; neuropsychiatric in 17% of cases; renal, vascular, or diabetes mellitus in 6% of cases each; and pulmonary, cardiac, cutaneous, or a malignancy in 3% of cases each.

The incident rates of development of damage across the follow-up period were 73, 86, 82, 42, 24, and 112 cases per 1,000 patient-years for follow-up years 1-6, respectively, and about 70 cases per 1,000 patient-years overall.

As demonstrated by these data, the development of damage starts in the first year and most commonly affects the musculoskeletal, ophthalmic, and neuropsychiatric systems. The rate at which damage occurs, however, is slower compared with that seen in previous studies, Dr. Yee said, noting that antimalarials appear to confer some protection against damage and death.

Findings from previous studies have shown that hydroxychloroquine provides such protection, so this was not a surprising finding. In the current study, though, there was only a 2% reduction in risk with hydroxychloroquine, Dr. Yee said.

“Mepacrine, however, was strongly protective in our study, and this was somewhat surprising,” he added, noting that the finding should be interpreted with caution pending confirmation in future studies.

Dr. Yee said this study is the only one of which he is aware to report on the development of damage from a well-characterized inception cohort of SLE patients who were followed-up prospectively.

“My results highlight the importance of managing cardiovascular risk factors and carefully monitoring patients with associated antiphospholipid syndrome,” he said, noting that there is a need for more interventional studies on SLE patient with associated antiphospholipid syndrome, as this group of patients is often excluded from clinical trials.

Dr. Yee disclosed that he has received grant and/or research support from Aspreva/Vifor Pharma, and has served as a consultant for Genentech, Parexel, and Teva.

Researchers have identified a number of predictors of damage and/or death in patients with systemic lupus erythematosus.

Data from the inception cohort of 160 SLE patients show that predictors of new damage or death in this population include older age at diagnosis (odds ratio, 1.02), hypercholesterolemia (OR, 2.67), antiphospholipid syndrome (OR, 2.97), BILAG (British Isles Lupus Assessment Group)-2004 mucocutaneous grade A or B disease activity score (OR, 2.75), BILAG-2004 haematological grade A or B score (OR, 18.20), cumulative hydroxychloroquine (per gram) exposure (OR, 0.98), and cumulative mepacrine (per gram) exposure (OR, 1.96 × 10

Factors found not to be associated with damage or death were other BILAG-2004 system scores, sex, ethnicity, hypertension, smoking status, prior damage, and cumulative exposure to immunosuppressives/biologic therapies, Dr. Yee said at the annual European Congress of Rheumatology in London.

The investigators included only SLE patients from the multicenter study, which began in 2004, who achieved the fourth American College of Rheumatology criteria for an SLE diagnosis within 12 months at the time of recruitment. Patients had a mean age of 35 years, and the median follow-up was 39 months with a total follow-up of 497 patient years.

Two of the 160 patients died, and 35 instances of damage occurred in 30 patients.

Damage was musculoskeletal in 31% of cases; ophthalmic in 23% of cases; neuropsychiatric in 17% of cases; renal, vascular, or diabetes mellitus in 6% of cases each; and pulmonary, cardiac, cutaneous, or a malignancy in 3% of cases each.

The incident rates of development of damage across the follow-up period were 73, 86, 82, 42, 24, and 112 cases per 1,000 patient-years for follow-up years 1-6, respectively, and about 70 cases per 1,000 patient-years overall.

As demonstrated by these data, the development of damage starts in the first year and most commonly affects the musculoskeletal, ophthalmic, and neuropsychiatric systems. The rate at which damage occurs, however, is slower compared with that seen in previous studies, Dr. Yee said, noting that antimalarials appear to confer some protection against damage and death.

Findings from previous studies have shown that hydroxychloroquine provides such protection, so this was not a surprising finding. In the current study, though, there was only a 2% reduction in risk with hydroxychloroquine, Dr. Yee said.

“Mepacrine, however, was strongly protective in our study, and this was somewhat surprising,” he added, noting that the finding should be interpreted with caution pending confirmation in future studies.

Dr. Yee said this study is the only one of which he is aware to report on the development of damage from a well-characterized inception cohort of SLE patients who were followed-up prospectively.

“My results highlight the importance of managing cardiovascular risk factors and carefully monitoring patients with associated antiphospholipid syndrome,” he said, noting that there is a need for more interventional studies on SLE patient with associated antiphospholipid syndrome, as this group of patients is often excluded from clinical trials.

Dr. Yee disclosed that he has received grant and/or research support from Aspreva/Vifor Pharma, and has served as a consultant for Genentech, Parexel, and Teva.

Researchers have identified a number of predictors of damage and/or death in patients with systemic lupus erythematosus.

Data from the inception cohort of 160 SLE patients show that predictors of new damage or death in this population include older age at diagnosis (odds ratio, 1.02), hypercholesterolemia (OR, 2.67), antiphospholipid syndrome (OR, 2.97), BILAG (British Isles Lupus Assessment Group)-2004 mucocutaneous grade A or B disease activity score (OR, 2.75), BILAG-2004 haematological grade A or B score (OR, 18.20), cumulative hydroxychloroquine (per gram) exposure (OR, 0.98), and cumulative mepacrine (per gram) exposure (OR, 1.96 × 10

Factors found not to be associated with damage or death were other BILAG-2004 system scores, sex, ethnicity, hypertension, smoking status, prior damage, and cumulative exposure to immunosuppressives/biologic therapies, Dr. Yee said at the annual European Congress of Rheumatology in London.

The investigators included only SLE patients from the multicenter study, which began in 2004, who achieved the fourth American College of Rheumatology criteria for an SLE diagnosis within 12 months at the time of recruitment. Patients had a mean age of 35 years, and the median follow-up was 39 months with a total follow-up of 497 patient years.

Two of the 160 patients died, and 35 instances of damage occurred in 30 patients.

Damage was musculoskeletal in 31% of cases; ophthalmic in 23% of cases; neuropsychiatric in 17% of cases; renal, vascular, or diabetes mellitus in 6% of cases each; and pulmonary, cardiac, cutaneous, or a malignancy in 3% of cases each.

The incident rates of development of damage across the follow-up period were 73, 86, 82, 42, 24, and 112 cases per 1,000 patient-years for follow-up years 1-6, respectively, and about 70 cases per 1,000 patient-years overall.

As demonstrated by these data, the development of damage starts in the first year and most commonly affects the musculoskeletal, ophthalmic, and neuropsychiatric systems. The rate at which damage occurs, however, is slower compared with that seen in previous studies, Dr. Yee said, noting that antimalarials appear to confer some protection against damage and death.

Findings from previous studies have shown that hydroxychloroquine provides such protection, so this was not a surprising finding. In the current study, though, there was only a 2% reduction in risk with hydroxychloroquine, Dr. Yee said.

“Mepacrine, however, was strongly protective in our study, and this was somewhat surprising,” he added, noting that the finding should be interpreted with caution pending confirmation in future studies.

Dr. Yee said this study is the only one of which he is aware to report on the development of damage from a well-characterized inception cohort of SLE patients who were followed-up prospectively.

“My results highlight the importance of managing cardiovascular risk factors and carefully monitoring patients with associated antiphospholipid syndrome,” he said, noting that there is a need for more interventional studies on SLE patient with associated antiphospholipid syndrome, as this group of patients is often excluded from clinical trials.

Dr. Yee disclosed that he has received grant and/or research support from Aspreva/Vifor Pharma, and has served as a consultant for Genentech, Parexel, and Teva.

The burden of pain among older patients is great, and its consequences can be “serious and significant,” according to a presentation by Dr. Perry G. Fine.

The prevalence of pain ranges from 25% to 50% in the older population, and it increases with age, he said.

Indeed, among older nursing home residents, the prevalence is estimated at 45%-80%. In one study, 20% of individuals aged 65 and older admitted to having a day-long bout of pain in the past month, and about 60% said they had experienced pain for a year or more, said Dr. Fine, professor of anesthesiology at the University of Utah, Salt Lake City.

The sources of pain in these patients are many and varied, and the consequences can include mood disorders, sleep disturbances, decreased socialization, increased health care utilization and costs, limitations in activities of daily living, comorbidities, and polypharmacy, all of which can lead to diminished function and quality of life.

Further complicating the problem is the fact that studies have repeatedly shown that pain in older adults is frequently undertreated, Dr. Fine said.

This may be the result of one or more of the numerous, identified barriers to the management of pain in older patients.

These include language and cultural barriers, fear of judgment, fear of addiction, cognitive impairment, sensory impairment, and adverse effects such as fear of falling, constipation, sedation, and drug-drug interactions.

Barriers for clinicians can include the lack of objective measures of pain and pain response, concerns regarding addiction and/or drug seeking, fear of causing harm from medication-related adverse effects, lack of time in the office setting, and lack of pain management training, according to findings from two studies on the topic (Clin. J. Pain 2007;23[suppl. 1]:S1-43; J. Adv. Nurs. 2009;65:2-10).

Following a list of 10 “universal precautions” in pain management can help with overcoming some of these barriers, Dr. Fine said (Pain Med. 2005;6:107-12). These include the following:

▸ Making a diagnosis with appropriate differential diagnoses.

▸ Performing psychological assessment, including evaluation for risk of addictive disorders.

▸ Obtaining informed consent.

▸ Developing treatment agreements.

▸ Performing pain and function assessments.

▸ Using pain medication – and particularly opioids – on a trial basis.

▸ Reassessing pain, function, and behavior.

▸ Regularly reassessing the “Four As” (analgesia, activities of daily living, adverse events, and aberrant drug-taking behaviors).

▸ Periodically reviewing diagnosis and comorbidities.

▸ Documenting thoroughly.

Also, keep in mind that aging results in a number of physiological changes that will influence both pharmacokinetics and pharmacodynamics, including changes in body composition; decreases in gastrointestinal motility, hepatic metabolism, renal clearance, and protein binding; and increased central nervous system sensitivity to noxious stimuli and medication effects, Dr. Fine said (Neurobiol. Aging 2010; 31:494-503; Clin. J. Pain 2004;20:220-6).

While speaking at the Congress of Clinical Rheumatology, Dr. Fine listed the following general principles to follow when it comes to pharmacotherapy in light of these changes and the needs of older adults:

▸ Titrate according to individual circumstances.

▸ Anticipate and monitor for adverse effects, prevent them when possible, and treat them when necessary.

▸ Practice synergy by combining lower doses of drugs that mediate analgesia via different mechanisms.

▸ Know and understand the distinctions among tolerance, dependence, addiction, and pseudoaddiction.

In those with cognitive impairment, in whom pain assessment can be particularly challenging, clinicians should consider alternatives to standard numeric rating scales for pain assessment.

Patients who have difficulty reporting pain based on these types of scales may do better with the Iowa Pain Thermometer, which allows a patient to rate pain using increments on a picture of a thermometer (Pain Med. 2007;8:585-600), or with the Brief Pain Inventory. Reports from caregivers may also be useful, Dr. Fine said.

Dr. Fine reported having no conflicts of interest that were relevant to his presentation.

The burden of pain among older patients is great, and its consequences can be “serious and significant,” according to a presentation by Dr. Perry G. Fine.

The prevalence of pain ranges from 25% to 50% in the older population, and it increases with age, he said.

Indeed, among older nursing home residents, the prevalence is estimated at 45%-80%. In one study, 20% of individuals aged 65 and older admitted to having a day-long bout of pain in the past month, and about 60% said they had experienced pain for a year or more, said Dr. Fine, professor of anesthesiology at the University of Utah, Salt Lake City.

The sources of pain in these patients are many and varied, and the consequences can include mood disorders, sleep disturbances, decreased socialization, increased health care utilization and costs, limitations in activities of daily living, comorbidities, and polypharmacy, all of which can lead to diminished function and quality of life.

Further complicating the problem is the fact that studies have repeatedly shown that pain in older adults is frequently undertreated, Dr. Fine said.

This may be the result of one or more of the numerous, identified barriers to the management of pain in older patients.

These include language and cultural barriers, fear of judgment, fear of addiction, cognitive impairment, sensory impairment, and adverse effects such as fear of falling, constipation, sedation, and drug-drug interactions.

Barriers for clinicians can include the lack of objective measures of pain and pain response, concerns regarding addiction and/or drug seeking, fear of causing harm from medication-related adverse effects, lack of time in the office setting, and lack of pain management training, according to findings from two studies on the topic (Clin. J. Pain 2007;23[suppl. 1]:S1-43; J. Adv. Nurs. 2009;65:2-10).

Following a list of 10 “universal precautions” in pain management can help with overcoming some of these barriers, Dr. Fine said (Pain Med. 2005;6:107-12). These include the following:

▸ Making a diagnosis with appropriate differential diagnoses.

▸ Performing psychological assessment, including evaluation for risk of addictive disorders.

▸ Obtaining informed consent.

▸ Developing treatment agreements.

▸ Performing pain and function assessments.

▸ Using pain medication – and particularly opioids – on a trial basis.

▸ Reassessing pain, function, and behavior.

▸ Regularly reassessing the “Four As” (analgesia, activities of daily living, adverse events, and aberrant drug-taking behaviors).

▸ Periodically reviewing diagnosis and comorbidities.

▸ Documenting thoroughly.

Also, keep in mind that aging results in a number of physiological changes that will influence both pharmacokinetics and pharmacodynamics, including changes in body composition; decreases in gastrointestinal motility, hepatic metabolism, renal clearance, and protein binding; and increased central nervous system sensitivity to noxious stimuli and medication effects, Dr. Fine said (Neurobiol. Aging 2010; 31:494-503; Clin. J. Pain 2004;20:220-6).

While speaking at the Congress of Clinical Rheumatology, Dr. Fine listed the following general principles to follow when it comes to pharmacotherapy in light of these changes and the needs of older adults:

▸ Titrate according to individual circumstances.

▸ Anticipate and monitor for adverse effects, prevent them when possible, and treat them when necessary.

▸ Practice synergy by combining lower doses of drugs that mediate analgesia via different mechanisms.

▸ Know and understand the distinctions among tolerance, dependence, addiction, and pseudoaddiction.

In those with cognitive impairment, in whom pain assessment can be particularly challenging, clinicians should consider alternatives to standard numeric rating scales for pain assessment.

Patients who have difficulty reporting pain based on these types of scales may do better with the Iowa Pain Thermometer, which allows a patient to rate pain using increments on a picture of a thermometer (Pain Med. 2007;8:585-600), or with the Brief Pain Inventory. Reports from caregivers may also be useful, Dr. Fine said.

Dr. Fine reported having no conflicts of interest that were relevant to his presentation.

The burden of pain among older patients is great, and its consequences can be “serious and significant,” according to a presentation by Dr. Perry G. Fine.

The prevalence of pain ranges from 25% to 50% in the older population, and it increases with age, he said.

Indeed, among older nursing home residents, the prevalence is estimated at 45%-80%. In one study, 20% of individuals aged 65 and older admitted to having a day-long bout of pain in the past month, and about 60% said they had experienced pain for a year or more, said Dr. Fine, professor of anesthesiology at the University of Utah, Salt Lake City.

The sources of pain in these patients are many and varied, and the consequences can include mood disorders, sleep disturbances, decreased socialization, increased health care utilization and costs, limitations in activities of daily living, comorbidities, and polypharmacy, all of which can lead to diminished function and quality of life.

Further complicating the problem is the fact that studies have repeatedly shown that pain in older adults is frequently undertreated, Dr. Fine said.

This may be the result of one or more of the numerous, identified barriers to the management of pain in older patients.

These include language and cultural barriers, fear of judgment, fear of addiction, cognitive impairment, sensory impairment, and adverse effects such as fear of falling, constipation, sedation, and drug-drug interactions.

Barriers for clinicians can include the lack of objective measures of pain and pain response, concerns regarding addiction and/or drug seeking, fear of causing harm from medication-related adverse effects, lack of time in the office setting, and lack of pain management training, according to findings from two studies on the topic (Clin. J. Pain 2007;23[suppl. 1]:S1-43; J. Adv. Nurs. 2009;65:2-10).

Following a list of 10 “universal precautions” in pain management can help with overcoming some of these barriers, Dr. Fine said (Pain Med. 2005;6:107-12). These include the following:

▸ Making a diagnosis with appropriate differential diagnoses.

▸ Performing psychological assessment, including evaluation for risk of addictive disorders.

▸ Obtaining informed consent.

▸ Developing treatment agreements.

▸ Performing pain and function assessments.

▸ Using pain medication – and particularly opioids – on a trial basis.

▸ Reassessing pain, function, and behavior.

▸ Regularly reassessing the “Four As” (analgesia, activities of daily living, adverse events, and aberrant drug-taking behaviors).

▸ Periodically reviewing diagnosis and comorbidities.

▸ Documenting thoroughly.

Also, keep in mind that aging results in a number of physiological changes that will influence both pharmacokinetics and pharmacodynamics, including changes in body composition; decreases in gastrointestinal motility, hepatic metabolism, renal clearance, and protein binding; and increased central nervous system sensitivity to noxious stimuli and medication effects, Dr. Fine said (Neurobiol. Aging 2010; 31:494-503; Clin. J. Pain 2004;20:220-6).

While speaking at the Congress of Clinical Rheumatology, Dr. Fine listed the following general principles to follow when it comes to pharmacotherapy in light of these changes and the needs of older adults:

▸ Titrate according to individual circumstances.

▸ Anticipate and monitor for adverse effects, prevent them when possible, and treat them when necessary.

▸ Practice synergy by combining lower doses of drugs that mediate analgesia via different mechanisms.

▸ Know and understand the distinctions among tolerance, dependence, addiction, and pseudoaddiction.

In those with cognitive impairment, in whom pain assessment can be particularly challenging, clinicians should consider alternatives to standard numeric rating scales for pain assessment.

Patients who have difficulty reporting pain based on these types of scales may do better with the Iowa Pain Thermometer, which allows a patient to rate pain using increments on a picture of a thermometer (Pain Med. 2007;8:585-600), or with the Brief Pain Inventory. Reports from caregivers may also be useful, Dr. Fine said.

Dr. Fine reported having no conflicts of interest that were relevant to his presentation.