Caroline Helwick

CHICAGO – Several modifiable technical factors can influence detection of colorectal adenomas, as can lifestyle factors, based on data from a large study conducted in the United Kingdom.

The findings came from the National Health Service (NHS) Bowel Cancer Screening Program, the largest study to examine the effects of patient and physician factors on adenoma detection during colonoscopy. The colonoscopies in this study were done to follow-up on positive fecal occult blood test (FOBT) results, said Dr. Tom J. Lee of Newcastle (U.K.) University, who presented the data at the annual Digestive Disease Week.

"Many factors affect the chance of an adenoma being detected," he said, "including patient factors, both modifiable and nonmodifiable, and colonoscopy factors, which are usually technical."

The NHS program offers a colonoscopy to any person aged 60-74 years who has a positive FOBT result. "It is a unique opportunity to study the interplay of factors that influence adenoma detection," Dr. Lee said.

From 2006 to 2009, fecal occult blood tests were returned by 2,269,983 persons (mean age 66 years; 60% male), and 2% of these were positive. The total number of colonoscopies (performed by 177 experienced endoscopists at 50 screening centers) was 36,460, of which 31,088 were included in this analysis. Of the patients who underwent colonoscopy, 14,423 (46%) had at least one adenoma.

Data were collected on cecal intubation, rectal retroversion, mean withdrawal time for the endoscopist, quality of bowel prep, use of the antispasmodic hyoscine butylbromide, start time of the procedure, and sedation use. Patient factors included gender, age, smoking and alcohol status, and geographic area.

Adverse lifestyle can negate protection for women

In the multivariate analysis, risk for adenomas was significantly associated with male gender, older age, current or previous smoking, and current alcohol use.

Men were more likely than women to have adenomas, and poor lifestyle habits elevated the risk further beyond that from gender alone. Among patients who did not drink or smoke, 45% of men had one or more adenomas, compared with 32% of women.

In men, this rate rose progressively according to alcohol and smoking status, exceeding 60% for men who reported current smoking and alcohol intake, Dr. Lee said. The same pattern held true for women; those reporting current alcohol intake and cigarette use had a 43% risk of having an adenoma.

All the associations were highly significant for the detection of any adenomas, advanced adenomas, and right-sided adenomas at a P value less than .001.

"Female smokers who drink had a significantly higher risk than men who did not smoke or drink. We found that adverse lifestyle factors can overcome gender protection from adenomas in females," Dr. Lee reported. "This stresses the importance of lifestyle factors in the development of adenomas."

In addition, older age was a significant factor, as was geographic area, even after adjustment for other factors. "There was a significant variation in risk depending on where the procedure was done," he said.

Technical factors linked to detection rate

The technical or procedural factors that were significantly associated with detection of adenomas were cecal intubation, longer withdrawal time, higher-quality bowel preparation, use of an intravenous antispasmodic, earlier procedure start time, and greater colonoscopist experience, Dr. Lee reported.

Similar results were found for the effect of these factors on detection of advanced adenomas and right-sided adenomas.

Procedures in which the cecum was reached had a threefold greater likelihood of detecting adenomas overall (P less than .001), and a more than fivefold greater likelihood in the right colon (P less than .001). A mean withdrawal time for the endoscopist greater than or equal to 10 minutes increased the detection rate by 10% overall and by 28% in the right colon (P less than .001). Bowel prep that was adequate or better was associated with an almost 40% increased chance for detection (P less than .001) and the use of hyoscine was associated with a 30% increase (P less than .001), although it is possible that hyoscine use is "an indicator of a good colonoscopist," Dr. Lee suggested.

The association with the time of day offers "fascinating insight into colonoscopists’ behavior," he added. As the day progressed from 8 a.m. to noon, there was no change in cecal intubation, bowel prep, or withdrawal times, but adenoma detection diminished from nearly 48% to 45%. Adenoma detection rates rose again until 3 p.m., then dropped back to around 45%, creating a "biphasic" pattern, he noted.

"Interestingly, procedures in which rectal retroversion was performed were not associated with increased detection of one or more adenomas and did not increase the detection of rectal adenomas," he added. There was also no association with sedation.

Dr. Lee acknowledged the study’s limitations: it was not a randomized controlled trial, certain risk factors (family history, NSAID use) were not accounted for, and the scoring tools were also not validated, especially for bowel prep quality.

"Our study probably raises more questions than it answers," he acknowledged. Further study of geographical variations, time of day variations, and nontechnical colonoscopy factors should be performed, he suggested. Meanwhile, at least one current recommendation can be emphasized: that colonoscope withdrawal time should be at least 10 minutes, he said.

Dr. Lee had no relevant financial disclosures.

CHICAGO – Several modifiable technical factors can influence detection of colorectal adenomas, as can lifestyle factors, based on data from a large study conducted in the United Kingdom.

The findings came from the National Health Service (NHS) Bowel Cancer Screening Program, the largest study to examine the effects of patient and physician factors on adenoma detection during colonoscopy. The colonoscopies in this study were done to follow-up on positive fecal occult blood test (FOBT) results, said Dr. Tom J. Lee of Newcastle (U.K.) University, who presented the data at the annual Digestive Disease Week.

"Many factors affect the chance of an adenoma being detected," he said, "including patient factors, both modifiable and nonmodifiable, and colonoscopy factors, which are usually technical."

The NHS program offers a colonoscopy to any person aged 60-74 years who has a positive FOBT result. "It is a unique opportunity to study the interplay of factors that influence adenoma detection," Dr. Lee said.

From 2006 to 2009, fecal occult blood tests were returned by 2,269,983 persons (mean age 66 years; 60% male), and 2% of these were positive. The total number of colonoscopies (performed by 177 experienced endoscopists at 50 screening centers) was 36,460, of which 31,088 were included in this analysis. Of the patients who underwent colonoscopy, 14,423 (46%) had at least one adenoma.

Data were collected on cecal intubation, rectal retroversion, mean withdrawal time for the endoscopist, quality of bowel prep, use of the antispasmodic hyoscine butylbromide, start time of the procedure, and sedation use. Patient factors included gender, age, smoking and alcohol status, and geographic area.

Adverse lifestyle can negate protection for women

In the multivariate analysis, risk for adenomas was significantly associated with male gender, older age, current or previous smoking, and current alcohol use.

Men were more likely than women to have adenomas, and poor lifestyle habits elevated the risk further beyond that from gender alone. Among patients who did not drink or smoke, 45% of men had one or more adenomas, compared with 32% of women.

In men, this rate rose progressively according to alcohol and smoking status, exceeding 60% for men who reported current smoking and alcohol intake, Dr. Lee said. The same pattern held true for women; those reporting current alcohol intake and cigarette use had a 43% risk of having an adenoma.

All the associations were highly significant for the detection of any adenomas, advanced adenomas, and right-sided adenomas at a P value less than .001.

"Female smokers who drink had a significantly higher risk than men who did not smoke or drink. We found that adverse lifestyle factors can overcome gender protection from adenomas in females," Dr. Lee reported. "This stresses the importance of lifestyle factors in the development of adenomas."

In addition, older age was a significant factor, as was geographic area, even after adjustment for other factors. "There was a significant variation in risk depending on where the procedure was done," he said.

Technical factors linked to detection rate

The technical or procedural factors that were significantly associated with detection of adenomas were cecal intubation, longer withdrawal time, higher-quality bowel preparation, use of an intravenous antispasmodic, earlier procedure start time, and greater colonoscopist experience, Dr. Lee reported.

Similar results were found for the effect of these factors on detection of advanced adenomas and right-sided adenomas.

Procedures in which the cecum was reached had a threefold greater likelihood of detecting adenomas overall (P less than .001), and a more than fivefold greater likelihood in the right colon (P less than .001). A mean withdrawal time for the endoscopist greater than or equal to 10 minutes increased the detection rate by 10% overall and by 28% in the right colon (P less than .001). Bowel prep that was adequate or better was associated with an almost 40% increased chance for detection (P less than .001) and the use of hyoscine was associated with a 30% increase (P less than .001), although it is possible that hyoscine use is "an indicator of a good colonoscopist," Dr. Lee suggested.

The association with the time of day offers "fascinating insight into colonoscopists’ behavior," he added. As the day progressed from 8 a.m. to noon, there was no change in cecal intubation, bowel prep, or withdrawal times, but adenoma detection diminished from nearly 48% to 45%. Adenoma detection rates rose again until 3 p.m., then dropped back to around 45%, creating a "biphasic" pattern, he noted.

"Interestingly, procedures in which rectal retroversion was performed were not associated with increased detection of one or more adenomas and did not increase the detection of rectal adenomas," he added. There was also no association with sedation.

Dr. Lee acknowledged the study’s limitations: it was not a randomized controlled trial, certain risk factors (family history, NSAID use) were not accounted for, and the scoring tools were also not validated, especially for bowel prep quality.

"Our study probably raises more questions than it answers," he acknowledged. Further study of geographical variations, time of day variations, and nontechnical colonoscopy factors should be performed, he suggested. Meanwhile, at least one current recommendation can be emphasized: that colonoscope withdrawal time should be at least 10 minutes, he said.

Dr. Lee had no relevant financial disclosures.

CHICAGO – Several modifiable technical factors can influence detection of colorectal adenomas, as can lifestyle factors, based on data from a large study conducted in the United Kingdom.

The findings came from the National Health Service (NHS) Bowel Cancer Screening Program, the largest study to examine the effects of patient and physician factors on adenoma detection during colonoscopy. The colonoscopies in this study were done to follow-up on positive fecal occult blood test (FOBT) results, said Dr. Tom J. Lee of Newcastle (U.K.) University, who presented the data at the annual Digestive Disease Week.

"Many factors affect the chance of an adenoma being detected," he said, "including patient factors, both modifiable and nonmodifiable, and colonoscopy factors, which are usually technical."

The NHS program offers a colonoscopy to any person aged 60-74 years who has a positive FOBT result. "It is a unique opportunity to study the interplay of factors that influence adenoma detection," Dr. Lee said.

From 2006 to 2009, fecal occult blood tests were returned by 2,269,983 persons (mean age 66 years; 60% male), and 2% of these were positive. The total number of colonoscopies (performed by 177 experienced endoscopists at 50 screening centers) was 36,460, of which 31,088 were included in this analysis. Of the patients who underwent colonoscopy, 14,423 (46%) had at least one adenoma.

Data were collected on cecal intubation, rectal retroversion, mean withdrawal time for the endoscopist, quality of bowel prep, use of the antispasmodic hyoscine butylbromide, start time of the procedure, and sedation use. Patient factors included gender, age, smoking and alcohol status, and geographic area.

Adverse lifestyle can negate protection for women

In the multivariate analysis, risk for adenomas was significantly associated with male gender, older age, current or previous smoking, and current alcohol use.

Men were more likely than women to have adenomas, and poor lifestyle habits elevated the risk further beyond that from gender alone. Among patients who did not drink or smoke, 45% of men had one or more adenomas, compared with 32% of women.

In men, this rate rose progressively according to alcohol and smoking status, exceeding 60% for men who reported current smoking and alcohol intake, Dr. Lee said. The same pattern held true for women; those reporting current alcohol intake and cigarette use had a 43% risk of having an adenoma.

All the associations were highly significant for the detection of any adenomas, advanced adenomas, and right-sided adenomas at a P value less than .001.

"Female smokers who drink had a significantly higher risk than men who did not smoke or drink. We found that adverse lifestyle factors can overcome gender protection from adenomas in females," Dr. Lee reported. "This stresses the importance of lifestyle factors in the development of adenomas."

In addition, older age was a significant factor, as was geographic area, even after adjustment for other factors. "There was a significant variation in risk depending on where the procedure was done," he said.

Technical factors linked to detection rate

The technical or procedural factors that were significantly associated with detection of adenomas were cecal intubation, longer withdrawal time, higher-quality bowel preparation, use of an intravenous antispasmodic, earlier procedure start time, and greater colonoscopist experience, Dr. Lee reported.

Similar results were found for the effect of these factors on detection of advanced adenomas and right-sided adenomas.

Procedures in which the cecum was reached had a threefold greater likelihood of detecting adenomas overall (P less than .001), and a more than fivefold greater likelihood in the right colon (P less than .001). A mean withdrawal time for the endoscopist greater than or equal to 10 minutes increased the detection rate by 10% overall and by 28% in the right colon (P less than .001). Bowel prep that was adequate or better was associated with an almost 40% increased chance for detection (P less than .001) and the use of hyoscine was associated with a 30% increase (P less than .001), although it is possible that hyoscine use is "an indicator of a good colonoscopist," Dr. Lee suggested.

The association with the time of day offers "fascinating insight into colonoscopists’ behavior," he added. As the day progressed from 8 a.m. to noon, there was no change in cecal intubation, bowel prep, or withdrawal times, but adenoma detection diminished from nearly 48% to 45%. Adenoma detection rates rose again until 3 p.m., then dropped back to around 45%, creating a "biphasic" pattern, he noted.

"Interestingly, procedures in which rectal retroversion was performed were not associated with increased detection of one or more adenomas and did not increase the detection of rectal adenomas," he added. There was also no association with sedation.

Dr. Lee acknowledged the study’s limitations: it was not a randomized controlled trial, certain risk factors (family history, NSAID use) were not accounted for, and the scoring tools were also not validated, especially for bowel prep quality.

"Our study probably raises more questions than it answers," he acknowledged. Further study of geographical variations, time of day variations, and nontechnical colonoscopy factors should be performed, he suggested. Meanwhile, at least one current recommendation can be emphasized: that colonoscope withdrawal time should be at least 10 minutes, he said.

Dr. Lee had no relevant financial disclosures.

CHICAGO – Regular use of proton pump inhibitors is associated with an elevated risk of hip fractures, even after adjusting for important lifestyle risk factors, according to the findings of a prospective evaluation from the Nurses’ Health Study.

The association was most striking for women with a history of smoking, observed Dr. Hamed Khalili of Massachusetts General Hospital, Boston.

The Food and Drug Association recently issued an advisory regarding a potential link between PPIs and fractures. While acid-suppressing medications have been hypothesized to increase the risk of osteoporotic fractures, studies examining this association have been inconsistent. These analyses have mostly been based on retrospective studies of small populations that have not controlled for important dietary and lifestyle confounders, and they have ascertained PPI use only at a single time point, Dr. Khalili said.

The current study aimed to be more definitive by prospectively examining the relationship between chronic PPI use and incident hip fracture among 79,899 postmenopausal women enrolled in the Nurses’ Health Study, he said.

"We found that longer duration of use was associated with increased risk, and the strongest risk was confined to individuals with a history of smoking. ... Our findings support the recent decision of the FDA to revise labeling of PPIs to incorporate concerns about a possible increase in the risk of fractures," he said at the annual Digestive Disease Week.

In 1982, participants in the Nurses’ Health Study were first asked to report all previous fractures and were queried biennially for new fractures. Among the nearly 80,000 subjects, with 565,786 person-years of follow-up, there were 893 incident hip fractures over 8 years. PPI use was reported by 7% of participants in 2000 and by 19% of participants in 2008.

Regular use of PPIs posed fracture risks of 35%-45% when adjusted for age, calcium intake, and body mass index. The fully adjusted hazard ratio was 1.37, Dr. Khalili reported.

Current smoking status stood out as a significant effect modifier. Women who were current or past smokers and who regularly took a PPI had a 51% increased risk for fracture. In contrast, women who never smoked had only a 6% increased risk, "almost equal to women who never used PPIs," he noted.

Longer duration of use was associated with greater risk. Compared with never-users, risk in the multivariate analysis was 36% after 2 years of use, 42% after 4 years and 54% when PPIs were used for 6 years or longer (P less than 0.001), he said.

The investigators adjusted for multiple other risk factors, including physical activity; alcohol intake; total daily calcium and vitamin D intake; history of osteoporosis; and use of hormone replacement therapy, bisphosphonates, and thiazides. "This did not materially alter this association," he noted.

When PPIs were discontinued, the risks declined. Two or more years after discontinuation, the risk of hip fracture was just 9%-10%, he noted.

"The strengths of our study are that it offers detailed, prospectively collected and validated information on PPI use and other risk factors. We had a high response rate, and the participants are educated health professionals," he said. "But the study lacks information about PPI use prior to 2000, and it lacks specific information about brand and dose of PPI. It’s not clear whether this is generalizable to other populations."

The study, however, is in line with other reports of an association, and adds weight to the recommendation that clinicians carefully monitor the need for postmenopausal women to continue long-term on PPIs, especially those who smoke.

Response from the audience was robust, with one attendee noting, "This is truly excellent work," and another calling the study "impressive."

Dr. Khalili reported having no conflicts of interest.

CHICAGO – Regular use of proton pump inhibitors is associated with an elevated risk of hip fractures, even after adjusting for important lifestyle risk factors, according to the findings of a prospective evaluation from the Nurses’ Health Study.

The association was most striking for women with a history of smoking, observed Dr. Hamed Khalili of Massachusetts General Hospital, Boston.

The Food and Drug Association recently issued an advisory regarding a potential link between PPIs and fractures. While acid-suppressing medications have been hypothesized to increase the risk of osteoporotic fractures, studies examining this association have been inconsistent. These analyses have mostly been based on retrospective studies of small populations that have not controlled for important dietary and lifestyle confounders, and they have ascertained PPI use only at a single time point, Dr. Khalili said.

The current study aimed to be more definitive by prospectively examining the relationship between chronic PPI use and incident hip fracture among 79,899 postmenopausal women enrolled in the Nurses’ Health Study, he said.

"We found that longer duration of use was associated with increased risk, and the strongest risk was confined to individuals with a history of smoking. ... Our findings support the recent decision of the FDA to revise labeling of PPIs to incorporate concerns about a possible increase in the risk of fractures," he said at the annual Digestive Disease Week.

In 1982, participants in the Nurses’ Health Study were first asked to report all previous fractures and were queried biennially for new fractures. Among the nearly 80,000 subjects, with 565,786 person-years of follow-up, there were 893 incident hip fractures over 8 years. PPI use was reported by 7% of participants in 2000 and by 19% of participants in 2008.

Regular use of PPIs posed fracture risks of 35%-45% when adjusted for age, calcium intake, and body mass index. The fully adjusted hazard ratio was 1.37, Dr. Khalili reported.

Current smoking status stood out as a significant effect modifier. Women who were current or past smokers and who regularly took a PPI had a 51% increased risk for fracture. In contrast, women who never smoked had only a 6% increased risk, "almost equal to women who never used PPIs," he noted.

Longer duration of use was associated with greater risk. Compared with never-users, risk in the multivariate analysis was 36% after 2 years of use, 42% after 4 years and 54% when PPIs were used for 6 years or longer (P less than 0.001), he said.

The investigators adjusted for multiple other risk factors, including physical activity; alcohol intake; total daily calcium and vitamin D intake; history of osteoporosis; and use of hormone replacement therapy, bisphosphonates, and thiazides. "This did not materially alter this association," he noted.

When PPIs were discontinued, the risks declined. Two or more years after discontinuation, the risk of hip fracture was just 9%-10%, he noted.

"The strengths of our study are that it offers detailed, prospectively collected and validated information on PPI use and other risk factors. We had a high response rate, and the participants are educated health professionals," he said. "But the study lacks information about PPI use prior to 2000, and it lacks specific information about brand and dose of PPI. It’s not clear whether this is generalizable to other populations."

The study, however, is in line with other reports of an association, and adds weight to the recommendation that clinicians carefully monitor the need for postmenopausal women to continue long-term on PPIs, especially those who smoke.

Response from the audience was robust, with one attendee noting, "This is truly excellent work," and another calling the study "impressive."

Dr. Khalili reported having no conflicts of interest.

CHICAGO – Regular use of proton pump inhibitors is associated with an elevated risk of hip fractures, even after adjusting for important lifestyle risk factors, according to the findings of a prospective evaluation from the Nurses’ Health Study.

The association was most striking for women with a history of smoking, observed Dr. Hamed Khalili of Massachusetts General Hospital, Boston.

The Food and Drug Association recently issued an advisory regarding a potential link between PPIs and fractures. While acid-suppressing medications have been hypothesized to increase the risk of osteoporotic fractures, studies examining this association have been inconsistent. These analyses have mostly been based on retrospective studies of small populations that have not controlled for important dietary and lifestyle confounders, and they have ascertained PPI use only at a single time point, Dr. Khalili said.

The current study aimed to be more definitive by prospectively examining the relationship between chronic PPI use and incident hip fracture among 79,899 postmenopausal women enrolled in the Nurses’ Health Study, he said.

"We found that longer duration of use was associated with increased risk, and the strongest risk was confined to individuals with a history of smoking. ... Our findings support the recent decision of the FDA to revise labeling of PPIs to incorporate concerns about a possible increase in the risk of fractures," he said at the annual Digestive Disease Week.

In 1982, participants in the Nurses’ Health Study were first asked to report all previous fractures and were queried biennially for new fractures. Among the nearly 80,000 subjects, with 565,786 person-years of follow-up, there were 893 incident hip fractures over 8 years. PPI use was reported by 7% of participants in 2000 and by 19% of participants in 2008.

Regular use of PPIs posed fracture risks of 35%-45% when adjusted for age, calcium intake, and body mass index. The fully adjusted hazard ratio was 1.37, Dr. Khalili reported.

Current smoking status stood out as a significant effect modifier. Women who were current or past smokers and who regularly took a PPI had a 51% increased risk for fracture. In contrast, women who never smoked had only a 6% increased risk, "almost equal to women who never used PPIs," he noted.

Longer duration of use was associated with greater risk. Compared with never-users, risk in the multivariate analysis was 36% after 2 years of use, 42% after 4 years and 54% when PPIs were used for 6 years or longer (P less than 0.001), he said.

The investigators adjusted for multiple other risk factors, including physical activity; alcohol intake; total daily calcium and vitamin D intake; history of osteoporosis; and use of hormone replacement therapy, bisphosphonates, and thiazides. "This did not materially alter this association," he noted.

When PPIs were discontinued, the risks declined. Two or more years after discontinuation, the risk of hip fracture was just 9%-10%, he noted.

"The strengths of our study are that it offers detailed, prospectively collected and validated information on PPI use and other risk factors. We had a high response rate, and the participants are educated health professionals," he said. "But the study lacks information about PPI use prior to 2000, and it lacks specific information about brand and dose of PPI. It’s not clear whether this is generalizable to other populations."

The study, however, is in line with other reports of an association, and adds weight to the recommendation that clinicians carefully monitor the need for postmenopausal women to continue long-term on PPIs, especially those who smoke.

Response from the audience was robust, with one attendee noting, "This is truly excellent work," and another calling the study "impressive."

Dr. Khalili reported having no conflicts of interest.

CHICAGO – Regular use of proton pump inhibitors is associated with an elevated risk of hip fractures, even after adjusting for important lifestyle risk factors, according to the findings of a prospective evaluation from the Nurses’ Health Study.

The association was most striking for women with a history of smoking, observed Dr. Hamed Khalili of Massachusetts General Hospital, Boston.

The Food and Drug Association recently issued an advisory regarding a potential link between PPIs and fractures. While acid-suppressing medications have been hypothesized to increase the risk of osteoporotic fractures, studies examining this association have been inconsistent. These analyses have mostly been based on retrospective studies of small populations that have not controlled for important dietary and lifestyle confounders, and they have ascertained PPI use only at a single time point, Dr. Khalili said.

The current study aimed to be more definitive by prospectively examining the relationship between chronic PPI use and incident hip fracture among 79,899 postmenopausal women enrolled in the Nurses’ Health Study, he said.

"We found that longer duration of use was associated with increased risk, and the strongest risk was confined to individuals with a history of smoking. ... Our findings support the recent decision of the FDA to revise labeling of PPIs to incorporate concerns about a possible increase in the risk of fractures," he said at the annual Digestive Disease Week.

In 1982, participants in the Nurses’ Health Study were first asked to report all previous fractures and were queried biennially for new fractures. Among the nearly 80,000 subjects, with 565,786 person-years of follow-up, there were 893 incident hip fractures over 8 years. PPI use was reported by 7% of participants in 2000 and by 19% of participants in 2008.

Regular use of PPIs posed fracture risks of 35%-45% when adjusted for age, calcium intake, and body mass index. The fully adjusted hazard ratio was 1.37, Dr. Khalili reported.

Current smoking status stood out as a significant effect modifier. Women who were current or past smokers and who regularly took a PPI had a 51% increased risk for fracture. In contrast, women who never smoked had only a 6% increased risk, "almost equal to women who never used PPIs," he noted.

Longer duration of use was associated with greater risk. Compared with never-users, risk in the multivariate analysis was 36% after 2 years of use, 42% after 4 years and 54% when PPIs were used for 6 years or longer (P less than 0.001), he said.

The investigators adjusted for multiple other risk factors, including physical activity; alcohol intake; total daily calcium and vitamin D intake; history of osteoporosis; and use of hormone replacement therapy, bisphosphonates, and thiazides. "This did not materially alter this association," he noted.

When PPIs were discontinued, the risks declined. Two or more years after discontinuation, the risk of hip fracture was just 9%-10%, he noted.

"The strengths of our study are that it offers detailed, prospectively collected and validated information on PPI use and other risk factors. We had a high response rate, and the participants are educated health professionals," he said. "But the study lacks information about PPI use prior to 2000, and it lacks specific information about brand and dose of PPI. It’s not clear whether this is generalizable to other populations."

The study, however, is in line with other reports of an association, and adds weight to the recommendation that clinicians carefully monitor the need for postmenopausal women to continue long-term on PPIs, especially those who smoke.

Response from the audience was robust, with one attendee noting, "This is truly excellent work," and another calling the study "impressive."

Dr. Khalili reported having no conflicts of interest.

CHICAGO – Regular use of proton pump inhibitors is associated with an elevated risk of hip fractures, even after adjusting for important lifestyle risk factors, according to the findings of a prospective evaluation from the Nurses’ Health Study.

The association was most striking for women with a history of smoking, observed Dr. Hamed Khalili of Massachusetts General Hospital, Boston.

The Food and Drug Association recently issued an advisory regarding a potential link between PPIs and fractures. While acid-suppressing medications have been hypothesized to increase the risk of osteoporotic fractures, studies examining this association have been inconsistent. These analyses have mostly been based on retrospective studies of small populations that have not controlled for important dietary and lifestyle confounders, and they have ascertained PPI use only at a single time point, Dr. Khalili said.

The current study aimed to be more definitive by prospectively examining the relationship between chronic PPI use and incident hip fracture among 79,899 postmenopausal women enrolled in the Nurses’ Health Study, he said.

"We found that longer duration of use was associated with increased risk, and the strongest risk was confined to individuals with a history of smoking. ... Our findings support the recent decision of the FDA to revise labeling of PPIs to incorporate concerns about a possible increase in the risk of fractures," he said at the annual Digestive Disease Week.

In 1982, participants in the Nurses’ Health Study were first asked to report all previous fractures and were queried biennially for new fractures. Among the nearly 80,000 subjects, with 565,786 person-years of follow-up, there were 893 incident hip fractures over 8 years. PPI use was reported by 7% of participants in 2000 and by 19% of participants in 2008.

Regular use of PPIs posed fracture risks of 35%-45% when adjusted for age, calcium intake, and body mass index. The fully adjusted hazard ratio was 1.37, Dr. Khalili reported.

Current smoking status stood out as a significant effect modifier. Women who were current or past smokers and who regularly took a PPI had a 51% increased risk for fracture. In contrast, women who never smoked had only a 6% increased risk, "almost equal to women who never used PPIs," he noted.

Longer duration of use was associated with greater risk. Compared with never-users, risk in the multivariate analysis was 36% after 2 years of use, 42% after 4 years and 54% when PPIs were used for 6 years or longer (P less than 0.001), he said.

The investigators adjusted for multiple other risk factors, including physical activity; alcohol intake; total daily calcium and vitamin D intake; history of osteoporosis; and use of hormone replacement therapy, bisphosphonates, and thiazides. "This did not materially alter this association," he noted.

When PPIs were discontinued, the risks declined. Two or more years after discontinuation, the risk of hip fracture was just 9%-10%, he noted.

"The strengths of our study are that it offers detailed, prospectively collected and validated information on PPI use and other risk factors. We had a high response rate, and the participants are educated health professionals," he said. "But the study lacks information about PPI use prior to 2000, and it lacks specific information about brand and dose of PPI. It’s not clear whether this is generalizable to other populations."

The study, however, is in line with other reports of an association, and adds weight to the recommendation that clinicians carefully monitor the need for postmenopausal women to continue long-term on PPIs, especially those who smoke.

Response from the audience was robust, with one attendee noting, "This is truly excellent work," and another calling the study "impressive."

Dr. Khalili reported having no conflicts of interest.

CHICAGO – Regular use of proton pump inhibitors is associated with an elevated risk of hip fractures, even after adjusting for important lifestyle risk factors, according to the findings of a prospective evaluation from the Nurses’ Health Study.

The association was most striking for women with a history of smoking, observed Dr. Hamed Khalili of Massachusetts General Hospital, Boston.

The Food and Drug Association recently issued an advisory regarding a potential link between PPIs and fractures. While acid-suppressing medications have been hypothesized to increase the risk of osteoporotic fractures, studies examining this association have been inconsistent. These analyses have mostly been based on retrospective studies of small populations that have not controlled for important dietary and lifestyle confounders, and they have ascertained PPI use only at a single time point, Dr. Khalili said.

The current study aimed to be more definitive by prospectively examining the relationship between chronic PPI use and incident hip fracture among 79,899 postmenopausal women enrolled in the Nurses’ Health Study, he said.

"We found that longer duration of use was associated with increased risk, and the strongest risk was confined to individuals with a history of smoking. ... Our findings support the recent decision of the FDA to revise labeling of PPIs to incorporate concerns about a possible increase in the risk of fractures," he said at the annual Digestive Disease Week.

In 1982, participants in the Nurses’ Health Study were first asked to report all previous fractures and were queried biennially for new fractures. Among the nearly 80,000 subjects, with 565,786 person-years of follow-up, there were 893 incident hip fractures over 8 years. PPI use was reported by 7% of participants in 2000 and by 19% of participants in 2008.

Regular use of PPIs posed fracture risks of 35%-45% when adjusted for age, calcium intake, and body mass index. The fully adjusted hazard ratio was 1.37, Dr. Khalili reported.

Current smoking status stood out as a significant effect modifier. Women who were current or past smokers and who regularly took a PPI had a 51% increased risk for fracture. In contrast, women who never smoked had only a 6% increased risk, "almost equal to women who never used PPIs," he noted.

Longer duration of use was associated with greater risk. Compared with never-users, risk in the multivariate analysis was 36% after 2 years of use, 42% after 4 years and 54% when PPIs were used for 6 years or longer (P less than 0.001), he said.

The investigators adjusted for multiple other risk factors, including physical activity; alcohol intake; total daily calcium and vitamin D intake; history of osteoporosis; and use of hormone replacement therapy, bisphosphonates, and thiazides. "This did not materially alter this association," he noted.

When PPIs were discontinued, the risks declined. Two or more years after discontinuation, the risk of hip fracture was just 9%-10%, he noted.

"The strengths of our study are that it offers detailed, prospectively collected and validated information on PPI use and other risk factors. We had a high response rate, and the participants are educated health professionals," he said. "But the study lacks information about PPI use prior to 2000, and it lacks specific information about brand and dose of PPI. It’s not clear whether this is generalizable to other populations."

The study, however, is in line with other reports of an association, and adds weight to the recommendation that clinicians carefully monitor the need for postmenopausal women to continue long-term on PPIs, especially those who smoke.

Response from the audience was robust, with one attendee noting, "This is truly excellent work," and another calling the study "impressive."

Dr. Khalili reported having no conflicts of interest.

CHICAGO – The recommended 5-year interval between screening sigmoidoscopies probably cannot be safely extended, according to an analysis of data on more than 70,000 enrollees of Kaiser Permanente of Northern California.

"We found that rates of colorectal cancer are low for at least 10 years after a negative sigmoidoscopy," reported Dr. Vincent P. Doria-Rose of Kaiser Permanente in Oakland. "But there may be consequences to waiting 10 years between endoscopies," he said at the annual Digestive Disease Week.

Current screening guidelines recommend a 10-year interval for colonoscopy and a 5-year interval for sigmoidoscopy. Prior investigations have suggested that there is a long duration of low risk for colorectal cancer (CRC) after endoscopy – up to 20 years in some series – but these studies have been limited. For example, many rely on patient self-reports, and others are case-control studies, he said.

Dr. Doria-Rose and his colleagues analyzed data from the colorectal cancer prevention program at Kaiser Permanente, through which individuals with an average risk for CRC underwent screening sigmoidoscopy once every 10 years starting at age 50. The study evaluated CRC incidence after 10.5 years of follow-up in persons screened between 1994 and 1996.

The evaluable population included 72,483 individuals with negative results on screening and excluded persons with a personal history of colorectal polyps, CRC or inflammatory bowel disease, or a high-risk family history of CRC. Of the study population, 50% were female, 51% were at least 60 years old, and 65% were white.

Within 10.5 years of index sigmoidoscopy, 103 cases of distal CRC (rectum and sigmoid) were diagnosed, as were 333 cases of proximal CRCs. The incidence rates per 100,000 person-years of both proximal and distal CRC increased over time, but did so especially during the second half of the interval, the study found.

The mean incidence rate of distal CRC during years 6-10 was approximately twice as high as that in years 1-5. The mean incidence rates were 28/100,000 person-years for the second half of the screening interval, compared with a rate of 13 during the first 5 years, for a difference of 15 cases per 100,000 person-years, Dr. Doria-Rose reported.

The rate ratio (RR) was 2.1 for all tumors diagnosed after 6 years compared with years 1-5. By age, the RR was 1.1 for those younger than 60 and 2.5 for those aged 60 and older.

The standardized incidence ratio (SIR) in the distal colon increased gradually from 0.40/100,000 in the first year post screening to 0.49 in the 10th year. For proximal cancers, increasing SIRs were due mostly to the aging of the population, and there was no clear increase over time, with a mean SIR of 0.75 for the entire follow-up period.

By subgroup analyses, the results of the current study were consistent, except for the age group that was younger than age 60 years at baseline, who experienced no increase in risk over the second half of follow-up, he said.

"The incidence rates of distal CRC increased considerably in years 6 and up as compared to that in years 1 through 5," he noted, "but remained low for the entire follow-up period."

He explained that the incidence rate in the current study is lower than has been observed in the SEER (Surveillance, Epidemiology, and End Results) population of the San Francisco Bay area, a finding that could be due to patient selection. The current study involved an insured population that presented for screening and whose lifestyle and behaviors would reduce their inherent risk, he suggested.

"The rate is low for 10 years of follow-up, compared with the SEER rate, but there was still a doubling in the second half," Dr. Doria-Rose emphasized.

"These data do not suggest that there is one obvious, clear-cut interval for screening sigmoidoscopy," he concluded, "and they provide no information regarding the duration of [a low-risk period] following the endoscopic examination of the right colon."

He added that to evaluate the relative benefits of sigmoidoscopy every 5 years, versus colonoscopy every 10 years, similar analyses in large cohorts of individuals screened by colonoscopy will be required.

Dr. Doria-Rose reported no relevant financial disclosures.

CHICAGO – The recommended 5-year interval between screening sigmoidoscopies probably cannot be safely extended, according to an analysis of data on more than 70,000 enrollees of Kaiser Permanente of Northern California.

"We found that rates of colorectal cancer are low for at least 10 years after a negative sigmoidoscopy," reported Dr. Vincent P. Doria-Rose of Kaiser Permanente in Oakland. "But there may be consequences to waiting 10 years between endoscopies," he said at the annual Digestive Disease Week.

Current screening guidelines recommend a 10-year interval for colonoscopy and a 5-year interval for sigmoidoscopy. Prior investigations have suggested that there is a long duration of low risk for colorectal cancer (CRC) after endoscopy – up to 20 years in some series – but these studies have been limited. For example, many rely on patient self-reports, and others are case-control studies, he said.

Dr. Doria-Rose and his colleagues analyzed data from the colorectal cancer prevention program at Kaiser Permanente, through which individuals with an average risk for CRC underwent screening sigmoidoscopy once every 10 years starting at age 50. The study evaluated CRC incidence after 10.5 years of follow-up in persons screened between 1994 and 1996.

The evaluable population included 72,483 individuals with negative results on screening and excluded persons with a personal history of colorectal polyps, CRC or inflammatory bowel disease, or a high-risk family history of CRC. Of the study population, 50% were female, 51% were at least 60 years old, and 65% were white.

Within 10.5 years of index sigmoidoscopy, 103 cases of distal CRC (rectum and sigmoid) were diagnosed, as were 333 cases of proximal CRCs. The incidence rates per 100,000 person-years of both proximal and distal CRC increased over time, but did so especially during the second half of the interval, the study found.

The mean incidence rate of distal CRC during years 6-10 was approximately twice as high as that in years 1-5. The mean incidence rates were 28/100,000 person-years for the second half of the screening interval, compared with a rate of 13 during the first 5 years, for a difference of 15 cases per 100,000 person-years, Dr. Doria-Rose reported.

The rate ratio (RR) was 2.1 for all tumors diagnosed after 6 years compared with years 1-5. By age, the RR was 1.1 for those younger than 60 and 2.5 for those aged 60 and older.

The standardized incidence ratio (SIR) in the distal colon increased gradually from 0.40/100,000 in the first year post screening to 0.49 in the 10th year. For proximal cancers, increasing SIRs were due mostly to the aging of the population, and there was no clear increase over time, with a mean SIR of 0.75 for the entire follow-up period.

By subgroup analyses, the results of the current study were consistent, except for the age group that was younger than age 60 years at baseline, who experienced no increase in risk over the second half of follow-up, he said.

"The incidence rates of distal CRC increased considerably in years 6 and up as compared to that in years 1 through 5," he noted, "but remained low for the entire follow-up period."

He explained that the incidence rate in the current study is lower than has been observed in the SEER (Surveillance, Epidemiology, and End Results) population of the San Francisco Bay area, a finding that could be due to patient selection. The current study involved an insured population that presented for screening and whose lifestyle and behaviors would reduce their inherent risk, he suggested.

"The rate is low for 10 years of follow-up, compared with the SEER rate, but there was still a doubling in the second half," Dr. Doria-Rose emphasized.

"These data do not suggest that there is one obvious, clear-cut interval for screening sigmoidoscopy," he concluded, "and they provide no information regarding the duration of [a low-risk period] following the endoscopic examination of the right colon."

He added that to evaluate the relative benefits of sigmoidoscopy every 5 years, versus colonoscopy every 10 years, similar analyses in large cohorts of individuals screened by colonoscopy will be required.

Dr. Doria-Rose reported no relevant financial disclosures.

CHICAGO – The recommended 5-year interval between screening sigmoidoscopies probably cannot be safely extended, according to an analysis of data on more than 70,000 enrollees of Kaiser Permanente of Northern California.

"We found that rates of colorectal cancer are low for at least 10 years after a negative sigmoidoscopy," reported Dr. Vincent P. Doria-Rose of Kaiser Permanente in Oakland. "But there may be consequences to waiting 10 years between endoscopies," he said at the annual Digestive Disease Week.

Current screening guidelines recommend a 10-year interval for colonoscopy and a 5-year interval for sigmoidoscopy. Prior investigations have suggested that there is a long duration of low risk for colorectal cancer (CRC) after endoscopy – up to 20 years in some series – but these studies have been limited. For example, many rely on patient self-reports, and others are case-control studies, he said.

Dr. Doria-Rose and his colleagues analyzed data from the colorectal cancer prevention program at Kaiser Permanente, through which individuals with an average risk for CRC underwent screening sigmoidoscopy once every 10 years starting at age 50. The study evaluated CRC incidence after 10.5 years of follow-up in persons screened between 1994 and 1996.

The evaluable population included 72,483 individuals with negative results on screening and excluded persons with a personal history of colorectal polyps, CRC or inflammatory bowel disease, or a high-risk family history of CRC. Of the study population, 50% were female, 51% were at least 60 years old, and 65% were white.

Within 10.5 years of index sigmoidoscopy, 103 cases of distal CRC (rectum and sigmoid) were diagnosed, as were 333 cases of proximal CRCs. The incidence rates per 100,000 person-years of both proximal and distal CRC increased over time, but did so especially during the second half of the interval, the study found.

The mean incidence rate of distal CRC during years 6-10 was approximately twice as high as that in years 1-5. The mean incidence rates were 28/100,000 person-years for the second half of the screening interval, compared with a rate of 13 during the first 5 years, for a difference of 15 cases per 100,000 person-years, Dr. Doria-Rose reported.

The rate ratio (RR) was 2.1 for all tumors diagnosed after 6 years compared with years 1-5. By age, the RR was 1.1 for those younger than 60 and 2.5 for those aged 60 and older.

The standardized incidence ratio (SIR) in the distal colon increased gradually from 0.40/100,000 in the first year post screening to 0.49 in the 10th year. For proximal cancers, increasing SIRs were due mostly to the aging of the population, and there was no clear increase over time, with a mean SIR of 0.75 for the entire follow-up period.

By subgroup analyses, the results of the current study were consistent, except for the age group that was younger than age 60 years at baseline, who experienced no increase in risk over the second half of follow-up, he said.

"The incidence rates of distal CRC increased considerably in years 6 and up as compared to that in years 1 through 5," he noted, "but remained low for the entire follow-up period."

He explained that the incidence rate in the current study is lower than has been observed in the SEER (Surveillance, Epidemiology, and End Results) population of the San Francisco Bay area, a finding that could be due to patient selection. The current study involved an insured population that presented for screening and whose lifestyle and behaviors would reduce their inherent risk, he suggested.

"The rate is low for 10 years of follow-up, compared with the SEER rate, but there was still a doubling in the second half," Dr. Doria-Rose emphasized.

"These data do not suggest that there is one obvious, clear-cut interval for screening sigmoidoscopy," he concluded, "and they provide no information regarding the duration of [a low-risk period] following the endoscopic examination of the right colon."

He added that to evaluate the relative benefits of sigmoidoscopy every 5 years, versus colonoscopy every 10 years, similar analyses in large cohorts of individuals screened by colonoscopy will be required.

Dr. Doria-Rose reported no relevant financial disclosures.

CHICAGO – The recommended 5-year interval between screening sigmoidoscopies probably cannot be safely extended, according to an analysis of data on more than 70,000 enrollees of Kaiser Permanente of Northern California.

"We found that rates of colorectal cancer are low for at least 10 years after a negative sigmoidoscopy," reported Dr. Vincent P. Doria-Rose of Kaiser Permanente in Oakland. "But there may be consequences to waiting 10 years between endoscopies," he said at the annual Digestive Disease Week.

Current screening guidelines recommend a 10-year interval for colonoscopy and a 5-year interval for sigmoidoscopy. Prior investigations have suggested that there is a long duration of low risk for colorectal cancer (CRC) after endoscopy – up to 20 years in some series – but these studies have been limited. For example, many rely on patient self-reports, and others are case-control studies, he said.

Dr. Doria-Rose and his colleagues analyzed data from the colorectal cancer prevention program at Kaiser Permanente, through which individuals with an average risk for CRC underwent screening sigmoidoscopy once every 10 years starting at age 50. The study evaluated CRC incidence after 10.5 years of follow-up in persons screened between 1994 and 1996.

The evaluable population included 72,483 individuals with negative results on screening and excluded persons with a personal history of colorectal polyps, CRC or inflammatory bowel disease, or a high-risk family history of CRC. Of the study population, 50% were female, 51% were at least 60 years old, and 65% were white.

Within 10.5 years of index sigmoidoscopy, 103 cases of distal CRC (rectum and sigmoid) were diagnosed, as were 333 cases of proximal CRCs. The incidence rates per 100,000 person-years of both proximal and distal CRC increased over time, but did so especially during the second half of the interval, the study found.

The mean incidence rate of distal CRC during years 6-10 was approximately twice as high as that in years 1-5. The mean incidence rates were 28/100,000 person-years for the second half of the screening interval, compared with a rate of 13 during the first 5 years, for a difference of 15 cases per 100,000 person-years, Dr. Doria-Rose reported.

The rate ratio (RR) was 2.1 for all tumors diagnosed after 6 years compared with years 1-5. By age, the RR was 1.1 for those younger than 60 and 2.5 for those aged 60 and older.

The standardized incidence ratio (SIR) in the distal colon increased gradually from 0.40/100,000 in the first year post screening to 0.49 in the 10th year. For proximal cancers, increasing SIRs were due mostly to the aging of the population, and there was no clear increase over time, with a mean SIR of 0.75 for the entire follow-up period.

By subgroup analyses, the results of the current study were consistent, except for the age group that was younger than age 60 years at baseline, who experienced no increase in risk over the second half of follow-up, he said.

"The incidence rates of distal CRC increased considerably in years 6 and up as compared to that in years 1 through 5," he noted, "but remained low for the entire follow-up period."

He explained that the incidence rate in the current study is lower than has been observed in the SEER (Surveillance, Epidemiology, and End Results) population of the San Francisco Bay area, a finding that could be due to patient selection. The current study involved an insured population that presented for screening and whose lifestyle and behaviors would reduce their inherent risk, he suggested.

"The rate is low for 10 years of follow-up, compared with the SEER rate, but there was still a doubling in the second half," Dr. Doria-Rose emphasized.

"These data do not suggest that there is one obvious, clear-cut interval for screening sigmoidoscopy," he concluded, "and they provide no information regarding the duration of [a low-risk period] following the endoscopic examination of the right colon."

He added that to evaluate the relative benefits of sigmoidoscopy every 5 years, versus colonoscopy every 10 years, similar analyses in large cohorts of individuals screened by colonoscopy will be required.

Dr. Doria-Rose reported no relevant financial disclosures.

CHICAGO – The recommended 5-year interval between screening sigmoidoscopies probably cannot be safely extended, according to an analysis of data on more than 70,000 enrollees of Kaiser Permanente of Northern California.

"We found that rates of colorectal cancer are low for at least 10 years after a negative sigmoidoscopy," reported Dr. Vincent P. Doria-Rose of Kaiser Permanente in Oakland. "But there may be consequences to waiting 10 years between endoscopies," he said at the annual Digestive Disease Week.

Current screening guidelines recommend a 10-year interval for colonoscopy and a 5-year interval for sigmoidoscopy. Prior investigations have suggested that there is a long duration of low risk for colorectal cancer (CRC) after endoscopy – up to 20 years in some series – but these studies have been limited. For example, many rely on patient self-reports, and others are case-control studies, he said.

Dr. Doria-Rose and his colleagues analyzed data from the colorectal cancer prevention program at Kaiser Permanente, through which individuals with an average risk for CRC underwent screening sigmoidoscopy once every 10 years starting at age 50. The study evaluated CRC incidence after 10.5 years of follow-up in persons screened between 1994 and 1996.

The evaluable population included 72,483 individuals with negative results on screening and excluded persons with a personal history of colorectal polyps, CRC or inflammatory bowel disease, or a high-risk family history of CRC. Of the study population, 50% were female, 51% were at least 60 years old, and 65% were white.

Within 10.5 years of index sigmoidoscopy, 103 cases of distal CRC (rectum and sigmoid) were diagnosed, as were 333 cases of proximal CRCs. The incidence rates per 100,000 person-years of both proximal and distal CRC increased over time, but did so especially during the second half of the interval, the study found.

The mean incidence rate of distal CRC during years 6-10 was approximately twice as high as that in years 1-5. The mean incidence rates were 28/100,000 person-years for the second half of the screening interval, compared with a rate of 13 during the first 5 years, for a difference of 15 cases per 100,000 person-years, Dr. Doria-Rose reported.

The rate ratio (RR) was 2.1 for all tumors diagnosed after 6 years compared with years 1-5. By age, the RR was 1.1 for those younger than 60 and 2.5 for those aged 60 and older.

The standardized incidence ratio (SIR) in the distal colon increased gradually from 0.40/100,000 in the first year post screening to 0.49 in the 10th year. For proximal cancers, increasing SIRs were due mostly to the aging of the population, and there was no clear increase over time, with a mean SIR of 0.75 for the entire follow-up period.

By subgroup analyses, the results of the current study were consistent, except for the age group that was younger than age 60 years at baseline, who experienced no increase in risk over the second half of follow-up, he said.

"The incidence rates of distal CRC increased considerably in years 6 and up as compared to that in years 1 through 5," he noted, "but remained low for the entire follow-up period."

He explained that the incidence rate in the current study is lower than has been observed in the SEER (Surveillance, Epidemiology, and End Results) population of the San Francisco Bay area, a finding that could be due to patient selection. The current study involved an insured population that presented for screening and whose lifestyle and behaviors would reduce their inherent risk, he suggested.

"The rate is low for 10 years of follow-up, compared with the SEER rate, but there was still a doubling in the second half," Dr. Doria-Rose emphasized.

"These data do not suggest that there is one obvious, clear-cut interval for screening sigmoidoscopy," he concluded, "and they provide no information regarding the duration of [a low-risk period] following the endoscopic examination of the right colon."

He added that to evaluate the relative benefits of sigmoidoscopy every 5 years, versus colonoscopy every 10 years, similar analyses in large cohorts of individuals screened by colonoscopy will be required.

Dr. Doria-Rose reported no relevant financial disclosures.

CHICAGO – The recommended 5-year interval between screening sigmoidoscopies probably cannot be safely extended, according to an analysis of data on more than 70,000 enrollees of Kaiser Permanente of Northern California.

"We found that rates of colorectal cancer are low for at least 10 years after a negative sigmoidoscopy," reported Dr. Vincent P. Doria-Rose of Kaiser Permanente in Oakland. "But there may be consequences to waiting 10 years between endoscopies," he said at the annual Digestive Disease Week.

Current screening guidelines recommend a 10-year interval for colonoscopy and a 5-year interval for sigmoidoscopy. Prior investigations have suggested that there is a long duration of low risk for colorectal cancer (CRC) after endoscopy – up to 20 years in some series – but these studies have been limited. For example, many rely on patient self-reports, and others are case-control studies, he said.

Dr. Doria-Rose and his colleagues analyzed data from the colorectal cancer prevention program at Kaiser Permanente, through which individuals with an average risk for CRC underwent screening sigmoidoscopy once every 10 years starting at age 50. The study evaluated CRC incidence after 10.5 years of follow-up in persons screened between 1994 and 1996.

The evaluable population included 72,483 individuals with negative results on screening and excluded persons with a personal history of colorectal polyps, CRC or inflammatory bowel disease, or a high-risk family history of CRC. Of the study population, 50% were female, 51% were at least 60 years old, and 65% were white.

Within 10.5 years of index sigmoidoscopy, 103 cases of distal CRC (rectum and sigmoid) were diagnosed, as were 333 cases of proximal CRCs. The incidence rates per 100,000 person-years of both proximal and distal CRC increased over time, but did so especially during the second half of the interval, the study found.

The mean incidence rate of distal CRC during years 6-10 was approximately twice as high as that in years 1-5. The mean incidence rates were 28/100,000 person-years for the second half of the screening interval, compared with a rate of 13 during the first 5 years, for a difference of 15 cases per 100,000 person-years, Dr. Doria-Rose reported.

The rate ratio (RR) was 2.1 for all tumors diagnosed after 6 years compared with years 1-5. By age, the RR was 1.1 for those younger than 60 and 2.5 for those aged 60 and older.

The standardized incidence ratio (SIR) in the distal colon increased gradually from 0.40/100,000 in the first year post screening to 0.49 in the 10th year. For proximal cancers, increasing SIRs were due mostly to the aging of the population, and there was no clear increase over time, with a mean SIR of 0.75 for the entire follow-up period.

By subgroup analyses, the results of the current study were consistent, except for the age group that was younger than age 60 years at baseline, who experienced no increase in risk over the second half of follow-up, he said.

"The incidence rates of distal CRC increased considerably in years 6 and up as compared to that in years 1 through 5," he noted, "but remained low for the entire follow-up period."

He explained that the incidence rate in the current study is lower than has been observed in the SEER (Surveillance, Epidemiology, and End Results) population of the San Francisco Bay area, a finding that could be due to patient selection. The current study involved an insured population that presented for screening and whose lifestyle and behaviors would reduce their inherent risk, he suggested.

"The rate is low for 10 years of follow-up, compared with the SEER rate, but there was still a doubling in the second half," Dr. Doria-Rose emphasized.

"These data do not suggest that there is one obvious, clear-cut interval for screening sigmoidoscopy," he concluded, "and they provide no information regarding the duration of [a low-risk period] following the endoscopic examination of the right colon."

He added that to evaluate the relative benefits of sigmoidoscopy every 5 years, versus colonoscopy every 10 years, similar analyses in large cohorts of individuals screened by colonoscopy will be required.

Dr. Doria-Rose reported no relevant financial disclosures.

Major Finding: The rates of 12-month TVF were 4.7% for drug-eluting stent recipients given 6months of clopidogrel and aspirin and 4.4% for those given 12 months of antiplatelet therapy. By Kaplan-Meier analysis, the cumulative proportional estimate of target vessel failure at 1 year was 5.2% for the 6-month regimen and 4.3% for the 12-month regimen.

Data Source: A study of 1,443 patients receiving everolimus- or sirolimus-eluting stents and randomized to either 6 or 12 months of clopidogrel and aspirin.

Disclosures: Dr. Gwon reported consulting fees and honoraria from Cordis and Medtronic as well as research support from Abbott Korea and Medtronic Korea. Dr. Kaul has received consulting fees and honoraria from Novo Nordisk and Hoffman-LaRoche.

NEW ORLEANS – Short and standard durations of dual-antiplatelet therapy were equally protective against target vessel failure in drug-eluting stent recipients, Korean researchers reported at the meeting.

With the exception of patients who had diabetes, the overall 12-month clinical event rates were not different between 6- and 12-month treatment duration groups for all-cause mortality, cardiac death, MI cerebrovascular accident, target vessel revascularization (TVR), stent thrombosis, major bleeding, or various composites of the above end points, reported Dr. Hyeon-Cheol Gwon of Samsung Medical Center at Sungkyunkwan University in Seoul.

“At least in low-risk patients getting drug-eluting stents, that is, nondiabetics, maybe we can safely discontinue clopidogrel at 6 months,” he said. Current guidelines recommend at least 12 months of anticoagulation to prevent venous thromboembolism. Current guidelines recommend at least 12 months of anticoagulation to prevent venous thromboembolism.

Early discontinuation of antiplatelet therapy might be particularly relevant for patients at high risk of bleeding or those anticipating subsequent procedures, which are often delayed while the drugs are withdrawn.

But Dr. Sanjay Kaul of Cedars-Sinai Medical Center, Los Angeles, questioned the researchers' use of target vessel failure (TVF) as the primary study end point. TVF was defined as a composite of cardiac death, MI, or TVR. Dr. Gwon acknowledged that, saying “We recognize our study is hypothesis generating.”

The trial involved 1,443 patients with greater than 50% stenosis and evidence of myocardial ischemia. Patients receiving everolimus- or sirolimus-eluting stents were randomized to receive 6 or 12 months of dual-antiplatelet therapy with clopidogrel and aspirin.

The study found that discontinuing clopidogrel and aspirin after 6 months did not increase the rate of 12-month TVF. The rates were 4.7% for the 6-month group and 4.4% for the 12-month group. By Kaplan-Meier analysis, the cumulative proportional TVF estimate at 1 year was 5.2% for the 6-month regimen and 4.3% for the 12-month regimen, which met the noninferiority end point “in a highly significant manner” (P = .0031; upper 1-sided 97.5% confidence interval 0.9%-3.6%), Dr. Gwon said.

The cumulative incidence of major adverse cardiac or coronary events was 7.5% with 6-month therapy and 8.4% with 12-month therapy.

There was, however, a significantly higher risk for primary TVF with early discontinuation of antiplatelet therapy for patients with diabetes. Diabetes patients receiving 6 months of dual-antiplatelet therapy had a TVF rate of 8.9%, vs. 2.9% with 12 months of treatment.

There were no other significant subgroup differences.

Major Finding: The rates of 12-month TVF were 4.7% for drug-eluting stent recipients given 6months of clopidogrel and aspirin and 4.4% for those given 12 months of antiplatelet therapy. By Kaplan-Meier analysis, the cumulative proportional estimate of target vessel failure at 1 year was 5.2% for the 6-month regimen and 4.3% for the 12-month regimen.

Data Source: A study of 1,443 patients receiving everolimus- or sirolimus-eluting stents and randomized to either 6 or 12 months of clopidogrel and aspirin.

Disclosures: Dr. Gwon reported consulting fees and honoraria from Cordis and Medtronic as well as research support from Abbott Korea and Medtronic Korea. Dr. Kaul has received consulting fees and honoraria from Novo Nordisk and Hoffman-LaRoche.

NEW ORLEANS – Short and standard durations of dual-antiplatelet therapy were equally protective against target vessel failure in drug-eluting stent recipients, Korean researchers reported at the meeting.

With the exception of patients who had diabetes, the overall 12-month clinical event rates were not different between 6- and 12-month treatment duration groups for all-cause mortality, cardiac death, MI cerebrovascular accident, target vessel revascularization (TVR), stent thrombosis, major bleeding, or various composites of the above end points, reported Dr. Hyeon-Cheol Gwon of Samsung Medical Center at Sungkyunkwan University in Seoul.

“At least in low-risk patients getting drug-eluting stents, that is, nondiabetics, maybe we can safely discontinue clopidogrel at 6 months,” he said. Current guidelines recommend at least 12 months of anticoagulation to prevent venous thromboembolism. Current guidelines recommend at least 12 months of anticoagulation to prevent venous thromboembolism.

Early discontinuation of antiplatelet therapy might be particularly relevant for patients at high risk of bleeding or those anticipating subsequent procedures, which are often delayed while the drugs are withdrawn.

But Dr. Sanjay Kaul of Cedars-Sinai Medical Center, Los Angeles, questioned the researchers' use of target vessel failure (TVF) as the primary study end point. TVF was defined as a composite of cardiac death, MI, or TVR. Dr. Gwon acknowledged that, saying “We recognize our study is hypothesis generating.”

The trial involved 1,443 patients with greater than 50% stenosis and evidence of myocardial ischemia. Patients receiving everolimus- or sirolimus-eluting stents were randomized to receive 6 or 12 months of dual-antiplatelet therapy with clopidogrel and aspirin.

The study found that discontinuing clopidogrel and aspirin after 6 months did not increase the rate of 12-month TVF. The rates were 4.7% for the 6-month group and 4.4% for the 12-month group. By Kaplan-Meier analysis, the cumulative proportional TVF estimate at 1 year was 5.2% for the 6-month regimen and 4.3% for the 12-month regimen, which met the noninferiority end point “in a highly significant manner” (P = .0031; upper 1-sided 97.5% confidence interval 0.9%-3.6%), Dr. Gwon said.

The cumulative incidence of major adverse cardiac or coronary events was 7.5% with 6-month therapy and 8.4% with 12-month therapy.

There was, however, a significantly higher risk for primary TVF with early discontinuation of antiplatelet therapy for patients with diabetes. Diabetes patients receiving 6 months of dual-antiplatelet therapy had a TVF rate of 8.9%, vs. 2.9% with 12 months of treatment.

There were no other significant subgroup differences.

Major Finding: The rates of 12-month TVF were 4.7% for drug-eluting stent recipients given 6months of clopidogrel and aspirin and 4.4% for those given 12 months of antiplatelet therapy. By Kaplan-Meier analysis, the cumulative proportional estimate of target vessel failure at 1 year was 5.2% for the 6-month regimen and 4.3% for the 12-month regimen.

Data Source: A study of 1,443 patients receiving everolimus- or sirolimus-eluting stents and randomized to either 6 or 12 months of clopidogrel and aspirin.

Disclosures: Dr. Gwon reported consulting fees and honoraria from Cordis and Medtronic as well as research support from Abbott Korea and Medtronic Korea. Dr. Kaul has received consulting fees and honoraria from Novo Nordisk and Hoffman-LaRoche.

NEW ORLEANS – Short and standard durations of dual-antiplatelet therapy were equally protective against target vessel failure in drug-eluting stent recipients, Korean researchers reported at the meeting.

With the exception of patients who had diabetes, the overall 12-month clinical event rates were not different between 6- and 12-month treatment duration groups for all-cause mortality, cardiac death, MI cerebrovascular accident, target vessel revascularization (TVR), stent thrombosis, major bleeding, or various composites of the above end points, reported Dr. Hyeon-Cheol Gwon of Samsung Medical Center at Sungkyunkwan University in Seoul.

“At least in low-risk patients getting drug-eluting stents, that is, nondiabetics, maybe we can safely discontinue clopidogrel at 6 months,” he said. Current guidelines recommend at least 12 months of anticoagulation to prevent venous thromboembolism. Current guidelines recommend at least 12 months of anticoagulation to prevent venous thromboembolism.

Early discontinuation of antiplatelet therapy might be particularly relevant for patients at high risk of bleeding or those anticipating subsequent procedures, which are often delayed while the drugs are withdrawn.

But Dr. Sanjay Kaul of Cedars-Sinai Medical Center, Los Angeles, questioned the researchers' use of target vessel failure (TVF) as the primary study end point. TVF was defined as a composite of cardiac death, MI, or TVR. Dr. Gwon acknowledged that, saying “We recognize our study is hypothesis generating.”

The trial involved 1,443 patients with greater than 50% stenosis and evidence of myocardial ischemia. Patients receiving everolimus- or sirolimus-eluting stents were randomized to receive 6 or 12 months of dual-antiplatelet therapy with clopidogrel and aspirin.

The study found that discontinuing clopidogrel and aspirin after 6 months did not increase the rate of 12-month TVF. The rates were 4.7% for the 6-month group and 4.4% for the 12-month group. By Kaplan-Meier analysis, the cumulative proportional TVF estimate at 1 year was 5.2% for the 6-month regimen and 4.3% for the 12-month regimen, which met the noninferiority end point “in a highly significant manner” (P = .0031; upper 1-sided 97.5% confidence interval 0.9%-3.6%), Dr. Gwon said.

The cumulative incidence of major adverse cardiac or coronary events was 7.5% with 6-month therapy and 8.4% with 12-month therapy.

There was, however, a significantly higher risk for primary TVF with early discontinuation of antiplatelet therapy for patients with diabetes. Diabetes patients receiving 6 months of dual-antiplatelet therapy had a TVF rate of 8.9%, vs. 2.9% with 12 months of treatment.

There were no other significant subgroup differences.

NEW ORLEANS – Patients with chronic cardiomyopathy can be successfully weaned from ventricular assist devices, and certain parameters can predict long-term cardiac stability after explantation, according to German investigators.

"Unloading-promoted reversal of heart failure allows for long-term transplant-free outcomes after patients are removed from VADs. However, few patients with chronic cardiomyopathy have been weaned from VADs, and the majority only recently," said principal investigator Dr. Michael Dandel of the German Heart Institute Berlin. "The long-term outcomes of patients, therefore, and the reliability of criteria for making weaning decisions, are not well known."

At his clinic, 91 patients with chronic cardiomyopathy (CCM) as the underlying cause of heart failure were weaned from VADs between 1995 and 2010, including 75 weaned from left ventricular assist devices, 13 weaned from biventricular assist devices, and 3 weaned from right ventricular assist devices. Before VAD implantation, the patients had left ventricular ejection fraction (LVEF) values of 10%-20%.

These patients were evaluated as to the feasibility of weaning and to establish criteria that could predict long-term cardiac stability after VAD removal. "With this information, we can improve future weaning decisions and postweaning patient management," Dr. Dandel said at the annual meeting of the American College of Cardiology.

A total of 47 patients were evaluated. Of these 41 (87.2%) had idiopathic cardiomyopathy, 4 (8.5%) had histologic evidence of chronic myocarditis before VAD implantation, and 2 (4.3%) had chronic ischemic cardiomyopathy with severe left ventricular dilation.

Before VAD insertion, all patients had irreversible end-stage heart failure and required continuous positive inotropic support. No attempts were made to use VADs electively with the aim of myocardial recovery only, he said.

Postweaning results. Cardiac stability lasting at least 15 years was achieved by 2 patients, while 10 patients have been stable at least 10 years and 3 at least 5 years, he reported.

"At 5 years, only five patients, 10.6%, had died due to heart failure recurrence or weaning-related complications. Several patients died of other causes," he said.

Postweaning freedom from heart failure recurrence for all evaluated patients was 74% at 3 years and 66% at 5 years, but these results included nine patients at very high risk for poor outcomes. After 2002, when the investigators tightened their criteria for weaning, freedom from heart failure recurrence reached 100% at 3 years, he noted.

Pre-explantation variables predictive of outcomes. "Echo data obtained during ‘off pump’ trials proved to be reliable for detection of recovery during mechanical unloading," Dr. Dandel said. "In particular, off-pump [left ventricle] size, geometry, and ejection fraction were predictive of outcome after weaning, especially when history of heart failure was also considered."

For cardiac stability lasting at least 5 years, pre-explantation "off pump" LVEF of 50% or more was associated with a positive predictive value of 91.7%, while LVEF of 45% or more had a positive predictive value of 79.1%.

The positive predictive value of LVEF of 45% or more was approximately 90% if additional parameters were considered: pre-explantation left ventricle size and geometry, stability of unloading-induced cardiac improvement before VAD removal, and heart failure duration before VAD implantation.

Time to cardiac recovery seemed important, Dr. Dandel said. "Patients who had recurrences needed more time to show an improvement. They needed twice the duration of VAD support as patients who did not have a recurrence," he said.

"Definite cutoff values for certain parameters – including tissue Doppler-derived LV wall motion velocity – allowed us to formulate weaning criteria with high predictability for postweaning stability," he said.

Risk factors for heart failure recurrence. Dr. Dandel and his colleagues also identified several risk factors that predicted heart failure recurrence during the first 3 years after VAD removal. These factors, and their associated probability for recurrence, were:

• Preweaning off-pump LVEF less than 45% plus history of heart failure longer than 5 years (100%).

• Preweaning LVEF less than 45% (88.9%).

• Preweaning off-pump LVEF less than 50% plus left ventricular internal diastolic diameter greater than 55 mm (90%).

• Pre-explantation LVEF less than 50% and preexisting alteration of greater than 10% best value (87.5%).

• LVEF less than 50% plus relative wall thickness decrease of less than 10% during final off-pump trial (83.3%).

Of these, he emphasized the importance of the final off-pump trial values. "An off-pump ejection fraction less than 45% in patients with a history of heart failure for more than 5 years is an absolute contraindication for VAD removal," he noted. "All such patients in our study had a recurrence of heart failure."

Early instability of ejection fraction and unstable geometry also confer a high probability of recurrence. "A wall thickness increase by more than 10% means the reverse in modeling is not stable enough," he added.

"The notion that we can actually wean patients from VADs is still a fairly new concept, and the European experience is larger than that of the United States. This is still a field that is wide open for determining patient selection and predictors of outcome after VAD removal," session moderator Dr. Gregory A. Ewald, medical director of heart transplantation at Barnes-Jewish Hospital, St. Louis, said in an interview.

"Clearly, the echocardiographic appearance of the heart on and off support is a good predictor," Dr. Ewald said, but he noted that nonechocardiographic factors such as exercise tolerance were not studied. He also noted that the field has moved to continuous-flow pumps rather than pulsatile pumps, which constituted much of the German experience. It remains to be determined if the same parameters are completely applicable to the newer-generation devices.

Dr. Dandel and Dr. Ewald reported having no relevant conflicts of interest.

NEW ORLEANS – Patients with chronic cardiomyopathy can be successfully weaned from ventricular assist devices, and certain parameters can predict long-term cardiac stability after explantation, according to German investigators.

"Unloading-promoted reversal of heart failure allows for long-term transplant-free outcomes after patients are removed from VADs. However, few patients with chronic cardiomyopathy have been weaned from VADs, and the majority only recently," said principal investigator Dr. Michael Dandel of the German Heart Institute Berlin. "The long-term outcomes of patients, therefore, and the reliability of criteria for making weaning decisions, are not well known."

At his clinic, 91 patients with chronic cardiomyopathy (CCM) as the underlying cause of heart failure were weaned from VADs between 1995 and 2010, including 75 weaned from left ventricular assist devices, 13 weaned from biventricular assist devices, and 3 weaned from right ventricular assist devices. Before VAD implantation, the patients had left ventricular ejection fraction (LVEF) values of 10%-20%.

These patients were evaluated as to the feasibility of weaning and to establish criteria that could predict long-term cardiac stability after VAD removal. "With this information, we can improve future weaning decisions and postweaning patient management," Dr. Dandel said at the annual meeting of the American College of Cardiology.

A total of 47 patients were evaluated. Of these 41 (87.2%) had idiopathic cardiomyopathy, 4 (8.5%) had histologic evidence of chronic myocarditis before VAD implantation, and 2 (4.3%) had chronic ischemic cardiomyopathy with severe left ventricular dilation.

Before VAD insertion, all patients had irreversible end-stage heart failure and required continuous positive inotropic support. No attempts were made to use VADs electively with the aim of myocardial recovery only, he said.

Postweaning results. Cardiac stability lasting at least 15 years was achieved by 2 patients, while 10 patients have been stable at least 10 years and 3 at least 5 years, he reported.

"At 5 years, only five patients, 10.6%, had died due to heart failure recurrence or weaning-related complications. Several patients died of other causes," he said.

Postweaning freedom from heart failure recurrence for all evaluated patients was 74% at 3 years and 66% at 5 years, but these results included nine patients at very high risk for poor outcomes. After 2002, when the investigators tightened their criteria for weaning, freedom from heart failure recurrence reached 100% at 3 years, he noted.

Pre-explantation variables predictive of outcomes. "Echo data obtained during ‘off pump’ trials proved to be reliable for detection of recovery during mechanical unloading," Dr. Dandel said. "In particular, off-pump [left ventricle] size, geometry, and ejection fraction were predictive of outcome after weaning, especially when history of heart failure was also considered."

For cardiac stability lasting at least 5 years, pre-explantation "off pump" LVEF of 50% or more was associated with a positive predictive value of 91.7%, while LVEF of 45% or more had a positive predictive value of 79.1%.

The positive predictive value of LVEF of 45% or more was approximately 90% if additional parameters were considered: pre-explantation left ventricle size and geometry, stability of unloading-induced cardiac improvement before VAD removal, and heart failure duration before VAD implantation.

Time to cardiac recovery seemed important, Dr. Dandel said. "Patients who had recurrences needed more time to show an improvement. They needed twice the duration of VAD support as patients who did not have a recurrence," he said.

"Definite cutoff values for certain parameters – including tissue Doppler-derived LV wall motion velocity – allowed us to formulate weaning criteria with high predictability for postweaning stability," he said.

Risk factors for heart failure recurrence. Dr. Dandel and his colleagues also identified several risk factors that predicted heart failure recurrence during the first 3 years after VAD removal. These factors, and their associated probability for recurrence, were:

• Preweaning off-pump LVEF less than 45% plus history of heart failure longer than 5 years (100%).

• Preweaning LVEF less than 45% (88.9%).

• Preweaning off-pump LVEF less than 50% plus left ventricular internal diastolic diameter greater than 55 mm (90%).

• Pre-explantation LVEF less than 50% and preexisting alteration of greater than 10% best value (87.5%).

• LVEF less than 50% plus relative wall thickness decrease of less than 10% during final off-pump trial (83.3%).

Of these, he emphasized the importance of the final off-pump trial values. "An off-pump ejection fraction less than 45% in patients with a history of heart failure for more than 5 years is an absolute contraindication for VAD removal," he noted. "All such patients in our study had a recurrence of heart failure."

Early instability of ejection fraction and unstable geometry also confer a high probability of recurrence. "A wall thickness increase by more than 10% means the reverse in modeling is not stable enough," he added.

"The notion that we can actually wean patients from VADs is still a fairly new concept, and the European experience is larger than that of the United States. This is still a field that is wide open for determining patient selection and predictors of outcome after VAD removal," session moderator Dr. Gregory A. Ewald, medical director of heart transplantation at Barnes-Jewish Hospital, St. Louis, said in an interview.

"Clearly, the echocardiographic appearance of the heart on and off support is a good predictor," Dr. Ewald said, but he noted that nonechocardiographic factors such as exercise tolerance were not studied. He also noted that the field has moved to continuous-flow pumps rather than pulsatile pumps, which constituted much of the German experience. It remains to be determined if the same parameters are completely applicable to the newer-generation devices.

Dr. Dandel and Dr. Ewald reported having no relevant conflicts of interest.

NEW ORLEANS – Patients with chronic cardiomyopathy can be successfully weaned from ventricular assist devices, and certain parameters can predict long-term cardiac stability after explantation, according to German investigators.

"Unloading-promoted reversal of heart failure allows for long-term transplant-free outcomes after patients are removed from VADs. However, few patients with chronic cardiomyopathy have been weaned from VADs, and the majority only recently," said principal investigator Dr. Michael Dandel of the German Heart Institute Berlin. "The long-term outcomes of patients, therefore, and the reliability of criteria for making weaning decisions, are not well known."

At his clinic, 91 patients with chronic cardiomyopathy (CCM) as the underlying cause of heart failure were weaned from VADs between 1995 and 2010, including 75 weaned from left ventricular assist devices, 13 weaned from biventricular assist devices, and 3 weaned from right ventricular assist devices. Before VAD implantation, the patients had left ventricular ejection fraction (LVEF) values of 10%-20%.

These patients were evaluated as to the feasibility of weaning and to establish criteria that could predict long-term cardiac stability after VAD removal. "With this information, we can improve future weaning decisions and postweaning patient management," Dr. Dandel said at the annual meeting of the American College of Cardiology.

A total of 47 patients were evaluated. Of these 41 (87.2%) had idiopathic cardiomyopathy, 4 (8.5%) had histologic evidence of chronic myocarditis before VAD implantation, and 2 (4.3%) had chronic ischemic cardiomyopathy with severe left ventricular dilation.

Before VAD insertion, all patients had irreversible end-stage heart failure and required continuous positive inotropic support. No attempts were made to use VADs electively with the aim of myocardial recovery only, he said.

Postweaning results. Cardiac stability lasting at least 15 years was achieved by 2 patients, while 10 patients have been stable at least 10 years and 3 at least 5 years, he reported.

"At 5 years, only five patients, 10.6%, had died due to heart failure recurrence or weaning-related complications. Several patients died of other causes," he said.

Postweaning freedom from heart failure recurrence for all evaluated patients was 74% at 3 years and 66% at 5 years, but these results included nine patients at very high risk for poor outcomes. After 2002, when the investigators tightened their criteria for weaning, freedom from heart failure recurrence reached 100% at 3 years, he noted.

Pre-explantation variables predictive of outcomes. "Echo data obtained during ‘off pump’ trials proved to be reliable for detection of recovery during mechanical unloading," Dr. Dandel said. "In particular, off-pump [left ventricle] size, geometry, and ejection fraction were predictive of outcome after weaning, especially when history of heart failure was also considered."

For cardiac stability lasting at least 5 years, pre-explantation "off pump" LVEF of 50% or more was associated with a positive predictive value of 91.7%, while LVEF of 45% or more had a positive predictive value of 79.1%.

The positive predictive value of LVEF of 45% or more was approximately 90% if additional parameters were considered: pre-explantation left ventricle size and geometry, stability of unloading-induced cardiac improvement before VAD removal, and heart failure duration before VAD implantation.

Time to cardiac recovery seemed important, Dr. Dandel said. "Patients who had recurrences needed more time to show an improvement. They needed twice the duration of VAD support as patients who did not have a recurrence," he said.

"Definite cutoff values for certain parameters – including tissue Doppler-derived LV wall motion velocity – allowed us to formulate weaning criteria with high predictability for postweaning stability," he said.

Risk factors for heart failure recurrence. Dr. Dandel and his colleagues also identified several risk factors that predicted heart failure recurrence during the first 3 years after VAD removal. These factors, and their associated probability for recurrence, were:

• Preweaning off-pump LVEF less than 45% plus history of heart failure longer than 5 years (100%).

• Preweaning LVEF less than 45% (88.9%).

• Preweaning off-pump LVEF less than 50% plus left ventricular internal diastolic diameter greater than 55 mm (90%).

• Pre-explantation LVEF less than 50% and preexisting alteration of greater than 10% best value (87.5%).

• LVEF less than 50% plus relative wall thickness decrease of less than 10% during final off-pump trial (83.3%).

Of these, he emphasized the importance of the final off-pump trial values. "An off-pump ejection fraction less than 45% in patients with a history of heart failure for more than 5 years is an absolute contraindication for VAD removal," he noted. "All such patients in our study had a recurrence of heart failure."

Early instability of ejection fraction and unstable geometry also confer a high probability of recurrence. "A wall thickness increase by more than 10% means the reverse in modeling is not stable enough," he added.

"The notion that we can actually wean patients from VADs is still a fairly new concept, and the European experience is larger than that of the United States. This is still a field that is wide open for determining patient selection and predictors of outcome after VAD removal," session moderator Dr. Gregory A. Ewald, medical director of heart transplantation at Barnes-Jewish Hospital, St. Louis, said in an interview.

"Clearly, the echocardiographic appearance of the heart on and off support is a good predictor," Dr. Ewald said, but he noted that nonechocardiographic factors such as exercise tolerance were not studied. He also noted that the field has moved to continuous-flow pumps rather than pulsatile pumps, which constituted much of the German experience. It remains to be determined if the same parameters are completely applicable to the newer-generation devices.

Dr. Dandel and Dr. Ewald reported having no relevant conflicts of interest.

NEW ORLEANS – Patients with chronic cardiomyopathy can be successfully weaned from ventricular assist devices, and certain parameters can predict long-term cardiac stability after explantation, according to German investigators.

"Unloading-promoted reversal of heart failure allows for long-term transplant-free outcomes after patients are removed from VADs. However, few patients with chronic cardiomyopathy have been weaned from VADs, and the majority only recently," said principal investigator Dr. Michael Dandel of the German Heart Institute Berlin. "The long-term outcomes of patients, therefore, and the reliability of criteria for making weaning decisions, are not well known."

At his clinic, 91 patients with chronic cardiomyopathy (CCM) as the underlying cause of heart failure were weaned from VADs between 1995 and 2010, including 75 weaned from left ventricular assist devices, 13 weaned from biventricular assist devices, and 3 weaned from right ventricular assist devices. Before VAD implantation, the patients had left ventricular ejection fraction (LVEF) values of 10%-20%.

These patients were evaluated as to the feasibility of weaning and to establish criteria that could predict long-term cardiac stability after VAD removal. "With this information, we can improve future weaning decisions and postweaning patient management," Dr. Dandel said at the annual meeting of the American College of Cardiology.

A total of 47 patients were evaluated. Of these 41 (87.2%) had idiopathic cardiomyopathy, 4 (8.5%) had histologic evidence of chronic myocarditis before VAD implantation, and 2 (4.3%) had chronic ischemic cardiomyopathy with severe left ventricular dilation.

Before VAD insertion, all patients had irreversible end-stage heart failure and required continuous positive inotropic support. No attempts were made to use VADs electively with the aim of myocardial recovery only, he said.

Postweaning results. Cardiac stability lasting at least 15 years was achieved by 2 patients, while 10 patients have been stable at least 10 years and 3 at least 5 years, he reported.

"At 5 years, only five patients, 10.6%, had died due to heart failure recurrence or weaning-related complications. Several patients died of other causes," he said.

Postweaning freedom from heart failure recurrence for all evaluated patients was 74% at 3 years and 66% at 5 years, but these results included nine patients at very high risk for poor outcomes. After 2002, when the investigators tightened their criteria for weaning, freedom from heart failure recurrence reached 100% at 3 years, he noted.

Pre-explantation variables predictive of outcomes. "Echo data obtained during ‘off pump’ trials proved to be reliable for detection of recovery during mechanical unloading," Dr. Dandel said. "In particular, off-pump [left ventricle] size, geometry, and ejection fraction were predictive of outcome after weaning, especially when history of heart failure was also considered."

For cardiac stability lasting at least 5 years, pre-explantation "off pump" LVEF of 50% or more was associated with a positive predictive value of 91.7%, while LVEF of 45% or more had a positive predictive value of 79.1%.

The positive predictive value of LVEF of 45% or more was approximately 90% if additional parameters were considered: pre-explantation left ventricle size and geometry, stability of unloading-induced cardiac improvement before VAD removal, and heart failure duration before VAD implantation.

Time to cardiac recovery seemed important, Dr. Dandel said. "Patients who had recurrences needed more time to show an improvement. They needed twice the duration of VAD support as patients who did not have a recurrence," he said.

"Definite cutoff values for certain parameters – including tissue Doppler-derived LV wall motion velocity – allowed us to formulate weaning criteria with high predictability for postweaning stability," he said.

Risk factors for heart failure recurrence. Dr. Dandel and his colleagues also identified several risk factors that predicted heart failure recurrence during the first 3 years after VAD removal. These factors, and their associated probability for recurrence, were:

• Preweaning off-pump LVEF less than 45% plus history of heart failure longer than 5 years (100%).

• Preweaning LVEF less than 45% (88.9%).

• Preweaning off-pump LVEF less than 50% plus left ventricular internal diastolic diameter greater than 55 mm (90%).

• Pre-explantation LVEF less than 50% and preexisting alteration of greater than 10% best value (87.5%).

• LVEF less than 50% plus relative wall thickness decrease of less than 10% during final off-pump trial (83.3%).

Of these, he emphasized the importance of the final off-pump trial values. "An off-pump ejection fraction less than 45% in patients with a history of heart failure for more than 5 years is an absolute contraindication for VAD removal," he noted. "All such patients in our study had a recurrence of heart failure."

Early instability of ejection fraction and unstable geometry also confer a high probability of recurrence. "A wall thickness increase by more than 10% means the reverse in modeling is not stable enough," he added.

"The notion that we can actually wean patients from VADs is still a fairly new concept, and the European experience is larger than that of the United States. This is still a field that is wide open for determining patient selection and predictors of outcome after VAD removal," session moderator Dr. Gregory A. Ewald, medical director of heart transplantation at Barnes-Jewish Hospital, St. Louis, said in an interview.

"Clearly, the echocardiographic appearance of the heart on and off support is a good predictor," Dr. Ewald said, but he noted that nonechocardiographic factors such as exercise tolerance were not studied. He also noted that the field has moved to continuous-flow pumps rather than pulsatile pumps, which constituted much of the German experience. It remains to be determined if the same parameters are completely applicable to the newer-generation devices.

Dr. Dandel and Dr. Ewald reported having no relevant conflicts of interest.

NEW ORLEANS – Patients with chronic cardiomyopathy can be successfully weaned from ventricular assist devices, and certain parameters can predict long-term cardiac stability after explantation, according to German investigators.

"Unloading-promoted reversal of heart failure allows for long-term transplant-free outcomes after patients are removed from VADs. However, few patients with chronic cardiomyopathy have been weaned from VADs, and the majority only recently," said principal investigator Dr. Michael Dandel of the German Heart Institute Berlin. "The long-term outcomes of patients, therefore, and the reliability of criteria for making weaning decisions, are not well known."

At his clinic, 91 patients with chronic cardiomyopathy (CCM) as the underlying cause of heart failure were weaned from VADs between 1995 and 2010, including 75 weaned from left ventricular assist devices, 13 weaned from biventricular assist devices, and 3 weaned from right ventricular assist devices. Before VAD implantation, the patients had left ventricular ejection fraction (LVEF) values of 10%-20%.

These patients were evaluated as to the feasibility of weaning and to establish criteria that could predict long-term cardiac stability after VAD removal. "With this information, we can improve future weaning decisions and postweaning patient management," Dr. Dandel said at the annual meeting of the American College of Cardiology.

A total of 47 patients were evaluated. Of these 41 (87.2%) had idiopathic cardiomyopathy, 4 (8.5%) had histologic evidence of chronic myocarditis before VAD implantation, and 2 (4.3%) had chronic ischemic cardiomyopathy with severe left ventricular dilation.

Before VAD insertion, all patients had irreversible end-stage heart failure and required continuous positive inotropic support. No attempts were made to use VADs electively with the aim of myocardial recovery only, he said.

Postweaning results. Cardiac stability lasting at least 15 years was achieved by 2 patients, while 10 patients have been stable at least 10 years and 3 at least 5 years, he reported.

"At 5 years, only five patients, 10.6%, had died due to heart failure recurrence or weaning-related complications. Several patients died of other causes," he said.

Postweaning freedom from heart failure recurrence for all evaluated patients was 74% at 3 years and 66% at 5 years, but these results included nine patients at very high risk for poor outcomes. After 2002, when the investigators tightened their criteria for weaning, freedom from heart failure recurrence reached 100% at 3 years, he noted.

Pre-explantation variables predictive of outcomes. "Echo data obtained during ‘off pump’ trials proved to be reliable for detection of recovery during mechanical unloading," Dr. Dandel said. "In particular, off-pump [left ventricle] size, geometry, and ejection fraction were predictive of outcome after weaning, especially when history of heart failure was also considered."

For cardiac stability lasting at least 5 years, pre-explantation "off pump" LVEF of 50% or more was associated with a positive predictive value of 91.7%, while LVEF of 45% or more had a positive predictive value of 79.1%.

The positive predictive value of LVEF of 45% or more was approximately 90% if additional parameters were considered: pre-explantation left ventricle size and geometry, stability of unloading-induced cardiac improvement before VAD removal, and heart failure duration before VAD implantation.

Time to cardiac recovery seemed important, Dr. Dandel said. "Patients who had recurrences needed more time to show an improvement. They needed twice the duration of VAD support as patients who did not have a recurrence," he said.

"Definite cutoff values for certain parameters – including tissue Doppler-derived LV wall motion velocity – allowed us to formulate weaning criteria with high predictability for postweaning stability," he said.

Risk factors for heart failure recurrence. Dr. Dandel and his colleagues also identified several risk factors that predicted heart failure recurrence during the first 3 years after VAD removal. These factors, and their associated probability for recurrence, were:

• Preweaning off-pump LVEF less than 45% plus history of heart failure longer than 5 years (100%).

• Preweaning LVEF less than 45% (88.9%).

• Preweaning off-pump LVEF less than 50% plus left ventricular internal diastolic diameter greater than 55 mm (90%).

• Pre-explantation LVEF less than 50% and preexisting alteration of greater than 10% best value (87.5%).

• LVEF less than 50% plus relative wall thickness decrease of less than 10% during final off-pump trial (83.3%).

Of these, he emphasized the importance of the final off-pump trial values. "An off-pump ejection fraction less than 45% in patients with a history of heart failure for more than 5 years is an absolute contraindication for VAD removal," he noted. "All such patients in our study had a recurrence of heart failure."

Early instability of ejection fraction and unstable geometry also confer a high probability of recurrence. "A wall thickness increase by more than 10% means the reverse in modeling is not stable enough," he added.

"The notion that we can actually wean patients from VADs is still a fairly new concept, and the European experience is larger than that of the United States. This is still a field that is wide open for determining patient selection and predictors of outcome after VAD removal," session moderator Dr. Gregory A. Ewald, medical director of heart transplantation at Barnes-Jewish Hospital, St. Louis, said in an interview.

"Clearly, the echocardiographic appearance of the heart on and off support is a good predictor," Dr. Ewald said, but he noted that nonechocardiographic factors such as exercise tolerance were not studied. He also noted that the field has moved to continuous-flow pumps rather than pulsatile pumps, which constituted much of the German experience. It remains to be determined if the same parameters are completely applicable to the newer-generation devices.

Dr. Dandel and Dr. Ewald reported having no relevant conflicts of interest.

NEW ORLEANS – Patients with chronic cardiomyopathy can be successfully weaned from ventricular assist devices, and certain parameters can predict long-term cardiac stability after explantation, according to German investigators.

"Unloading-promoted reversal of heart failure allows for long-term transplant-free outcomes after patients are removed from VADs. However, few patients with chronic cardiomyopathy have been weaned from VADs, and the majority only recently," said principal investigator Dr. Michael Dandel of the German Heart Institute Berlin. "The long-term outcomes of patients, therefore, and the reliability of criteria for making weaning decisions, are not well known."

At his clinic, 91 patients with chronic cardiomyopathy (CCM) as the underlying cause of heart failure were weaned from VADs between 1995 and 2010, including 75 weaned from left ventricular assist devices, 13 weaned from biventricular assist devices, and 3 weaned from right ventricular assist devices. Before VAD implantation, the patients had left ventricular ejection fraction (LVEF) values of 10%-20%.

These patients were evaluated as to the feasibility of weaning and to establish criteria that could predict long-term cardiac stability after VAD removal. "With this information, we can improve future weaning decisions and postweaning patient management," Dr. Dandel said at the annual meeting of the American College of Cardiology.

A total of 47 patients were evaluated. Of these 41 (87.2%) had idiopathic cardiomyopathy, 4 (8.5%) had histologic evidence of chronic myocarditis before VAD implantation, and 2 (4.3%) had chronic ischemic cardiomyopathy with severe left ventricular dilation.

Before VAD insertion, all patients had irreversible end-stage heart failure and required continuous positive inotropic support. No attempts were made to use VADs electively with the aim of myocardial recovery only, he said.

Postweaning results. Cardiac stability lasting at least 15 years was achieved by 2 patients, while 10 patients have been stable at least 10 years and 3 at least 5 years, he reported.

"At 5 years, only five patients, 10.6%, had died due to heart failure recurrence or weaning-related complications. Several patients died of other causes," he said.

Postweaning freedom from heart failure recurrence for all evaluated patients was 74% at 3 years and 66% at 5 years, but these results included nine patients at very high risk for poor outcomes. After 2002, when the investigators tightened their criteria for weaning, freedom from heart failure recurrence reached 100% at 3 years, he noted.

Pre-explantation variables predictive of outcomes. "Echo data obtained during ‘off pump’ trials proved to be reliable for detection of recovery during mechanical unloading," Dr. Dandel said. "In particular, off-pump [left ventricle] size, geometry, and ejection fraction were predictive of outcome after weaning, especially when history of heart failure was also considered."

For cardiac stability lasting at least 5 years, pre-explantation "off pump" LVEF of 50% or more was associated with a positive predictive value of 91.7%, while LVEF of 45% or more had a positive predictive value of 79.1%.

The positive predictive value of LVEF of 45% or more was approximately 90% if additional parameters were considered: pre-explantation left ventricle size and geometry, stability of unloading-induced cardiac improvement before VAD removal, and heart failure duration before VAD implantation.

Time to cardiac recovery seemed important, Dr. Dandel said. "Patients who had recurrences needed more time to show an improvement. They needed twice the duration of VAD support as patients who did not have a recurrence," he said.

"Definite cutoff values for certain parameters – including tissue Doppler-derived LV wall motion velocity – allowed us to formulate weaning criteria with high predictability for postweaning stability," he said.

Risk factors for heart failure recurrence. Dr. Dandel and his colleagues also identified several risk factors that predicted heart failure recurrence during the first 3 years after VAD removal. These factors, and their associated probability for recurrence, were:

• Preweaning off-pump LVEF less than 45% plus history of heart failure longer than 5 years (100%).

• Preweaning LVEF less than 45% (88.9%).

• Preweaning off-pump LVEF less than 50% plus left ventricular internal diastolic diameter greater than 55 mm (90%).

• Pre-explantation LVEF less than 50% and preexisting alteration of greater than 10% best value (87.5%).

• LVEF less than 50% plus relative wall thickness decrease of less than 10% during final off-pump trial (83.3%).

Of these, he emphasized the importance of the final off-pump trial values. "An off-pump ejection fraction less than 45% in patients with a history of heart failure for more than 5 years is an absolute contraindication for VAD removal," he noted. "All such patients in our study had a recurrence of heart failure."

Early instability of ejection fraction and unstable geometry also confer a high probability of recurrence. "A wall thickness increase by more than 10% means the reverse in modeling is not stable enough," he added.

"The notion that we can actually wean patients from VADs is still a fairly new concept, and the European experience is larger than that of the United States. This is still a field that is wide open for determining patient selection and predictors of outcome after VAD removal," session moderator Dr. Gregory A. Ewald, medical director of heart transplantation at Barnes-Jewish Hospital, St. Louis, said in an interview.

"Clearly, the echocardiographic appearance of the heart on and off support is a good predictor," Dr. Ewald said, but he noted that nonechocardiographic factors such as exercise tolerance were not studied. He also noted that the field has moved to continuous-flow pumps rather than pulsatile pumps, which constituted much of the German experience. It remains to be determined if the same parameters are completely applicable to the newer-generation devices.

Dr. Dandel and Dr. Ewald reported having no relevant conflicts of interest.

NEW ORLEANS – BRAF mutation is a valuable molecular marker for worse clinicopathological outcomes in papillary thyroid cancer – one that will be useful preoperatively in risk stratification and decision making, according to a leading investigator in this area, Dr. Michael Mingzhao Xing.

"BRAF mutation, as a prognostic marker, could be particularly helpful in some of the more controversial areas related to the management of PTC [papillary thyroid cancer], such as areas where current standard guidelines may not give clear guidance," Dr. Xing suggested at the symposium on thyroid and parathyroid diseases, which was sponsored by Tulane University.

Although Dr. Xing, chief of the laboratory for cellular and molecular thyroid research at Johns Hopkins University in Baltimore, advocated strongly for the potential of BRAF to guide treatment, he added that its routine use still needs to be specifically defined..

The T1799A mutation in BRAF, a kinase in the MPA kinase signaling pathway, leads to uncontrolled cell growth, unlimited cell proliferation, and – ultimately – tumorigenesis, he said. It is most common in PTC (44%), and to a lesser degree in anaplastic thyroid carcinoma (24%), according to his series of nearly 2,000 tumors (Endocr. Relat. Cancer 2005;12:245-62). The mutation was not found in any medullary thyroid carcinomas or follicular thyroid carcinomas.

Among the subtypes of PTC, the mutation was present in 77% of tall-cell PTCs, 60% of conventional PTCs, and 12% of follicular-variant PTCs.

Multiple Studies Are Consistent

In a multicenter study of 219 patients by Dr. Xing and colleagues, the association between BRAF mutation and clinical aggressiveness was clear. Extrathyroidal invasion was observed in 41% of BRAF-positive patients, compared with 16% of BRAF-negative patients, whereas lymph node metastases occurred in 54% and 21%, respectively (both P less than .001) (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other associations were seen between the mutation and advanced tumor stage (P = .007) and tumor recurrence (P = .004). Age at diagnosis, sex, tumor size, and multifocality were not consistently related to mutation status, he added.

This more-aggressive clinicopathological picture translated into significantly more recurrences among BRAF-positive patients in the study at 9 years (25% vs. 9%, for a threefold increase in risk; P = .03). BRAF mutation was even an independent and stronger predictor of recurrence in patients with stage I and II disease (22% vs. 5%, respectively; P = .002).

A Korean study also calculated an odds ratio of 4.6 for recurrence in the presence of the BRAF mutation (P = 0.037), although statistical significance was lost in a multivariate model (Clin. Endocrinol. 2006;65:364-8). In a 2008 study performed in the Middle East, BRAF mutation was associated with metastasis (P = .0274) and poor disease-free survival (P = .0121). A meta-analysis validated the association of the BRAF mutation with extrathyroidal invasion, lymph node metastasis, and advanced stage (Endocr. Rev. 2007;28:742-62).

Dr. Xing noted the universality of the association: "Among studies of patients with a variety of ethnic backgrounds, there is a strong association with disease recurrence," he observed.

Low-Risk Patients Rendered High Risk

Even in populations that are conventionally considered at low risk for recurrence, the BRAF mutation is not uncommon, Dr. Xing said, citing prevalence figures of 36% among stage I and II PTC patients, and 18%-24% among papillary thyroid microcarcinoma (PTMC) patients. In these low-risk populations, aggressive features and recurrence are associated with BRAF positivity.

In studies of stage I and II patients and others with PTMC, BRAF-positive patients were three to four times more likely to have extrathyroidal extension, lymph node metastasis, and advanced disease (Ann. Surg. Oncol. 2009;16:240-5). One study of stage I and II patients found the odds ratio for recurrence to be 11.4 (P = .004) "with adjustment for conventional clinicopathological factors and radioiodine treatment." (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other Concerning Associations

Importantly, BRAF mutations are associated with a loss of radioiodine avidity in recurrent PTC, "which means the patient may not respond to radioactive iodine treatment," he said. Dr. Xing has observed a loss of avidity in 54% of patients with the mutation, but in none of the patients who lacked the BRAF mutation.

Dr. David S. Cooper, professor of medicine at Johns Hopkins and former president of the American Thyroid Association, commented on this issue during the discussion. "Knowing beforehand when a patient is BRAF positive may inform our aggressiveness with regard to surgery, [that is,] central neck dissection," he said.

"And there is the thought that because [such cancers] are more aggressive, we will be more likely to treat with radioactive iodine. The BRAF mutation also confers the inability to take up radioactive iodine, though, so this is not necessarily going to be the case." However, radioiodine treatment to ablate residual normal thyroid tissue may be more important in BRAF mutation–positive patients, as it can enhance the reliability of serum thyroglobulin testing for the surveillance of thyroid cancer recurrence in these patients who may need more vigilant monitoring because of the increased aggressiveness of their cancer.

Also of concern is the finding that these patients are likely to require additional surgery. "We were the first to show a higher need for reoperation," Dr. Xing noted.

In his 2005 series, 69% of BRAF-positive patients required more aggressive treatment (additional surgery or external radiation), compared with 14% of BRAF-negative patients (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other recent studies have shown the same (Surgery 2010;148:1139-46). In a study at the University of Pittsburgh, the investigators determined that preoperative knowledge of BRAF mutation positivity could have productively altered the initial PTC surgical management in 24% of patients (Surgery 2009;146:1215-23).

Testing Biopsy for BRAF Mutation

"If you have the results of BRAF testing preoperatively, they can help with risk stratification and surgical planning," Dr. Xing said.

In a 2010 study, researchers analyzed the utility of BRAF mutation screening of 61 fine-needle aspiration biopsy (FNAB) specimens for predicting aggressive clinicopathological characteristics of PTMC (Ann. Surg. Oncol. 2010;17:3294-300). The BRAF mutation was significantly associated with multifocality, extrathyroidal invasion, lateral lymph-node metastasis (LNM) and advanced tumor stages. In a multivariate analysis, the BRAF mutation carried an odds ratio of 18 for central LNM (P = .01). The authors concluded that BRAF mutation screening of FNAB specimens can be used to predict aggressive clinicopathological characteristics of PTMC, and that lateral neck nodes should be meticulously analyzed for cases of PTMC demonstrating mutated BRAF.

These results were consistent with those of an earlier study in which Dr. Xing and colleagues calculated odds ratios to show the predictive power of BRAF mutations found in FNAB specimens to preoperatively risk-stratify PTC patients (J. Clin. Oncol. 2009;27:2977-82). (See box.) The positive predictive value of BRAF mutation status was 36%, and the negative predictive value was 88%.

In summary, Dr. Xing emphasized that the BRAF mutation plays a critical role in PTC tumorigenesis and aggressiveness and can be used preoperatively to risk-stratify patients and assist the physician in planning treatment. He joked to attendees: "Send your patients to me first, before you treat, to check for the mutation."

Dr. Xing reported receiving royalties as a coholder of a licensed patent on the discovery of BRAF mutation and its clinical characterization in thyroid cancer.

NEW ORLEANS – BRAF mutation is a valuable molecular marker for worse clinicopathological outcomes in papillary thyroid cancer – one that will be useful preoperatively in risk stratification and decision making, according to a leading investigator in this area, Dr. Michael Mingzhao Xing.

"BRAF mutation, as a prognostic marker, could be particularly helpful in some of the more controversial areas related to the management of PTC [papillary thyroid cancer], such as areas where current standard guidelines may not give clear guidance," Dr. Xing suggested at the symposium on thyroid and parathyroid diseases, which was sponsored by Tulane University.

Although Dr. Xing, chief of the laboratory for cellular and molecular thyroid research at Johns Hopkins University in Baltimore, advocated strongly for the potential of BRAF to guide treatment, he added that its routine use still needs to be specifically defined..

The T1799A mutation in BRAF, a kinase in the MPA kinase signaling pathway, leads to uncontrolled cell growth, unlimited cell proliferation, and – ultimately – tumorigenesis, he said. It is most common in PTC (44%), and to a lesser degree in anaplastic thyroid carcinoma (24%), according to his series of nearly 2,000 tumors (Endocr. Relat. Cancer 2005;12:245-62). The mutation was not found in any medullary thyroid carcinomas or follicular thyroid carcinomas.

Among the subtypes of PTC, the mutation was present in 77% of tall-cell PTCs, 60% of conventional PTCs, and 12% of follicular-variant PTCs.

Multiple Studies Are Consistent

In a multicenter study of 219 patients by Dr. Xing and colleagues, the association between BRAF mutation and clinical aggressiveness was clear. Extrathyroidal invasion was observed in 41% of BRAF-positive patients, compared with 16% of BRAF-negative patients, whereas lymph node metastases occurred in 54% and 21%, respectively (both P less than .001) (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other associations were seen between the mutation and advanced tumor stage (P = .007) and tumor recurrence (P = .004). Age at diagnosis, sex, tumor size, and multifocality were not consistently related to mutation status, he added.

This more-aggressive clinicopathological picture translated into significantly more recurrences among BRAF-positive patients in the study at 9 years (25% vs. 9%, for a threefold increase in risk; P = .03). BRAF mutation was even an independent and stronger predictor of recurrence in patients with stage I and II disease (22% vs. 5%, respectively; P = .002).

A Korean study also calculated an odds ratio of 4.6 for recurrence in the presence of the BRAF mutation (P = 0.037), although statistical significance was lost in a multivariate model (Clin. Endocrinol. 2006;65:364-8). In a 2008 study performed in the Middle East, BRAF mutation was associated with metastasis (P = .0274) and poor disease-free survival (P = .0121). A meta-analysis validated the association of the BRAF mutation with extrathyroidal invasion, lymph node metastasis, and advanced stage (Endocr. Rev. 2007;28:742-62).

Dr. Xing noted the universality of the association: "Among studies of patients with a variety of ethnic backgrounds, there is a strong association with disease recurrence," he observed.

Low-Risk Patients Rendered High Risk

Even in populations that are conventionally considered at low risk for recurrence, the BRAF mutation is not uncommon, Dr. Xing said, citing prevalence figures of 36% among stage I and II PTC patients, and 18%-24% among papillary thyroid microcarcinoma (PTMC) patients. In these low-risk populations, aggressive features and recurrence are associated with BRAF positivity.

In studies of stage I and II patients and others with PTMC, BRAF-positive patients were three to four times more likely to have extrathyroidal extension, lymph node metastasis, and advanced disease (Ann. Surg. Oncol. 2009;16:240-5). One study of stage I and II patients found the odds ratio for recurrence to be 11.4 (P = .004) "with adjustment for conventional clinicopathological factors and radioiodine treatment." (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other Concerning Associations

Importantly, BRAF mutations are associated with a loss of radioiodine avidity in recurrent PTC, "which means the patient may not respond to radioactive iodine treatment," he said. Dr. Xing has observed a loss of avidity in 54% of patients with the mutation, but in none of the patients who lacked the BRAF mutation.

Dr. David S. Cooper, professor of medicine at Johns Hopkins and former president of the American Thyroid Association, commented on this issue during the discussion. "Knowing beforehand when a patient is BRAF positive may inform our aggressiveness with regard to surgery, [that is,] central neck dissection," he said.

"And there is the thought that because [such cancers] are more aggressive, we will be more likely to treat with radioactive iodine. The BRAF mutation also confers the inability to take up radioactive iodine, though, so this is not necessarily going to be the case." However, radioiodine treatment to ablate residual normal thyroid tissue may be more important in BRAF mutation–positive patients, as it can enhance the reliability of serum thyroglobulin testing for the surveillance of thyroid cancer recurrence in these patients who may need more vigilant monitoring because of the increased aggressiveness of their cancer.

Also of concern is the finding that these patients are likely to require additional surgery. "We were the first to show a higher need for reoperation," Dr. Xing noted.

In his 2005 series, 69% of BRAF-positive patients required more aggressive treatment (additional surgery or external radiation), compared with 14% of BRAF-negative patients (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other recent studies have shown the same (Surgery 2010;148:1139-46). In a study at the University of Pittsburgh, the investigators determined that preoperative knowledge of BRAF mutation positivity could have productively altered the initial PTC surgical management in 24% of patients (Surgery 2009;146:1215-23).

Testing Biopsy for BRAF Mutation

"If you have the results of BRAF testing preoperatively, they can help with risk stratification and surgical planning," Dr. Xing said.

In a 2010 study, researchers analyzed the utility of BRAF mutation screening of 61 fine-needle aspiration biopsy (FNAB) specimens for predicting aggressive clinicopathological characteristics of PTMC (Ann. Surg. Oncol. 2010;17:3294-300). The BRAF mutation was significantly associated with multifocality, extrathyroidal invasion, lateral lymph-node metastasis (LNM) and advanced tumor stages. In a multivariate analysis, the BRAF mutation carried an odds ratio of 18 for central LNM (P = .01). The authors concluded that BRAF mutation screening of FNAB specimens can be used to predict aggressive clinicopathological characteristics of PTMC, and that lateral neck nodes should be meticulously analyzed for cases of PTMC demonstrating mutated BRAF.

These results were consistent with those of an earlier study in which Dr. Xing and colleagues calculated odds ratios to show the predictive power of BRAF mutations found in FNAB specimens to preoperatively risk-stratify PTC patients (J. Clin. Oncol. 2009;27:2977-82). (See box.) The positive predictive value of BRAF mutation status was 36%, and the negative predictive value was 88%.

In summary, Dr. Xing emphasized that the BRAF mutation plays a critical role in PTC tumorigenesis and aggressiveness and can be used preoperatively to risk-stratify patients and assist the physician in planning treatment. He joked to attendees: "Send your patients to me first, before you treat, to check for the mutation."

Dr. Xing reported receiving royalties as a coholder of a licensed patent on the discovery of BRAF mutation and its clinical characterization in thyroid cancer.

NEW ORLEANS – BRAF mutation is a valuable molecular marker for worse clinicopathological outcomes in papillary thyroid cancer – one that will be useful preoperatively in risk stratification and decision making, according to a leading investigator in this area, Dr. Michael Mingzhao Xing.

"BRAF mutation, as a prognostic marker, could be particularly helpful in some of the more controversial areas related to the management of PTC [papillary thyroid cancer], such as areas where current standard guidelines may not give clear guidance," Dr. Xing suggested at the symposium on thyroid and parathyroid diseases, which was sponsored by Tulane University.

Although Dr. Xing, chief of the laboratory for cellular and molecular thyroid research at Johns Hopkins University in Baltimore, advocated strongly for the potential of BRAF to guide treatment, he added that its routine use still needs to be specifically defined..

The T1799A mutation in BRAF, a kinase in the MPA kinase signaling pathway, leads to uncontrolled cell growth, unlimited cell proliferation, and – ultimately – tumorigenesis, he said. It is most common in PTC (44%), and to a lesser degree in anaplastic thyroid carcinoma (24%), according to his series of nearly 2,000 tumors (Endocr. Relat. Cancer 2005;12:245-62). The mutation was not found in any medullary thyroid carcinomas or follicular thyroid carcinomas.

Among the subtypes of PTC, the mutation was present in 77% of tall-cell PTCs, 60% of conventional PTCs, and 12% of follicular-variant PTCs.

Multiple Studies Are Consistent

In a multicenter study of 219 patients by Dr. Xing and colleagues, the association between BRAF mutation and clinical aggressiveness was clear. Extrathyroidal invasion was observed in 41% of BRAF-positive patients, compared with 16% of BRAF-negative patients, whereas lymph node metastases occurred in 54% and 21%, respectively (both P less than .001) (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other associations were seen between the mutation and advanced tumor stage (P = .007) and tumor recurrence (P = .004). Age at diagnosis, sex, tumor size, and multifocality were not consistently related to mutation status, he added.

This more-aggressive clinicopathological picture translated into significantly more recurrences among BRAF-positive patients in the study at 9 years (25% vs. 9%, for a threefold increase in risk; P = .03). BRAF mutation was even an independent and stronger predictor of recurrence in patients with stage I and II disease (22% vs. 5%, respectively; P = .002).

A Korean study also calculated an odds ratio of 4.6 for recurrence in the presence of the BRAF mutation (P = 0.037), although statistical significance was lost in a multivariate model (Clin. Endocrinol. 2006;65:364-8). In a 2008 study performed in the Middle East, BRAF mutation was associated with metastasis (P = .0274) and poor disease-free survival (P = .0121). A meta-analysis validated the association of the BRAF mutation with extrathyroidal invasion, lymph node metastasis, and advanced stage (Endocr. Rev. 2007;28:742-62).

Dr. Xing noted the universality of the association: "Among studies of patients with a variety of ethnic backgrounds, there is a strong association with disease recurrence," he observed.

Low-Risk Patients Rendered High Risk

Even in populations that are conventionally considered at low risk for recurrence, the BRAF mutation is not uncommon, Dr. Xing said, citing prevalence figures of 36% among stage I and II PTC patients, and 18%-24% among papillary thyroid microcarcinoma (PTMC) patients. In these low-risk populations, aggressive features and recurrence are associated with BRAF positivity.

In studies of stage I and II patients and others with PTMC, BRAF-positive patients were three to four times more likely to have extrathyroidal extension, lymph node metastasis, and advanced disease (Ann. Surg. Oncol. 2009;16:240-5). One study of stage I and II patients found the odds ratio for recurrence to be 11.4 (P = .004) "with adjustment for conventional clinicopathological factors and radioiodine treatment." (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other Concerning Associations

Importantly, BRAF mutations are associated with a loss of radioiodine avidity in recurrent PTC, "which means the patient may not respond to radioactive iodine treatment," he said. Dr. Xing has observed a loss of avidity in 54% of patients with the mutation, but in none of the patients who lacked the BRAF mutation.

Dr. David S. Cooper, professor of medicine at Johns Hopkins and former president of the American Thyroid Association, commented on this issue during the discussion. "Knowing beforehand when a patient is BRAF positive may inform our aggressiveness with regard to surgery, [that is,] central neck dissection," he said.

"And there is the thought that because [such cancers] are more aggressive, we will be more likely to treat with radioactive iodine. The BRAF mutation also confers the inability to take up radioactive iodine, though, so this is not necessarily going to be the case." However, radioiodine treatment to ablate residual normal thyroid tissue may be more important in BRAF mutation–positive patients, as it can enhance the reliability of serum thyroglobulin testing for the surveillance of thyroid cancer recurrence in these patients who may need more vigilant monitoring because of the increased aggressiveness of their cancer.

Also of concern is the finding that these patients are likely to require additional surgery. "We were the first to show a higher need for reoperation," Dr. Xing noted.

In his 2005 series, 69% of BRAF-positive patients required more aggressive treatment (additional surgery or external radiation), compared with 14% of BRAF-negative patients (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other recent studies have shown the same (Surgery 2010;148:1139-46). In a study at the University of Pittsburgh, the investigators determined that preoperative knowledge of BRAF mutation positivity could have productively altered the initial PTC surgical management in 24% of patients (Surgery 2009;146:1215-23).

Testing Biopsy for BRAF Mutation

"If you have the results of BRAF testing preoperatively, they can help with risk stratification and surgical planning," Dr. Xing said.

In a 2010 study, researchers analyzed the utility of BRAF mutation screening of 61 fine-needle aspiration biopsy (FNAB) specimens for predicting aggressive clinicopathological characteristics of PTMC (Ann. Surg. Oncol. 2010;17:3294-300). The BRAF mutation was significantly associated with multifocality, extrathyroidal invasion, lateral lymph-node metastasis (LNM) and advanced tumor stages. In a multivariate analysis, the BRAF mutation carried an odds ratio of 18 for central LNM (P = .01). The authors concluded that BRAF mutation screening of FNAB specimens can be used to predict aggressive clinicopathological characteristics of PTMC, and that lateral neck nodes should be meticulously analyzed for cases of PTMC demonstrating mutated BRAF.

These results were consistent with those of an earlier study in which Dr. Xing and colleagues calculated odds ratios to show the predictive power of BRAF mutations found in FNAB specimens to preoperatively risk-stratify PTC patients (J. Clin. Oncol. 2009;27:2977-82). (See box.) The positive predictive value of BRAF mutation status was 36%, and the negative predictive value was 88%.

In summary, Dr. Xing emphasized that the BRAF mutation plays a critical role in PTC tumorigenesis and aggressiveness and can be used preoperatively to risk-stratify patients and assist the physician in planning treatment. He joked to attendees: "Send your patients to me first, before you treat, to check for the mutation."

Dr. Xing reported receiving royalties as a coholder of a licensed patent on the discovery of BRAF mutation and its clinical characterization in thyroid cancer.

NEW ORLEANS – BRAF mutation is a valuable molecular marker for worse clinicopathological outcomes in papillary thyroid cancer – one that will be useful preoperatively in risk stratification and decision making, according to a leading investigator in this area, Dr. Michael Mingzhao Xing.

"BRAF mutation, as a prognostic marker, could be particularly helpful in some of the more controversial areas related to the management of PTC [papillary thyroid cancer], such as areas where current standard guidelines may not give clear guidance," Dr. Xing suggested at the symposium on thyroid and parathyroid diseases, which was sponsored by Tulane University.

Although Dr. Xing, chief of the laboratory for cellular and molecular thyroid research at Johns Hopkins University in Baltimore, advocated strongly for the potential of BRAF to guide treatment, he added that its routine use still needs to be specifically defined..

The T1799A mutation in BRAF, a kinase in the MPA kinase signaling pathway, leads to uncontrolled cell growth, unlimited cell proliferation, and – ultimately – tumorigenesis, he said. It is most common in PTC (44%), and to a lesser degree in anaplastic thyroid carcinoma (24%), according to his series of nearly 2,000 tumors (Endocr. Relat. Cancer 2005;12:245-62). The mutation was not found in any medullary thyroid carcinomas or follicular thyroid carcinomas.

Among the subtypes of PTC, the mutation was present in 77% of tall-cell PTCs, 60% of conventional PTCs, and 12% of follicular-variant PTCs.

Multiple Studies Are Consistent

In a multicenter study of 219 patients by Dr. Xing and colleagues, the association between BRAF mutation and clinical aggressiveness was clear. Extrathyroidal invasion was observed in 41% of BRAF-positive patients, compared with 16% of BRAF-negative patients, whereas lymph node metastases occurred in 54% and 21%, respectively (both P less than .001) (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other associations were seen between the mutation and advanced tumor stage (P = .007) and tumor recurrence (P = .004). Age at diagnosis, sex, tumor size, and multifocality were not consistently related to mutation status, he added.

This more-aggressive clinicopathological picture translated into significantly more recurrences among BRAF-positive patients in the study at 9 years (25% vs. 9%, for a threefold increase in risk; P = .03). BRAF mutation was even an independent and stronger predictor of recurrence in patients with stage I and II disease (22% vs. 5%, respectively; P = .002).

A Korean study also calculated an odds ratio of 4.6 for recurrence in the presence of the BRAF mutation (P = 0.037), although statistical significance was lost in a multivariate model (Clin. Endocrinol. 2006;65:364-8). In a 2008 study performed in the Middle East, BRAF mutation was associated with metastasis (P = .0274) and poor disease-free survival (P = .0121). A meta-analysis validated the association of the BRAF mutation with extrathyroidal invasion, lymph node metastasis, and advanced stage (Endocr. Rev. 2007;28:742-62).

Dr. Xing noted the universality of the association: "Among studies of patients with a variety of ethnic backgrounds, there is a strong association with disease recurrence," he observed.

Low-Risk Patients Rendered High Risk

Even in populations that are conventionally considered at low risk for recurrence, the BRAF mutation is not uncommon, Dr. Xing said, citing prevalence figures of 36% among stage I and II PTC patients, and 18%-24% among papillary thyroid microcarcinoma (PTMC) patients. In these low-risk populations, aggressive features and recurrence are associated with BRAF positivity.

In studies of stage I and II patients and others with PTMC, BRAF-positive patients were three to four times more likely to have extrathyroidal extension, lymph node metastasis, and advanced disease (Ann. Surg. Oncol. 2009;16:240-5). One study of stage I and II patients found the odds ratio for recurrence to be 11.4 (P = .004) "with adjustment for conventional clinicopathological factors and radioiodine treatment." (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other Concerning Associations

Importantly, BRAF mutations are associated with a loss of radioiodine avidity in recurrent PTC, "which means the patient may not respond to radioactive iodine treatment," he said. Dr. Xing has observed a loss of avidity in 54% of patients with the mutation, but in none of the patients who lacked the BRAF mutation.

Dr. David S. Cooper, professor of medicine at Johns Hopkins and former president of the American Thyroid Association, commented on this issue during the discussion. "Knowing beforehand when a patient is BRAF positive may inform our aggressiveness with regard to surgery, [that is,] central neck dissection," he said.

"And there is the thought that because [such cancers] are more aggressive, we will be more likely to treat with radioactive iodine. The BRAF mutation also confers the inability to take up radioactive iodine, though, so this is not necessarily going to be the case." However, radioiodine treatment to ablate residual normal thyroid tissue may be more important in BRAF mutation–positive patients, as it can enhance the reliability of serum thyroglobulin testing for the surveillance of thyroid cancer recurrence in these patients who may need more vigilant monitoring because of the increased aggressiveness of their cancer.

Also of concern is the finding that these patients are likely to require additional surgery. "We were the first to show a higher need for reoperation," Dr. Xing noted.

In his 2005 series, 69% of BRAF-positive patients required more aggressive treatment (additional surgery or external radiation), compared with 14% of BRAF-negative patients (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other recent studies have shown the same (Surgery 2010;148:1139-46). In a study at the University of Pittsburgh, the investigators determined that preoperative knowledge of BRAF mutation positivity could have productively altered the initial PTC surgical management in 24% of patients (Surgery 2009;146:1215-23).

Testing Biopsy for BRAF Mutation

"If you have the results of BRAF testing preoperatively, they can help with risk stratification and surgical planning," Dr. Xing said.

In a 2010 study, researchers analyzed the utility of BRAF mutation screening of 61 fine-needle aspiration biopsy (FNAB) specimens for predicting aggressive clinicopathological characteristics of PTMC (Ann. Surg. Oncol. 2010;17:3294-300). The BRAF mutation was significantly associated with multifocality, extrathyroidal invasion, lateral lymph-node metastasis (LNM) and advanced tumor stages. In a multivariate analysis, the BRAF mutation carried an odds ratio of 18 for central LNM (P = .01). The authors concluded that BRAF mutation screening of FNAB specimens can be used to predict aggressive clinicopathological characteristics of PTMC, and that lateral neck nodes should be meticulously analyzed for cases of PTMC demonstrating mutated BRAF.

These results were consistent with those of an earlier study in which Dr. Xing and colleagues calculated odds ratios to show the predictive power of BRAF mutations found in FNAB specimens to preoperatively risk-stratify PTC patients (J. Clin. Oncol. 2009;27:2977-82). (See box.) The positive predictive value of BRAF mutation status was 36%, and the negative predictive value was 88%.

In summary, Dr. Xing emphasized that the BRAF mutation plays a critical role in PTC tumorigenesis and aggressiveness and can be used preoperatively to risk-stratify patients and assist the physician in planning treatment. He joked to attendees: "Send your patients to me first, before you treat, to check for the mutation."

Dr. Xing reported receiving royalties as a coholder of a licensed patent on the discovery of BRAF mutation and its clinical characterization in thyroid cancer.

NEW ORLEANS – BRAF mutation is a valuable molecular marker for worse clinicopathological outcomes in papillary thyroid cancer – one that will be useful preoperatively in risk stratification and decision making, according to a leading investigator in this area, Dr. Michael Mingzhao Xing.

"BRAF mutation, as a prognostic marker, could be particularly helpful in some of the more controversial areas related to the management of PTC [papillary thyroid cancer], such as areas where current standard guidelines may not give clear guidance," Dr. Xing suggested at the symposium on thyroid and parathyroid diseases, which was sponsored by Tulane University.

Although Dr. Xing, chief of the laboratory for cellular and molecular thyroid research at Johns Hopkins University in Baltimore, advocated strongly for the potential of BRAF to guide treatment, he added that its routine use still needs to be specifically defined..

The T1799A mutation in BRAF, a kinase in the MPA kinase signaling pathway, leads to uncontrolled cell growth, unlimited cell proliferation, and – ultimately – tumorigenesis, he said. It is most common in PTC (44%), and to a lesser degree in anaplastic thyroid carcinoma (24%), according to his series of nearly 2,000 tumors (Endocr. Relat. Cancer 2005;12:245-62). The mutation was not found in any medullary thyroid carcinomas or follicular thyroid carcinomas.

Among the subtypes of PTC, the mutation was present in 77% of tall-cell PTCs, 60% of conventional PTCs, and 12% of follicular-variant PTCs.

Multiple Studies Are Consistent

In a multicenter study of 219 patients by Dr. Xing and colleagues, the association between BRAF mutation and clinical aggressiveness was clear. Extrathyroidal invasion was observed in 41% of BRAF-positive patients, compared with 16% of BRAF-negative patients, whereas lymph node metastases occurred in 54% and 21%, respectively (both P less than .001) (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other associations were seen between the mutation and advanced tumor stage (P = .007) and tumor recurrence (P = .004). Age at diagnosis, sex, tumor size, and multifocality were not consistently related to mutation status, he added.

This more-aggressive clinicopathological picture translated into significantly more recurrences among BRAF-positive patients in the study at 9 years (25% vs. 9%, for a threefold increase in risk; P = .03). BRAF mutation was even an independent and stronger predictor of recurrence in patients with stage I and II disease (22% vs. 5%, respectively; P = .002).

A Korean study also calculated an odds ratio of 4.6 for recurrence in the presence of the BRAF mutation (P = 0.037), although statistical significance was lost in a multivariate model (Clin. Endocrinol. 2006;65:364-8). In a 2008 study performed in the Middle East, BRAF mutation was associated with metastasis (P = .0274) and poor disease-free survival (P = .0121). A meta-analysis validated the association of the BRAF mutation with extrathyroidal invasion, lymph node metastasis, and advanced stage (Endocr. Rev. 2007;28:742-62).

Dr. Xing noted the universality of the association: "Among studies of patients with a variety of ethnic backgrounds, there is a strong association with disease recurrence," he observed.

Low-Risk Patients Rendered High Risk

Even in populations that are conventionally considered at low risk for recurrence, the BRAF mutation is not uncommon, Dr. Xing said, citing prevalence figures of 36% among stage I and II PTC patients, and 18%-24% among papillary thyroid microcarcinoma (PTMC) patients. In these low-risk populations, aggressive features and recurrence are associated with BRAF positivity.

In studies of stage I and II patients and others with PTMC, BRAF-positive patients were three to four times more likely to have extrathyroidal extension, lymph node metastasis, and advanced disease (Ann. Surg. Oncol. 2009;16:240-5). One study of stage I and II patients found the odds ratio for recurrence to be 11.4 (P = .004) "with adjustment for conventional clinicopathological factors and radioiodine treatment." (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other Concerning Associations

Importantly, BRAF mutations are associated with a loss of radioiodine avidity in recurrent PTC, "which means the patient may not respond to radioactive iodine treatment," he said. Dr. Xing has observed a loss of avidity in 54% of patients with the mutation, but in none of the patients who lacked the BRAF mutation.

Dr. David S. Cooper, professor of medicine at Johns Hopkins and former president of the American Thyroid Association, commented on this issue during the discussion. "Knowing beforehand when a patient is BRAF positive may inform our aggressiveness with regard to surgery, [that is,] central neck dissection," he said.

"And there is the thought that because [such cancers] are more aggressive, we will be more likely to treat with radioactive iodine. The BRAF mutation also confers the inability to take up radioactive iodine, though, so this is not necessarily going to be the case." However, radioiodine treatment to ablate residual normal thyroid tissue may be more important in BRAF mutation–positive patients, as it can enhance the reliability of serum thyroglobulin testing for the surveillance of thyroid cancer recurrence in these patients who may need more vigilant monitoring because of the increased aggressiveness of their cancer.

Also of concern is the finding that these patients are likely to require additional surgery. "We were the first to show a higher need for reoperation," Dr. Xing noted.

In his 2005 series, 69% of BRAF-positive patients required more aggressive treatment (additional surgery or external radiation), compared with 14% of BRAF-negative patients (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other recent studies have shown the same (Surgery 2010;148:1139-46). In a study at the University of Pittsburgh, the investigators determined that preoperative knowledge of BRAF mutation positivity could have productively altered the initial PTC surgical management in 24% of patients (Surgery 2009;146:1215-23).

Testing Biopsy for BRAF Mutation

"If you have the results of BRAF testing preoperatively, they can help with risk stratification and surgical planning," Dr. Xing said.

In a 2010 study, researchers analyzed the utility of BRAF mutation screening of 61 fine-needle aspiration biopsy (FNAB) specimens for predicting aggressive clinicopathological characteristics of PTMC (Ann. Surg. Oncol. 2010;17:3294-300). The BRAF mutation was significantly associated with multifocality, extrathyroidal invasion, lateral lymph-node metastasis (LNM) and advanced tumor stages. In a multivariate analysis, the BRAF mutation carried an odds ratio of 18 for central LNM (P = .01). The authors concluded that BRAF mutation screening of FNAB specimens can be used to predict aggressive clinicopathological characteristics of PTMC, and that lateral neck nodes should be meticulously analyzed for cases of PTMC demonstrating mutated BRAF.

These results were consistent with those of an earlier study in which Dr. Xing and colleagues calculated odds ratios to show the predictive power of BRAF mutations found in FNAB specimens to preoperatively risk-stratify PTC patients (J. Clin. Oncol. 2009;27:2977-82). (See box.) The positive predictive value of BRAF mutation status was 36%, and the negative predictive value was 88%.

In summary, Dr. Xing emphasized that the BRAF mutation plays a critical role in PTC tumorigenesis and aggressiveness and can be used preoperatively to risk-stratify patients and assist the physician in planning treatment. He joked to attendees: "Send your patients to me first, before you treat, to check for the mutation."

Dr. Xing reported receiving royalties as a coholder of a licensed patent on the discovery of BRAF mutation and its clinical characterization in thyroid cancer.

NEW ORLEANS – BRAF mutation is a valuable molecular marker for worse clinicopathological outcomes in papillary thyroid cancer – one that will be useful preoperatively in risk stratification and decision making, according to a leading investigator in this area, Dr. Michael Mingzhao Xing.

"BRAF mutation, as a prognostic marker, could be particularly helpful in some of the more controversial areas related to the management of PTC [papillary thyroid cancer], such as areas where current standard guidelines may not give clear guidance," Dr. Xing suggested at the symposium on thyroid and parathyroid diseases, which was sponsored by Tulane University.

Although Dr. Xing, chief of the laboratory for cellular and molecular thyroid research at Johns Hopkins University in Baltimore, advocated strongly for the potential of BRAF to guide treatment, he added that its routine use still needs to be specifically defined..

The T1799A mutation in BRAF, a kinase in the MPA kinase signaling pathway, leads to uncontrolled cell growth, unlimited cell proliferation, and – ultimately – tumorigenesis, he said. It is most common in PTC (44%), and to a lesser degree in anaplastic thyroid carcinoma (24%), according to his series of nearly 2,000 tumors (Endocr. Relat. Cancer 2005;12:245-62). The mutation was not found in any medullary thyroid carcinomas or follicular thyroid carcinomas.

Among the subtypes of PTC, the mutation was present in 77% of tall-cell PTCs, 60% of conventional PTCs, and 12% of follicular-variant PTCs.

Multiple Studies Are Consistent

In a multicenter study of 219 patients by Dr. Xing and colleagues, the association between BRAF mutation and clinical aggressiveness was clear. Extrathyroidal invasion was observed in 41% of BRAF-positive patients, compared with 16% of BRAF-negative patients, whereas lymph node metastases occurred in 54% and 21%, respectively (both P less than .001) (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other associations were seen between the mutation and advanced tumor stage (P = .007) and tumor recurrence (P = .004). Age at diagnosis, sex, tumor size, and multifocality were not consistently related to mutation status, he added.

This more-aggressive clinicopathological picture translated into significantly more recurrences among BRAF-positive patients in the study at 9 years (25% vs. 9%, for a threefold increase in risk; P = .03). BRAF mutation was even an independent and stronger predictor of recurrence in patients with stage I and II disease (22% vs. 5%, respectively; P = .002).

A Korean study also calculated an odds ratio of 4.6 for recurrence in the presence of the BRAF mutation (P = 0.037), although statistical significance was lost in a multivariate model (Clin. Endocrinol. 2006;65:364-8). In a 2008 study performed in the Middle East, BRAF mutation was associated with metastasis (P = .0274) and poor disease-free survival (P = .0121). A meta-analysis validated the association of the BRAF mutation with extrathyroidal invasion, lymph node metastasis, and advanced stage (Endocr. Rev. 2007;28:742-62).

Dr. Xing noted the universality of the association: "Among studies of patients with a variety of ethnic backgrounds, there is a strong association with disease recurrence," he observed.

Low-Risk Patients Rendered High Risk

Even in populations that are conventionally considered at low risk for recurrence, the BRAF mutation is not uncommon, Dr. Xing said, citing prevalence figures of 36% among stage I and II PTC patients, and 18%-24% among papillary thyroid microcarcinoma (PTMC) patients. In these low-risk populations, aggressive features and recurrence are associated with BRAF positivity.

In studies of stage I and II patients and others with PTMC, BRAF-positive patients were three to four times more likely to have extrathyroidal extension, lymph node metastasis, and advanced disease (Ann. Surg. Oncol. 2009;16:240-5). One study of stage I and II patients found the odds ratio for recurrence to be 11.4 (P = .004) "with adjustment for conventional clinicopathological factors and radioiodine treatment." (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other Concerning Associations

Importantly, BRAF mutations are associated with a loss of radioiodine avidity in recurrent PTC, "which means the patient may not respond to radioactive iodine treatment," he said. Dr. Xing has observed a loss of avidity in 54% of patients with the mutation, but in none of the patients who lacked the BRAF mutation.

Dr. David S. Cooper, professor of medicine at Johns Hopkins and former president of the American Thyroid Association, commented on this issue during the discussion. "Knowing beforehand when a patient is BRAF positive may inform our aggressiveness with regard to surgery, [that is,] central neck dissection," he said.

"And there is the thought that because [such cancers] are more aggressive, we will be more likely to treat with radioactive iodine. The BRAF mutation also confers the inability to take up radioactive iodine, though, so this is not necessarily going to be the case." However, radioiodine treatment to ablate residual normal thyroid tissue may be more important in BRAF mutation–positive patients, as it can enhance the reliability of serum thyroglobulin testing for the surveillance of thyroid cancer recurrence in these patients who may need more vigilant monitoring because of the increased aggressiveness of their cancer.

Also of concern is the finding that these patients are likely to require additional surgery. "We were the first to show a higher need for reoperation," Dr. Xing noted.

In his 2005 series, 69% of BRAF-positive patients required more aggressive treatment (additional surgery or external radiation), compared with 14% of BRAF-negative patients (J. Clin. Endocrinol. Metab. 2005;90:6373-9).

Other recent studies have shown the same (Surgery 2010;148:1139-46). In a study at the University of Pittsburgh, the investigators determined that preoperative knowledge of BRAF mutation positivity could have productively altered the initial PTC surgical management in 24% of patients (Surgery 2009;146:1215-23).

Testing Biopsy for BRAF Mutation

"If you have the results of BRAF testing preoperatively, they can help with risk stratification and surgical planning," Dr. Xing said.

In a 2010 study, researchers analyzed the utility of BRAF mutation screening of 61 fine-needle aspiration biopsy (FNAB) specimens for predicting aggressive clinicopathological characteristics of PTMC (Ann. Surg. Oncol. 2010;17:3294-300). The BRAF mutation was significantly associated with multifocality, extrathyroidal invasion, lateral lymph-node metastasis (LNM) and advanced tumor stages. In a multivariate analysis, the BRAF mutation carried an odds ratio of 18 for central LNM (P = .01). The authors concluded that BRAF mutation screening of FNAB specimens can be used to predict aggressive clinicopathological characteristics of PTMC, and that lateral neck nodes should be meticulously analyzed for cases of PTMC demonstrating mutated BRAF.

These results were consistent with those of an earlier study in which Dr. Xing and colleagues calculated odds ratios to show the predictive power of BRAF mutations found in FNAB specimens to preoperatively risk-stratify PTC patients (J. Clin. Oncol. 2009;27:2977-82). (See box.) The positive predictive value of BRAF mutation status was 36%, and the negative predictive value was 88%.

In summary, Dr. Xing emphasized that the BRAF mutation plays a critical role in PTC tumorigenesis and aggressiveness and can be used preoperatively to risk-stratify patients and assist the physician in planning treatment. He joked to attendees: "Send your patients to me first, before you treat, to check for the mutation."

Dr. Xing reported receiving royalties as a coholder of a licensed patent on the discovery of BRAF mutation and its clinical characterization in thyroid cancer.