Sharon Worcester

ATLANTA – A Kansas-based program that aims to improve sepsis-related outcomes in rural hospital settings is proving successful and could serve as a model for rural hospitals nationwide.

The program, known as "The Kansas Sepsis Project," was initiated by the Midwest Critical Care Collaborative, and focuses on a simplified approach to sepsis resuscitation for the purpose of reducing sepsis mortality, Dr. Steven Q. Simpson reported at the annual meeting of the American College of Chest Physicians.

Sepsis affects more than 10,000 Kansans each year, and the sepsis-related mortality rate is 30%-50% in most Kansas hospitals, which exceeds the mortality rate associated with acute myocardial infarction, said Dr. Simpson of the University of Kansas Medical Center, Kansas City.

One goal of the sepsis project is to reduce that rate by 10% by the end of 2015.

According to the Midwest Critical Care Collaborative website, a 20% reduction is possible if specific plans for recognition and treatment as outlined by the project are put in place.

The project, which is open to any interested facility including those not based in Kansas, involves baseline surveys, live and online training, ongoing data collection and analysis, formation of performance improvement planning based on those analyses, and – hopefully – changed behavior and reduced sepsis mortality, said Dr. Simpson.

The website states that participants learn to:

• Recognize cardinal features of severe sepsis.

• Initiate rapid, organized care for severe sepsis.

• Evaluate in-house data for recognizing and caring for severe sepsis patients.

• Initiate a performance improvement program, and improve outcomes for patients with severe sepsis.

Participants also have access to useful Web-based tools, such as a severe sepsis screener and a severe sepsis tracker for small hospitals, both of which help to ensure that proper protocols are followed, and that data are tracked.

A severe sepsis protocol for emergency management in small, referring hospitals states that whenever possible, nine steps should be completed within 2 hours for patients with infection, systemic inflammatory response syndrome, and dysfunction of one or more organs. The steps are, if possible:

• Draw blood for serum lactate measurement.

• Draw two sets of blood cultures – before antibiotics are initiated, if possible; however, do not delay antibiotics for the sake of completing this step.

• Start two peripheral intravenous lines (use 18 gauge or larger).

• Initiate broad-spectrum antibiotics as soon as possible.

• Give 2 L of normal saline solution or lactated Ringer’s solution, wide open.

• Draw blood for a complete blood count with a differential, basic chemistry panel if this has not already been done.

• Administer supplemental oxygen to maintain oxygen saturation measured by pulse oximeter above 90%.

• Initiate norepinephrine or dopamine if shock is present. This maintains a mean arterial pressure of 65 mm Hg or greater. Continue intravenous crystalloid at 250 mL/hr.

• Transfer the patient if serum lactate is 4 mmol/L or greater, if systolic blood pressure remains below 90 mm Hg, or if mean arterial pressure is less than 60 mm Hg after 2 L of crystalloid. Place a central venous catheter only if this can be accomplished without delaying transfer.

Following this protocol and using the tools available through the project is leading to dramatic improvements in outcomes. At one hospital, for example, a review of 67 charts from 2009 and 2010 revealed that of 28 cases that met criteria for sepsis, none was identified as such.

Since the hospital entered the project, an additional 61 patients screened positive. Of those, 59 had the severe sepsis tracker completed, 56 had blood cultures drawn prior to administration of broad-spectrum antibiotics, and 57 received broad-spectrum antibiotics within 1 hour of presentation.

Additionally, 22 of the 59 patients for whom the severe sepsis tracker was completed had hypotension, and 18 of those received a 20-mL/kg fluid bolus within 2 hours of diagnosis.

Overall, 54 of the 59 patients who had the severe sepsis tracker completed survived their hospitalization. Only 2 of 35 patients with severe sepsis (5.7%) required transfer to a larger facility because of deterioration in their condition, compared with 7 of 28 patients (25%) in the group from the 2009-2010 preproject chart review.

Numerous states across the United States, especially in the Midwest and Northwest, have rural populations of less than 86 per square mile, similar to Kansas, with 1.330 small facilities serving rural populations located many miles from the nearest referral hospital, and could benefit from this approach to sepsis resuscitation, Dr. Simpson said.

The need for attention to the problem of sepsis is apparent not only based on the high mortality rates, but also in the outcomes of focus group research showing that only 42% of responding physicians from rural settings consider themselves to be "very knowledgeable" about sepsis diagnosis, treatments, and complications; while the same percentage consider themselves "not too knowledgeable," 4% say they are not at all knowledgeable, and 12% say they aren’t sure how knowledgeable they are, he said.

Similarly, only 2% of respondents said they are extremely knowledgeable about the differences among uncomplicated sepsis, severe sepsis, and septic shock; 27% said they are very knowledgeable; 61% said they are not too knowledgeable; 4% said they are not at all knowledgeable; and 6% said they are unsure how knowledgeable they are.

Few respondents were familiar with the Early Goal-Directed Therapy protocol or the Surviving Sepsis Campaign, and most admitted that the likelihood of missed sepsis diagnoses is high at their institution.

Most (about 85%) agreed that additional training would be extremely beneficial.

Although several challenges and hurdles exist with respect to improving sepsis outcomes in rural settings, including staffing issues, the lack of recognition of the extent of the problem, and the fact that sepsis is not yet a Joint Commission core measure, the results thus far of the Kansas Sepsis Project suggest positive change is within reach, Dr. Simpson said.

For more information about the project, click here.

The Kansas Sepsis Project is supported by the One Breath Foundation in the form of the Third Eli Lilly Distinguished Scholar in Critical Care Medicine Award. Dr. Simpson reported having no relevant financial disclosures.

ATLANTA – A Kansas-based program that aims to improve sepsis-related outcomes in rural hospital settings is proving successful and could serve as a model for rural hospitals nationwide.

The program, known as "The Kansas Sepsis Project," was initiated by the Midwest Critical Care Collaborative, and focuses on a simplified approach to sepsis resuscitation for the purpose of reducing sepsis mortality, Dr. Steven Q. Simpson reported at the annual meeting of the American College of Chest Physicians.

Sepsis affects more than 10,000 Kansans each year, and the sepsis-related mortality rate is 30%-50% in most Kansas hospitals, which exceeds the mortality rate associated with acute myocardial infarction, said Dr. Simpson of the University of Kansas Medical Center, Kansas City.

One goal of the sepsis project is to reduce that rate by 10% by the end of 2015.

According to the Midwest Critical Care Collaborative website, a 20% reduction is possible if specific plans for recognition and treatment as outlined by the project are put in place.

The project, which is open to any interested facility including those not based in Kansas, involves baseline surveys, live and online training, ongoing data collection and analysis, formation of performance improvement planning based on those analyses, and – hopefully – changed behavior and reduced sepsis mortality, said Dr. Simpson.

The website states that participants learn to:

• Recognize cardinal features of severe sepsis.

• Initiate rapid, organized care for severe sepsis.

• Evaluate in-house data for recognizing and caring for severe sepsis patients.

• Initiate a performance improvement program, and improve outcomes for patients with severe sepsis.

Participants also have access to useful Web-based tools, such as a severe sepsis screener and a severe sepsis tracker for small hospitals, both of which help to ensure that proper protocols are followed, and that data are tracked.

A severe sepsis protocol for emergency management in small, referring hospitals states that whenever possible, nine steps should be completed within 2 hours for patients with infection, systemic inflammatory response syndrome, and dysfunction of one or more organs. The steps are, if possible:

• Draw blood for serum lactate measurement.

• Draw two sets of blood cultures – before antibiotics are initiated, if possible; however, do not delay antibiotics for the sake of completing this step.

• Start two peripheral intravenous lines (use 18 gauge or larger).

• Initiate broad-spectrum antibiotics as soon as possible.

• Give 2 L of normal saline solution or lactated Ringer’s solution, wide open.

• Draw blood for a complete blood count with a differential, basic chemistry panel if this has not already been done.

• Administer supplemental oxygen to maintain oxygen saturation measured by pulse oximeter above 90%.

• Initiate norepinephrine or dopamine if shock is present. This maintains a mean arterial pressure of 65 mm Hg or greater. Continue intravenous crystalloid at 250 mL/hr.

• Transfer the patient if serum lactate is 4 mmol/L or greater, if systolic blood pressure remains below 90 mm Hg, or if mean arterial pressure is less than 60 mm Hg after 2 L of crystalloid. Place a central venous catheter only if this can be accomplished without delaying transfer.

Following this protocol and using the tools available through the project is leading to dramatic improvements in outcomes. At one hospital, for example, a review of 67 charts from 2009 and 2010 revealed that of 28 cases that met criteria for sepsis, none was identified as such.

Since the hospital entered the project, an additional 61 patients screened positive. Of those, 59 had the severe sepsis tracker completed, 56 had blood cultures drawn prior to administration of broad-spectrum antibiotics, and 57 received broad-spectrum antibiotics within 1 hour of presentation.

Additionally, 22 of the 59 patients for whom the severe sepsis tracker was completed had hypotension, and 18 of those received a 20-mL/kg fluid bolus within 2 hours of diagnosis.

Overall, 54 of the 59 patients who had the severe sepsis tracker completed survived their hospitalization. Only 2 of 35 patients with severe sepsis (5.7%) required transfer to a larger facility because of deterioration in their condition, compared with 7 of 28 patients (25%) in the group from the 2009-2010 preproject chart review.

Numerous states across the United States, especially in the Midwest and Northwest, have rural populations of less than 86 per square mile, similar to Kansas, with 1.330 small facilities serving rural populations located many miles from the nearest referral hospital, and could benefit from this approach to sepsis resuscitation, Dr. Simpson said.

The need for attention to the problem of sepsis is apparent not only based on the high mortality rates, but also in the outcomes of focus group research showing that only 42% of responding physicians from rural settings consider themselves to be "very knowledgeable" about sepsis diagnosis, treatments, and complications; while the same percentage consider themselves "not too knowledgeable," 4% say they are not at all knowledgeable, and 12% say they aren’t sure how knowledgeable they are, he said.

Similarly, only 2% of respondents said they are extremely knowledgeable about the differences among uncomplicated sepsis, severe sepsis, and septic shock; 27% said they are very knowledgeable; 61% said they are not too knowledgeable; 4% said they are not at all knowledgeable; and 6% said they are unsure how knowledgeable they are.

Few respondents were familiar with the Early Goal-Directed Therapy protocol or the Surviving Sepsis Campaign, and most admitted that the likelihood of missed sepsis diagnoses is high at their institution.

Most (about 85%) agreed that additional training would be extremely beneficial.

Although several challenges and hurdles exist with respect to improving sepsis outcomes in rural settings, including staffing issues, the lack of recognition of the extent of the problem, and the fact that sepsis is not yet a Joint Commission core measure, the results thus far of the Kansas Sepsis Project suggest positive change is within reach, Dr. Simpson said.

For more information about the project, click here.

The Kansas Sepsis Project is supported by the One Breath Foundation in the form of the Third Eli Lilly Distinguished Scholar in Critical Care Medicine Award. Dr. Simpson reported having no relevant financial disclosures.

ATLANTA – A Kansas-based program that aims to improve sepsis-related outcomes in rural hospital settings is proving successful and could serve as a model for rural hospitals nationwide.

The program, known as "The Kansas Sepsis Project," was initiated by the Midwest Critical Care Collaborative, and focuses on a simplified approach to sepsis resuscitation for the purpose of reducing sepsis mortality, Dr. Steven Q. Simpson reported at the annual meeting of the American College of Chest Physicians.

Sepsis affects more than 10,000 Kansans each year, and the sepsis-related mortality rate is 30%-50% in most Kansas hospitals, which exceeds the mortality rate associated with acute myocardial infarction, said Dr. Simpson of the University of Kansas Medical Center, Kansas City.

One goal of the sepsis project is to reduce that rate by 10% by the end of 2015.

According to the Midwest Critical Care Collaborative website, a 20% reduction is possible if specific plans for recognition and treatment as outlined by the project are put in place.

The project, which is open to any interested facility including those not based in Kansas, involves baseline surveys, live and online training, ongoing data collection and analysis, formation of performance improvement planning based on those analyses, and – hopefully – changed behavior and reduced sepsis mortality, said Dr. Simpson.

The website states that participants learn to:

• Recognize cardinal features of severe sepsis.

• Initiate rapid, organized care for severe sepsis.

• Evaluate in-house data for recognizing and caring for severe sepsis patients.

• Initiate a performance improvement program, and improve outcomes for patients with severe sepsis.

Participants also have access to useful Web-based tools, such as a severe sepsis screener and a severe sepsis tracker for small hospitals, both of which help to ensure that proper protocols are followed, and that data are tracked.

A severe sepsis protocol for emergency management in small, referring hospitals states that whenever possible, nine steps should be completed within 2 hours for patients with infection, systemic inflammatory response syndrome, and dysfunction of one or more organs. The steps are, if possible:

• Draw blood for serum lactate measurement.

• Draw two sets of blood cultures – before antibiotics are initiated, if possible; however, do not delay antibiotics for the sake of completing this step.

• Start two peripheral intravenous lines (use 18 gauge or larger).

• Initiate broad-spectrum antibiotics as soon as possible.

• Give 2 L of normal saline solution or lactated Ringer’s solution, wide open.

• Draw blood for a complete blood count with a differential, basic chemistry panel if this has not already been done.

• Administer supplemental oxygen to maintain oxygen saturation measured by pulse oximeter above 90%.

• Initiate norepinephrine or dopamine if shock is present. This maintains a mean arterial pressure of 65 mm Hg or greater. Continue intravenous crystalloid at 250 mL/hr.

• Transfer the patient if serum lactate is 4 mmol/L or greater, if systolic blood pressure remains below 90 mm Hg, or if mean arterial pressure is less than 60 mm Hg after 2 L of crystalloid. Place a central venous catheter only if this can be accomplished without delaying transfer.

Following this protocol and using the tools available through the project is leading to dramatic improvements in outcomes. At one hospital, for example, a review of 67 charts from 2009 and 2010 revealed that of 28 cases that met criteria for sepsis, none was identified as such.

Since the hospital entered the project, an additional 61 patients screened positive. Of those, 59 had the severe sepsis tracker completed, 56 had blood cultures drawn prior to administration of broad-spectrum antibiotics, and 57 received broad-spectrum antibiotics within 1 hour of presentation.

Additionally, 22 of the 59 patients for whom the severe sepsis tracker was completed had hypotension, and 18 of those received a 20-mL/kg fluid bolus within 2 hours of diagnosis.

Overall, 54 of the 59 patients who had the severe sepsis tracker completed survived their hospitalization. Only 2 of 35 patients with severe sepsis (5.7%) required transfer to a larger facility because of deterioration in their condition, compared with 7 of 28 patients (25%) in the group from the 2009-2010 preproject chart review.

Numerous states across the United States, especially in the Midwest and Northwest, have rural populations of less than 86 per square mile, similar to Kansas, with 1.330 small facilities serving rural populations located many miles from the nearest referral hospital, and could benefit from this approach to sepsis resuscitation, Dr. Simpson said.

The need for attention to the problem of sepsis is apparent not only based on the high mortality rates, but also in the outcomes of focus group research showing that only 42% of responding physicians from rural settings consider themselves to be "very knowledgeable" about sepsis diagnosis, treatments, and complications; while the same percentage consider themselves "not too knowledgeable," 4% say they are not at all knowledgeable, and 12% say they aren’t sure how knowledgeable they are, he said.

Similarly, only 2% of respondents said they are extremely knowledgeable about the differences among uncomplicated sepsis, severe sepsis, and septic shock; 27% said they are very knowledgeable; 61% said they are not too knowledgeable; 4% said they are not at all knowledgeable; and 6% said they are unsure how knowledgeable they are.

Few respondents were familiar with the Early Goal-Directed Therapy protocol or the Surviving Sepsis Campaign, and most admitted that the likelihood of missed sepsis diagnoses is high at their institution.

Most (about 85%) agreed that additional training would be extremely beneficial.

Although several challenges and hurdles exist with respect to improving sepsis outcomes in rural settings, including staffing issues, the lack of recognition of the extent of the problem, and the fact that sepsis is not yet a Joint Commission core measure, the results thus far of the Kansas Sepsis Project suggest positive change is within reach, Dr. Simpson said.

For more information about the project, click here.

The Kansas Sepsis Project is supported by the One Breath Foundation in the form of the Third Eli Lilly Distinguished Scholar in Critical Care Medicine Award. Dr. Simpson reported having no relevant financial disclosures.

SAN ANTONIO – Vigorous aerobic exercise performed for 20 or 40 minutes, 5 days per week, improved fitness and was associated with dose-dependent benefits on insulin resistance and general and visceral adiposity in a randomized controlled trial involving 222 children who were overweight or obese and sedentary.

The intensity of the exercise appeared to be the most important factor for improving aerobic fitness, but volume of exercise was important for reducing adiposity and diabetes risk, Catherine L. Davis, Ph.D., reported at the annual meeting of the Obesity Society.

iStockphoto.com

Fitness, as measured using the adjusted mean difference in peak VO₂, was similar for 73 children randomized to 40 minutes of daily exercise (the high-dose exercise group) and 71 children randomized to 20 minutes of daily exercise (the low-dose group). Fitness was significantly greater for exercise groups compared with 78 controls. The adjusted mean difference in peak VO₂ was 2.4 mL/kg per minute from baseline to 13-weeks’ follow-up for both groups vs. the control group, said Dr. Davis of the Medical College of Georgia, Augusta.

Changes in body fat were measured using dual x-ray absorptiometry, and changes in visceral fat were measured using magnetic resonance imaging. The adjusted mean differences were -1.4% for the high-dose exercise group and -0.8% for the low-dose exercise group compared with controls. For visceral fat, the differences were -3.9% and -2.8%, respectively.

Reductions in the insulin area under the curve were measured using an oral glucose tolerance test. The adjusted mean difference was -3.56 x 10³ microU/mL for the high-dose exercise group and -2.96 x 10³ microU/mL for the low-dose exercise group compared with controls. There were no differences in outcomes based on sex or race.

The presentation of the findings coincided with their publication (JAMA 2012;308:1103-12).

Children in the study were aged 7-11 years (mean of 9.4 years) with an average body mass index of 26. Most (85%) were obese and 28% had prediabetes. The students were recruited from 15 public schools between 2003 and 2006, and were randomized to the high-dose or low-dose exercise groups or to a control group, Dr. Davis said. Six cohorts of 30-40 students participated during the study period.

Both the high- and low-dose groups exercised during an after-school program 5 days each week; exercise was vigorous, but game based, with an emphasis on intensity, fun, and safety rather than competition or skill enhancement. Average daily heart rate was calculated, and students earned bonus points for achieving a rate above 150 beats per minute. These points were used to "purchase" various prizes.

The control group did not participate in an after-school program but met monthly for a "lifestyle class," mainly for the purpose of maintaining contact for follow-up.

One-third of elementary school students in the United States are either overweight or obese, Dr. Davis said. The risk of diabetes in this population has increased as a result – often developing by puberty, with potentially dire consequences for long-term health. Prior to this study, dose-response data with respect to physical activity among children had been lacking.

"Even just 20 minutes of vigorous physical activity on a daily basis makes a big difference after just a few months," she said.

Recent data suggesting a benefit of such activity on cognition and math achievement also could convince schools to make efforts to offer daily exercise for children, she added.

This study was supported by grants from the National Institutes of Health and the Salvador de Madariaga Program of the Spanish Ministry of Education and Science. Dr. Davis and her colleagues reported having no conflicts of interest.

SAN ANTONIO – Vigorous aerobic exercise performed for 20 or 40 minutes, 5 days per week, improved fitness and was associated with dose-dependent benefits on insulin resistance and general and visceral adiposity in a randomized controlled trial involving 222 children who were overweight or obese and sedentary.

The intensity of the exercise appeared to be the most important factor for improving aerobic fitness, but volume of exercise was important for reducing adiposity and diabetes risk, Catherine L. Davis, Ph.D., reported at the annual meeting of the Obesity Society.

iStockphoto.com

Fitness, as measured using the adjusted mean difference in peak VO₂, was similar for 73 children randomized to 40 minutes of daily exercise (the high-dose exercise group) and 71 children randomized to 20 minutes of daily exercise (the low-dose group). Fitness was significantly greater for exercise groups compared with 78 controls. The adjusted mean difference in peak VO₂ was 2.4 mL/kg per minute from baseline to 13-weeks’ follow-up for both groups vs. the control group, said Dr. Davis of the Medical College of Georgia, Augusta.

Changes in body fat were measured using dual x-ray absorptiometry, and changes in visceral fat were measured using magnetic resonance imaging. The adjusted mean differences were -1.4% for the high-dose exercise group and -0.8% for the low-dose exercise group compared with controls. For visceral fat, the differences were -3.9% and -2.8%, respectively.

Reductions in the insulin area under the curve were measured using an oral glucose tolerance test. The adjusted mean difference was -3.56 x 10³ microU/mL for the high-dose exercise group and -2.96 x 10³ microU/mL for the low-dose exercise group compared with controls. There were no differences in outcomes based on sex or race.

The presentation of the findings coincided with their publication (JAMA 2012;308:1103-12).

Children in the study were aged 7-11 years (mean of 9.4 years) with an average body mass index of 26. Most (85%) were obese and 28% had prediabetes. The students were recruited from 15 public schools between 2003 and 2006, and were randomized to the high-dose or low-dose exercise groups or to a control group, Dr. Davis said. Six cohorts of 30-40 students participated during the study period.

Both the high- and low-dose groups exercised during an after-school program 5 days each week; exercise was vigorous, but game based, with an emphasis on intensity, fun, and safety rather than competition or skill enhancement. Average daily heart rate was calculated, and students earned bonus points for achieving a rate above 150 beats per minute. These points were used to "purchase" various prizes.

The control group did not participate in an after-school program but met monthly for a "lifestyle class," mainly for the purpose of maintaining contact for follow-up.

One-third of elementary school students in the United States are either overweight or obese, Dr. Davis said. The risk of diabetes in this population has increased as a result – often developing by puberty, with potentially dire consequences for long-term health. Prior to this study, dose-response data with respect to physical activity among children had been lacking.

"Even just 20 minutes of vigorous physical activity on a daily basis makes a big difference after just a few months," she said.

Recent data suggesting a benefit of such activity on cognition and math achievement also could convince schools to make efforts to offer daily exercise for children, she added.

This study was supported by grants from the National Institutes of Health and the Salvador de Madariaga Program of the Spanish Ministry of Education and Science. Dr. Davis and her colleagues reported having no conflicts of interest.

SAN ANTONIO – Vigorous aerobic exercise performed for 20 or 40 minutes, 5 days per week, improved fitness and was associated with dose-dependent benefits on insulin resistance and general and visceral adiposity in a randomized controlled trial involving 222 children who were overweight or obese and sedentary.

The intensity of the exercise appeared to be the most important factor for improving aerobic fitness, but volume of exercise was important for reducing adiposity and diabetes risk, Catherine L. Davis, Ph.D., reported at the annual meeting of the Obesity Society.

iStockphoto.com

Fitness, as measured using the adjusted mean difference in peak VO₂, was similar for 73 children randomized to 40 minutes of daily exercise (the high-dose exercise group) and 71 children randomized to 20 minutes of daily exercise (the low-dose group). Fitness was significantly greater for exercise groups compared with 78 controls. The adjusted mean difference in peak VO₂ was 2.4 mL/kg per minute from baseline to 13-weeks’ follow-up for both groups vs. the control group, said Dr. Davis of the Medical College of Georgia, Augusta.

Changes in body fat were measured using dual x-ray absorptiometry, and changes in visceral fat were measured using magnetic resonance imaging. The adjusted mean differences were -1.4% for the high-dose exercise group and -0.8% for the low-dose exercise group compared with controls. For visceral fat, the differences were -3.9% and -2.8%, respectively.

Reductions in the insulin area under the curve were measured using an oral glucose tolerance test. The adjusted mean difference was -3.56 x 10³ microU/mL for the high-dose exercise group and -2.96 x 10³ microU/mL for the low-dose exercise group compared with controls. There were no differences in outcomes based on sex or race.

The presentation of the findings coincided with their publication (JAMA 2012;308:1103-12).

Children in the study were aged 7-11 years (mean of 9.4 years) with an average body mass index of 26. Most (85%) were obese and 28% had prediabetes. The students were recruited from 15 public schools between 2003 and 2006, and were randomized to the high-dose or low-dose exercise groups or to a control group, Dr. Davis said. Six cohorts of 30-40 students participated during the study period.

Both the high- and low-dose groups exercised during an after-school program 5 days each week; exercise was vigorous, but game based, with an emphasis on intensity, fun, and safety rather than competition or skill enhancement. Average daily heart rate was calculated, and students earned bonus points for achieving a rate above 150 beats per minute. These points were used to "purchase" various prizes.

The control group did not participate in an after-school program but met monthly for a "lifestyle class," mainly for the purpose of maintaining contact for follow-up.

One-third of elementary school students in the United States are either overweight or obese, Dr. Davis said. The risk of diabetes in this population has increased as a result – often developing by puberty, with potentially dire consequences for long-term health. Prior to this study, dose-response data with respect to physical activity among children had been lacking.

"Even just 20 minutes of vigorous physical activity on a daily basis makes a big difference after just a few months," she said.

Recent data suggesting a benefit of such activity on cognition and math achievement also could convince schools to make efforts to offer daily exercise for children, she added.

This study was supported by grants from the National Institutes of Health and the Salvador de Madariaga Program of the Spanish Ministry of Education and Science. Dr. Davis and her colleagues reported having no conflicts of interest.

WASHINGTON – Exposure to anti-tumor necrosis factor therapy does not appear to be associated with a greater short-term risk of ischemic stroke in patients with rheumatoid arthritis when compared with exposure to nonbiologic disease-modifying antirheumatic drug therapy, according to findings from the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis.

Of 130 verified incident ischemic cerebrovascular accidents that occurred among participants in that large prospective cohort study of RA patients, 109 occurred in 11,642 patients treated with anti–tumor necrosis factor drugs (anti-TNFs) for an incidence rate of 178/100,000 person-years, and 21 occurred in 3,271 patients in a comparator group of biologic-naive patients who had been treated with only nonbiologic disease-modifying antirheumatic drugs (nbDMARDs) for an incident rate of 175/100,000 person-years, Dr. Audrey S. Low reported at the annual meeting of the American College of Rheumatology.

The incident rates did not differ significantly, and no association was seen between ever exposure to anti-TNF drugs and ischemic stroke risk after adjustment for confounders using a propensity score based on age, sex, ethnicity, body mass index, disease activity score, disease duration, Health Assessment Questionnaire score, prior nbDMARD use, steroid use at baseline, year of entry to the study, smoking, baseline drugs, and history of cancer, hypertension, ischemic heart disease, diabetes, depression, and chronic lung disease (hazard ratio, 0.88), said Dr. Low of the University of Manchester (England).

Patients in the British Society for Rheumatology Biologics Register–Rheumatoid Arthritis (BSRBR-RA) were recruited during 2001-2008 and were followed semiannually for 3 years, then annually thereafter. All serious adverse events, such as stroke, and all drug therapy were reported. Events reported through Oct. 21, 2010, were included in this analysis.

The investigators also linked study subjects to the national death register and collected information from medical records; a concerted effort was made to classify stroke types.

The anti-TNF and nbDMARD groups differed with respect to several factors: The anti-TNF cohort was younger, included more women, and had higher disease activity, longer disease duration, and higher levels of disability. That cohort also used more DMARDs, more steroids, and more nonsteroidal cyclo-oxygenase-2 (COX-2) inhibitors. However, the rates of hypertension and diabetes were similar in the anti-TNF and nbDMARD cohorts.

This study is among the largest to show that anti-TNF therapy does not increase stroke risk in RA patients, when compared with nbDMARDS, Dr. Low said.

"We know that patients with RA are at risk of increased cardiovascular morbidity and mortality, and that includes stroke," she said, noting that several other observational studies and meta-analyses have demonstrated an overall increase in that risk.

However, outcomes have varied in studies comparing anti-TNF–treated RA patients and controls, with some showing as much as a 60% increase in ischemic stroke risk and others demonstrating a 30% reduction in risk.

In this large cohort of European patients with RA, no association was seen between the short-term risk of ischemic stroke and the use of anti-TNF therapy, she said, adding that additional follow-up is needed to assess risk over time.

Dr. Low reported having no relevant financial disclosures.

WASHINGTON – Exposure to anti-tumor necrosis factor therapy does not appear to be associated with a greater short-term risk of ischemic stroke in patients with rheumatoid arthritis when compared with exposure to nonbiologic disease-modifying antirheumatic drug therapy, according to findings from the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis.

Of 130 verified incident ischemic cerebrovascular accidents that occurred among participants in that large prospective cohort study of RA patients, 109 occurred in 11,642 patients treated with anti–tumor necrosis factor drugs (anti-TNFs) for an incidence rate of 178/100,000 person-years, and 21 occurred in 3,271 patients in a comparator group of biologic-naive patients who had been treated with only nonbiologic disease-modifying antirheumatic drugs (nbDMARDs) for an incident rate of 175/100,000 person-years, Dr. Audrey S. Low reported at the annual meeting of the American College of Rheumatology.

The incident rates did not differ significantly, and no association was seen between ever exposure to anti-TNF drugs and ischemic stroke risk after adjustment for confounders using a propensity score based on age, sex, ethnicity, body mass index, disease activity score, disease duration, Health Assessment Questionnaire score, prior nbDMARD use, steroid use at baseline, year of entry to the study, smoking, baseline drugs, and history of cancer, hypertension, ischemic heart disease, diabetes, depression, and chronic lung disease (hazard ratio, 0.88), said Dr. Low of the University of Manchester (England).

Patients in the British Society for Rheumatology Biologics Register–Rheumatoid Arthritis (BSRBR-RA) were recruited during 2001-2008 and were followed semiannually for 3 years, then annually thereafter. All serious adverse events, such as stroke, and all drug therapy were reported. Events reported through Oct. 21, 2010, were included in this analysis.

The investigators also linked study subjects to the national death register and collected information from medical records; a concerted effort was made to classify stroke types.

The anti-TNF and nbDMARD groups differed with respect to several factors: The anti-TNF cohort was younger, included more women, and had higher disease activity, longer disease duration, and higher levels of disability. That cohort also used more DMARDs, more steroids, and more nonsteroidal cyclo-oxygenase-2 (COX-2) inhibitors. However, the rates of hypertension and diabetes were similar in the anti-TNF and nbDMARD cohorts.

This study is among the largest to show that anti-TNF therapy does not increase stroke risk in RA patients, when compared with nbDMARDS, Dr. Low said.

"We know that patients with RA are at risk of increased cardiovascular morbidity and mortality, and that includes stroke," she said, noting that several other observational studies and meta-analyses have demonstrated an overall increase in that risk.

However, outcomes have varied in studies comparing anti-TNF–treated RA patients and controls, with some showing as much as a 60% increase in ischemic stroke risk and others demonstrating a 30% reduction in risk.

In this large cohort of European patients with RA, no association was seen between the short-term risk of ischemic stroke and the use of anti-TNF therapy, she said, adding that additional follow-up is needed to assess risk over time.

Dr. Low reported having no relevant financial disclosures.

WASHINGTON – Exposure to anti-tumor necrosis factor therapy does not appear to be associated with a greater short-term risk of ischemic stroke in patients with rheumatoid arthritis when compared with exposure to nonbiologic disease-modifying antirheumatic drug therapy, according to findings from the British Society for Rheumatology Biologics Register-Rheumatoid Arthritis.

Of 130 verified incident ischemic cerebrovascular accidents that occurred among participants in that large prospective cohort study of RA patients, 109 occurred in 11,642 patients treated with anti–tumor necrosis factor drugs (anti-TNFs) for an incidence rate of 178/100,000 person-years, and 21 occurred in 3,271 patients in a comparator group of biologic-naive patients who had been treated with only nonbiologic disease-modifying antirheumatic drugs (nbDMARDs) for an incident rate of 175/100,000 person-years, Dr. Audrey S. Low reported at the annual meeting of the American College of Rheumatology.

The incident rates did not differ significantly, and no association was seen between ever exposure to anti-TNF drugs and ischemic stroke risk after adjustment for confounders using a propensity score based on age, sex, ethnicity, body mass index, disease activity score, disease duration, Health Assessment Questionnaire score, prior nbDMARD use, steroid use at baseline, year of entry to the study, smoking, baseline drugs, and history of cancer, hypertension, ischemic heart disease, diabetes, depression, and chronic lung disease (hazard ratio, 0.88), said Dr. Low of the University of Manchester (England).

Patients in the British Society for Rheumatology Biologics Register–Rheumatoid Arthritis (BSRBR-RA) were recruited during 2001-2008 and were followed semiannually for 3 years, then annually thereafter. All serious adverse events, such as stroke, and all drug therapy were reported. Events reported through Oct. 21, 2010, were included in this analysis.

The investigators also linked study subjects to the national death register and collected information from medical records; a concerted effort was made to classify stroke types.

The anti-TNF and nbDMARD groups differed with respect to several factors: The anti-TNF cohort was younger, included more women, and had higher disease activity, longer disease duration, and higher levels of disability. That cohort also used more DMARDs, more steroids, and more nonsteroidal cyclo-oxygenase-2 (COX-2) inhibitors. However, the rates of hypertension and diabetes were similar in the anti-TNF and nbDMARD cohorts.

This study is among the largest to show that anti-TNF therapy does not increase stroke risk in RA patients, when compared with nbDMARDS, Dr. Low said.

"We know that patients with RA are at risk of increased cardiovascular morbidity and mortality, and that includes stroke," she said, noting that several other observational studies and meta-analyses have demonstrated an overall increase in that risk.

However, outcomes have varied in studies comparing anti-TNF–treated RA patients and controls, with some showing as much as a 60% increase in ischemic stroke risk and others demonstrating a 30% reduction in risk.

In this large cohort of European patients with RA, no association was seen between the short-term risk of ischemic stroke and the use of anti-TNF therapy, she said, adding that additional follow-up is needed to assess risk over time.

Dr. Low reported having no relevant financial disclosures.

ATLANTA – Indacaterol significantly improves bronchodilation and health status in patients with chronic obstructive pulmonary disease, and is safe and well tolerated, according to findings from studies presented at the annual meeting of the American College of Chest Physicians.

In a pooled analysis of efficacy and safety data from two randomized controlled studies, the inhaled long-acting beta₂-agonist bronchodilator given at the approved dose of 75 mcg daily was found to be of benefit regardless of age, sex, smoking status, or severity of airflow limitation. In another analysis of pooled data, treatment was shown to have an acceptable cardiovascular and cerebrovascular safety profile.

The efficacy analysis included 640 patients from two identically designed studies who were randomized to receive indacaterol or placebo for 12 weeks. Trough (24 hours post dose) forced expiratory volume in 1 second (FEV₁) improved by least-squares mean differences of 150 and 110 mL among men and women, respectively; by 110 and 150 mL among those under age 65 and those aged 65 or older; by 150 and 110 mL among those with moderate and severe airflow limitation; and by 140 and 130 mL in ex-smokers and current smokers, Dr. Thomas Siler of Midwest Chest Consultants in St. Charles, Mo., reported.

Health status scores, as measured using the St. George’s Respiratory Questionnaire, improved similarly in men and women (by 3.8 and 3.7 units, respectively), and also improved in all of the other groups. Improvement was greater, however, in those aged 65 years and older (by 4.5 units vs. 3.3 units in those under age 65), those with severe airflow limitation (by 4.6 units vs. 3.3 units in those with moderate airflow limitation), and in ex-smokers (by 4.1 vs. 3.5 units in current smokers).

Adverse events occurred in 44%-57% of patients receiving indacaterol and in 40%-48% of patients receiving placebo. More adverse events in both groups occurred in older patients, women, those with moderate disease, and ex-smokers.

Patients in this study had a mean age of 63 years, and a mean post-albuterol FEV₁ of 54% predicted. About 40% were receiving inhaled corticosteroids.

The findings suggest that indacaterol can be successfully used to treat a range of COPD patients, Dr. Siler concluded. Treatment can be expected to lead to "substantial and worthwhile improvements in bronchodilation and health status," he added.

According to findings from a separate analysis of pooled data from nearly 2,500 patients, these improvements come without an increase in the risk of cerebro- and cardiovascular adverse events (CCV AEs).

The overall frequency of CCV AEs was similar in 449 patients treated for up to 3 months and 2,012 control patients who received placebo (2.0% and 2.58%, respectively), and no type of CCV AE occurred in more than 2 patients in the active treatment group, Dr. James Donohue reported.

Serious CCV AEs occurred in 2 patients in the treatment group and 13 in the placebo group, and an Antiplatelet Trialists’ Collaboration (APTC) event (a cerebrovascular accident not believed to be related to study treatment) occurred in 1 patient in the treatment group, compared with 8 patients in the control group, said Dr. Donohue of the University of North Carolina, Chapel Hill.

The overall frequency of patients with CCV AEs in a 6-month study population ranged from 3.3% to 5.8%, and no dose-response relationship was seen between the 75-mcg dose and up to 600 mcg daily for CCV AEs.

No deaths were reported in those receiving indacaterol 75.

These findings, which used pooled data from previous studies and a database of U.S. and Canadian patients, indicate that indacaterol given at the 75-mcg dose has an acceptable CCV safety profile in patients with moderate to severe COPD, Dr. Donohue said.

When considered in the context of the efficacy data, the findings should be very reassuring to clinicians, he concluded.

The studies included in the safety analysis were sponsored by Novartis. Dr. Donohue and Dr. Siler reported financial relationships with Novartis, which makes indacaterol, as well as with other industry companies. Dr. Donohue reported receiving fees for consulting and/or serving on speakers bureaus or advisory committees for Novartis, GSK, Boehringer-Ingelheim, and other companies. Dr. Siler reported receiving grant monies from GSK, Novartis, Boehringer-Ingelheim, and other companies. He also reported receiving fees for consulting, serving on speakers bureaus, and/or serving on advisory committees for Boehringer-Ingelheim, AstraZeneca, and Forest Research Institute.

ATLANTA – Indacaterol significantly improves bronchodilation and health status in patients with chronic obstructive pulmonary disease, and is safe and well tolerated, according to findings from studies presented at the annual meeting of the American College of Chest Physicians.

In a pooled analysis of efficacy and safety data from two randomized controlled studies, the inhaled long-acting beta₂-agonist bronchodilator given at the approved dose of 75 mcg daily was found to be of benefit regardless of age, sex, smoking status, or severity of airflow limitation. In another analysis of pooled data, treatment was shown to have an acceptable cardiovascular and cerebrovascular safety profile.

The efficacy analysis included 640 patients from two identically designed studies who were randomized to receive indacaterol or placebo for 12 weeks. Trough (24 hours post dose) forced expiratory volume in 1 second (FEV₁) improved by least-squares mean differences of 150 and 110 mL among men and women, respectively; by 110 and 150 mL among those under age 65 and those aged 65 or older; by 150 and 110 mL among those with moderate and severe airflow limitation; and by 140 and 130 mL in ex-smokers and current smokers, Dr. Thomas Siler of Midwest Chest Consultants in St. Charles, Mo., reported.

Health status scores, as measured using the St. George’s Respiratory Questionnaire, improved similarly in men and women (by 3.8 and 3.7 units, respectively), and also improved in all of the other groups. Improvement was greater, however, in those aged 65 years and older (by 4.5 units vs. 3.3 units in those under age 65), those with severe airflow limitation (by 4.6 units vs. 3.3 units in those with moderate airflow limitation), and in ex-smokers (by 4.1 vs. 3.5 units in current smokers).

Adverse events occurred in 44%-57% of patients receiving indacaterol and in 40%-48% of patients receiving placebo. More adverse events in both groups occurred in older patients, women, those with moderate disease, and ex-smokers.

Patients in this study had a mean age of 63 years, and a mean post-albuterol FEV₁ of 54% predicted. About 40% were receiving inhaled corticosteroids.

The findings suggest that indacaterol can be successfully used to treat a range of COPD patients, Dr. Siler concluded. Treatment can be expected to lead to "substantial and worthwhile improvements in bronchodilation and health status," he added.

According to findings from a separate analysis of pooled data from nearly 2,500 patients, these improvements come without an increase in the risk of cerebro- and cardiovascular adverse events (CCV AEs).

The overall frequency of CCV AEs was similar in 449 patients treated for up to 3 months and 2,012 control patients who received placebo (2.0% and 2.58%, respectively), and no type of CCV AE occurred in more than 2 patients in the active treatment group, Dr. James Donohue reported.

Serious CCV AEs occurred in 2 patients in the treatment group and 13 in the placebo group, and an Antiplatelet Trialists’ Collaboration (APTC) event (a cerebrovascular accident not believed to be related to study treatment) occurred in 1 patient in the treatment group, compared with 8 patients in the control group, said Dr. Donohue of the University of North Carolina, Chapel Hill.

The overall frequency of patients with CCV AEs in a 6-month study population ranged from 3.3% to 5.8%, and no dose-response relationship was seen between the 75-mcg dose and up to 600 mcg daily for CCV AEs.

No deaths were reported in those receiving indacaterol 75.

These findings, which used pooled data from previous studies and a database of U.S. and Canadian patients, indicate that indacaterol given at the 75-mcg dose has an acceptable CCV safety profile in patients with moderate to severe COPD, Dr. Donohue said.

When considered in the context of the efficacy data, the findings should be very reassuring to clinicians, he concluded.

The studies included in the safety analysis were sponsored by Novartis. Dr. Donohue and Dr. Siler reported financial relationships with Novartis, which makes indacaterol, as well as with other industry companies. Dr. Donohue reported receiving fees for consulting and/or serving on speakers bureaus or advisory committees for Novartis, GSK, Boehringer-Ingelheim, and other companies. Dr. Siler reported receiving grant monies from GSK, Novartis, Boehringer-Ingelheim, and other companies. He also reported receiving fees for consulting, serving on speakers bureaus, and/or serving on advisory committees for Boehringer-Ingelheim, AstraZeneca, and Forest Research Institute.

ATLANTA – Indacaterol significantly improves bronchodilation and health status in patients with chronic obstructive pulmonary disease, and is safe and well tolerated, according to findings from studies presented at the annual meeting of the American College of Chest Physicians.

In a pooled analysis of efficacy and safety data from two randomized controlled studies, the inhaled long-acting beta₂-agonist bronchodilator given at the approved dose of 75 mcg daily was found to be of benefit regardless of age, sex, smoking status, or severity of airflow limitation. In another analysis of pooled data, treatment was shown to have an acceptable cardiovascular and cerebrovascular safety profile.

The efficacy analysis included 640 patients from two identically designed studies who were randomized to receive indacaterol or placebo for 12 weeks. Trough (24 hours post dose) forced expiratory volume in 1 second (FEV₁) improved by least-squares mean differences of 150 and 110 mL among men and women, respectively; by 110 and 150 mL among those under age 65 and those aged 65 or older; by 150 and 110 mL among those with moderate and severe airflow limitation; and by 140 and 130 mL in ex-smokers and current smokers, Dr. Thomas Siler of Midwest Chest Consultants in St. Charles, Mo., reported.

Health status scores, as measured using the St. George’s Respiratory Questionnaire, improved similarly in men and women (by 3.8 and 3.7 units, respectively), and also improved in all of the other groups. Improvement was greater, however, in those aged 65 years and older (by 4.5 units vs. 3.3 units in those under age 65), those with severe airflow limitation (by 4.6 units vs. 3.3 units in those with moderate airflow limitation), and in ex-smokers (by 4.1 vs. 3.5 units in current smokers).

Adverse events occurred in 44%-57% of patients receiving indacaterol and in 40%-48% of patients receiving placebo. More adverse events in both groups occurred in older patients, women, those with moderate disease, and ex-smokers.

Patients in this study had a mean age of 63 years, and a mean post-albuterol FEV₁ of 54% predicted. About 40% were receiving inhaled corticosteroids.

The findings suggest that indacaterol can be successfully used to treat a range of COPD patients, Dr. Siler concluded. Treatment can be expected to lead to "substantial and worthwhile improvements in bronchodilation and health status," he added.

According to findings from a separate analysis of pooled data from nearly 2,500 patients, these improvements come without an increase in the risk of cerebro- and cardiovascular adverse events (CCV AEs).

The overall frequency of CCV AEs was similar in 449 patients treated for up to 3 months and 2,012 control patients who received placebo (2.0% and 2.58%, respectively), and no type of CCV AE occurred in more than 2 patients in the active treatment group, Dr. James Donohue reported.

Serious CCV AEs occurred in 2 patients in the treatment group and 13 in the placebo group, and an Antiplatelet Trialists’ Collaboration (APTC) event (a cerebrovascular accident not believed to be related to study treatment) occurred in 1 patient in the treatment group, compared with 8 patients in the control group, said Dr. Donohue of the University of North Carolina, Chapel Hill.

The overall frequency of patients with CCV AEs in a 6-month study population ranged from 3.3% to 5.8%, and no dose-response relationship was seen between the 75-mcg dose and up to 600 mcg daily for CCV AEs.

No deaths were reported in those receiving indacaterol 75.

These findings, which used pooled data from previous studies and a database of U.S. and Canadian patients, indicate that indacaterol given at the 75-mcg dose has an acceptable CCV safety profile in patients with moderate to severe COPD, Dr. Donohue said.

When considered in the context of the efficacy data, the findings should be very reassuring to clinicians, he concluded.

The studies included in the safety analysis were sponsored by Novartis. Dr. Donohue and Dr. Siler reported financial relationships with Novartis, which makes indacaterol, as well as with other industry companies. Dr. Donohue reported receiving fees for consulting and/or serving on speakers bureaus or advisory committees for Novartis, GSK, Boehringer-Ingelheim, and other companies. Dr. Siler reported receiving grant monies from GSK, Novartis, Boehringer-Ingelheim, and other companies. He also reported receiving fees for consulting, serving on speakers bureaus, and/or serving on advisory committees for Boehringer-Ingelheim, AstraZeneca, and Forest Research Institute.

WASHINGTON – Low bone mineral density and the presence of vertebral fractures in patients with rheumatoid arthritis not only signal the likely presence of osteoporosis but also appear to signal increased cardiovascular disease risk, according to findings from a cross-sectional study.*

The findings suggest that dual-energy x-ray absorptiometry (DEXA) scans commonly performed in rheumatoid arthritis (RA) patients to assess for osteoporosis could also serve as an assessment of cardiovascular disease risk, Dr. Ausaf Mohammad reported at the annual meeting of the American College of Rheumatology.

Of 603 patients from a convenience sample of adults who met 1987 ACR criteria for RA classification, 230 had at least one documented cardiovascular disease event, and those patients, compared with patients without a cardiovascular disease event, had significantly lower total hip and lumbar spine bone mineral density, and were four times as likely to have osteoporosis (60% vs. 15%) and twice as likely to have a vertebral fracture (24% vs. 12%), said Dr. Mohammad of Galway (Ireland) University Hospitals.

Low bone mineral density and the presence of vertebral fractures were independently associated with cardiovascular disease after adjustment for age, sex, smoking, hypertension, diabetes, and hypercholesterolemia. These measures outperformed traditional risk factors and RA disease activity scores for predicting cardiovascular disease.*

For example, the age- and sex-adjusted odds ratios for osteoporosis and vertebral fractures in those with cardiovascular disease were 2.70 and 2.67; the odds ratios for diabetes mellitus, smoking history, hypertension, hyperlipidemia, C-reactive protein, and Disease Activity Score (DAS-28) indicative of active RA were 1.61, 1.18, 1.58, 1.02, 1.73, and 1.63, respectively.

Patients in the RA cohort included 446 women and 157 men over age 40 years (mean, 56 years) who had a prior DEXA scan with vertebral fracture assessment available for analysis. The scans were evaluated by blinded musculoskeletal radiologists, and osteoporosis diagnoses were made using World Health Organization DEXA criteria; 32% of patients had osteoporosis by bone mineral density criteria, and 13% had one or more vertebral fractures on vertebral fracture assessment.

Cardiovascular events in the cohort included myocardial infarction in 45 patients, stent in 145, heart failure in 33, and stroke in 7.

The findings are of note given that traditional risk factors for cardiovascular disease tend to underperform in patients with RA, and that cardiovascular disease remains the leading cause of mortality in this population, Dr. Mohammad said.

"The risk of cardiovascular disease rises shortly after onset of arthritis, but does not precede it, and the risk appears similar to what is seen in non-RA subjects with diabetes and non-RA subjects who are 5-10 years older, so this tells us we are looking at a very high-risk population," he said.

However, despite a similar distribution in RA and non-RA patients, risk factors for cardiovascular disease "behave differently" in RA patients, and multiple studies have shown that methods for assessing risk, such as the Framingham risk score, underestimate risk in those with RA.

Indeed, the Framingham risk score did not differ significantly between those with and without cardiovascular disease events in the current study, Dr. Mohammad said, adding: "This poses a significant challenge. Therefore we need better markers and better prediction tools."

It appears, based on these findings, that bone mineral density could serve as such a marker, and that DEXA scans could be a good prediction tool, he said.

Since RA patients are also at increased risk for osteoporosis and fractures, many are already referred for DEXA scans.

"So DEXA may provide an opportunity to assess RA subjects at the time of osteoporosis for cardiovascular disease without the need for additional testing," he said.

Although this study has inherent limitations associated with its cross-sectional design, it does have several strengths, including the large cohort size and the fact that participating radiologists were blinded to patient status. Also, the findings are in keeping with those from multiple prior studies in non-RA populations, demonstrating strong associations between osteoporosis and cardiovascular disease, he added, noting that the findings underscore a need for interventions to reduce cardiovascular disease risk in RA patients with osteoporosis.

Dr. Mohammad reported having no relevant financial disclosures.

*Correction: 12/04/2012: An earlier version of this story misstated Dr. Mohammad's findings. 

WASHINGTON – Low bone mineral density and the presence of vertebral fractures in patients with rheumatoid arthritis not only signal the likely presence of osteoporosis but also appear to signal increased cardiovascular disease risk, according to findings from a cross-sectional study.*

The findings suggest that dual-energy x-ray absorptiometry (DEXA) scans commonly performed in rheumatoid arthritis (RA) patients to assess for osteoporosis could also serve as an assessment of cardiovascular disease risk, Dr. Ausaf Mohammad reported at the annual meeting of the American College of Rheumatology.

Of 603 patients from a convenience sample of adults who met 1987 ACR criteria for RA classification, 230 had at least one documented cardiovascular disease event, and those patients, compared with patients without a cardiovascular disease event, had significantly lower total hip and lumbar spine bone mineral density, and were four times as likely to have osteoporosis (60% vs. 15%) and twice as likely to have a vertebral fracture (24% vs. 12%), said Dr. Mohammad of Galway (Ireland) University Hospitals.

Low bone mineral density and the presence of vertebral fractures were independently associated with cardiovascular disease after adjustment for age, sex, smoking, hypertension, diabetes, and hypercholesterolemia. These measures outperformed traditional risk factors and RA disease activity scores for predicting cardiovascular disease.*

For example, the age- and sex-adjusted odds ratios for osteoporosis and vertebral fractures in those with cardiovascular disease were 2.70 and 2.67; the odds ratios for diabetes mellitus, smoking history, hypertension, hyperlipidemia, C-reactive protein, and Disease Activity Score (DAS-28) indicative of active RA were 1.61, 1.18, 1.58, 1.02, 1.73, and 1.63, respectively.

Patients in the RA cohort included 446 women and 157 men over age 40 years (mean, 56 years) who had a prior DEXA scan with vertebral fracture assessment available for analysis. The scans were evaluated by blinded musculoskeletal radiologists, and osteoporosis diagnoses were made using World Health Organization DEXA criteria; 32% of patients had osteoporosis by bone mineral density criteria, and 13% had one or more vertebral fractures on vertebral fracture assessment.

Cardiovascular events in the cohort included myocardial infarction in 45 patients, stent in 145, heart failure in 33, and stroke in 7.

The findings are of note given that traditional risk factors for cardiovascular disease tend to underperform in patients with RA, and that cardiovascular disease remains the leading cause of mortality in this population, Dr. Mohammad said.

"The risk of cardiovascular disease rises shortly after onset of arthritis, but does not precede it, and the risk appears similar to what is seen in non-RA subjects with diabetes and non-RA subjects who are 5-10 years older, so this tells us we are looking at a very high-risk population," he said.

However, despite a similar distribution in RA and non-RA patients, risk factors for cardiovascular disease "behave differently" in RA patients, and multiple studies have shown that methods for assessing risk, such as the Framingham risk score, underestimate risk in those with RA.

Indeed, the Framingham risk score did not differ significantly between those with and without cardiovascular disease events in the current study, Dr. Mohammad said, adding: "This poses a significant challenge. Therefore we need better markers and better prediction tools."

It appears, based on these findings, that bone mineral density could serve as such a marker, and that DEXA scans could be a good prediction tool, he said.

Since RA patients are also at increased risk for osteoporosis and fractures, many are already referred for DEXA scans.

"So DEXA may provide an opportunity to assess RA subjects at the time of osteoporosis for cardiovascular disease without the need for additional testing," he said.

Although this study has inherent limitations associated with its cross-sectional design, it does have several strengths, including the large cohort size and the fact that participating radiologists were blinded to patient status. Also, the findings are in keeping with those from multiple prior studies in non-RA populations, demonstrating strong associations between osteoporosis and cardiovascular disease, he added, noting that the findings underscore a need for interventions to reduce cardiovascular disease risk in RA patients with osteoporosis.

Dr. Mohammad reported having no relevant financial disclosures.

*Correction: 12/04/2012: An earlier version of this story misstated Dr. Mohammad's findings. 

WASHINGTON – Low bone mineral density and the presence of vertebral fractures in patients with rheumatoid arthritis not only signal the likely presence of osteoporosis but also appear to signal increased cardiovascular disease risk, according to findings from a cross-sectional study.*

The findings suggest that dual-energy x-ray absorptiometry (DEXA) scans commonly performed in rheumatoid arthritis (RA) patients to assess for osteoporosis could also serve as an assessment of cardiovascular disease risk, Dr. Ausaf Mohammad reported at the annual meeting of the American College of Rheumatology.

Of 603 patients from a convenience sample of adults who met 1987 ACR criteria for RA classification, 230 had at least one documented cardiovascular disease event, and those patients, compared with patients without a cardiovascular disease event, had significantly lower total hip and lumbar spine bone mineral density, and were four times as likely to have osteoporosis (60% vs. 15%) and twice as likely to have a vertebral fracture (24% vs. 12%), said Dr. Mohammad of Galway (Ireland) University Hospitals.

Low bone mineral density and the presence of vertebral fractures were independently associated with cardiovascular disease after adjustment for age, sex, smoking, hypertension, diabetes, and hypercholesterolemia. These measures outperformed traditional risk factors and RA disease activity scores for predicting cardiovascular disease.*

For example, the age- and sex-adjusted odds ratios for osteoporosis and vertebral fractures in those with cardiovascular disease were 2.70 and 2.67; the odds ratios for diabetes mellitus, smoking history, hypertension, hyperlipidemia, C-reactive protein, and Disease Activity Score (DAS-28) indicative of active RA were 1.61, 1.18, 1.58, 1.02, 1.73, and 1.63, respectively.

Patients in the RA cohort included 446 women and 157 men over age 40 years (mean, 56 years) who had a prior DEXA scan with vertebral fracture assessment available for analysis. The scans were evaluated by blinded musculoskeletal radiologists, and osteoporosis diagnoses were made using World Health Organization DEXA criteria; 32% of patients had osteoporosis by bone mineral density criteria, and 13% had one or more vertebral fractures on vertebral fracture assessment.

Cardiovascular events in the cohort included myocardial infarction in 45 patients, stent in 145, heart failure in 33, and stroke in 7.

The findings are of note given that traditional risk factors for cardiovascular disease tend to underperform in patients with RA, and that cardiovascular disease remains the leading cause of mortality in this population, Dr. Mohammad said.

"The risk of cardiovascular disease rises shortly after onset of arthritis, but does not precede it, and the risk appears similar to what is seen in non-RA subjects with diabetes and non-RA subjects who are 5-10 years older, so this tells us we are looking at a very high-risk population," he said.

However, despite a similar distribution in RA and non-RA patients, risk factors for cardiovascular disease "behave differently" in RA patients, and multiple studies have shown that methods for assessing risk, such as the Framingham risk score, underestimate risk in those with RA.

Indeed, the Framingham risk score did not differ significantly between those with and without cardiovascular disease events in the current study, Dr. Mohammad said, adding: "This poses a significant challenge. Therefore we need better markers and better prediction tools."

It appears, based on these findings, that bone mineral density could serve as such a marker, and that DEXA scans could be a good prediction tool, he said.

Since RA patients are also at increased risk for osteoporosis and fractures, many are already referred for DEXA scans.

"So DEXA may provide an opportunity to assess RA subjects at the time of osteoporosis for cardiovascular disease without the need for additional testing," he said.

Although this study has inherent limitations associated with its cross-sectional design, it does have several strengths, including the large cohort size and the fact that participating radiologists were blinded to patient status. Also, the findings are in keeping with those from multiple prior studies in non-RA populations, demonstrating strong associations between osteoporosis and cardiovascular disease, he added, noting that the findings underscore a need for interventions to reduce cardiovascular disease risk in RA patients with osteoporosis.

Dr. Mohammad reported having no relevant financial disclosures.

*Correction: 12/04/2012: An earlier version of this story misstated Dr. Mohammad's findings. 

To sustain the role of expert in cutaneous medicine, dermatologists and dermatopathologists must embrace the molecular advances in medicine, according to Dr. Pedram Gerami.

"For the vast majority of dermatologists and dermatopathologists trained in traditional clinical medicine, the sheer volume of newly identified gene mutations, chromosomal aberrations, and related molecular tests, even within a focused area of specialization, is truly overwhelming. As in many aspects of life, such rapid and transformative changes may be met with welcome or resistance," wrote Dr. Gerami, who was a guest editor of the December issue of Seminars in Cutaneous Medicine and Surgery, which focused on molecular medicine.

Rather than giving in to the common fear that new technological advancements may replace years of clinical training, it is important to recognize that these advances are meant to supplement – not replace – the clinical expertise of dermatologists and dermatopathologists (Sem. Cut. Med. Surg. 2012;31:203).

"The greatest threat to our practice is not the technologic advancement but rather loss of certain aspects of our practice to other specialties [that] better embrace the molecular revolution," he said, adding that active leadership with respect to integrating molecular medicine into the specialty will have a protective effect.

The first step is gaining a deeper understanding of these rapidly emerging advances. Among them are:

Diagnosis of Cutaneous Soft-Tissue Tumors

The identification of genetic abnormalities that characterize soft-tissue tumors has led to the development of diagnostic molecular testing, according to Dr. Alison L. Cheah and Dr. Steven D. Billings, both of the department of anatomic pathology at the Cleveland Clinic.

"Specific genetic signatures characterize a growing number of soft-tissue tumors that affect the skin. Molecular testing on FFPE [formalin-fixed paraffin-embedded tissue] complements histology and immunohistochemistry in the diagnosis of these tumors, especially in challenging cases with atypical morphology, nonspecific immunophenotype, and/or limited sampling," they wrote.

Molecular diagnostics also has implications for more accurate classification and prognostication of poorly understood entities (Sem. Cut. Med. Surg. 2012;31:221-33). "The identification of these disease-defining genetic signatures is the basis for the development of targeted therapies," they wrote.

Take dermatofibrosarcoma protuberans (DFSP), for example. "In practice, molecular testing in DFSP has utility both as a diagnostic aid in challenging cases and to guide therapy," they explained.

While most cases are easily diagnosed based on histopathologic features, significant diagnostic challenges can arise in certain cases, such as in CD34-negative tumors that are superficially sampled, or in tumors with varying histology or an unusual presentation.

For guiding treatment, molecular testing can be helpful for confirmation of COL1A1-PDGF-beta, which is vital if treatment with imatinib mesylate is being considered, because tumors lacking the fusion gene do not respond to this drug, they noted. Imatinib mesylate recently received Food and Drug Administration approval for the treatment of unresectable metastatic or recurrent DFSP.

Real-time polymerase chain reaction (RT-PCR) is the most studied test for detecting COL1A1-PDGF-beta and has a reported sensitivity between 74% and 96%. Though not as well studied, fluorescence in situ hybridization (FISH) assays also show promise.

"FISH assays using both PDGF-beta break-apart and COL1A1-PDGF-beta dual-color dual-fusion probe techniques have also been used," they wrote, noting that some reports show a greater sensitivity of FISH than RT-PCR for DFSP.

Molecular assays can also be helpful in confirming the diagnosis of angiomatoid fibrous histiocytoma (AFH).

In a study of 17 cases, FISH assays with dual-color break-apart probes had a sensitivity of 76% for identifying EWSR1 and FUS gene rearrangements, regardless of the translocation partner, they noted. FISH results should be interpreted with caution, though, because a negative result does not rule out the diagnosis of AFH, as rearrangements that are not detectable with the particular FISH probes used, or translocations with different chromosomes altogether, could explain a negative FISH result.

"Of note, EWSR1 rearrangements occur in several other soft tissue sarcomas, including Ewing sarcoma family of tumors, desmoplastic small round-cell tumors, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and a subset of myoepithelial tumors," they noted, adding that correlation with the histologic and immunohistochemical findings remains paramount.

RT-PCR is also a sensitive and specific assay for AFH, but its practical utility is limited by the multiple primers to account for the various fusion transcripts described in AFH.

Another area in which molecular testing plays an important role – albeit complementary– is in the diagnosis of low-grade fibromyxoid sarcoma (LGFMS), they reported. On the basis of RT-PCR results, for example, a significant number of cases previously diagnosed as LGMFS had to be reclassified.

RT-PCR assays performed on FFPE tissues had a sensitivity of 81%-88%, and FISH testing for FUS gene rearrangement is less sensitive at about 70%, but is nonetheless a good alternative to PCR, particularly in paraffin blocks with poor quality RNA.

These are just a few of the areas discussed by Dr. Cheah and Dr. Billings, with respect to molecular testing for cutaneous soft tissue tumors. Others addressed in their article were clear-cell sarcoma (melanoma of the soft parts), postradiation angiosarcoma, epithelioid hemangioendothelioma, and Ewing sarcoma family of tumors.

Knowledge and identification of the recurrent molecular aberrations in these cutaneous mesenchymal tumors allow for more accurate diagnosis and advancement of understanding about their underlying biology.

BRAF V600E Mutation Detection

The identification of BRAF mutations in the mitogen-activated protein kinase pathway revolutionized the treatment of advanced-stage melanoma, bringing selective small-molecule RAF inhibitors, such as vemurafenib, to the clinical trial stage. In the phase III BRIM-3 trial, vemurafenib was associated with a higher response rate and a significant improvement in survival, compared with dacarbazine.

"The knowledge that melanomas harbor recurring hot spot mutations in the BRAF gene has rapidly brought molecular testing to the clinical stage," wrote Dr. Jonathan L. Curry of the department of pathology at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

The cobas 4800 BRAF V600 Mutation Test from Roche, for example, was approved by the FDA as an in vitro diagnostic device to detect mutant BRAF V600E in DNA extracted from a FFPE patient’s sample of melanoma (Sem. Cut. Med. Surg. 2012;31:268-74). The presence of the mutation aids in selecting patients for treatment with vemurafenib.

The authors noted that a number of molecular platforms for BRAF testing have been developed and continue to evolve, offering a more thorough and complex analysis of the genetic components of melanoma.

"The next generation sequencing or massively parallel sequencing will allow sequencing of the entire exon or whole genome. Multiple sequencing molecular platforms are available to examine for BRAF mutations in cutaneous melanoma, and the best technological approach continues to be developed," they wrote.

Among those they described are:

• Sanger Sequencing. Sanger chain–termination sequencing of amplified DNA by PCR was the method used to sequence the human genome, and the Sanger method of sequencing led to the detection of BRAF mutations in cutaneous melanoma. Sensitivity is high (fewer than 5% of tumor cells are necessary in a given specimen), but use in the clinical setting is limited to BRAF testing. Although it remains the gold standard for gene sequencing, the Sanger method has technical and practical limitations. For example, it takes 18-19 hours to perform the test, other tests are more sensitive, and it cannot detect changes in the chromosomal copy number and the translocations.

• Pyrosequencing. Also known as sequencing by synthesis, pyrosequencing is among the platforms more sensitive than Sanger sequencing. The detection ratio of mutant BRAF V600E to wild type is 1:5 for Sanger sequencing, and 1:50 for pyrosequencing. Its clinical application is to detect the presence or absence of known mutations within a specific segment of DNA of a single nucleotide polymorphism.

"Because mutations in melanoma appear to cluster in the BRAF, NRAS, and KIT genes, this molecular platform has been readily incorporated into the mutational analysis of melanoma," the authors explained, noting that pyrosequencing is a rapid and sensitive test for detection of more common BRAF V600E mutations, as well as other variants. It is limited to the length of the DNA template sequenced, and is prone to errors reading through homopolymer sequences.

• Allele-Specific Real-Time PCR. This molecular platform, also known as the amplification-refractory mutation system, enriches known mutations in clinical samples to increase sensitivity of detection, and is particularly useful in FFPE biopsies with low tumor content. It is highly sensitive and is confined to known BRAF mutations that occur in melanomas, but demonstrates greater sensitivity in detecting BRAF V600E mutations in FFPE clinical samples.

• Mass Spectrometry–Based Sequencing (Sequenom). Sequenom uses mass spectrometry to determine the sequence of the FFPE tissue samples of melanoma. The platform allows for simultaneous amplification of multiple genetic hot spots, allowing for analysis of several known mutations in a single clinical sample. In the authors’ experience, it has slightly higher sensitivity than pyrosequencing.

• High Resolution Melting (HRM). Also a highly sensitive method for screening for mutations in clinical samples, high-resolution melting relies on PCR amplification of the DNA template and analysis of the temperature gradient in which the double strands of the PCR products are melted. The strands melt at different temperatures, depending on the sequence of the constituent bases, allowing for detection of the mutant allele in the FFPE tissue sample. An important limitation of this approach is that specific nucleotide alteration is not reported, thus tissues samples that are positive for mutations will require additional sequencing by another method to determine the specific nucleotide alteration.

• The 454 Pyrosequencing (Roche). This powerful platform, one of several next generation sequencing technologies that allows ultra deep sequencing of entire exons, was used to resolve mutation discrepancies between the cobas 4800 BRAF V600 test and the Sanger sequencing method during the vemurafenib trials, the authors noted. It has a mean error rate of only 1.07%, with more than half of the errors at sites of homopolymers, has the lengths of individual reads of DNA sequences of more than 500 base pairs, and can be performed in less than a day.

• Cobas 4800 BRAF V600 Mutation Test. The cobas 4800 BRAF V600 Mutation Test is based on the principles of allele-specific real time PCR, and targets a predefined 116-base pair sequence of the BRAF gene on exon 15. The device, which is intended to identify those with BRAF V600E who might benefit from therapy with vemurafenib, has a sensitivity for detecting BRAF V600E on FFPE samples of melanoma of more than 99%, and a specificity of 88%. The sensitivity appears comparable with the other platforms, including Sequenom and HRM.

Although the platform is not designed to screen for nonrecurrent genetic mutations in melanoma, BRAF V600E appears to account for the highest percentage of mutations in cutaneous melanomas, the authors said.

Cutaneous Lymphoma Analysis

In cutaneous lymphomas, molecular analysis serves to confirm the diagnosis in cases in which the clinical and/or pathologic presentations do not provide a diagnosis and to further characterize the nature of the lymphoma, according to Dr. Janyana M.D. Deonizio and Dr. Joan Guitart.

While the gold standard for diagnosis is a solid clinicopathologic correlation, molecular analysis provides for a more concrete diagnosis that helps both the patient in facing the diagnosis, and the clinician in proceeding with the most appropriate treatment plan (Sem. Cut. Med. Surg. 2012;31:234-40).

Specifically, through immunophenotyping and clonality analysis, molecular analysis helps discern whether the lymphoma is primarily cutaneous or systemic with secondary skin involvement, and it subclassifies the tumor.

Methods for establishing T-cell clonality include Southern blot analysis (SBA) and PCR for detection of specific T-cell receptor gene arrangements (TCR-GR). SBA used to be the gold standard, but has been gradually replaced by PCR techniques which are less laborious and lengthy. PCR sensitivity for T-cell clonality detection ranges from 70% to 90%.

"Ideally, TCR clonality should be checked at the time of diagnosis in skin and blood. ... The detection of a dominant clone is important not only to confirm diagnosis but also for some prognostic guidance," they wrote, explaining that T-cell cloning is particularly helpful when early-stage mycosis fungoides is being considered in the differential diagnosis.

It does have limitations, however. False-positive monoclonal or oligoclonal bands may be identified in inflammatory dermatoses when T-cell infiltrates are sparse, resulting in "pseudomonoclonality," which is infrequently associated with a malignant T-cell process, they noted.

"Repeating the analysis using the same DNA template or fresh DNA extraction may solve the problem because in reactive conditions, the predominant PCR products typically vary in repeated PCR analyses of the same sample. In contrast, in neoplastic T-cell proliferations, dominant TCR clones are reproducible and should be routinely verified to confirm monoclonality," they noted.

Some studies suggest a correlation between TCR clonality by PCR and response to treatment; the absence of a detectable clone in cutaneous T-cell lymphoma (CTCL) has been associated with a higher rate of complete remission – although not necessarily with improved survival.

Immunophenotypic and immunogenotypic assays have been used to monitor the response of CTCL to therapy, define remission, and detect early relapse, thereby improving assessment of disease activity.

Flow cytometry analysis, for example, is "an efficient and sensitive method to detect and enumerate abnormal cells in the peripheral blood or any other cell suspension," they wrote. It can also be performed on leukocyte suspension from skin biopsies, and it provides prognostic information.

"Lower counts of circulating CD8+ lymphocytes and higher white cell counts in CTCL patients are associated with a less favorable prognosis," the authors noted.

FISH is used to detect major chromosomal gains or losses and specific translocations using a target-specific probe. Although FISH is not routinely used in the diagnosis of cutaneous lymphomas, it does appear to have potential future applications in various areas, according to recent publications.

Finally, genomic analysis by microarray-based comparative genomic hybridization is allowing quantification and appositional defining of chromosomal imbalances. While still confined to the research arena, this technology is providing some insight into the molecular pathogenesis of CTCL, the reported.

The advances in molecular diagnostics that are outlined in this series of articles are not limited to skin cancers and tumors. Additional articles, for example, addressed the role of genetic and molecular analysis in alopecia and in genodermatoses. Together they underscore the need for, and substantiate the ability of the specialty to take on leadership roles in molecular medicine, noted Dr. Gerami, of the department of dermatology at Northwestern University in Chicago.

"I am hopeful that they can assist other practicing dermatologists and dermatopathologists acquire a better foundation in molecular medicine, allowing them to sustain their primary roles in cutaneous medicine," Dr. Gerami concluded.

The authors reported having no conflicts of interest.

To sustain the role of expert in cutaneous medicine, dermatologists and dermatopathologists must embrace the molecular advances in medicine, according to Dr. Pedram Gerami.

"For the vast majority of dermatologists and dermatopathologists trained in traditional clinical medicine, the sheer volume of newly identified gene mutations, chromosomal aberrations, and related molecular tests, even within a focused area of specialization, is truly overwhelming. As in many aspects of life, such rapid and transformative changes may be met with welcome or resistance," wrote Dr. Gerami, who was a guest editor of the December issue of Seminars in Cutaneous Medicine and Surgery, which focused on molecular medicine.

Rather than giving in to the common fear that new technological advancements may replace years of clinical training, it is important to recognize that these advances are meant to supplement – not replace – the clinical expertise of dermatologists and dermatopathologists (Sem. Cut. Med. Surg. 2012;31:203).

"The greatest threat to our practice is not the technologic advancement but rather loss of certain aspects of our practice to other specialties [that] better embrace the molecular revolution," he said, adding that active leadership with respect to integrating molecular medicine into the specialty will have a protective effect.

The first step is gaining a deeper understanding of these rapidly emerging advances. Among them are:

Diagnosis of Cutaneous Soft-Tissue Tumors

The identification of genetic abnormalities that characterize soft-tissue tumors has led to the development of diagnostic molecular testing, according to Dr. Alison L. Cheah and Dr. Steven D. Billings, both of the department of anatomic pathology at the Cleveland Clinic.

"Specific genetic signatures characterize a growing number of soft-tissue tumors that affect the skin. Molecular testing on FFPE [formalin-fixed paraffin-embedded tissue] complements histology and immunohistochemistry in the diagnosis of these tumors, especially in challenging cases with atypical morphology, nonspecific immunophenotype, and/or limited sampling," they wrote.

Molecular diagnostics also has implications for more accurate classification and prognostication of poorly understood entities (Sem. Cut. Med. Surg. 2012;31:221-33). "The identification of these disease-defining genetic signatures is the basis for the development of targeted therapies," they wrote.

Take dermatofibrosarcoma protuberans (DFSP), for example. "In practice, molecular testing in DFSP has utility both as a diagnostic aid in challenging cases and to guide therapy," they explained.

While most cases are easily diagnosed based on histopathologic features, significant diagnostic challenges can arise in certain cases, such as in CD34-negative tumors that are superficially sampled, or in tumors with varying histology or an unusual presentation.

For guiding treatment, molecular testing can be helpful for confirmation of COL1A1-PDGF-beta, which is vital if treatment with imatinib mesylate is being considered, because tumors lacking the fusion gene do not respond to this drug, they noted. Imatinib mesylate recently received Food and Drug Administration approval for the treatment of unresectable metastatic or recurrent DFSP.

Real-time polymerase chain reaction (RT-PCR) is the most studied test for detecting COL1A1-PDGF-beta and has a reported sensitivity between 74% and 96%. Though not as well studied, fluorescence in situ hybridization (FISH) assays also show promise.

"FISH assays using both PDGF-beta break-apart and COL1A1-PDGF-beta dual-color dual-fusion probe techniques have also been used," they wrote, noting that some reports show a greater sensitivity of FISH than RT-PCR for DFSP.

Molecular assays can also be helpful in confirming the diagnosis of angiomatoid fibrous histiocytoma (AFH).

In a study of 17 cases, FISH assays with dual-color break-apart probes had a sensitivity of 76% for identifying EWSR1 and FUS gene rearrangements, regardless of the translocation partner, they noted. FISH results should be interpreted with caution, though, because a negative result does not rule out the diagnosis of AFH, as rearrangements that are not detectable with the particular FISH probes used, or translocations with different chromosomes altogether, could explain a negative FISH result.

"Of note, EWSR1 rearrangements occur in several other soft tissue sarcomas, including Ewing sarcoma family of tumors, desmoplastic small round-cell tumors, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and a subset of myoepithelial tumors," they noted, adding that correlation with the histologic and immunohistochemical findings remains paramount.

RT-PCR is also a sensitive and specific assay for AFH, but its practical utility is limited by the multiple primers to account for the various fusion transcripts described in AFH.

Another area in which molecular testing plays an important role – albeit complementary– is in the diagnosis of low-grade fibromyxoid sarcoma (LGFMS), they reported. On the basis of RT-PCR results, for example, a significant number of cases previously diagnosed as LGMFS had to be reclassified.

RT-PCR assays performed on FFPE tissues had a sensitivity of 81%-88%, and FISH testing for FUS gene rearrangement is less sensitive at about 70%, but is nonetheless a good alternative to PCR, particularly in paraffin blocks with poor quality RNA.

These are just a few of the areas discussed by Dr. Cheah and Dr. Billings, with respect to molecular testing for cutaneous soft tissue tumors. Others addressed in their article were clear-cell sarcoma (melanoma of the soft parts), postradiation angiosarcoma, epithelioid hemangioendothelioma, and Ewing sarcoma family of tumors.

Knowledge and identification of the recurrent molecular aberrations in these cutaneous mesenchymal tumors allow for more accurate diagnosis and advancement of understanding about their underlying biology.

BRAF V600E Mutation Detection

The identification of BRAF mutations in the mitogen-activated protein kinase pathway revolutionized the treatment of advanced-stage melanoma, bringing selective small-molecule RAF inhibitors, such as vemurafenib, to the clinical trial stage. In the phase III BRIM-3 trial, vemurafenib was associated with a higher response rate and a significant improvement in survival, compared with dacarbazine.

"The knowledge that melanomas harbor recurring hot spot mutations in the BRAF gene has rapidly brought molecular testing to the clinical stage," wrote Dr. Jonathan L. Curry of the department of pathology at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

The cobas 4800 BRAF V600 Mutation Test from Roche, for example, was approved by the FDA as an in vitro diagnostic device to detect mutant BRAF V600E in DNA extracted from a FFPE patient’s sample of melanoma (Sem. Cut. Med. Surg. 2012;31:268-74). The presence of the mutation aids in selecting patients for treatment with vemurafenib.

The authors noted that a number of molecular platforms for BRAF testing have been developed and continue to evolve, offering a more thorough and complex analysis of the genetic components of melanoma.

"The next generation sequencing or massively parallel sequencing will allow sequencing of the entire exon or whole genome. Multiple sequencing molecular platforms are available to examine for BRAF mutations in cutaneous melanoma, and the best technological approach continues to be developed," they wrote.

Among those they described are:

• Sanger Sequencing. Sanger chain–termination sequencing of amplified DNA by PCR was the method used to sequence the human genome, and the Sanger method of sequencing led to the detection of BRAF mutations in cutaneous melanoma. Sensitivity is high (fewer than 5% of tumor cells are necessary in a given specimen), but use in the clinical setting is limited to BRAF testing. Although it remains the gold standard for gene sequencing, the Sanger method has technical and practical limitations. For example, it takes 18-19 hours to perform the test, other tests are more sensitive, and it cannot detect changes in the chromosomal copy number and the translocations.

• Pyrosequencing. Also known as sequencing by synthesis, pyrosequencing is among the platforms more sensitive than Sanger sequencing. The detection ratio of mutant BRAF V600E to wild type is 1:5 for Sanger sequencing, and 1:50 for pyrosequencing. Its clinical application is to detect the presence or absence of known mutations within a specific segment of DNA of a single nucleotide polymorphism.

"Because mutations in melanoma appear to cluster in the BRAF, NRAS, and KIT genes, this molecular platform has been readily incorporated into the mutational analysis of melanoma," the authors explained, noting that pyrosequencing is a rapid and sensitive test for detection of more common BRAF V600E mutations, as well as other variants. It is limited to the length of the DNA template sequenced, and is prone to errors reading through homopolymer sequences.

• Allele-Specific Real-Time PCR. This molecular platform, also known as the amplification-refractory mutation system, enriches known mutations in clinical samples to increase sensitivity of detection, and is particularly useful in FFPE biopsies with low tumor content. It is highly sensitive and is confined to known BRAF mutations that occur in melanomas, but demonstrates greater sensitivity in detecting BRAF V600E mutations in FFPE clinical samples.

• Mass Spectrometry–Based Sequencing (Sequenom). Sequenom uses mass spectrometry to determine the sequence of the FFPE tissue samples of melanoma. The platform allows for simultaneous amplification of multiple genetic hot spots, allowing for analysis of several known mutations in a single clinical sample. In the authors’ experience, it has slightly higher sensitivity than pyrosequencing.

• High Resolution Melting (HRM). Also a highly sensitive method for screening for mutations in clinical samples, high-resolution melting relies on PCR amplification of the DNA template and analysis of the temperature gradient in which the double strands of the PCR products are melted. The strands melt at different temperatures, depending on the sequence of the constituent bases, allowing for detection of the mutant allele in the FFPE tissue sample. An important limitation of this approach is that specific nucleotide alteration is not reported, thus tissues samples that are positive for mutations will require additional sequencing by another method to determine the specific nucleotide alteration.

• The 454 Pyrosequencing (Roche). This powerful platform, one of several next generation sequencing technologies that allows ultra deep sequencing of entire exons, was used to resolve mutation discrepancies between the cobas 4800 BRAF V600 test and the Sanger sequencing method during the vemurafenib trials, the authors noted. It has a mean error rate of only 1.07%, with more than half of the errors at sites of homopolymers, has the lengths of individual reads of DNA sequences of more than 500 base pairs, and can be performed in less than a day.

• Cobas 4800 BRAF V600 Mutation Test. The cobas 4800 BRAF V600 Mutation Test is based on the principles of allele-specific real time PCR, and targets a predefined 116-base pair sequence of the BRAF gene on exon 15. The device, which is intended to identify those with BRAF V600E who might benefit from therapy with vemurafenib, has a sensitivity for detecting BRAF V600E on FFPE samples of melanoma of more than 99%, and a specificity of 88%. The sensitivity appears comparable with the other platforms, including Sequenom and HRM.

Although the platform is not designed to screen for nonrecurrent genetic mutations in melanoma, BRAF V600E appears to account for the highest percentage of mutations in cutaneous melanomas, the authors said.

Cutaneous Lymphoma Analysis

In cutaneous lymphomas, molecular analysis serves to confirm the diagnosis in cases in which the clinical and/or pathologic presentations do not provide a diagnosis and to further characterize the nature of the lymphoma, according to Dr. Janyana M.D. Deonizio and Dr. Joan Guitart.

While the gold standard for diagnosis is a solid clinicopathologic correlation, molecular analysis provides for a more concrete diagnosis that helps both the patient in facing the diagnosis, and the clinician in proceeding with the most appropriate treatment plan (Sem. Cut. Med. Surg. 2012;31:234-40).

Specifically, through immunophenotyping and clonality analysis, molecular analysis helps discern whether the lymphoma is primarily cutaneous or systemic with secondary skin involvement, and it subclassifies the tumor.

Methods for establishing T-cell clonality include Southern blot analysis (SBA) and PCR for detection of specific T-cell receptor gene arrangements (TCR-GR). SBA used to be the gold standard, but has been gradually replaced by PCR techniques which are less laborious and lengthy. PCR sensitivity for T-cell clonality detection ranges from 70% to 90%.

"Ideally, TCR clonality should be checked at the time of diagnosis in skin and blood. ... The detection of a dominant clone is important not only to confirm diagnosis but also for some prognostic guidance," they wrote, explaining that T-cell cloning is particularly helpful when early-stage mycosis fungoides is being considered in the differential diagnosis.

It does have limitations, however. False-positive monoclonal or oligoclonal bands may be identified in inflammatory dermatoses when T-cell infiltrates are sparse, resulting in "pseudomonoclonality," which is infrequently associated with a malignant T-cell process, they noted.

"Repeating the analysis using the same DNA template or fresh DNA extraction may solve the problem because in reactive conditions, the predominant PCR products typically vary in repeated PCR analyses of the same sample. In contrast, in neoplastic T-cell proliferations, dominant TCR clones are reproducible and should be routinely verified to confirm monoclonality," they noted.

Some studies suggest a correlation between TCR clonality by PCR and response to treatment; the absence of a detectable clone in cutaneous T-cell lymphoma (CTCL) has been associated with a higher rate of complete remission – although not necessarily with improved survival.

Immunophenotypic and immunogenotypic assays have been used to monitor the response of CTCL to therapy, define remission, and detect early relapse, thereby improving assessment of disease activity.

Flow cytometry analysis, for example, is "an efficient and sensitive method to detect and enumerate abnormal cells in the peripheral blood or any other cell suspension," they wrote. It can also be performed on leukocyte suspension from skin biopsies, and it provides prognostic information.

"Lower counts of circulating CD8+ lymphocytes and higher white cell counts in CTCL patients are associated with a less favorable prognosis," the authors noted.

FISH is used to detect major chromosomal gains or losses and specific translocations using a target-specific probe. Although FISH is not routinely used in the diagnosis of cutaneous lymphomas, it does appear to have potential future applications in various areas, according to recent publications.

Finally, genomic analysis by microarray-based comparative genomic hybridization is allowing quantification and appositional defining of chromosomal imbalances. While still confined to the research arena, this technology is providing some insight into the molecular pathogenesis of CTCL, the reported.

The advances in molecular diagnostics that are outlined in this series of articles are not limited to skin cancers and tumors. Additional articles, for example, addressed the role of genetic and molecular analysis in alopecia and in genodermatoses. Together they underscore the need for, and substantiate the ability of the specialty to take on leadership roles in molecular medicine, noted Dr. Gerami, of the department of dermatology at Northwestern University in Chicago.

"I am hopeful that they can assist other practicing dermatologists and dermatopathologists acquire a better foundation in molecular medicine, allowing them to sustain their primary roles in cutaneous medicine," Dr. Gerami concluded.

The authors reported having no conflicts of interest.

To sustain the role of expert in cutaneous medicine, dermatologists and dermatopathologists must embrace the molecular advances in medicine, according to Dr. Pedram Gerami.

"For the vast majority of dermatologists and dermatopathologists trained in traditional clinical medicine, the sheer volume of newly identified gene mutations, chromosomal aberrations, and related molecular tests, even within a focused area of specialization, is truly overwhelming. As in many aspects of life, such rapid and transformative changes may be met with welcome or resistance," wrote Dr. Gerami, who was a guest editor of the December issue of Seminars in Cutaneous Medicine and Surgery, which focused on molecular medicine.

Rather than giving in to the common fear that new technological advancements may replace years of clinical training, it is important to recognize that these advances are meant to supplement – not replace – the clinical expertise of dermatologists and dermatopathologists (Sem. Cut. Med. Surg. 2012;31:203).

"The greatest threat to our practice is not the technologic advancement but rather loss of certain aspects of our practice to other specialties [that] better embrace the molecular revolution," he said, adding that active leadership with respect to integrating molecular medicine into the specialty will have a protective effect.

The first step is gaining a deeper understanding of these rapidly emerging advances. Among them are:

Diagnosis of Cutaneous Soft-Tissue Tumors

The identification of genetic abnormalities that characterize soft-tissue tumors has led to the development of diagnostic molecular testing, according to Dr. Alison L. Cheah and Dr. Steven D. Billings, both of the department of anatomic pathology at the Cleveland Clinic.

"Specific genetic signatures characterize a growing number of soft-tissue tumors that affect the skin. Molecular testing on FFPE [formalin-fixed paraffin-embedded tissue] complements histology and immunohistochemistry in the diagnosis of these tumors, especially in challenging cases with atypical morphology, nonspecific immunophenotype, and/or limited sampling," they wrote.

Molecular diagnostics also has implications for more accurate classification and prognostication of poorly understood entities (Sem. Cut. Med. Surg. 2012;31:221-33). "The identification of these disease-defining genetic signatures is the basis for the development of targeted therapies," they wrote.

Take dermatofibrosarcoma protuberans (DFSP), for example. "In practice, molecular testing in DFSP has utility both as a diagnostic aid in challenging cases and to guide therapy," they explained.

While most cases are easily diagnosed based on histopathologic features, significant diagnostic challenges can arise in certain cases, such as in CD34-negative tumors that are superficially sampled, or in tumors with varying histology or an unusual presentation.

For guiding treatment, molecular testing can be helpful for confirmation of COL1A1-PDGF-beta, which is vital if treatment with imatinib mesylate is being considered, because tumors lacking the fusion gene do not respond to this drug, they noted. Imatinib mesylate recently received Food and Drug Administration approval for the treatment of unresectable metastatic or recurrent DFSP.

Real-time polymerase chain reaction (RT-PCR) is the most studied test for detecting COL1A1-PDGF-beta and has a reported sensitivity between 74% and 96%. Though not as well studied, fluorescence in situ hybridization (FISH) assays also show promise.

"FISH assays using both PDGF-beta break-apart and COL1A1-PDGF-beta dual-color dual-fusion probe techniques have also been used," they wrote, noting that some reports show a greater sensitivity of FISH than RT-PCR for DFSP.

Molecular assays can also be helpful in confirming the diagnosis of angiomatoid fibrous histiocytoma (AFH).

In a study of 17 cases, FISH assays with dual-color break-apart probes had a sensitivity of 76% for identifying EWSR1 and FUS gene rearrangements, regardless of the translocation partner, they noted. FISH results should be interpreted with caution, though, because a negative result does not rule out the diagnosis of AFH, as rearrangements that are not detectable with the particular FISH probes used, or translocations with different chromosomes altogether, could explain a negative FISH result.

"Of note, EWSR1 rearrangements occur in several other soft tissue sarcomas, including Ewing sarcoma family of tumors, desmoplastic small round-cell tumors, clear cell sarcoma, extraskeletal myxoid chondrosarcoma, and a subset of myoepithelial tumors," they noted, adding that correlation with the histologic and immunohistochemical findings remains paramount.

RT-PCR is also a sensitive and specific assay for AFH, but its practical utility is limited by the multiple primers to account for the various fusion transcripts described in AFH.

Another area in which molecular testing plays an important role – albeit complementary– is in the diagnosis of low-grade fibromyxoid sarcoma (LGFMS), they reported. On the basis of RT-PCR results, for example, a significant number of cases previously diagnosed as LGMFS had to be reclassified.

RT-PCR assays performed on FFPE tissues had a sensitivity of 81%-88%, and FISH testing for FUS gene rearrangement is less sensitive at about 70%, but is nonetheless a good alternative to PCR, particularly in paraffin blocks with poor quality RNA.

These are just a few of the areas discussed by Dr. Cheah and Dr. Billings, with respect to molecular testing for cutaneous soft tissue tumors. Others addressed in their article were clear-cell sarcoma (melanoma of the soft parts), postradiation angiosarcoma, epithelioid hemangioendothelioma, and Ewing sarcoma family of tumors.

Knowledge and identification of the recurrent molecular aberrations in these cutaneous mesenchymal tumors allow for more accurate diagnosis and advancement of understanding about their underlying biology.

BRAF V600E Mutation Detection

The identification of BRAF mutations in the mitogen-activated protein kinase pathway revolutionized the treatment of advanced-stage melanoma, bringing selective small-molecule RAF inhibitors, such as vemurafenib, to the clinical trial stage. In the phase III BRIM-3 trial, vemurafenib was associated with a higher response rate and a significant improvement in survival, compared with dacarbazine.

"The knowledge that melanomas harbor recurring hot spot mutations in the BRAF gene has rapidly brought molecular testing to the clinical stage," wrote Dr. Jonathan L. Curry of the department of pathology at the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

The cobas 4800 BRAF V600 Mutation Test from Roche, for example, was approved by the FDA as an in vitro diagnostic device to detect mutant BRAF V600E in DNA extracted from a FFPE patient’s sample of melanoma (Sem. Cut. Med. Surg. 2012;31:268-74). The presence of the mutation aids in selecting patients for treatment with vemurafenib.

The authors noted that a number of molecular platforms for BRAF testing have been developed and continue to evolve, offering a more thorough and complex analysis of the genetic components of melanoma.

"The next generation sequencing or massively parallel sequencing will allow sequencing of the entire exon or whole genome. Multiple sequencing molecular platforms are available to examine for BRAF mutations in cutaneous melanoma, and the best technological approach continues to be developed," they wrote.

Among those they described are:

• Sanger Sequencing. Sanger chain–termination sequencing of amplified DNA by PCR was the method used to sequence the human genome, and the Sanger method of sequencing led to the detection of BRAF mutations in cutaneous melanoma. Sensitivity is high (fewer than 5% of tumor cells are necessary in a given specimen), but use in the clinical setting is limited to BRAF testing. Although it remains the gold standard for gene sequencing, the Sanger method has technical and practical limitations. For example, it takes 18-19 hours to perform the test, other tests are more sensitive, and it cannot detect changes in the chromosomal copy number and the translocations.

• Pyrosequencing. Also known as sequencing by synthesis, pyrosequencing is among the platforms more sensitive than Sanger sequencing. The detection ratio of mutant BRAF V600E to wild type is 1:5 for Sanger sequencing, and 1:50 for pyrosequencing. Its clinical application is to detect the presence or absence of known mutations within a specific segment of DNA of a single nucleotide polymorphism.

"Because mutations in melanoma appear to cluster in the BRAF, NRAS, and KIT genes, this molecular platform has been readily incorporated into the mutational analysis of melanoma," the authors explained, noting that pyrosequencing is a rapid and sensitive test for detection of more common BRAF V600E mutations, as well as other variants. It is limited to the length of the DNA template sequenced, and is prone to errors reading through homopolymer sequences.

• Allele-Specific Real-Time PCR. This molecular platform, also known as the amplification-refractory mutation system, enriches known mutations in clinical samples to increase sensitivity of detection, and is particularly useful in FFPE biopsies with low tumor content. It is highly sensitive and is confined to known BRAF mutations that occur in melanomas, but demonstrates greater sensitivity in detecting BRAF V600E mutations in FFPE clinical samples.

• Mass Spectrometry–Based Sequencing (Sequenom). Sequenom uses mass spectrometry to determine the sequence of the FFPE tissue samples of melanoma. The platform allows for simultaneous amplification of multiple genetic hot spots, allowing for analysis of several known mutations in a single clinical sample. In the authors’ experience, it has slightly higher sensitivity than pyrosequencing.

• High Resolution Melting (HRM). Also a highly sensitive method for screening for mutations in clinical samples, high-resolution melting relies on PCR amplification of the DNA template and analysis of the temperature gradient in which the double strands of the PCR products are melted. The strands melt at different temperatures, depending on the sequence of the constituent bases, allowing for detection of the mutant allele in the FFPE tissue sample. An important limitation of this approach is that specific nucleotide alteration is not reported, thus tissues samples that are positive for mutations will require additional sequencing by another method to determine the specific nucleotide alteration.

• The 454 Pyrosequencing (Roche). This powerful platform, one of several next generation sequencing technologies that allows ultra deep sequencing of entire exons, was used to resolve mutation discrepancies between the cobas 4800 BRAF V600 test and the Sanger sequencing method during the vemurafenib trials, the authors noted. It has a mean error rate of only 1.07%, with more than half of the errors at sites of homopolymers, has the lengths of individual reads of DNA sequences of more than 500 base pairs, and can be performed in less than a day.

• Cobas 4800 BRAF V600 Mutation Test. The cobas 4800 BRAF V600 Mutation Test is based on the principles of allele-specific real time PCR, and targets a predefined 116-base pair sequence of the BRAF gene on exon 15. The device, which is intended to identify those with BRAF V600E who might benefit from therapy with vemurafenib, has a sensitivity for detecting BRAF V600E on FFPE samples of melanoma of more than 99%, and a specificity of 88%. The sensitivity appears comparable with the other platforms, including Sequenom and HRM.

Although the platform is not designed to screen for nonrecurrent genetic mutations in melanoma, BRAF V600E appears to account for the highest percentage of mutations in cutaneous melanomas, the authors said.

Cutaneous Lymphoma Analysis

In cutaneous lymphomas, molecular analysis serves to confirm the diagnosis in cases in which the clinical and/or pathologic presentations do not provide a diagnosis and to further characterize the nature of the lymphoma, according to Dr. Janyana M.D. Deonizio and Dr. Joan Guitart.

While the gold standard for diagnosis is a solid clinicopathologic correlation, molecular analysis provides for a more concrete diagnosis that helps both the patient in facing the diagnosis, and the clinician in proceeding with the most appropriate treatment plan (Sem. Cut. Med. Surg. 2012;31:234-40).

Specifically, through immunophenotyping and clonality analysis, molecular analysis helps discern whether the lymphoma is primarily cutaneous or systemic with secondary skin involvement, and it subclassifies the tumor.

Methods for establishing T-cell clonality include Southern blot analysis (SBA) and PCR for detection of specific T-cell receptor gene arrangements (TCR-GR). SBA used to be the gold standard, but has been gradually replaced by PCR techniques which are less laborious and lengthy. PCR sensitivity for T-cell clonality detection ranges from 70% to 90%.

"Ideally, TCR clonality should be checked at the time of diagnosis in skin and blood. ... The detection of a dominant clone is important not only to confirm diagnosis but also for some prognostic guidance," they wrote, explaining that T-cell cloning is particularly helpful when early-stage mycosis fungoides is being considered in the differential diagnosis.

It does have limitations, however. False-positive monoclonal or oligoclonal bands may be identified in inflammatory dermatoses when T-cell infiltrates are sparse, resulting in "pseudomonoclonality," which is infrequently associated with a malignant T-cell process, they noted.

"Repeating the analysis using the same DNA template or fresh DNA extraction may solve the problem because in reactive conditions, the predominant PCR products typically vary in repeated PCR analyses of the same sample. In contrast, in neoplastic T-cell proliferations, dominant TCR clones are reproducible and should be routinely verified to confirm monoclonality," they noted.

Some studies suggest a correlation between TCR clonality by PCR and response to treatment; the absence of a detectable clone in cutaneous T-cell lymphoma (CTCL) has been associated with a higher rate of complete remission – although not necessarily with improved survival.

Immunophenotypic and immunogenotypic assays have been used to monitor the response of CTCL to therapy, define remission, and detect early relapse, thereby improving assessment of disease activity.

Flow cytometry analysis, for example, is "an efficient and sensitive method to detect and enumerate abnormal cells in the peripheral blood or any other cell suspension," they wrote. It can also be performed on leukocyte suspension from skin biopsies, and it provides prognostic information.

"Lower counts of circulating CD8+ lymphocytes and higher white cell counts in CTCL patients are associated with a less favorable prognosis," the authors noted.

FISH is used to detect major chromosomal gains or losses and specific translocations using a target-specific probe. Although FISH is not routinely used in the diagnosis of cutaneous lymphomas, it does appear to have potential future applications in various areas, according to recent publications.

Finally, genomic analysis by microarray-based comparative genomic hybridization is allowing quantification and appositional defining of chromosomal imbalances. While still confined to the research arena, this technology is providing some insight into the molecular pathogenesis of CTCL, the reported.

The advances in molecular diagnostics that are outlined in this series of articles are not limited to skin cancers and tumors. Additional articles, for example, addressed the role of genetic and molecular analysis in alopecia and in genodermatoses. Together they underscore the need for, and substantiate the ability of the specialty to take on leadership roles in molecular medicine, noted Dr. Gerami, of the department of dermatology at Northwestern University in Chicago.

"I am hopeful that they can assist other practicing dermatologists and dermatopathologists acquire a better foundation in molecular medicine, allowing them to sustain their primary roles in cutaneous medicine," Dr. Gerami concluded.

The authors reported having no conflicts of interest.

When it comes to androgenetic alopecia, female pattern hair loss, and alopecia areata, the role of molecular genetic testing remains limited, but that’s not to say it won’t play a major role in the future, noted Dr. Pedram Yazdan.

In fact, molecular genetic testing will likely play a prominent role with respect to prediction and diagnosis of hair loss, disease severity, and expected response to therapy, he noted.

Genetic factors appear to play a significant role in hair-loss pathogenesis, but the remarkable advances in genomic discovery and molecular diagnostic testing seen in other areas of medicine haven’t quite made their way to this indication (Sem. Cut. Med. Surg. 2012;31:259-67).

"The current gold standard in diagnosis of these alopecias is by clinical history, examination, and, when necessary, scalp biopsy for histopathologic evaluation," wrote Dr. Yazdan of the department of dermatology at Northwestern University, Chicago.

An important role for molecular diagnostics likely lies in the small number of cases in which the diagnosis cannot be ascertained by the existing modalities – cases in which the clinical and histopathologic features of the condition are ambiguous and thus make a definitive diagnosis difficult, Dr. Yazdan noted.

Another role may relate to predicting the course and severity of hair loss, which is currently difficult to accomplish as "there are no reliable and validated clinical or histologic features that can provide patients with prognostic information," he wrote.

"It is conceivable that once the underlying genetic risk profiles of these forms of hair loss are more fully established, this information can potentially be used to aid in more definitively elucidating pathogenesis of the hair loss," which in turn, would aid in the development of diagnostic testing, he noted.

Molecular diagnostic testing for alopecia would also allow for risk stratification in terms of development and severity, and, importantly, would advance the field of pharmacogenetics for alopecia. Currently, treatment options are limited in both number and effectiveness.

Dr. Yazdan described a future in which both therapeutic and targeted preventive therapies, coupled with testing to determine treatment response potential, will allow for personalized treatment of these common and complex conditions, which cause patients substantial anxiety.

He reported having no conflicts of interest.

When it comes to androgenetic alopecia, female pattern hair loss, and alopecia areata, the role of molecular genetic testing remains limited, but that’s not to say it won’t play a major role in the future, noted Dr. Pedram Yazdan.

In fact, molecular genetic testing will likely play a prominent role with respect to prediction and diagnosis of hair loss, disease severity, and expected response to therapy, he noted.

Genetic factors appear to play a significant role in hair-loss pathogenesis, but the remarkable advances in genomic discovery and molecular diagnostic testing seen in other areas of medicine haven’t quite made their way to this indication (Sem. Cut. Med. Surg. 2012;31:259-67).

"The current gold standard in diagnosis of these alopecias is by clinical history, examination, and, when necessary, scalp biopsy for histopathologic evaluation," wrote Dr. Yazdan of the department of dermatology at Northwestern University, Chicago.

An important role for molecular diagnostics likely lies in the small number of cases in which the diagnosis cannot be ascertained by the existing modalities – cases in which the clinical and histopathologic features of the condition are ambiguous and thus make a definitive diagnosis difficult, Dr. Yazdan noted.

Another role may relate to predicting the course and severity of hair loss, which is currently difficult to accomplish as "there are no reliable and validated clinical or histologic features that can provide patients with prognostic information," he wrote.

"It is conceivable that once the underlying genetic risk profiles of these forms of hair loss are more fully established, this information can potentially be used to aid in more definitively elucidating pathogenesis of the hair loss," which in turn, would aid in the development of diagnostic testing, he noted.

Molecular diagnostic testing for alopecia would also allow for risk stratification in terms of development and severity, and, importantly, would advance the field of pharmacogenetics for alopecia. Currently, treatment options are limited in both number and effectiveness.

Dr. Yazdan described a future in which both therapeutic and targeted preventive therapies, coupled with testing to determine treatment response potential, will allow for personalized treatment of these common and complex conditions, which cause patients substantial anxiety.

He reported having no conflicts of interest.

When it comes to androgenetic alopecia, female pattern hair loss, and alopecia areata, the role of molecular genetic testing remains limited, but that’s not to say it won’t play a major role in the future, noted Dr. Pedram Yazdan.

In fact, molecular genetic testing will likely play a prominent role with respect to prediction and diagnosis of hair loss, disease severity, and expected response to therapy, he noted.

Genetic factors appear to play a significant role in hair-loss pathogenesis, but the remarkable advances in genomic discovery and molecular diagnostic testing seen in other areas of medicine haven’t quite made their way to this indication (Sem. Cut. Med. Surg. 2012;31:259-67).

"The current gold standard in diagnosis of these alopecias is by clinical history, examination, and, when necessary, scalp biopsy for histopathologic evaluation," wrote Dr. Yazdan of the department of dermatology at Northwestern University, Chicago.

An important role for molecular diagnostics likely lies in the small number of cases in which the diagnosis cannot be ascertained by the existing modalities – cases in which the clinical and histopathologic features of the condition are ambiguous and thus make a definitive diagnosis difficult, Dr. Yazdan noted.

Another role may relate to predicting the course and severity of hair loss, which is currently difficult to accomplish as "there are no reliable and validated clinical or histologic features that can provide patients with prognostic information," he wrote.

"It is conceivable that once the underlying genetic risk profiles of these forms of hair loss are more fully established, this information can potentially be used to aid in more definitively elucidating pathogenesis of the hair loss," which in turn, would aid in the development of diagnostic testing, he noted.

Molecular diagnostic testing for alopecia would also allow for risk stratification in terms of development and severity, and, importantly, would advance the field of pharmacogenetics for alopecia. Currently, treatment options are limited in both number and effectiveness.

Dr. Yazdan described a future in which both therapeutic and targeted preventive therapies, coupled with testing to determine treatment response potential, will allow for personalized treatment of these common and complex conditions, which cause patients substantial anxiety.

He reported having no conflicts of interest.

ATLANTA – Regardless of disease severity, guideline-concordant treatment is not provided to nearly half of all patients who have stable chronic obstructive pulmonary disease and are treated in the ambulatory care setting, findings from an observational study suggest.

The study also indicated that guideline-concordant treatment was more likely to be provided when patients were comanaged by a pulmonologist and a primary care physician.

Of 450 patients, 56% received guideline-concordant care as outlined by the 2010 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage-specific recommendations, Dr. Gulshan Sharma reported at the annual meeting of the American College of Chest Physicians.

No differences were found in treatment level with respect to age, gender, race, disease severity, or comorbidities on multivariate analysis, but patients comanaged by a primary care physician and a pulmonologist were more likely to receive an appropriate level of care, as compared to patients treated by a primary care physician (odds ratio, 4.6), said Dr. Sharma of the University of Texas Medical Branch, Galveston.

Clinical practice guidelines for the treatment of patients with COPD in the ambulatory care setting are issued and updated regularly. Previous studies have demonstrated the value of these guidelines for improving the quality of care of patients with COPD and for reducing exacerbations and hospitalizations.

However, the degree to which these guidelines are implemented in clinical practice has been unclear, Dr. Sharma said. The study findings suggest that they are underutilized, particularly by primary care physicians.

Patients included in the study were adults with a clinical diagnosis of COPD and at least one outpatient visit between January and December 2010. The mean age of participants was 67 years, 46% were women, 20% had no comorbidities, and 75% had one or two comorbidities.

About 7% had GOLD stage I disease, almost half (more than 46%) had GOLD stage II disease, 33% had stage III disease, and 13% had stage IV disease.

Additionally, 47% were managed by a primary care physician alone, 41% were comanaged by a primary care physician and a pulmonologist, 10% did not have a primary care physician and received care mainly from a specialist, and about 2% had no regular care provider.

The findings indicate a need for efforts to increase awareness of clinical practice guidelines and the importance of adherence to the guidelines in patients with COPD, particularly among primary care physicians, Dr. Sharma concluded.

Dr. Sharma reported having no disclosures.

ATLANTA – Regardless of disease severity, guideline-concordant treatment is not provided to nearly half of all patients who have stable chronic obstructive pulmonary disease and are treated in the ambulatory care setting, findings from an observational study suggest.

The study also indicated that guideline-concordant treatment was more likely to be provided when patients were comanaged by a pulmonologist and a primary care physician.

Of 450 patients, 56% received guideline-concordant care as outlined by the 2010 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage-specific recommendations, Dr. Gulshan Sharma reported at the annual meeting of the American College of Chest Physicians.

No differences were found in treatment level with respect to age, gender, race, disease severity, or comorbidities on multivariate analysis, but patients comanaged by a primary care physician and a pulmonologist were more likely to receive an appropriate level of care, as compared to patients treated by a primary care physician (odds ratio, 4.6), said Dr. Sharma of the University of Texas Medical Branch, Galveston.

Clinical practice guidelines for the treatment of patients with COPD in the ambulatory care setting are issued and updated regularly. Previous studies have demonstrated the value of these guidelines for improving the quality of care of patients with COPD and for reducing exacerbations and hospitalizations.

However, the degree to which these guidelines are implemented in clinical practice has been unclear, Dr. Sharma said. The study findings suggest that they are underutilized, particularly by primary care physicians.

Patients included in the study were adults with a clinical diagnosis of COPD and at least one outpatient visit between January and December 2010. The mean age of participants was 67 years, 46% were women, 20% had no comorbidities, and 75% had one or two comorbidities.

About 7% had GOLD stage I disease, almost half (more than 46%) had GOLD stage II disease, 33% had stage III disease, and 13% had stage IV disease.

Additionally, 47% were managed by a primary care physician alone, 41% were comanaged by a primary care physician and a pulmonologist, 10% did not have a primary care physician and received care mainly from a specialist, and about 2% had no regular care provider.

The findings indicate a need for efforts to increase awareness of clinical practice guidelines and the importance of adherence to the guidelines in patients with COPD, particularly among primary care physicians, Dr. Sharma concluded.

Dr. Sharma reported having no disclosures.

ATLANTA – Regardless of disease severity, guideline-concordant treatment is not provided to nearly half of all patients who have stable chronic obstructive pulmonary disease and are treated in the ambulatory care setting, findings from an observational study suggest.

The study also indicated that guideline-concordant treatment was more likely to be provided when patients were comanaged by a pulmonologist and a primary care physician.

Of 450 patients, 56% received guideline-concordant care as outlined by the 2010 Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage-specific recommendations, Dr. Gulshan Sharma reported at the annual meeting of the American College of Chest Physicians.

No differences were found in treatment level with respect to age, gender, race, disease severity, or comorbidities on multivariate analysis, but patients comanaged by a primary care physician and a pulmonologist were more likely to receive an appropriate level of care, as compared to patients treated by a primary care physician (odds ratio, 4.6), said Dr. Sharma of the University of Texas Medical Branch, Galveston.

Clinical practice guidelines for the treatment of patients with COPD in the ambulatory care setting are issued and updated regularly. Previous studies have demonstrated the value of these guidelines for improving the quality of care of patients with COPD and for reducing exacerbations and hospitalizations.

However, the degree to which these guidelines are implemented in clinical practice has been unclear, Dr. Sharma said. The study findings suggest that they are underutilized, particularly by primary care physicians.

Patients included in the study were adults with a clinical diagnosis of COPD and at least one outpatient visit between January and December 2010. The mean age of participants was 67 years, 46% were women, 20% had no comorbidities, and 75% had one or two comorbidities.

About 7% had GOLD stage I disease, almost half (more than 46%) had GOLD stage II disease, 33% had stage III disease, and 13% had stage IV disease.

Additionally, 47% were managed by a primary care physician alone, 41% were comanaged by a primary care physician and a pulmonologist, 10% did not have a primary care physician and received care mainly from a specialist, and about 2% had no regular care provider.

The findings indicate a need for efforts to increase awareness of clinical practice guidelines and the importance of adherence to the guidelines in patients with COPD, particularly among primary care physicians, Dr. Sharma concluded.

Dr. Sharma reported having no disclosures.

The implantation of subdural electrodes for the treatment of intractable epilepsy is beneficial, but requires careful surveillance during the monitoring period, according to findings from a study of 91 consecutive patients.

This is especially true for those who undergo large subdural grid placement, as these patients have an increased risk for complications, Dr. Fernando L. Vale of the University of South Florida, Tampa, and his colleagues reported online in Clinical Neurology and Neurosurgery.

Of 508 patients who underwent surgical intervention for the evaluation and treatment of medically resistant epilepsy at a single center from 1999 to 2010, 91 (18%) required invasive subdural electrode placement and were included in this study.

Twenty-eight of those patients (31%) had a radiographic lesion on preoperative high-resolution magnetic resonance imaging (MRI), including 13 with evidence of neuronal migrational disorder, 9 with radiographic evidence of gliosis or encephalomalacia of unknown origin, 3 with benign neoplastic lesions, 2 with documented arachnoid cysts, and 1 with radiographic evidence of mesial temporal lobe sclerosis. Resective epilepsy surgery was performed in 70 (77%) of these patients, and 24 of those (34%) were seizure free at last follow-up, the investigators said (Clin. Neurol. Neurosurg. 2012 Nov. 5 [doi: 10.1016/j.clineuro.2012.10.007]).

A very strong trend was seen for improved outcomes in those with positive lesions on preoperative MRI, compared with those with a normal brain MRI, the investigators said.

No significant associations were found between outcomes and preoperative positron emission tomography (PET) results, ictal single photon emission computed tomography (SPECT) results, type of implant, or lateralization or localization of subdural implants, they noted.

Ten surgical complications occurred, including radiographically evident subdural or epidural hemorrhage in eight patients, a transient cerebrospinal fluid leak in one patient, and a subdural empyema following removal of the electrodes in one patient. The latter required prolonged intravenous antibiotics and removal of the bone flap.

Of the eight patients with hemorrhage, four were symptomatic and required evacuation of the hematoma, and two underwent removal of the electrodes during emergency craniotomy. All required observation with a prolonged intensive care unit stay.

"All but one of these patients had undergone placement of an electrode array that included a grid[,] and more significant[ly], all symptomatic subdural hemorrhage patients had undergone placement of a grid with or without additional subdural strip electrodes," the investigators noted.

Indeed, placement of a subdural grid in any combination was significantly associated with complications, they said.

However, none of the patients died or experienced permanent morbidity.

The patients included in the study were 55 men and 36 women with an average age of 32.2 years who underwent subdural electrode placement between 1999 and 2010. The electrodes were placed when ictal recordings were inadequate due to extensive muscle artifact or poorly localized ictal onset, when preoperative scalp electrode encephalogram and neuroimaging findings were discordant, and/or when the epileptogenic zone was localized near eloquent cortex. More than half (57%) of the patients underwent strip placement only, 5 (5.5%) underwent grid placement only, and 34 (37%) underwent both. The mean duration of monitoring was 7 days, and patients were followed for at least 18 months (mean of 42 months).

The findings indicate that although the use of subdural electrode placement has diminished over the last two decades due to improvements in brain imaging, better definition of syndromes amenable to surgery, and better patient selection, such invasive monitoring can improve seizure control and the possibility of cure. Subdural electrode placement thus remains "a useful and necessary technique for the surgical treatment of intractable epilepsy," despite the possibility of complications, they said.

Careful surveillance during the monitoring period, along with a good working hypothesis, assessment of the risk-benefit ratio, patient selection, and meticulous surgical technique, is a must for minimizing complications and achieving better outcomes, they concluded.

Given the limitations of a single-center, retrospective study, however, the authors recommend additional study to corroborate the clinical findings.

Dr. Vale said there are no disclosures for any of the authors of this article.

The implantation of subdural electrodes for the treatment of intractable epilepsy is beneficial, but requires careful surveillance during the monitoring period, according to findings from a study of 91 consecutive patients.

This is especially true for those who undergo large subdural grid placement, as these patients have an increased risk for complications, Dr. Fernando L. Vale of the University of South Florida, Tampa, and his colleagues reported online in Clinical Neurology and Neurosurgery.

Of 508 patients who underwent surgical intervention for the evaluation and treatment of medically resistant epilepsy at a single center from 1999 to 2010, 91 (18%) required invasive subdural electrode placement and were included in this study.

Twenty-eight of those patients (31%) had a radiographic lesion on preoperative high-resolution magnetic resonance imaging (MRI), including 13 with evidence of neuronal migrational disorder, 9 with radiographic evidence of gliosis or encephalomalacia of unknown origin, 3 with benign neoplastic lesions, 2 with documented arachnoid cysts, and 1 with radiographic evidence of mesial temporal lobe sclerosis. Resective epilepsy surgery was performed in 70 (77%) of these patients, and 24 of those (34%) were seizure free at last follow-up, the investigators said (Clin. Neurol. Neurosurg. 2012 Nov. 5 [doi: 10.1016/j.clineuro.2012.10.007]).

A very strong trend was seen for improved outcomes in those with positive lesions on preoperative MRI, compared with those with a normal brain MRI, the investigators said.

No significant associations were found between outcomes and preoperative positron emission tomography (PET) results, ictal single photon emission computed tomography (SPECT) results, type of implant, or lateralization or localization of subdural implants, they noted.

Ten surgical complications occurred, including radiographically evident subdural or epidural hemorrhage in eight patients, a transient cerebrospinal fluid leak in one patient, and a subdural empyema following removal of the electrodes in one patient. The latter required prolonged intravenous antibiotics and removal of the bone flap.

Of the eight patients with hemorrhage, four were symptomatic and required evacuation of the hematoma, and two underwent removal of the electrodes during emergency craniotomy. All required observation with a prolonged intensive care unit stay.

"All but one of these patients had undergone placement of an electrode array that included a grid[,] and more significant[ly], all symptomatic subdural hemorrhage patients had undergone placement of a grid with or without additional subdural strip electrodes," the investigators noted.

Indeed, placement of a subdural grid in any combination was significantly associated with complications, they said.

However, none of the patients died or experienced permanent morbidity.

The patients included in the study were 55 men and 36 women with an average age of 32.2 years who underwent subdural electrode placement between 1999 and 2010. The electrodes were placed when ictal recordings were inadequate due to extensive muscle artifact or poorly localized ictal onset, when preoperative scalp electrode encephalogram and neuroimaging findings were discordant, and/or when the epileptogenic zone was localized near eloquent cortex. More than half (57%) of the patients underwent strip placement only, 5 (5.5%) underwent grid placement only, and 34 (37%) underwent both. The mean duration of monitoring was 7 days, and patients were followed for at least 18 months (mean of 42 months).

The findings indicate that although the use of subdural electrode placement has diminished over the last two decades due to improvements in brain imaging, better definition of syndromes amenable to surgery, and better patient selection, such invasive monitoring can improve seizure control and the possibility of cure. Subdural electrode placement thus remains "a useful and necessary technique for the surgical treatment of intractable epilepsy," despite the possibility of complications, they said.

Careful surveillance during the monitoring period, along with a good working hypothesis, assessment of the risk-benefit ratio, patient selection, and meticulous surgical technique, is a must for minimizing complications and achieving better outcomes, they concluded.

Given the limitations of a single-center, retrospective study, however, the authors recommend additional study to corroborate the clinical findings.

Dr. Vale said there are no disclosures for any of the authors of this article.

The implantation of subdural electrodes for the treatment of intractable epilepsy is beneficial, but requires careful surveillance during the monitoring period, according to findings from a study of 91 consecutive patients.

This is especially true for those who undergo large subdural grid placement, as these patients have an increased risk for complications, Dr. Fernando L. Vale of the University of South Florida, Tampa, and his colleagues reported online in Clinical Neurology and Neurosurgery.

Of 508 patients who underwent surgical intervention for the evaluation and treatment of medically resistant epilepsy at a single center from 1999 to 2010, 91 (18%) required invasive subdural electrode placement and were included in this study.

Twenty-eight of those patients (31%) had a radiographic lesion on preoperative high-resolution magnetic resonance imaging (MRI), including 13 with evidence of neuronal migrational disorder, 9 with radiographic evidence of gliosis or encephalomalacia of unknown origin, 3 with benign neoplastic lesions, 2 with documented arachnoid cysts, and 1 with radiographic evidence of mesial temporal lobe sclerosis. Resective epilepsy surgery was performed in 70 (77%) of these patients, and 24 of those (34%) were seizure free at last follow-up, the investigators said (Clin. Neurol. Neurosurg. 2012 Nov. 5 [doi: 10.1016/j.clineuro.2012.10.007]).

A very strong trend was seen for improved outcomes in those with positive lesions on preoperative MRI, compared with those with a normal brain MRI, the investigators said.

No significant associations were found between outcomes and preoperative positron emission tomography (PET) results, ictal single photon emission computed tomography (SPECT) results, type of implant, or lateralization or localization of subdural implants, they noted.

Ten surgical complications occurred, including radiographically evident subdural or epidural hemorrhage in eight patients, a transient cerebrospinal fluid leak in one patient, and a subdural empyema following removal of the electrodes in one patient. The latter required prolonged intravenous antibiotics and removal of the bone flap.

Of the eight patients with hemorrhage, four were symptomatic and required evacuation of the hematoma, and two underwent removal of the electrodes during emergency craniotomy. All required observation with a prolonged intensive care unit stay.

"All but one of these patients had undergone placement of an electrode array that included a grid[,] and more significant[ly], all symptomatic subdural hemorrhage patients had undergone placement of a grid with or without additional subdural strip electrodes," the investigators noted.

Indeed, placement of a subdural grid in any combination was significantly associated with complications, they said.

However, none of the patients died or experienced permanent morbidity.

The patients included in the study were 55 men and 36 women with an average age of 32.2 years who underwent subdural electrode placement between 1999 and 2010. The electrodes were placed when ictal recordings were inadequate due to extensive muscle artifact or poorly localized ictal onset, when preoperative scalp electrode encephalogram and neuroimaging findings were discordant, and/or when the epileptogenic zone was localized near eloquent cortex. More than half (57%) of the patients underwent strip placement only, 5 (5.5%) underwent grid placement only, and 34 (37%) underwent both. The mean duration of monitoring was 7 days, and patients were followed for at least 18 months (mean of 42 months).

The findings indicate that although the use of subdural electrode placement has diminished over the last two decades due to improvements in brain imaging, better definition of syndromes amenable to surgery, and better patient selection, such invasive monitoring can improve seizure control and the possibility of cure. Subdural electrode placement thus remains "a useful and necessary technique for the surgical treatment of intractable epilepsy," despite the possibility of complications, they said.

Careful surveillance during the monitoring period, along with a good working hypothesis, assessment of the risk-benefit ratio, patient selection, and meticulous surgical technique, is a must for minimizing complications and achieving better outcomes, they concluded.

Given the limitations of a single-center, retrospective study, however, the authors recommend additional study to corroborate the clinical findings.

Dr. Vale said there are no disclosures for any of the authors of this article.

ATLANTA – Data suggest that only about a third of patients hospitalized for chronic obstructive pulmonary disease receive appropriate care, but a number of steps – beginning with decisions about when to admit and ending with proper discharge management – can be taken to improve outcomes, according to Dr. Darcy Marciniuk.

Although scientific guidance on when patients should be admitted is lacking, guidelines and consensus statements suggest that patients with an exacerbation should be admitted:

• If they experience a marked increase in dyspnea.

• If they have severe underlying COPD with little reserve, "such that there’s no room for error."

• If they fail to respond to initial management.

• If they have comorbidities, including heart failure, arrhythmias, or renal impairment.

• If they have advanced age.

• If they experience frequent severe exacerbations.

• If they have insufficient home support.

Once a patient is admitted, controlled appropriate supplemental oxygen should be administered as directed by Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, noninvasive ventilation should be used when indicated, aggressive therapies should be used at the outset, and use of antibiotics or systemic corticosteroids should be considered, said Dr. Marciniuk, AACP president, and head of the division of respirology, critical care, and sleep medicine at the University of Saskatchewan, Saskatoon, Canada.

An effort should also be made to identify the precipitating factor, to recognize and optimize, or prevent comorbid conditions, to prevent complications, and to address depressions and anxiety, he said.

With respect to supplemental oxygen, the GOLD guidelines will help ensure there is "always enough, but never too much," Dr. Marciniuk said.

"Now, with saturation monitors, life is good; it’s very easy to make sure patients receive appropriate therapy," he added.

He also spotlighted noninvasive ventilation. It has revolutionized in-hospital COPD management, lowering intubation rates by 60% and substantially decreasing in-hospital mortality, he said.

"Noninvasive ventilation has been incredible for our patients," he said.

Although it was first used in the 1980s, it is now "really the treatment of choice for acute hypercapnic respiratory failure in this setting," he added.

Contrary to some beliefs about outcomes with COPD in the intensive care unit, mortality is actually much lower than for many other conditions. For example, mortality in COPD patients in the ICU is about half that of patients with sepsis or acute respiratory distress syndrome.

"So, even though a patient may look short of breath, and someone may think they have a poor quality of life, it is the patients who should be judging that," he said, adding: "There needs to be that comfort, that back-up, of the ICU, because data would suggest the outcomes are pretty good."

There is significant evidence of benefit with the use of noninvasive ventilation, particularly with respiratory acidosis of pH less than 7.35, PCO₂ greater than 45, and significant dyspnea, which is easily detected by clinical means, he added.

Depression in COPD patients is also particularly important to address.

Studies show that patients with depression have longer hospital stays (twice as long, according to one observational study), more frequent exacerbations in the year following discharge, and higher mortality rates, he said, acknowledging that "our understanding of the co-presence of depression and anxiety (in COPD patients) is growing, but our understanding that it appears to [have an impact] in this setting is also growing."

As for discharge planning, appropriate methods and practices must be put in place for reducing the future risk of acute exacerbations, he said.

Dr. Marciniuk reported having no financial disclosures, with the exception of research funding directed to and managed by his institution.

ATLANTA – Data suggest that only about a third of patients hospitalized for chronic obstructive pulmonary disease receive appropriate care, but a number of steps – beginning with decisions about when to admit and ending with proper discharge management – can be taken to improve outcomes, according to Dr. Darcy Marciniuk.

Although scientific guidance on when patients should be admitted is lacking, guidelines and consensus statements suggest that patients with an exacerbation should be admitted:

• If they experience a marked increase in dyspnea.

• If they have severe underlying COPD with little reserve, "such that there’s no room for error."

• If they fail to respond to initial management.

• If they have comorbidities, including heart failure, arrhythmias, or renal impairment.

• If they have advanced age.

• If they experience frequent severe exacerbations.

• If they have insufficient home support.

Once a patient is admitted, controlled appropriate supplemental oxygen should be administered as directed by Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, noninvasive ventilation should be used when indicated, aggressive therapies should be used at the outset, and use of antibiotics or systemic corticosteroids should be considered, said Dr. Marciniuk, AACP president, and head of the division of respirology, critical care, and sleep medicine at the University of Saskatchewan, Saskatoon, Canada.

An effort should also be made to identify the precipitating factor, to recognize and optimize, or prevent comorbid conditions, to prevent complications, and to address depressions and anxiety, he said.

With respect to supplemental oxygen, the GOLD guidelines will help ensure there is "always enough, but never too much," Dr. Marciniuk said.

"Now, with saturation monitors, life is good; it’s very easy to make sure patients receive appropriate therapy," he added.

He also spotlighted noninvasive ventilation. It has revolutionized in-hospital COPD management, lowering intubation rates by 60% and substantially decreasing in-hospital mortality, he said.

"Noninvasive ventilation has been incredible for our patients," he said.

Although it was first used in the 1980s, it is now "really the treatment of choice for acute hypercapnic respiratory failure in this setting," he added.

Contrary to some beliefs about outcomes with COPD in the intensive care unit, mortality is actually much lower than for many other conditions. For example, mortality in COPD patients in the ICU is about half that of patients with sepsis or acute respiratory distress syndrome.

"So, even though a patient may look short of breath, and someone may think they have a poor quality of life, it is the patients who should be judging that," he said, adding: "There needs to be that comfort, that back-up, of the ICU, because data would suggest the outcomes are pretty good."

There is significant evidence of benefit with the use of noninvasive ventilation, particularly with respiratory acidosis of pH less than 7.35, PCO₂ greater than 45, and significant dyspnea, which is easily detected by clinical means, he added.

Depression in COPD patients is also particularly important to address.

Studies show that patients with depression have longer hospital stays (twice as long, according to one observational study), more frequent exacerbations in the year following discharge, and higher mortality rates, he said, acknowledging that "our understanding of the co-presence of depression and anxiety (in COPD patients) is growing, but our understanding that it appears to [have an impact] in this setting is also growing."

As for discharge planning, appropriate methods and practices must be put in place for reducing the future risk of acute exacerbations, he said.

Dr. Marciniuk reported having no financial disclosures, with the exception of research funding directed to and managed by his institution.

ATLANTA – Data suggest that only about a third of patients hospitalized for chronic obstructive pulmonary disease receive appropriate care, but a number of steps – beginning with decisions about when to admit and ending with proper discharge management – can be taken to improve outcomes, according to Dr. Darcy Marciniuk.

Although scientific guidance on when patients should be admitted is lacking, guidelines and consensus statements suggest that patients with an exacerbation should be admitted:

• If they experience a marked increase in dyspnea.

• If they have severe underlying COPD with little reserve, "such that there’s no room for error."

• If they fail to respond to initial management.

• If they have comorbidities, including heart failure, arrhythmias, or renal impairment.

• If they have advanced age.

• If they experience frequent severe exacerbations.

• If they have insufficient home support.

Once a patient is admitted, controlled appropriate supplemental oxygen should be administered as directed by Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, noninvasive ventilation should be used when indicated, aggressive therapies should be used at the outset, and use of antibiotics or systemic corticosteroids should be considered, said Dr. Marciniuk, AACP president, and head of the division of respirology, critical care, and sleep medicine at the University of Saskatchewan, Saskatoon, Canada.

An effort should also be made to identify the precipitating factor, to recognize and optimize, or prevent comorbid conditions, to prevent complications, and to address depressions and anxiety, he said.

With respect to supplemental oxygen, the GOLD guidelines will help ensure there is "always enough, but never too much," Dr. Marciniuk said.

"Now, with saturation monitors, life is good; it’s very easy to make sure patients receive appropriate therapy," he added.

He also spotlighted noninvasive ventilation. It has revolutionized in-hospital COPD management, lowering intubation rates by 60% and substantially decreasing in-hospital mortality, he said.

"Noninvasive ventilation has been incredible for our patients," he said.

Although it was first used in the 1980s, it is now "really the treatment of choice for acute hypercapnic respiratory failure in this setting," he added.

Contrary to some beliefs about outcomes with COPD in the intensive care unit, mortality is actually much lower than for many other conditions. For example, mortality in COPD patients in the ICU is about half that of patients with sepsis or acute respiratory distress syndrome.

"So, even though a patient may look short of breath, and someone may think they have a poor quality of life, it is the patients who should be judging that," he said, adding: "There needs to be that comfort, that back-up, of the ICU, because data would suggest the outcomes are pretty good."

There is significant evidence of benefit with the use of noninvasive ventilation, particularly with respiratory acidosis of pH less than 7.35, PCO₂ greater than 45, and significant dyspnea, which is easily detected by clinical means, he added.

Depression in COPD patients is also particularly important to address.

Studies show that patients with depression have longer hospital stays (twice as long, according to one observational study), more frequent exacerbations in the year following discharge, and higher mortality rates, he said, acknowledging that "our understanding of the co-presence of depression and anxiety (in COPD patients) is growing, but our understanding that it appears to [have an impact] in this setting is also growing."

As for discharge planning, appropriate methods and practices must be put in place for reducing the future risk of acute exacerbations, he said.

Dr. Marciniuk reported having no financial disclosures, with the exception of research funding directed to and managed by his institution.