Sharon Worcester

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.

WASHINGTON – A new model for estimating 10-year cardiovascular disease risk in patients with rheumatoid arthritis that draws on a combination of demographic factors, cardiovascular risk factors, and RA-related factors appears to more accurately predict risk than do currently available models.

The new model was developed based on findings from the prospective longitudinal CARRE study, Dr. Alper M. van Sijl reported at the annual meeting of the American College of Rheumatology.

In that study of 353 RA patients, 58 cardiovascular events occurred over 2,361 patient years of follow-up. The cardiovascular disease incidence was 16.4%, but existing, commonly used risk prediction models, including the Reynolds Risk Score, the Systemic Coronary Risk Evaluation (SCORE), and the Framingham Risk Score, underestimated the risk. At baseline, the SCORE and Framingham models, for example, estimated the incidence at 5.9% and 13%, respectively, said Dr. van Sijl of Jan van Breemen Research Institute, Reade, Amsterdam.

Using CARRE study information, including cardiovascular risk factors, RA-related factors, and surrogate markers of cardiovascular disease collected at baseline, predictive models using a number of variables alone or in combinations were tested. The new model for predicting risk in RA patients without prior cardiovascular disease that emerged included age, gender, use of statins and prednisone, body-mass index, diastolic blood pressure, low-density lipoprotein cholesterol, total cholesterol to high-density lipoprotein cholesterol ratio, C-reactive protein, Health Assessment Questionnaire scores, and erythrocyte sedimentation rate.

Using receiver operating curves analyses, the new model predicted cardiovascular disease incidence better than the other methods (area under the curve [AUC] 0.801 vs. 0.712), he said, noting that at a cutoff value of 10, the model had 85% sensitivity.

The findings are important because RA is associated with an increased risk of incident cardiovascular disease, which, according to the CARRE findings, has failed to decline significantly since 2000 despite the advent of effective anti-inflammatory therapies and the increased use of cardioprotective therapies. The risk is only partly explained by cardiovascular risk factors.

Additional external validation studies are needed to confirm these findings before the model can be implemented, and studies should also consider whether modification of existing risk models is necessary to improve the cardiovascular risk assessment of RA patients, he concluded.

Dr. van Sijl reported having no disclosures.

WASHINGTON – A new model for estimating 10-year cardiovascular disease risk in patients with rheumatoid arthritis that draws on a combination of demographic factors, cardiovascular risk factors, and RA-related factors appears to more accurately predict risk than do currently available models.

The new model was developed based on findings from the prospective longitudinal CARRE study, Dr. Alper M. van Sijl reported at the annual meeting of the American College of Rheumatology.

In that study of 353 RA patients, 58 cardiovascular events occurred over 2,361 patient years of follow-up. The cardiovascular disease incidence was 16.4%, but existing, commonly used risk prediction models, including the Reynolds Risk Score, the Systemic Coronary Risk Evaluation (SCORE), and the Framingham Risk Score, underestimated the risk. At baseline, the SCORE and Framingham models, for example, estimated the incidence at 5.9% and 13%, respectively, said Dr. van Sijl of Jan van Breemen Research Institute, Reade, Amsterdam.

Using CARRE study information, including cardiovascular risk factors, RA-related factors, and surrogate markers of cardiovascular disease collected at baseline, predictive models using a number of variables alone or in combinations were tested. The new model for predicting risk in RA patients without prior cardiovascular disease that emerged included age, gender, use of statins and prednisone, body-mass index, diastolic blood pressure, low-density lipoprotein cholesterol, total cholesterol to high-density lipoprotein cholesterol ratio, C-reactive protein, Health Assessment Questionnaire scores, and erythrocyte sedimentation rate.

Using receiver operating curves analyses, the new model predicted cardiovascular disease incidence better than the other methods (area under the curve [AUC] 0.801 vs. 0.712), he said, noting that at a cutoff value of 10, the model had 85% sensitivity.

The findings are important because RA is associated with an increased risk of incident cardiovascular disease, which, according to the CARRE findings, has failed to decline significantly since 2000 despite the advent of effective anti-inflammatory therapies and the increased use of cardioprotective therapies. The risk is only partly explained by cardiovascular risk factors.

Additional external validation studies are needed to confirm these findings before the model can be implemented, and studies should also consider whether modification of existing risk models is necessary to improve the cardiovascular risk assessment of RA patients, he concluded.

Dr. van Sijl reported having no disclosures.

WASHINGTON – A new model for estimating 10-year cardiovascular disease risk in patients with rheumatoid arthritis that draws on a combination of demographic factors, cardiovascular risk factors, and RA-related factors appears to more accurately predict risk than do currently available models.

The new model was developed based on findings from the prospective longitudinal CARRE study, Dr. Alper M. van Sijl reported at the annual meeting of the American College of Rheumatology.

In that study of 353 RA patients, 58 cardiovascular events occurred over 2,361 patient years of follow-up. The cardiovascular disease incidence was 16.4%, but existing, commonly used risk prediction models, including the Reynolds Risk Score, the Systemic Coronary Risk Evaluation (SCORE), and the Framingham Risk Score, underestimated the risk. At baseline, the SCORE and Framingham models, for example, estimated the incidence at 5.9% and 13%, respectively, said Dr. van Sijl of Jan van Breemen Research Institute, Reade, Amsterdam.

Using CARRE study information, including cardiovascular risk factors, RA-related factors, and surrogate markers of cardiovascular disease collected at baseline, predictive models using a number of variables alone or in combinations were tested. The new model for predicting risk in RA patients without prior cardiovascular disease that emerged included age, gender, use of statins and prednisone, body-mass index, diastolic blood pressure, low-density lipoprotein cholesterol, total cholesterol to high-density lipoprotein cholesterol ratio, C-reactive protein, Health Assessment Questionnaire scores, and erythrocyte sedimentation rate.

Using receiver operating curves analyses, the new model predicted cardiovascular disease incidence better than the other methods (area under the curve [AUC] 0.801 vs. 0.712), he said, noting that at a cutoff value of 10, the model had 85% sensitivity.

The findings are important because RA is associated with an increased risk of incident cardiovascular disease, which, according to the CARRE findings, has failed to decline significantly since 2000 despite the advent of effective anti-inflammatory therapies and the increased use of cardioprotective therapies. The risk is only partly explained by cardiovascular risk factors.

Additional external validation studies are needed to confirm these findings before the model can be implemented, and studies should also consider whether modification of existing risk models is necessary to improve the cardiovascular risk assessment of RA patients, he concluded.

Dr. van Sijl reported having no disclosures.

WASHINGTON – Rheumatoid arthritis–related autoantibodies are associated with subclinical and clinical atherosclerosis, according to findings from a prospective population-based study.

The results suggest that autoimmune factors play a role in the pathogenesis of atherosclerosis and cardiovascular disease (CVD) in rheumatoid arthritis (RA) patients, as well as in individuals without RA, Dr. Darcy S. Majka said at the annual meeting of the American College of Rheumatology.

Although the association between RA and CVD is well established, the exact mechanism is unknown.

"RA-related autoantibodies have been identified in individuals years before they develop RA, but most individuals with positive RA-related circulating autoantibodies do not develop clinical RA," said Dr. Majka of Northwestern University, Chicago.

In addition, preliminary data on stored serum samples from individuals without connective tissue disease demonstrated that circulating antiphospholipid antibodies measured in African Americans and whites were associated with subclinical atherosclerosis, she noted.

"This led us to develop the following conceptual model: We know that RA-related autoantibodies can produce inflammation and in some cases lead to possible progression to RA. In addition, the increased progression of subclinical atherosclerosis and cardiovascular events in RA is hypothesized to be mediated by the inflammation of clinically active RA. But we hypothesized that RA-related autoantibodies might be independently associated with subclinical atherosclerosis ... and this might potentially lead to progression to clinical cardiovascular events," she said, in describing the Multi-Ethnic Study of Atherosclerosis (MESA).

Indeed, in 6,557 middle-aged to elderly white, African American, Hispanic, and Chinese middle-aged to elderly adults who have been followed since 2000 as part of MESA, rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP-2) were associated with coronary artery calcium (CAC), a surrogate measure of subclinical atherosclerosis, in both white and African American women. The associations remained after investigators adjusted for traditional risk factors, including age, smoking status, blood pressure, body mass index, high-density lipoprotein cholesterol level, low-density lipoprotein cholesterol level, diabetes mellitus, aspirin use, and cholesterol and blood pressure medication use, she said.

A CAC level of at least 300 was present in 12.2% of participants at baseline, and after 7.1 years of follow-up, 3.0% experienced hard coronary heart disease (CHD) end points, including myocardial infarction, resuscitated cardiac arrest, and CHD death, and 4.8% experienced hard cardiovascular disease end points, including myocardial infarction, cardiac arrest, CHD death, stroke, and stroke death.

Rheumatoid factor (RF) IgM, RF IgA, and anti-CCP-2 were positive in 15.9%, 8.7%, and 2.0% of the MESA participants, respectively. In addition, 4.0% were positive for both RF IgM and RF IgA, and 20.6% were positive for one RF isotype.

The associations between baseline RF/anti-CCP and CAC were assessed and stratified based on race and sex, with adjustment for traditional cardiovascular risk factors.

Among the 1,323 white women in the study, those with RF IgA positivity, either RF IgM or RF IgA positivity, and/or anti-CCP-2 had an increased likelihood of having a CAC level greater than 300 (adjusted odds ratios of 2.3, 1.7, and 0.9 respectively, vs. a CAC of 0). Among 1,000 African American women in the study, those with RF IgA positivity or both RF IgM and RF IgA positivity had an increased likelihood of a CAC level between 100 and 300 (adjusted odds ratios, 2.2 and 2.7, respectively), and those with anti-CCP-2 had an increased likelihood of a CAC level greater than 300 (adjusted odds ratio, 4.0).

In addition, strong associations between RA-related autoantibodies and clinical cardiovascular disease events were seen in African American women in the study. For example, those with RF IgA positivity, either RF IgM or RF IgA positivity, or both RF isotypes were at increased risk of CHD hard end points (adjusted hazard ratios of 5, 2.5, and 4.5, respectively), Also, those with RF IgM positivity were at increased risk for CVD hard end points (adjusted hazard ratio, 2.1). Dr. Majka said.

No clear associations were seen between RA-related autoantibodies and CAC or CHD and CVD hard events in Hispanic and Chinese participants.

"RA-related autoantibodies appear to be independent risk factors for subclinical atherosclerosis and subsequent clinical CVD events," Dr. Majka concluded.

She reported having no relevant financial disclosures.

WASHINGTON – Rheumatoid arthritis–related autoantibodies are associated with subclinical and clinical atherosclerosis, according to findings from a prospective population-based study.

The results suggest that autoimmune factors play a role in the pathogenesis of atherosclerosis and cardiovascular disease (CVD) in rheumatoid arthritis (RA) patients, as well as in individuals without RA, Dr. Darcy S. Majka said at the annual meeting of the American College of Rheumatology.

Although the association between RA and CVD is well established, the exact mechanism is unknown.

"RA-related autoantibodies have been identified in individuals years before they develop RA, but most individuals with positive RA-related circulating autoantibodies do not develop clinical RA," said Dr. Majka of Northwestern University, Chicago.

In addition, preliminary data on stored serum samples from individuals without connective tissue disease demonstrated that circulating antiphospholipid antibodies measured in African Americans and whites were associated with subclinical atherosclerosis, she noted.

"This led us to develop the following conceptual model: We know that RA-related autoantibodies can produce inflammation and in some cases lead to possible progression to RA. In addition, the increased progression of subclinical atherosclerosis and cardiovascular events in RA is hypothesized to be mediated by the inflammation of clinically active RA. But we hypothesized that RA-related autoantibodies might be independently associated with subclinical atherosclerosis ... and this might potentially lead to progression to clinical cardiovascular events," she said, in describing the Multi-Ethnic Study of Atherosclerosis (MESA).

Indeed, in 6,557 middle-aged to elderly white, African American, Hispanic, and Chinese middle-aged to elderly adults who have been followed since 2000 as part of MESA, rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP-2) were associated with coronary artery calcium (CAC), a surrogate measure of subclinical atherosclerosis, in both white and African American women. The associations remained after investigators adjusted for traditional risk factors, including age, smoking status, blood pressure, body mass index, high-density lipoprotein cholesterol level, low-density lipoprotein cholesterol level, diabetes mellitus, aspirin use, and cholesterol and blood pressure medication use, she said.

A CAC level of at least 300 was present in 12.2% of participants at baseline, and after 7.1 years of follow-up, 3.0% experienced hard coronary heart disease (CHD) end points, including myocardial infarction, resuscitated cardiac arrest, and CHD death, and 4.8% experienced hard cardiovascular disease end points, including myocardial infarction, cardiac arrest, CHD death, stroke, and stroke death.

Rheumatoid factor (RF) IgM, RF IgA, and anti-CCP-2 were positive in 15.9%, 8.7%, and 2.0% of the MESA participants, respectively. In addition, 4.0% were positive for both RF IgM and RF IgA, and 20.6% were positive for one RF isotype.

The associations between baseline RF/anti-CCP and CAC were assessed and stratified based on race and sex, with adjustment for traditional cardiovascular risk factors.

Among the 1,323 white women in the study, those with RF IgA positivity, either RF IgM or RF IgA positivity, and/or anti-CCP-2 had an increased likelihood of having a CAC level greater than 300 (adjusted odds ratios of 2.3, 1.7, and 0.9 respectively, vs. a CAC of 0). Among 1,000 African American women in the study, those with RF IgA positivity or both RF IgM and RF IgA positivity had an increased likelihood of a CAC level between 100 and 300 (adjusted odds ratios, 2.2 and 2.7, respectively), and those with anti-CCP-2 had an increased likelihood of a CAC level greater than 300 (adjusted odds ratio, 4.0).

In addition, strong associations between RA-related autoantibodies and clinical cardiovascular disease events were seen in African American women in the study. For example, those with RF IgA positivity, either RF IgM or RF IgA positivity, or both RF isotypes were at increased risk of CHD hard end points (adjusted hazard ratios of 5, 2.5, and 4.5, respectively), Also, those with RF IgM positivity were at increased risk for CVD hard end points (adjusted hazard ratio, 2.1). Dr. Majka said.

No clear associations were seen between RA-related autoantibodies and CAC or CHD and CVD hard events in Hispanic and Chinese participants.

"RA-related autoantibodies appear to be independent risk factors for subclinical atherosclerosis and subsequent clinical CVD events," Dr. Majka concluded.

She reported having no relevant financial disclosures.

WASHINGTON – Rheumatoid arthritis–related autoantibodies are associated with subclinical and clinical atherosclerosis, according to findings from a prospective population-based study.

The results suggest that autoimmune factors play a role in the pathogenesis of atherosclerosis and cardiovascular disease (CVD) in rheumatoid arthritis (RA) patients, as well as in individuals without RA, Dr. Darcy S. Majka said at the annual meeting of the American College of Rheumatology.

Although the association between RA and CVD is well established, the exact mechanism is unknown.

"RA-related autoantibodies have been identified in individuals years before they develop RA, but most individuals with positive RA-related circulating autoantibodies do not develop clinical RA," said Dr. Majka of Northwestern University, Chicago.

In addition, preliminary data on stored serum samples from individuals without connective tissue disease demonstrated that circulating antiphospholipid antibodies measured in African Americans and whites were associated with subclinical atherosclerosis, she noted.

"This led us to develop the following conceptual model: We know that RA-related autoantibodies can produce inflammation and in some cases lead to possible progression to RA. In addition, the increased progression of subclinical atherosclerosis and cardiovascular events in RA is hypothesized to be mediated by the inflammation of clinically active RA. But we hypothesized that RA-related autoantibodies might be independently associated with subclinical atherosclerosis ... and this might potentially lead to progression to clinical cardiovascular events," she said, in describing the Multi-Ethnic Study of Atherosclerosis (MESA).

Indeed, in 6,557 middle-aged to elderly white, African American, Hispanic, and Chinese middle-aged to elderly adults who have been followed since 2000 as part of MESA, rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP-2) were associated with coronary artery calcium (CAC), a surrogate measure of subclinical atherosclerosis, in both white and African American women. The associations remained after investigators adjusted for traditional risk factors, including age, smoking status, blood pressure, body mass index, high-density lipoprotein cholesterol level, low-density lipoprotein cholesterol level, diabetes mellitus, aspirin use, and cholesterol and blood pressure medication use, she said.

A CAC level of at least 300 was present in 12.2% of participants at baseline, and after 7.1 years of follow-up, 3.0% experienced hard coronary heart disease (CHD) end points, including myocardial infarction, resuscitated cardiac arrest, and CHD death, and 4.8% experienced hard cardiovascular disease end points, including myocardial infarction, cardiac arrest, CHD death, stroke, and stroke death.

Rheumatoid factor (RF) IgM, RF IgA, and anti-CCP-2 were positive in 15.9%, 8.7%, and 2.0% of the MESA participants, respectively. In addition, 4.0% were positive for both RF IgM and RF IgA, and 20.6% were positive for one RF isotype.

The associations between baseline RF/anti-CCP and CAC were assessed and stratified based on race and sex, with adjustment for traditional cardiovascular risk factors.

Among the 1,323 white women in the study, those with RF IgA positivity, either RF IgM or RF IgA positivity, and/or anti-CCP-2 had an increased likelihood of having a CAC level greater than 300 (adjusted odds ratios of 2.3, 1.7, and 0.9 respectively, vs. a CAC of 0). Among 1,000 African American women in the study, those with RF IgA positivity or both RF IgM and RF IgA positivity had an increased likelihood of a CAC level between 100 and 300 (adjusted odds ratios, 2.2 and 2.7, respectively), and those with anti-CCP-2 had an increased likelihood of a CAC level greater than 300 (adjusted odds ratio, 4.0).

In addition, strong associations between RA-related autoantibodies and clinical cardiovascular disease events were seen in African American women in the study. For example, those with RF IgA positivity, either RF IgM or RF IgA positivity, or both RF isotypes were at increased risk of CHD hard end points (adjusted hazard ratios of 5, 2.5, and 4.5, respectively), Also, those with RF IgM positivity were at increased risk for CVD hard end points (adjusted hazard ratio, 2.1). Dr. Majka said.

No clear associations were seen between RA-related autoantibodies and CAC or CHD and CVD hard events in Hispanic and Chinese participants.

"RA-related autoantibodies appear to be independent risk factors for subclinical atherosclerosis and subsequent clinical CVD events," Dr. Majka concluded.

She reported having no relevant financial disclosures.

ATLANTA – Medical thoracoscopy is safe and feasible for performing lung biopsy in patients with diffuse parenchymal lung disease of unknown etiology on high-resolution computed tomography. And the approach could serve as an alternative to surgical biopsy in some patients, findings from a prospective study suggest.

In 10 patients who underwent medical thoracoscopic lung biopsies as part of the study, good biopsy specimens, with an average size of 0.5 x 0.4 cm were obtained, Dr. Mohamed Elnady said at the annual meeting of the American College of Chest Physicians.

Complications with this advanced technique included persistent air leak for 5-7 days in two patients, pneumothorax after removal of the intercostals tube in two patients, pain in six patients, and minor bleeding in one patient. The air leaks resolved spontaneously, and the pneumothoraces resolved with administration of high flow oxygen, said Dr. Elnady of Cairo (Egypt) University Hospitals.

The mean duration of intercostal tube placement was 3.1 days, with a range of 1-7 days; no infection, respiratory failure requiring intensive care unit admission, or mortality occurred within 30 days after the procedure, he noted.

Patients in the study included four women and six men with a mean age of 42 years. The lung biopsies obtained via medical thoracoscopy were sent for histopathologic examination, and patients underwent follow-up by chest x-ray for confirmation of lung expansion, as well as observation of the intercostal tube to detect complications. Among the ultimate diagnoses were metastatic adenocarcinoma, interstitial lung disease, and lymphangioleiomyomatosis.

"Thoracosopic lung biopsy by medical thoracoscopy is useful in the diagnosis of patient with diffuse pulmonary infiltrates of unknown etiology when lung biopsy is needed for an accurate diagnosis," Dr. Elnady concluded, noting that while the procedure does carry a risk of certain non–life-threatening complications, these can be minimized with good patient selection.

Commenting on the findings, Dr. Muthiah P. Muthiah, who moderated the session, said this novel approach to obtaining a lung biopsy is of interest, but also "something we still have to get comfortable with."

"I’m not ready to do this yet, but this is something to consider ... you will want to certainly do this with a surgeon’s back-up in your institution," said Dr. Muthiah of the University of Tennessee Health Science Center, Memphis.

Neither Dr. Muthiah nor Dr. Elnady had disclosures to report.

ATLANTA – Medical thoracoscopy is safe and feasible for performing lung biopsy in patients with diffuse parenchymal lung disease of unknown etiology on high-resolution computed tomography. And the approach could serve as an alternative to surgical biopsy in some patients, findings from a prospective study suggest.

In 10 patients who underwent medical thoracoscopic lung biopsies as part of the study, good biopsy specimens, with an average size of 0.5 x 0.4 cm were obtained, Dr. Mohamed Elnady said at the annual meeting of the American College of Chest Physicians.

Complications with this advanced technique included persistent air leak for 5-7 days in two patients, pneumothorax after removal of the intercostals tube in two patients, pain in six patients, and minor bleeding in one patient. The air leaks resolved spontaneously, and the pneumothoraces resolved with administration of high flow oxygen, said Dr. Elnady of Cairo (Egypt) University Hospitals.

The mean duration of intercostal tube placement was 3.1 days, with a range of 1-7 days; no infection, respiratory failure requiring intensive care unit admission, or mortality occurred within 30 days after the procedure, he noted.

Patients in the study included four women and six men with a mean age of 42 years. The lung biopsies obtained via medical thoracoscopy were sent for histopathologic examination, and patients underwent follow-up by chest x-ray for confirmation of lung expansion, as well as observation of the intercostal tube to detect complications. Among the ultimate diagnoses were metastatic adenocarcinoma, interstitial lung disease, and lymphangioleiomyomatosis.

"Thoracosopic lung biopsy by medical thoracoscopy is useful in the diagnosis of patient with diffuse pulmonary infiltrates of unknown etiology when lung biopsy is needed for an accurate diagnosis," Dr. Elnady concluded, noting that while the procedure does carry a risk of certain non–life-threatening complications, these can be minimized with good patient selection.

Commenting on the findings, Dr. Muthiah P. Muthiah, who moderated the session, said this novel approach to obtaining a lung biopsy is of interest, but also "something we still have to get comfortable with."

"I’m not ready to do this yet, but this is something to consider ... you will want to certainly do this with a surgeon’s back-up in your institution," said Dr. Muthiah of the University of Tennessee Health Science Center, Memphis.

Neither Dr. Muthiah nor Dr. Elnady had disclosures to report.

ATLANTA – Medical thoracoscopy is safe and feasible for performing lung biopsy in patients with diffuse parenchymal lung disease of unknown etiology on high-resolution computed tomography. And the approach could serve as an alternative to surgical biopsy in some patients, findings from a prospective study suggest.

In 10 patients who underwent medical thoracoscopic lung biopsies as part of the study, good biopsy specimens, with an average size of 0.5 x 0.4 cm were obtained, Dr. Mohamed Elnady said at the annual meeting of the American College of Chest Physicians.

Complications with this advanced technique included persistent air leak for 5-7 days in two patients, pneumothorax after removal of the intercostals tube in two patients, pain in six patients, and minor bleeding in one patient. The air leaks resolved spontaneously, and the pneumothoraces resolved with administration of high flow oxygen, said Dr. Elnady of Cairo (Egypt) University Hospitals.

The mean duration of intercostal tube placement was 3.1 days, with a range of 1-7 days; no infection, respiratory failure requiring intensive care unit admission, or mortality occurred within 30 days after the procedure, he noted.

Patients in the study included four women and six men with a mean age of 42 years. The lung biopsies obtained via medical thoracoscopy were sent for histopathologic examination, and patients underwent follow-up by chest x-ray for confirmation of lung expansion, as well as observation of the intercostal tube to detect complications. Among the ultimate diagnoses were metastatic adenocarcinoma, interstitial lung disease, and lymphangioleiomyomatosis.

"Thoracosopic lung biopsy by medical thoracoscopy is useful in the diagnosis of patient with diffuse pulmonary infiltrates of unknown etiology when lung biopsy is needed for an accurate diagnosis," Dr. Elnady concluded, noting that while the procedure does carry a risk of certain non–life-threatening complications, these can be minimized with good patient selection.

Commenting on the findings, Dr. Muthiah P. Muthiah, who moderated the session, said this novel approach to obtaining a lung biopsy is of interest, but also "something we still have to get comfortable with."

"I’m not ready to do this yet, but this is something to consider ... you will want to certainly do this with a surgeon’s back-up in your institution," said Dr. Muthiah of the University of Tennessee Health Science Center, Memphis.

Neither Dr. Muthiah nor Dr. Elnady had disclosures to report.