Michele G. Sullivan

Patients who initiated anti-TNF therapy for inflammatory diseases had no higher risk of developing herpes zoster than did those who took other disease-modifying antirheumatic drugs.

However, a large database review did find a doubling of risk among those taking at least 10 mg/day of corticosteroids, according to Dr. Kevin Winthrop and colleagues. The report is in the March 6 issue of the JAMA.

These findings shed important light on the current mixed-results in literature on the topic, wrote Dr. Winthrop of Oregon Health and Science University, Portland, and his coauthors. The study is more than twice as large as any other on the subject and looked at a large number of patients with elevated herpes zoster risk (JAMA 2013;309:887-95).

It comprised more than 61,000 patients: 33,324 with newly initiated anti-TNF alpha treatment for rheumatoid arthritis and 25,742 who took other nonbiologic disease modifying anti-rheumatic medications. It was a subanalysis of the ongoing Safety Assessment of Biologic Therapy, a U.S. multi-institutional project evaluating the safety of biologic therapies.

Patients were drawn from five large databases spanning 1998-2008: the National Medicaid and Medicare database; Tennessee Medicaid; New Jersey’s Pharmaceutical Assistance to the Aged and Disabled, Pennsylvania’s Pharmaceutical Assistance for the Elderly; and Kaiser Permanente of Northern California. Database selection was important in this study, the investigators said, "Because it contained a large number of Medicare and Medicaid recipients who might have had higher baseline herpes zoster risk due to comorbidities and other unknown factors."

The regression analysis was based on a propensity matching score that took into account a number of baseline factors, including demographics, markers of comorbidity and disease severity, and other potential risk factors for herpes including cancer or diabetes.

Patients were grouped according to disease: rheumatoid arthritis (36,212), inflammatory bowel disease. (10,717) and psoriasis, psoriatic arthritis, or ankylosing spondylitis (12,137). Across all of the groups, there were 470 cases of herpes zoster; 310 among those taking anti-TNF drugs (crude incidence rate of 10/1,000) and 160 among those taking other DMARDs (crude incidence rate of 11/1,000).

After the investigators adjusted for baseline corticosteroid use and the propensity matching score, they found no significant between-group differences in the risk of herpes zoster (hazard ratio of 11 for anti-TNFs; HR, 10 for DMARDs).

Daily use of at least 10 mg corticosteroids was associated with a significantly increased risk of the disease in all of the patient groups (HR, 2).

Most herpes cases (356) occurred in the rheumatoid arthritis group; the investigators analyzed this group separately. These patients were a median of 60 years old; 266 were taking the anti-TNF drugs and 90 other DMARDs. The median follow-up was almost 1 year (294 days). Herpes caused hospitalization in 16 (6%) of those using the medications and in five of the DMARD group (5.5%) – not a significant difference.

Limiting follow-up to 3-6 months did not change the results. When the researchers extended follow-up in the Medicaid/Medicare groups until the end of 2008, they found similar herpes crude incidence rates in the anti-TNF and DMARD groups, and similar disease risk (HR, 12.6 and HR, 12.4, respectively).

When the authors looked at risk in anti-TNF subgroups, they found the highest crude incidence rate among infliximab users (14/1,000) and the lowest for adalimumab users (10/1,000). However, this significant between-group difference disappeared when examined with the propensity matching score. "Furthermore," they noted, "A higher proportion of infliximab users used concomitant methotrexate at baseline and after [the] index date compared with those using etanercept or adalimumab."

The high herpes rate among patients with rheumatoid arthritis supports widespread use of the live attenuated herpes zoster vaccine in those aged 50 years and older, the authors contended.

"Currently, vaccination during active use of anti-TNF therapy is contraindicated due to theoretical safety concerns of using a live vaccine during such therapy; however, it is unclear if such concerns are valid. Our data suggest that patients who develop herpes zoster while taking anti-TNF therapy are no more likely to be hospitalized than persons with herpes zoster using nonbiologic DMARDs ... Given these findings, the potential importance of this vaccine within the rheumatoid arthritis setting and the difficulty in vaccinating patients given the widespread use of anti-TNF therapy, we believe that a trial to evaluate the safety of this live virus vaccine among current anti-TNF users is warranted."

Dr. Winthrop has consulted for Genentec, Abbott Pfizer, UCB Pharma, and Amgen, and received research grants from Pfizer. Other authors reported relationships with numerous pharmaceutical companies.

[email protected]

Patients who initiated anti-TNF therapy for inflammatory diseases had no higher risk of developing herpes zoster than did those who took other disease-modifying antirheumatic drugs.

However, a large database review did find a doubling of risk among those taking at least 10 mg/day of corticosteroids, according to Dr. Kevin Winthrop and colleagues. The report is in the March 6 issue of the JAMA.

These findings shed important light on the current mixed-results in literature on the topic, wrote Dr. Winthrop of Oregon Health and Science University, Portland, and his coauthors. The study is more than twice as large as any other on the subject and looked at a large number of patients with elevated herpes zoster risk (JAMA 2013;309:887-95).

It comprised more than 61,000 patients: 33,324 with newly initiated anti-TNF alpha treatment for rheumatoid arthritis and 25,742 who took other nonbiologic disease modifying anti-rheumatic medications. It was a subanalysis of the ongoing Safety Assessment of Biologic Therapy, a U.S. multi-institutional project evaluating the safety of biologic therapies.

Patients were drawn from five large databases spanning 1998-2008: the National Medicaid and Medicare database; Tennessee Medicaid; New Jersey’s Pharmaceutical Assistance to the Aged and Disabled, Pennsylvania’s Pharmaceutical Assistance for the Elderly; and Kaiser Permanente of Northern California. Database selection was important in this study, the investigators said, "Because it contained a large number of Medicare and Medicaid recipients who might have had higher baseline herpes zoster risk due to comorbidities and other unknown factors."

The regression analysis was based on a propensity matching score that took into account a number of baseline factors, including demographics, markers of comorbidity and disease severity, and other potential risk factors for herpes including cancer or diabetes.

Patients were grouped according to disease: rheumatoid arthritis (36,212), inflammatory bowel disease. (10,717) and psoriasis, psoriatic arthritis, or ankylosing spondylitis (12,137). Across all of the groups, there were 470 cases of herpes zoster; 310 among those taking anti-TNF drugs (crude incidence rate of 10/1,000) and 160 among those taking other DMARDs (crude incidence rate of 11/1,000).

After the investigators adjusted for baseline corticosteroid use and the propensity matching score, they found no significant between-group differences in the risk of herpes zoster (hazard ratio of 11 for anti-TNFs; HR, 10 for DMARDs).

Daily use of at least 10 mg corticosteroids was associated with a significantly increased risk of the disease in all of the patient groups (HR, 2).

Most herpes cases (356) occurred in the rheumatoid arthritis group; the investigators analyzed this group separately. These patients were a median of 60 years old; 266 were taking the anti-TNF drugs and 90 other DMARDs. The median follow-up was almost 1 year (294 days). Herpes caused hospitalization in 16 (6%) of those using the medications and in five of the DMARD group (5.5%) – not a significant difference.

Limiting follow-up to 3-6 months did not change the results. When the researchers extended follow-up in the Medicaid/Medicare groups until the end of 2008, they found similar herpes crude incidence rates in the anti-TNF and DMARD groups, and similar disease risk (HR, 12.6 and HR, 12.4, respectively).

When the authors looked at risk in anti-TNF subgroups, they found the highest crude incidence rate among infliximab users (14/1,000) and the lowest for adalimumab users (10/1,000). However, this significant between-group difference disappeared when examined with the propensity matching score. "Furthermore," they noted, "A higher proportion of infliximab users used concomitant methotrexate at baseline and after [the] index date compared with those using etanercept or adalimumab."

The high herpes rate among patients with rheumatoid arthritis supports widespread use of the live attenuated herpes zoster vaccine in those aged 50 years and older, the authors contended.

"Currently, vaccination during active use of anti-TNF therapy is contraindicated due to theoretical safety concerns of using a live vaccine during such therapy; however, it is unclear if such concerns are valid. Our data suggest that patients who develop herpes zoster while taking anti-TNF therapy are no more likely to be hospitalized than persons with herpes zoster using nonbiologic DMARDs ... Given these findings, the potential importance of this vaccine within the rheumatoid arthritis setting and the difficulty in vaccinating patients given the widespread use of anti-TNF therapy, we believe that a trial to evaluate the safety of this live virus vaccine among current anti-TNF users is warranted."

Dr. Winthrop has consulted for Genentec, Abbott Pfizer, UCB Pharma, and Amgen, and received research grants from Pfizer. Other authors reported relationships with numerous pharmaceutical companies.

[email protected]

Patients who initiated anti-TNF therapy for inflammatory diseases had no higher risk of developing herpes zoster than did those who took other disease-modifying antirheumatic drugs.

However, a large database review did find a doubling of risk among those taking at least 10 mg/day of corticosteroids, according to Dr. Kevin Winthrop and colleagues. The report is in the March 6 issue of the JAMA.

These findings shed important light on the current mixed-results in literature on the topic, wrote Dr. Winthrop of Oregon Health and Science University, Portland, and his coauthors. The study is more than twice as large as any other on the subject and looked at a large number of patients with elevated herpes zoster risk (JAMA 2013;309:887-95).

It comprised more than 61,000 patients: 33,324 with newly initiated anti-TNF alpha treatment for rheumatoid arthritis and 25,742 who took other nonbiologic disease modifying anti-rheumatic medications. It was a subanalysis of the ongoing Safety Assessment of Biologic Therapy, a U.S. multi-institutional project evaluating the safety of biologic therapies.

Patients were drawn from five large databases spanning 1998-2008: the National Medicaid and Medicare database; Tennessee Medicaid; New Jersey’s Pharmaceutical Assistance to the Aged and Disabled, Pennsylvania’s Pharmaceutical Assistance for the Elderly; and Kaiser Permanente of Northern California. Database selection was important in this study, the investigators said, "Because it contained a large number of Medicare and Medicaid recipients who might have had higher baseline herpes zoster risk due to comorbidities and other unknown factors."

The regression analysis was based on a propensity matching score that took into account a number of baseline factors, including demographics, markers of comorbidity and disease severity, and other potential risk factors for herpes including cancer or diabetes.

Patients were grouped according to disease: rheumatoid arthritis (36,212), inflammatory bowel disease. (10,717) and psoriasis, psoriatic arthritis, or ankylosing spondylitis (12,137). Across all of the groups, there were 470 cases of herpes zoster; 310 among those taking anti-TNF drugs (crude incidence rate of 10/1,000) and 160 among those taking other DMARDs (crude incidence rate of 11/1,000).

After the investigators adjusted for baseline corticosteroid use and the propensity matching score, they found no significant between-group differences in the risk of herpes zoster (hazard ratio of 11 for anti-TNFs; HR, 10 for DMARDs).

Daily use of at least 10 mg corticosteroids was associated with a significantly increased risk of the disease in all of the patient groups (HR, 2).

Most herpes cases (356) occurred in the rheumatoid arthritis group; the investigators analyzed this group separately. These patients were a median of 60 years old; 266 were taking the anti-TNF drugs and 90 other DMARDs. The median follow-up was almost 1 year (294 days). Herpes caused hospitalization in 16 (6%) of those using the medications and in five of the DMARD group (5.5%) – not a significant difference.

Limiting follow-up to 3-6 months did not change the results. When the researchers extended follow-up in the Medicaid/Medicare groups until the end of 2008, they found similar herpes crude incidence rates in the anti-TNF and DMARD groups, and similar disease risk (HR, 12.6 and HR, 12.4, respectively).

When the authors looked at risk in anti-TNF subgroups, they found the highest crude incidence rate among infliximab users (14/1,000) and the lowest for adalimumab users (10/1,000). However, this significant between-group difference disappeared when examined with the propensity matching score. "Furthermore," they noted, "A higher proportion of infliximab users used concomitant methotrexate at baseline and after [the] index date compared with those using etanercept or adalimumab."

The high herpes rate among patients with rheumatoid arthritis supports widespread use of the live attenuated herpes zoster vaccine in those aged 50 years and older, the authors contended.

"Currently, vaccination during active use of anti-TNF therapy is contraindicated due to theoretical safety concerns of using a live vaccine during such therapy; however, it is unclear if such concerns are valid. Our data suggest that patients who develop herpes zoster while taking anti-TNF therapy are no more likely to be hospitalized than persons with herpes zoster using nonbiologic DMARDs ... Given these findings, the potential importance of this vaccine within the rheumatoid arthritis setting and the difficulty in vaccinating patients given the widespread use of anti-TNF therapy, we believe that a trial to evaluate the safety of this live virus vaccine among current anti-TNF users is warranted."

Dr. Winthrop has consulted for Genentec, Abbott Pfizer, UCB Pharma, and Amgen, and received research grants from Pfizer. Other authors reported relationships with numerous pharmaceutical companies.

[email protected]

Patients with diabetes who take either sitagliptin or exenatide were twice as likely to experience acute pancreatitis as those who did not take the GLP-1 inhibitors, a large database review has determined.

The authors made no recommendations about using the drugs, instead saying that the findings call for confirmation by more rigorous studies.

"Further studies using new user designs should clarify the exact timing of these risks and determine whether susceptible subgroups, such as those with genetic mutations, or pancreatitis risks, such as obesity, may be at the highest risk," Dr. Sonal Singh and his colleagues wrote in the Feb. 25 online issue of JAMA Internal Medicine (formerly Archives of Internal Medicine) (doi: 10.1001/jamainternmed.2013.2720).

But the American Association of Clinical Endocrinologists (AACE), the American Diabetes Association, and the Endocrine Society are criticizing the study, saying that the risk of pancreatitis over a large population is very low, and that for most patients, the drugs’ benefits far outweigh that risk.

"This story is very simple," said Dr. Yehuda Handelsman, speaking for AACE. "Since day 1, we have been telling physicians there could be a bit of increase in the risk of pancreatitis with the drugs. But the risk is so minimal that we don’t believe anyone should change their practice based on this study."

The review included 1,269 controls and 1,269 patients who used the drugs and were hospitalized for acute pancreatitis during 2005-2008. Study subjects had a mean age of 52 years. Several comorbidities were significantly more common among the case patients than among controls, including elevated triglycerides (13% vs. 8%), alcohol use (3.2% vs. 0.2%), gallstones (9% vs. 1%), tobacco abuse (16% vs. 6%), obesity (20% vs. 10%), biliary and pancreatic cancer (3% vs. 0%), cystic fibrosis (1% vs. 0%), and any neoplasm (30% vs. 18%).

Photo courtesy of Dr. Yehuda Handelsman

Dr. Singh of Johns Hopkins University, Baltimore, and his associates controlled for all of these factors by using a multifactorial analysis, as well as an indicator of general morbidity level developed by the university.

After adjustment for these confounders and for metformin use, patients who had taking either sitagliptin or exenatide in the past 30 days were more than twice as likely to have experienced acute pancreatitis (odds ratio, 2.24). Those who had taken the drugs within the past 30 days to 2 years were twice as likely to have had the illness (OR, 2). Any use of the drugs – which included both 30-day and recent use – was associated with a doubling of the risk (OR, 2.1).

A sensitivity analysis excluded nine case-control pairs who were exposed to a combination of metformin and sitagliptin. After adjustment for the confounders, this subanalysis agreed with the primary findings. Current use of either drug within 30 days was associated with a doubled risk (OR, 2) as was recent use (OR, 1.95), and any use (OR, 2).

The study did not indicate the total number of patients in the database who were taking the drugs and who developed pancreatitis. This skewed the findings, said Dr. Handelsman, because it misrepresented the actual frequency of the illness in this group, which he said was very, very low. In an e-mail, Dr. Singh said, "Those numbers are not available in a case-control study."

And even though the study controlled for the significant baseline differences between the two groups, these also tainted the conclusions, said Dr. Handelsman, who is also the principal investigator at the Metabolic Institute of America in Tarzana, Calif. "Patients who are obese, who drink a lot and smoke a lot, who have gallstones – they are all more likely to get pancreatitis. We tell doctors, if you’re going to give the drugs to these patients, just watch them more carefully."

In a joint statement, AACE and ADA voiced concern that patients could stop taking their prescribed treatments. "We encourage patients to speak with their doctors to assess which treatments are best for them and not to stop therapy on their own without consulting their doctors."

A link between glucagonlike peptide–1(GLP-1) inhibitors and pancreatitis has never been firmly established. But, according to a recent review, questions remain – many centering around safety reviews performed by pharmaceutical companies, which were based on their own prospective studies (Gastroenterology 2011;141:20-3).

Animal studies have suggested a physiological link, wrote Dr. Joachim Spranger of the German Medical Association. "Exocrine pancreatic cells express the GLP-1 receptor [GLP-1R], and administering GLP-1 has biological effects on these cells. In animal experiments (Diabetes 2009;58:2148-61), 1 week of GLP-1R activation with liraglutide or exenatide increased pancreatic weight and changed pancreatitis-associated gene expression, although the DPP-4 [dipeptidyl peptidase–4] inhibitor sitagliptin had no such effects. Theoretically, the increased pancreatic weight may reflect edema or similar changes, although the underlying cause of the weight increase was not further analyzed and histopathology results were not reported."

Any pancreatic effect of the drugs could be directly related to the beneficial physiological changes they induce in the pancreas, Dr. Spranger wrote. GLP-1 agonists increase beta-cell mass in rodents, by enhancing beta-cell proliferation, inhibiting apoptosis, and enhancing stem cell differentiation in the ductal pancreatic epithelium.

"Although beta-cell proliferation may be beneficial with regard to progression of type 2 diabetes, similar trophic mechanisms in other cell types might be detrimental. Thus, the epidermal growth factor receptor system and the Src kinase have been implicated in the pathogenesis and progression of numerous malignant tumors, including pancreatic cancer; mechanisms increasing the activity of these pathways could promote tumor development or progression."

The observations raise safety concerns which should be heeded until proven unfounded, Dr. Spranger wrote.

More detailed data about the link between incretin-based therapies and pancreatitis should be forthcoming, as long-term prospective studies continue to collect a wide range of safety information.

"There are at least nine prospective trials looking at cardiovascular outcomes which are capturing a lot of other outcomes data as well – including pancreatitis," Dr. Handelsman said. "In a few years we might be able to identify the true risk. But a scare based on an observational study from one insurance database, from years ago, is not enough to change practice."

The Endocrine Society’s response to Dr. Singh’s study echoed that of AACE and ADA, and added that "an important but unanswered question is whether or not the morbidity and mortality from incretin-associated pancreatitis is the same as that of other causes of pancreatitis," in particular whether such cases would lead to an increased incidence of pancreatic cancer similar to that seen in some other causes of acute pancreatitis. The statement suggested that some of the ongoing trials "may also help elucidate the conflict between Singh’s finding of increased incidence of acute pancreatitis with these drugs and the four recent retrospective database analyses and 1 meta-analysis cited in Singh’s paper which found no such association."

Dr. Singh’s study was sponsored by Johns Hopkins University and the National Institutes of Health. He had no financial disclosures. Dr. Handelsman has been a consultant to numerous drug companies developing diabetes treatments. Dr. Spranger has lectured for or received consultant honoraria from Eli Lilly and NovoNordisk.

[email protected]

Patients with diabetes who take either sitagliptin or exenatide were twice as likely to experience acute pancreatitis as those who did not take the GLP-1 inhibitors, a large database review has determined.

The authors made no recommendations about using the drugs, instead saying that the findings call for confirmation by more rigorous studies.

"Further studies using new user designs should clarify the exact timing of these risks and determine whether susceptible subgroups, such as those with genetic mutations, or pancreatitis risks, such as obesity, may be at the highest risk," Dr. Sonal Singh and his colleagues wrote in the Feb. 25 online issue of JAMA Internal Medicine (formerly Archives of Internal Medicine) (doi: 10.1001/jamainternmed.2013.2720).

But the American Association of Clinical Endocrinologists (AACE), the American Diabetes Association, and the Endocrine Society are criticizing the study, saying that the risk of pancreatitis over a large population is very low, and that for most patients, the drugs’ benefits far outweigh that risk.

"This story is very simple," said Dr. Yehuda Handelsman, speaking for AACE. "Since day 1, we have been telling physicians there could be a bit of increase in the risk of pancreatitis with the drugs. But the risk is so minimal that we don’t believe anyone should change their practice based on this study."

The review included 1,269 controls and 1,269 patients who used the drugs and were hospitalized for acute pancreatitis during 2005-2008. Study subjects had a mean age of 52 years. Several comorbidities were significantly more common among the case patients than among controls, including elevated triglycerides (13% vs. 8%), alcohol use (3.2% vs. 0.2%), gallstones (9% vs. 1%), tobacco abuse (16% vs. 6%), obesity (20% vs. 10%), biliary and pancreatic cancer (3% vs. 0%), cystic fibrosis (1% vs. 0%), and any neoplasm (30% vs. 18%).

Photo courtesy of Dr. Yehuda Handelsman

Dr. Singh of Johns Hopkins University, Baltimore, and his associates controlled for all of these factors by using a multifactorial analysis, as well as an indicator of general morbidity level developed by the university.

After adjustment for these confounders and for metformin use, patients who had taking either sitagliptin or exenatide in the past 30 days were more than twice as likely to have experienced acute pancreatitis (odds ratio, 2.24). Those who had taken the drugs within the past 30 days to 2 years were twice as likely to have had the illness (OR, 2). Any use of the drugs – which included both 30-day and recent use – was associated with a doubling of the risk (OR, 2.1).

A sensitivity analysis excluded nine case-control pairs who were exposed to a combination of metformin and sitagliptin. After adjustment for the confounders, this subanalysis agreed with the primary findings. Current use of either drug within 30 days was associated with a doubled risk (OR, 2) as was recent use (OR, 1.95), and any use (OR, 2).

The study did not indicate the total number of patients in the database who were taking the drugs and who developed pancreatitis. This skewed the findings, said Dr. Handelsman, because it misrepresented the actual frequency of the illness in this group, which he said was very, very low. In an e-mail, Dr. Singh said, "Those numbers are not available in a case-control study."

And even though the study controlled for the significant baseline differences between the two groups, these also tainted the conclusions, said Dr. Handelsman, who is also the principal investigator at the Metabolic Institute of America in Tarzana, Calif. "Patients who are obese, who drink a lot and smoke a lot, who have gallstones – they are all more likely to get pancreatitis. We tell doctors, if you’re going to give the drugs to these patients, just watch them more carefully."

In a joint statement, AACE and ADA voiced concern that patients could stop taking their prescribed treatments. "We encourage patients to speak with their doctors to assess which treatments are best for them and not to stop therapy on their own without consulting their doctors."

A link between glucagonlike peptide–1(GLP-1) inhibitors and pancreatitis has never been firmly established. But, according to a recent review, questions remain – many centering around safety reviews performed by pharmaceutical companies, which were based on their own prospective studies (Gastroenterology 2011;141:20-3).

Animal studies have suggested a physiological link, wrote Dr. Joachim Spranger of the German Medical Association. "Exocrine pancreatic cells express the GLP-1 receptor [GLP-1R], and administering GLP-1 has biological effects on these cells. In animal experiments (Diabetes 2009;58:2148-61), 1 week of GLP-1R activation with liraglutide or exenatide increased pancreatic weight and changed pancreatitis-associated gene expression, although the DPP-4 [dipeptidyl peptidase–4] inhibitor sitagliptin had no such effects. Theoretically, the increased pancreatic weight may reflect edema or similar changes, although the underlying cause of the weight increase was not further analyzed and histopathology results were not reported."

Any pancreatic effect of the drugs could be directly related to the beneficial physiological changes they induce in the pancreas, Dr. Spranger wrote. GLP-1 agonists increase beta-cell mass in rodents, by enhancing beta-cell proliferation, inhibiting apoptosis, and enhancing stem cell differentiation in the ductal pancreatic epithelium.

"Although beta-cell proliferation may be beneficial with regard to progression of type 2 diabetes, similar trophic mechanisms in other cell types might be detrimental. Thus, the epidermal growth factor receptor system and the Src kinase have been implicated in the pathogenesis and progression of numerous malignant tumors, including pancreatic cancer; mechanisms increasing the activity of these pathways could promote tumor development or progression."

The observations raise safety concerns which should be heeded until proven unfounded, Dr. Spranger wrote.

More detailed data about the link between incretin-based therapies and pancreatitis should be forthcoming, as long-term prospective studies continue to collect a wide range of safety information.

"There are at least nine prospective trials looking at cardiovascular outcomes which are capturing a lot of other outcomes data as well – including pancreatitis," Dr. Handelsman said. "In a few years we might be able to identify the true risk. But a scare based on an observational study from one insurance database, from years ago, is not enough to change practice."

The Endocrine Society’s response to Dr. Singh’s study echoed that of AACE and ADA, and added that "an important but unanswered question is whether or not the morbidity and mortality from incretin-associated pancreatitis is the same as that of other causes of pancreatitis," in particular whether such cases would lead to an increased incidence of pancreatic cancer similar to that seen in some other causes of acute pancreatitis. The statement suggested that some of the ongoing trials "may also help elucidate the conflict between Singh’s finding of increased incidence of acute pancreatitis with these drugs and the four recent retrospective database analyses and 1 meta-analysis cited in Singh’s paper which found no such association."

Dr. Singh’s study was sponsored by Johns Hopkins University and the National Institutes of Health. He had no financial disclosures. Dr. Handelsman has been a consultant to numerous drug companies developing diabetes treatments. Dr. Spranger has lectured for or received consultant honoraria from Eli Lilly and NovoNordisk.

[email protected]

Patients with diabetes who take either sitagliptin or exenatide were twice as likely to experience acute pancreatitis as those who did not take the GLP-1 inhibitors, a large database review has determined.

The authors made no recommendations about using the drugs, instead saying that the findings call for confirmation by more rigorous studies.

"Further studies using new user designs should clarify the exact timing of these risks and determine whether susceptible subgroups, such as those with genetic mutations, or pancreatitis risks, such as obesity, may be at the highest risk," Dr. Sonal Singh and his colleagues wrote in the Feb. 25 online issue of JAMA Internal Medicine (formerly Archives of Internal Medicine) (doi: 10.1001/jamainternmed.2013.2720).

But the American Association of Clinical Endocrinologists (AACE), the American Diabetes Association, and the Endocrine Society are criticizing the study, saying that the risk of pancreatitis over a large population is very low, and that for most patients, the drugs’ benefits far outweigh that risk.

"This story is very simple," said Dr. Yehuda Handelsman, speaking for AACE. "Since day 1, we have been telling physicians there could be a bit of increase in the risk of pancreatitis with the drugs. But the risk is so minimal that we don’t believe anyone should change their practice based on this study."

The review included 1,269 controls and 1,269 patients who used the drugs and were hospitalized for acute pancreatitis during 2005-2008. Study subjects had a mean age of 52 years. Several comorbidities were significantly more common among the case patients than among controls, including elevated triglycerides (13% vs. 8%), alcohol use (3.2% vs. 0.2%), gallstones (9% vs. 1%), tobacco abuse (16% vs. 6%), obesity (20% vs. 10%), biliary and pancreatic cancer (3% vs. 0%), cystic fibrosis (1% vs. 0%), and any neoplasm (30% vs. 18%).

Photo courtesy of Dr. Yehuda Handelsman

Dr. Singh of Johns Hopkins University, Baltimore, and his associates controlled for all of these factors by using a multifactorial analysis, as well as an indicator of general morbidity level developed by the university.

After adjustment for these confounders and for metformin use, patients who had taking either sitagliptin or exenatide in the past 30 days were more than twice as likely to have experienced acute pancreatitis (odds ratio, 2.24). Those who had taken the drugs within the past 30 days to 2 years were twice as likely to have had the illness (OR, 2). Any use of the drugs – which included both 30-day and recent use – was associated with a doubling of the risk (OR, 2.1).

A sensitivity analysis excluded nine case-control pairs who were exposed to a combination of metformin and sitagliptin. After adjustment for the confounders, this subanalysis agreed with the primary findings. Current use of either drug within 30 days was associated with a doubled risk (OR, 2) as was recent use (OR, 1.95), and any use (OR, 2).

The study did not indicate the total number of patients in the database who were taking the drugs and who developed pancreatitis. This skewed the findings, said Dr. Handelsman, because it misrepresented the actual frequency of the illness in this group, which he said was very, very low. In an e-mail, Dr. Singh said, "Those numbers are not available in a case-control study."

And even though the study controlled for the significant baseline differences between the two groups, these also tainted the conclusions, said Dr. Handelsman, who is also the principal investigator at the Metabolic Institute of America in Tarzana, Calif. "Patients who are obese, who drink a lot and smoke a lot, who have gallstones – they are all more likely to get pancreatitis. We tell doctors, if you’re going to give the drugs to these patients, just watch them more carefully."

In a joint statement, AACE and ADA voiced concern that patients could stop taking their prescribed treatments. "We encourage patients to speak with their doctors to assess which treatments are best for them and not to stop therapy on their own without consulting their doctors."

A link between glucagonlike peptide–1(GLP-1) inhibitors and pancreatitis has never been firmly established. But, according to a recent review, questions remain – many centering around safety reviews performed by pharmaceutical companies, which were based on their own prospective studies (Gastroenterology 2011;141:20-3).

Animal studies have suggested a physiological link, wrote Dr. Joachim Spranger of the German Medical Association. "Exocrine pancreatic cells express the GLP-1 receptor [GLP-1R], and administering GLP-1 has biological effects on these cells. In animal experiments (Diabetes 2009;58:2148-61), 1 week of GLP-1R activation with liraglutide or exenatide increased pancreatic weight and changed pancreatitis-associated gene expression, although the DPP-4 [dipeptidyl peptidase–4] inhibitor sitagliptin had no such effects. Theoretically, the increased pancreatic weight may reflect edema or similar changes, although the underlying cause of the weight increase was not further analyzed and histopathology results were not reported."

Any pancreatic effect of the drugs could be directly related to the beneficial physiological changes they induce in the pancreas, Dr. Spranger wrote. GLP-1 agonists increase beta-cell mass in rodents, by enhancing beta-cell proliferation, inhibiting apoptosis, and enhancing stem cell differentiation in the ductal pancreatic epithelium.

"Although beta-cell proliferation may be beneficial with regard to progression of type 2 diabetes, similar trophic mechanisms in other cell types might be detrimental. Thus, the epidermal growth factor receptor system and the Src kinase have been implicated in the pathogenesis and progression of numerous malignant tumors, including pancreatic cancer; mechanisms increasing the activity of these pathways could promote tumor development or progression."

The observations raise safety concerns which should be heeded until proven unfounded, Dr. Spranger wrote.

More detailed data about the link between incretin-based therapies and pancreatitis should be forthcoming, as long-term prospective studies continue to collect a wide range of safety information.

"There are at least nine prospective trials looking at cardiovascular outcomes which are capturing a lot of other outcomes data as well – including pancreatitis," Dr. Handelsman said. "In a few years we might be able to identify the true risk. But a scare based on an observational study from one insurance database, from years ago, is not enough to change practice."

The Endocrine Society’s response to Dr. Singh’s study echoed that of AACE and ADA, and added that "an important but unanswered question is whether or not the morbidity and mortality from incretin-associated pancreatitis is the same as that of other causes of pancreatitis," in particular whether such cases would lead to an increased incidence of pancreatic cancer similar to that seen in some other causes of acute pancreatitis. The statement suggested that some of the ongoing trials "may also help elucidate the conflict between Singh’s finding of increased incidence of acute pancreatitis with these drugs and the four recent retrospective database analyses and 1 meta-analysis cited in Singh’s paper which found no such association."

Dr. Singh’s study was sponsored by Johns Hopkins University and the National Institutes of Health. He had no financial disclosures. Dr. Handelsman has been a consultant to numerous drug companies developing diabetes treatments. Dr. Spranger has lectured for or received consultant honoraria from Eli Lilly and NovoNordisk.

[email protected]

Deep suctioning and long lapses between suction treatments were associated with significantly increased lengths of stay in babies hospitalized with bronchiolitis.

Patients who never had deep suctioning stayed a little more than a day, but the length of stay was more than 2 days in patients for whom deep suctioning accounted for 60% or more of their treatments, Dr. Grant M. Mussman and his colleagues reported in the March 4 online issue of JAMA Pediatrics (2013[doi:10.1001/jamapediatrics.2013.36]).

Similarly, patients who experienced several lapses of 4 hours between treatments were hospitalized significantly longer than were those with no treatment lapses (mean of 2.3 days vs. 1.7 days).

Compared with a noninvasive nasal-type suction device, deep suctioning may aggravate the bronchial swelling and mucus sloughing that already causes breathing problems in these tiny patients, wrote Dr. Mussman of Cincinnati Children’s Hospital Medical Center.

"[It] may be that deep suctioning causes edema and irritation of the upper airway. Alternatively, noninvasive suctioning could be more effective in mobilizing nasal secretions through the larger caliber catheter."

Regular treatments with no lapses probably keep the airways open more consistently, they noted. "It is also possible that regular suctioning results in agitation of the patient, with resultant increased minute volume and secretion mobilization, resulting in shorter length of stay."

The study cohort consisted of 740 patients who were studied for device type (deep or noninvasive), 695 of which were studied for treatment timing. The patients were a mean of 6 months old, and all had been hospitalized for bronchiolitis.

Deep suction was defined as the insertion of a nasopharyngeal catheter, and noninvasive as the use of nasal-type aspirators, excluding bulb syringe. The exposure was the percentage of treatments that used deep suctioning (0%-35%; more than 35%-60%; and more then 60%).

The adjusted mean length of stay for infants who had no deep suctioning was 1.75 days. The stay was 1.91 days for those with up to 35% deep suctioning, 1.96 days for more than 35%-60% deep suctioning, and 2.35 days for more than 60% deep suctioning.

For the suction treatment timing group, a suctioning lapse was defined as two sequential suctioning events separated by more than 4 hours during the first 24 hours of admission. The investigators said that the 4-hour increment is the most common reassessment timing.

Infants with no treatment lapses had a mean adjusted hospital stay of 1.62 days. In contrast, the mean length of stay was 1.72 days for infants with one treatment lapse, 2.09 days for those with two lapses, and 2.64 days for those with three or four lapses.

"We believe the difference in geometric mean of up to 1 day between patients with no suctioning lapses and those with three or four lapses is clinically meaningful," the authors noted. However, "Because there is insufficient data to determine a causal relationship, we intend to continue to examine these associations as we incorporate these findings into clinical practice at our institution."

Dr. Mussman had no relevant financial disclosures.

[email protected]

Deep suctioning and long lapses between suction treatments were associated with significantly increased lengths of stay in babies hospitalized with bronchiolitis.

Patients who never had deep suctioning stayed a little more than a day, but the length of stay was more than 2 days in patients for whom deep suctioning accounted for 60% or more of their treatments, Dr. Grant M. Mussman and his colleagues reported in the March 4 online issue of JAMA Pediatrics (2013[doi:10.1001/jamapediatrics.2013.36]).

Similarly, patients who experienced several lapses of 4 hours between treatments were hospitalized significantly longer than were those with no treatment lapses (mean of 2.3 days vs. 1.7 days).

Compared with a noninvasive nasal-type suction device, deep suctioning may aggravate the bronchial swelling and mucus sloughing that already causes breathing problems in these tiny patients, wrote Dr. Mussman of Cincinnati Children’s Hospital Medical Center.

"[It] may be that deep suctioning causes edema and irritation of the upper airway. Alternatively, noninvasive suctioning could be more effective in mobilizing nasal secretions through the larger caliber catheter."

Regular treatments with no lapses probably keep the airways open more consistently, they noted. "It is also possible that regular suctioning results in agitation of the patient, with resultant increased minute volume and secretion mobilization, resulting in shorter length of stay."

The study cohort consisted of 740 patients who were studied for device type (deep or noninvasive), 695 of which were studied for treatment timing. The patients were a mean of 6 months old, and all had been hospitalized for bronchiolitis.

Deep suction was defined as the insertion of a nasopharyngeal catheter, and noninvasive as the use of nasal-type aspirators, excluding bulb syringe. The exposure was the percentage of treatments that used deep suctioning (0%-35%; more than 35%-60%; and more then 60%).

The adjusted mean length of stay for infants who had no deep suctioning was 1.75 days. The stay was 1.91 days for those with up to 35% deep suctioning, 1.96 days for more than 35%-60% deep suctioning, and 2.35 days for more than 60% deep suctioning.

For the suction treatment timing group, a suctioning lapse was defined as two sequential suctioning events separated by more than 4 hours during the first 24 hours of admission. The investigators said that the 4-hour increment is the most common reassessment timing.

Infants with no treatment lapses had a mean adjusted hospital stay of 1.62 days. In contrast, the mean length of stay was 1.72 days for infants with one treatment lapse, 2.09 days for those with two lapses, and 2.64 days for those with three or four lapses.

"We believe the difference in geometric mean of up to 1 day between patients with no suctioning lapses and those with three or four lapses is clinically meaningful," the authors noted. However, "Because there is insufficient data to determine a causal relationship, we intend to continue to examine these associations as we incorporate these findings into clinical practice at our institution."

Dr. Mussman had no relevant financial disclosures.

[email protected]

Deep suctioning and long lapses between suction treatments were associated with significantly increased lengths of stay in babies hospitalized with bronchiolitis.

Patients who never had deep suctioning stayed a little more than a day, but the length of stay was more than 2 days in patients for whom deep suctioning accounted for 60% or more of their treatments, Dr. Grant M. Mussman and his colleagues reported in the March 4 online issue of JAMA Pediatrics (2013[doi:10.1001/jamapediatrics.2013.36]).

Similarly, patients who experienced several lapses of 4 hours between treatments were hospitalized significantly longer than were those with no treatment lapses (mean of 2.3 days vs. 1.7 days).

Compared with a noninvasive nasal-type suction device, deep suctioning may aggravate the bronchial swelling and mucus sloughing that already causes breathing problems in these tiny patients, wrote Dr. Mussman of Cincinnati Children’s Hospital Medical Center.

"[It] may be that deep suctioning causes edema and irritation of the upper airway. Alternatively, noninvasive suctioning could be more effective in mobilizing nasal secretions through the larger caliber catheter."

Regular treatments with no lapses probably keep the airways open more consistently, they noted. "It is also possible that regular suctioning results in agitation of the patient, with resultant increased minute volume and secretion mobilization, resulting in shorter length of stay."

The study cohort consisted of 740 patients who were studied for device type (deep or noninvasive), 695 of which were studied for treatment timing. The patients were a mean of 6 months old, and all had been hospitalized for bronchiolitis.

Deep suction was defined as the insertion of a nasopharyngeal catheter, and noninvasive as the use of nasal-type aspirators, excluding bulb syringe. The exposure was the percentage of treatments that used deep suctioning (0%-35%; more than 35%-60%; and more then 60%).

The adjusted mean length of stay for infants who had no deep suctioning was 1.75 days. The stay was 1.91 days for those with up to 35% deep suctioning, 1.96 days for more than 35%-60% deep suctioning, and 2.35 days for more than 60% deep suctioning.

For the suction treatment timing group, a suctioning lapse was defined as two sequential suctioning events separated by more than 4 hours during the first 24 hours of admission. The investigators said that the 4-hour increment is the most common reassessment timing.

Infants with no treatment lapses had a mean adjusted hospital stay of 1.62 days. In contrast, the mean length of stay was 1.72 days for infants with one treatment lapse, 2.09 days for those with two lapses, and 2.64 days for those with three or four lapses.

"We believe the difference in geometric mean of up to 1 day between patients with no suctioning lapses and those with three or four lapses is clinically meaningful," the authors noted. However, "Because there is insufficient data to determine a causal relationship, we intend to continue to examine these associations as we incorporate these findings into clinical practice at our institution."

Dr. Mussman had no relevant financial disclosures.

[email protected]

New appropriate-use criteria outline how implantable cardioverter defibrillators and cardiac resynchronization therapy may be employed in any of 369 clinical scenarios.

Written by a joint committee of the American College of Cardiology and the Heart Rhythm Society, along with other specialty groups, the document focuses on the treatments’ uses in primary and secondary prevention and on how to gauge their use in the face of specific comorbidities It was published in the Feb. 28 issue of the Journal of the American Association of Cardiology (J. Am. Coll. Cardiol. 2013;61 [doi:10.1016/j.jacc.2012.12.017]).

Two years in the making, the criteria are based on a review of 61 clinical trials with widely differing inclusion and exclusion criteria encompassing an extremely broad group of patients. The writing group was cochaired by Dr. Andrea M. Russo, professor of medicine at UMDNJ/Robert Wood Johnson Medical School, and Dr. Raymond F. Stainback of Baylor College of Medicine, Houston. Although they cover a plentitude of situations, the paper represents a much-simplified universe, said Dr. Paul Hauptman, a member of the technical committee involved in the document’s construction.

In fact, an early draft of the criteria contained recommendations for many more clinical situations, Dr. Hauptman said in an interview. "It could have been double or even triple this number. The complete paper tries to bring some semblance of order to the decision-making process."

The clinical scenarios covered in the document fall into one of six areas: implantable cardioverter defibrillators (ICDs) for secondary prevention, ICDs for primary prevention, comorbidities, cardiac resynchronization therapy (CRT) devices, generator replacement, and dual- versus single-chamber ICDs.

Despite their detailed focus, the criteria must be seen – and used – as a guide, not as a cookbook. The individual patient’s situation must always be the primary point of decision-making, said Dr. Hauptman, professor of internal medicine and assistant dean of clinical-translational research at Saint Louis (Mo.) University.

What the document doesn’t take into account is just as important as what it does, he noted. "Patient preference still has to come into play. We can never forget that at the end of the day, our patient needs to be a full partner in the decision process."

Each of the 369 indications was scored on a scale of 1-9. Just under half of the scenarios (45%) received a rating of appropriate, 33% were rated "may be appropriate," and 22% "rarely appropriate." This is the first guideline to use this updated methodology (J. Am. Coll. Cardiol. 2013;61 [doi:10.1016/j.jacc.2013.01.025]). The criteria committee noted that, in this case, the rating of possibly appropriate may reflect the state of research as much as the true clinical utility.

"It is important to recognize ... that ratings in this middle category may represent either the lack of sufficient data to inform the decision or the fact that, depending on other clinical factors not considered in the brief scenario, device implantation may or may not be considered beneficial. The wide breadth of scenarios rated as ‘May Be Appropriate’ raises the importance of recognizing the role of applying clinical judgment to decision-making when encountering patients who broadly meet these criteria."

A rating of "appropriate" doesn’t mean that the treatment is mandatory. However, a rating of "rarely appropriate" is a strong judgment indicator. "Scenarios for which there were data showing harm, or nodata were available, and medical judgment deemed device therapy ill-advised were categorized [thus]. For example, comorbidities including life expectancy and cognitive function impacted appropriateness ratings," the authors wrote.

They maintained that the document’s primary impetus is to guide good medical care, not to be a reimbursement guide. "Some of the scenarios that are deemed ‘appropriate’ ... may not currently qualify for insurance coverage. For patients, physicians, and insurers, these distinctions are of critical importance because commitment to patient-centered care may warrant implantation of a device appropriate for the individual patient’s situation, but it may not fit precisely into a covered indication as defined by coverage policy and requires use of best clinical judgment."

The criteria committee, however, acknowledged that payers may use the document as such. In this light, they suggested that clinical information should support each treatment decision, whatever its appropriateness rating.

For example, "services rendered for ‘rarely appropriate’ indications should be considered in the context of the clinical situation. Namely, supporting documentation that informed the clinical decision should be sought, as other factors beyond those described in the brief clinical scenarios included in this document may have entered into clinical decision-making."

Dr. N.A. Mark Estes, director of the New England Cardiac Arrhythmia Center at Tufts Medical Center, Boston, said that the document’s intended purpose and its actual use may squeeze physicians in the middle.

"The document, by design, addresses good medical practice, independent of reimbursement. There are many scenarios in which an implantable cardioverter defibrillator or cardiac resynchronization therapy device may be deemed ‘clinically appropriate’ but may not currently qualify for coverage by Medicare National Coverage Decision. This can leave the physician in the difficult position of making appropriate recommendations for use of an ICD that fall outside of the scope of NCD coverage. Professional societies need to continue to work with the Centers for Medicare & Medicaid Services to resolve this issue and develop a mechanism for updating CMS ICD and CRT coverage on a regular basis," he said.

Dr. Hauptman and Dr. Estes serve on the Cardiology News Editorial Advisory Board. Dr. Russo has been a consultant to Biotronik, Guidant/Boston Scientific, Medtronic, and St. Jude Medical. Dr. Stainback had no relevant conflicts to disclose.

:[email protected]

New appropriate-use criteria outline how implantable cardioverter defibrillators and cardiac resynchronization therapy may be employed in any of 369 clinical scenarios.

Written by a joint committee of the American College of Cardiology and the Heart Rhythm Society, along with other specialty groups, the document focuses on the treatments’ uses in primary and secondary prevention and on how to gauge their use in the face of specific comorbidities It was published in the Feb. 28 issue of the Journal of the American Association of Cardiology (J. Am. Coll. Cardiol. 2013;61 [doi:10.1016/j.jacc.2012.12.017]).

Two years in the making, the criteria are based on a review of 61 clinical trials with widely differing inclusion and exclusion criteria encompassing an extremely broad group of patients. The writing group was cochaired by Dr. Andrea M. Russo, professor of medicine at UMDNJ/Robert Wood Johnson Medical School, and Dr. Raymond F. Stainback of Baylor College of Medicine, Houston. Although they cover a plentitude of situations, the paper represents a much-simplified universe, said Dr. Paul Hauptman, a member of the technical committee involved in the document’s construction.

In fact, an early draft of the criteria contained recommendations for many more clinical situations, Dr. Hauptman said in an interview. "It could have been double or even triple this number. The complete paper tries to bring some semblance of order to the decision-making process."

The clinical scenarios covered in the document fall into one of six areas: implantable cardioverter defibrillators (ICDs) for secondary prevention, ICDs for primary prevention, comorbidities, cardiac resynchronization therapy (CRT) devices, generator replacement, and dual- versus single-chamber ICDs.

Despite their detailed focus, the criteria must be seen – and used – as a guide, not as a cookbook. The individual patient’s situation must always be the primary point of decision-making, said Dr. Hauptman, professor of internal medicine and assistant dean of clinical-translational research at Saint Louis (Mo.) University.

What the document doesn’t take into account is just as important as what it does, he noted. "Patient preference still has to come into play. We can never forget that at the end of the day, our patient needs to be a full partner in the decision process."

Each of the 369 indications was scored on a scale of 1-9. Just under half of the scenarios (45%) received a rating of appropriate, 33% were rated "may be appropriate," and 22% "rarely appropriate." This is the first guideline to use this updated methodology (J. Am. Coll. Cardiol. 2013;61 [doi:10.1016/j.jacc.2013.01.025]). The criteria committee noted that, in this case, the rating of possibly appropriate may reflect the state of research as much as the true clinical utility.

"It is important to recognize ... that ratings in this middle category may represent either the lack of sufficient data to inform the decision or the fact that, depending on other clinical factors not considered in the brief scenario, device implantation may or may not be considered beneficial. The wide breadth of scenarios rated as ‘May Be Appropriate’ raises the importance of recognizing the role of applying clinical judgment to decision-making when encountering patients who broadly meet these criteria."

A rating of "appropriate" doesn’t mean that the treatment is mandatory. However, a rating of "rarely appropriate" is a strong judgment indicator. "Scenarios for which there were data showing harm, or nodata were available, and medical judgment deemed device therapy ill-advised were categorized [thus]. For example, comorbidities including life expectancy and cognitive function impacted appropriateness ratings," the authors wrote.

They maintained that the document’s primary impetus is to guide good medical care, not to be a reimbursement guide. "Some of the scenarios that are deemed ‘appropriate’ ... may not currently qualify for insurance coverage. For patients, physicians, and insurers, these distinctions are of critical importance because commitment to patient-centered care may warrant implantation of a device appropriate for the individual patient’s situation, but it may not fit precisely into a covered indication as defined by coverage policy and requires use of best clinical judgment."

The criteria committee, however, acknowledged that payers may use the document as such. In this light, they suggested that clinical information should support each treatment decision, whatever its appropriateness rating.

For example, "services rendered for ‘rarely appropriate’ indications should be considered in the context of the clinical situation. Namely, supporting documentation that informed the clinical decision should be sought, as other factors beyond those described in the brief clinical scenarios included in this document may have entered into clinical decision-making."

Dr. N.A. Mark Estes, director of the New England Cardiac Arrhythmia Center at Tufts Medical Center, Boston, said that the document’s intended purpose and its actual use may squeeze physicians in the middle.

"The document, by design, addresses good medical practice, independent of reimbursement. There are many scenarios in which an implantable cardioverter defibrillator or cardiac resynchronization therapy device may be deemed ‘clinically appropriate’ but may not currently qualify for coverage by Medicare National Coverage Decision. This can leave the physician in the difficult position of making appropriate recommendations for use of an ICD that fall outside of the scope of NCD coverage. Professional societies need to continue to work with the Centers for Medicare & Medicaid Services to resolve this issue and develop a mechanism for updating CMS ICD and CRT coverage on a regular basis," he said.

Dr. Hauptman and Dr. Estes serve on the Cardiology News Editorial Advisory Board. Dr. Russo has been a consultant to Biotronik, Guidant/Boston Scientific, Medtronic, and St. Jude Medical. Dr. Stainback had no relevant conflicts to disclose.

:[email protected]

New appropriate-use criteria outline how implantable cardioverter defibrillators and cardiac resynchronization therapy may be employed in any of 369 clinical scenarios.

Written by a joint committee of the American College of Cardiology and the Heart Rhythm Society, along with other specialty groups, the document focuses on the treatments’ uses in primary and secondary prevention and on how to gauge their use in the face of specific comorbidities It was published in the Feb. 28 issue of the Journal of the American Association of Cardiology (J. Am. Coll. Cardiol. 2013;61 [doi:10.1016/j.jacc.2012.12.017]).

Two years in the making, the criteria are based on a review of 61 clinical trials with widely differing inclusion and exclusion criteria encompassing an extremely broad group of patients. The writing group was cochaired by Dr. Andrea M. Russo, professor of medicine at UMDNJ/Robert Wood Johnson Medical School, and Dr. Raymond F. Stainback of Baylor College of Medicine, Houston. Although they cover a plentitude of situations, the paper represents a much-simplified universe, said Dr. Paul Hauptman, a member of the technical committee involved in the document’s construction.

In fact, an early draft of the criteria contained recommendations for many more clinical situations, Dr. Hauptman said in an interview. "It could have been double or even triple this number. The complete paper tries to bring some semblance of order to the decision-making process."

The clinical scenarios covered in the document fall into one of six areas: implantable cardioverter defibrillators (ICDs) for secondary prevention, ICDs for primary prevention, comorbidities, cardiac resynchronization therapy (CRT) devices, generator replacement, and dual- versus single-chamber ICDs.

Despite their detailed focus, the criteria must be seen – and used – as a guide, not as a cookbook. The individual patient’s situation must always be the primary point of decision-making, said Dr. Hauptman, professor of internal medicine and assistant dean of clinical-translational research at Saint Louis (Mo.) University.

What the document doesn’t take into account is just as important as what it does, he noted. "Patient preference still has to come into play. We can never forget that at the end of the day, our patient needs to be a full partner in the decision process."

Each of the 369 indications was scored on a scale of 1-9. Just under half of the scenarios (45%) received a rating of appropriate, 33% were rated "may be appropriate," and 22% "rarely appropriate." This is the first guideline to use this updated methodology (J. Am. Coll. Cardiol. 2013;61 [doi:10.1016/j.jacc.2013.01.025]). The criteria committee noted that, in this case, the rating of possibly appropriate may reflect the state of research as much as the true clinical utility.

"It is important to recognize ... that ratings in this middle category may represent either the lack of sufficient data to inform the decision or the fact that, depending on other clinical factors not considered in the brief scenario, device implantation may or may not be considered beneficial. The wide breadth of scenarios rated as ‘May Be Appropriate’ raises the importance of recognizing the role of applying clinical judgment to decision-making when encountering patients who broadly meet these criteria."

A rating of "appropriate" doesn’t mean that the treatment is mandatory. However, a rating of "rarely appropriate" is a strong judgment indicator. "Scenarios for which there were data showing harm, or nodata were available, and medical judgment deemed device therapy ill-advised were categorized [thus]. For example, comorbidities including life expectancy and cognitive function impacted appropriateness ratings," the authors wrote.

They maintained that the document’s primary impetus is to guide good medical care, not to be a reimbursement guide. "Some of the scenarios that are deemed ‘appropriate’ ... may not currently qualify for insurance coverage. For patients, physicians, and insurers, these distinctions are of critical importance because commitment to patient-centered care may warrant implantation of a device appropriate for the individual patient’s situation, but it may not fit precisely into a covered indication as defined by coverage policy and requires use of best clinical judgment."

The criteria committee, however, acknowledged that payers may use the document as such. In this light, they suggested that clinical information should support each treatment decision, whatever its appropriateness rating.

For example, "services rendered for ‘rarely appropriate’ indications should be considered in the context of the clinical situation. Namely, supporting documentation that informed the clinical decision should be sought, as other factors beyond those described in the brief clinical scenarios included in this document may have entered into clinical decision-making."

Dr. N.A. Mark Estes, director of the New England Cardiac Arrhythmia Center at Tufts Medical Center, Boston, said that the document’s intended purpose and its actual use may squeeze physicians in the middle.

"The document, by design, addresses good medical practice, independent of reimbursement. There are many scenarios in which an implantable cardioverter defibrillator or cardiac resynchronization therapy device may be deemed ‘clinically appropriate’ but may not currently qualify for coverage by Medicare National Coverage Decision. This can leave the physician in the difficult position of making appropriate recommendations for use of an ICD that fall outside of the scope of NCD coverage. Professional societies need to continue to work with the Centers for Medicare & Medicaid Services to resolve this issue and develop a mechanism for updating CMS ICD and CRT coverage on a regular basis," he said.

Dr. Hauptman and Dr. Estes serve on the Cardiology News Editorial Advisory Board. Dr. Russo has been a consultant to Biotronik, Guidant/Boston Scientific, Medtronic, and St. Jude Medical. Dr. Stainback had no relevant conflicts to disclose.

:[email protected]

Genetic variants at four chromosomal positions have now been linked to five diverse childhood- and adult-onset psychiatric illnesses: schizophrenia, autism spectrum disorders, attention-deficit/hyperactivity disorder, bipolar disorder, and major depressive disorder.

Two of the four loci encode for transmembranal calcium ion transport, a physiologic finding that could become a treatment target, Dr. Jordan W. Smoller and his colleagues wrote in the Feb. 28 online issue of the Lancet (2013 Feb. 28 [http://dx.doi.org/10.1016/S0140-6736(12)62129-1]).

"The finding that genetic variants have cross-disorder effects is an empirical step toward helping clinicians understand the common co-occurrence of clinical phenotypes in individual patients," wrote Dr. Smoller of the Massachusetts General Hospital, Boston, and his coauthors. "Our results implicate a specific biological pathway – voltage-gated calcium-channel signaling – as a contributor to the pathogenesis of several psychiatric disorders, and support the potential of this pathway as a therapeutic target for psychiatric disease."

The findings also could further the goal of "moving beyond descriptive syndromes in psychiatry and towards a nosology informed by disease cause," the investigators noted.

The genome-wide association study – the largest yet of its kind – analyzed single nucleotide polymorphisms (SNPs) for the five disorders among 33,332 cases and 27,888 controls, all of European ancestry. Four independent regions contained SNPs that were significantly related to the disorders. Three were related to all five disorders, and one to only bipolar disorder and schizophrenia.

The analysis also identified additional cross-disorder associations with a number of loci previously identified only with schizophrenia, although these associations were not as strong as those seen with the four primary regions.

Two of the four loci are related to voltage-gated transmembranal calcium channels, the authors noted. One of these has been previously identified as a risk gene for schizophrenia, bipolar disorder, and major depressive disorder. The gene facilitates the passage of calcium ions into the plasma membrane.

"Thus, our results suggest that voltage-gated calcium signaling, and, more broadly, calcium channel activity, could be an important biological process in psychiatric disorders," Dr. Smoller and his colleagues wrote. "Alterations in calcium channel signaling could represent a fundamental mechanism contributing to a broad vulnerability to psychopathology."

The authors cited several possible limitations. For example, diagnostic misclassification in cases of schizophrenia and bipolar disorder could produce "spurious evidence of genetic overlap between disorders." In addition, because their analyses were restricted to people of European ancestry, it is unclear whether their findings would apply to other populations.

Nevertheless, they said these result could provide "insights into the shared causation of psychiatric disorders."

Dr. Smoller and his coauthors are members of the Cross-Disorder Group of the Psychiatric Genomics Consortium. Their work was sponsored by the National Institutes of Health; none of the authors had any financial disclosures.

Genetic variants at four chromosomal positions have now been linked to five diverse childhood- and adult-onset psychiatric illnesses: schizophrenia, autism spectrum disorders, attention-deficit/hyperactivity disorder, bipolar disorder, and major depressive disorder.

Two of the four loci encode for transmembranal calcium ion transport, a physiologic finding that could become a treatment target, Dr. Jordan W. Smoller and his colleagues wrote in the Feb. 28 online issue of the Lancet (2013 Feb. 28 [http://dx.doi.org/10.1016/S0140-6736(12)62129-1]).

"The finding that genetic variants have cross-disorder effects is an empirical step toward helping clinicians understand the common co-occurrence of clinical phenotypes in individual patients," wrote Dr. Smoller of the Massachusetts General Hospital, Boston, and his coauthors. "Our results implicate a specific biological pathway – voltage-gated calcium-channel signaling – as a contributor to the pathogenesis of several psychiatric disorders, and support the potential of this pathway as a therapeutic target for psychiatric disease."

The findings also could further the goal of "moving beyond descriptive syndromes in psychiatry and towards a nosology informed by disease cause," the investigators noted.

The genome-wide association study – the largest yet of its kind – analyzed single nucleotide polymorphisms (SNPs) for the five disorders among 33,332 cases and 27,888 controls, all of European ancestry. Four independent regions contained SNPs that were significantly related to the disorders. Three were related to all five disorders, and one to only bipolar disorder and schizophrenia.

The analysis also identified additional cross-disorder associations with a number of loci previously identified only with schizophrenia, although these associations were not as strong as those seen with the four primary regions.

Two of the four loci are related to voltage-gated transmembranal calcium channels, the authors noted. One of these has been previously identified as a risk gene for schizophrenia, bipolar disorder, and major depressive disorder. The gene facilitates the passage of calcium ions into the plasma membrane.

"Thus, our results suggest that voltage-gated calcium signaling, and, more broadly, calcium channel activity, could be an important biological process in psychiatric disorders," Dr. Smoller and his colleagues wrote. "Alterations in calcium channel signaling could represent a fundamental mechanism contributing to a broad vulnerability to psychopathology."

The authors cited several possible limitations. For example, diagnostic misclassification in cases of schizophrenia and bipolar disorder could produce "spurious evidence of genetic overlap between disorders." In addition, because their analyses were restricted to people of European ancestry, it is unclear whether their findings would apply to other populations.

Nevertheless, they said these result could provide "insights into the shared causation of psychiatric disorders."

Dr. Smoller and his coauthors are members of the Cross-Disorder Group of the Psychiatric Genomics Consortium. Their work was sponsored by the National Institutes of Health; none of the authors had any financial disclosures.

Genetic variants at four chromosomal positions have now been linked to five diverse childhood- and adult-onset psychiatric illnesses: schizophrenia, autism spectrum disorders, attention-deficit/hyperactivity disorder, bipolar disorder, and major depressive disorder.

Two of the four loci encode for transmembranal calcium ion transport, a physiologic finding that could become a treatment target, Dr. Jordan W. Smoller and his colleagues wrote in the Feb. 28 online issue of the Lancet (2013 Feb. 28 [http://dx.doi.org/10.1016/S0140-6736(12)62129-1]).

"The finding that genetic variants have cross-disorder effects is an empirical step toward helping clinicians understand the common co-occurrence of clinical phenotypes in individual patients," wrote Dr. Smoller of the Massachusetts General Hospital, Boston, and his coauthors. "Our results implicate a specific biological pathway – voltage-gated calcium-channel signaling – as a contributor to the pathogenesis of several psychiatric disorders, and support the potential of this pathway as a therapeutic target for psychiatric disease."

The findings also could further the goal of "moving beyond descriptive syndromes in psychiatry and towards a nosology informed by disease cause," the investigators noted.

The genome-wide association study – the largest yet of its kind – analyzed single nucleotide polymorphisms (SNPs) for the five disorders among 33,332 cases and 27,888 controls, all of European ancestry. Four independent regions contained SNPs that were significantly related to the disorders. Three were related to all five disorders, and one to only bipolar disorder and schizophrenia.

The analysis also identified additional cross-disorder associations with a number of loci previously identified only with schizophrenia, although these associations were not as strong as those seen with the four primary regions.

Two of the four loci are related to voltage-gated transmembranal calcium channels, the authors noted. One of these has been previously identified as a risk gene for schizophrenia, bipolar disorder, and major depressive disorder. The gene facilitates the passage of calcium ions into the plasma membrane.

"Thus, our results suggest that voltage-gated calcium signaling, and, more broadly, calcium channel activity, could be an important biological process in psychiatric disorders," Dr. Smoller and his colleagues wrote. "Alterations in calcium channel signaling could represent a fundamental mechanism contributing to a broad vulnerability to psychopathology."

The authors cited several possible limitations. For example, diagnostic misclassification in cases of schizophrenia and bipolar disorder could produce "spurious evidence of genetic overlap between disorders." In addition, because their analyses were restricted to people of European ancestry, it is unclear whether their findings would apply to other populations.

Nevertheless, they said these result could provide "insights into the shared causation of psychiatric disorders."

Dr. Smoller and his coauthors are members of the Cross-Disorder Group of the Psychiatric Genomics Consortium. Their work was sponsored by the National Institutes of Health; none of the authors had any financial disclosures.

Older patients with small kidney tumors are up to 70% less likely to die from any cause when managed by watchful waiting rather than by surgery, based on findings from a large retrospective study.

Surveillance appears to be safe for these small lesions, with a kidney cancer mortality of just 3% over a 5-year period. In addition, watchful waiting seems to confer a cardiovascular benefit; these patients had a 49% lower cardiac mortality risk compared with that for patients who had kidney surgery, said lead author Dr. William C. Huang of New York University Medical Center.

The link between kidney surgery and heart problems is probably mediated by compromised kidney function, Dr. Huang said. "It’s believed that when surgery takes excess normal kidney tissue, it hastens the acceleration of kidney failure," leading to cardiovascular problems, he said.

The study findings are going to be increasingly valuable as imaging turns up more and more incidental asymptomatic kidney tumors. Last year alone, about 65,000 of these lesions were diagnosed, most of them during a work-up for other abdominal complaints.

While the trend toward surveillance of small asymptomatic lesions is growing, Dr. Huang said surgery is still the treatment mode for more than half of cases. Most procedures in the retrospective study were radical nephrectomies, with kidney removal in about half of those. "The majority of these small lesions could be removed laparoscopically, but even then you’re taking out normal kidney tissue that you might really want back someday," he said at a press briefing at the Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

"Physicians can comfortably tell an elderly patient, especially a patient who is not healthy enough to tolerate general anesthesia and surgery, that the likelihood of dying of kidney cancer is low and that kidney surgery is unlikely to extend their lives," he said. "However, since it is difficult to identify which tumors will become lethal, elderly patients who are completely healthy and have an extended life expectancy, may opt for surgery."

The study examined mortality data in the Surveillance, Epidemiology, and End Results database for 8,317 patients, aged 66 years or older, who were diagnosed from 2002 to 2007 with kidney tumors smaller than 1.5 cm. The patients were followed for a median of 59 months; 78% were managed with surgery and 22%, with surveillance. The use of surveillance increased over the course of the study, from about 25% in 2002 to almost 40% in 2007.

Over the study period, 2,078 (25%) of the patients died, including 277 (3%) who died of kidney cancer. At least one cardiovascular event occurred in 24% of the patients.

Kidney cancer mortality rates did not vary between the treatment groups. However, surgical patients had a significantly increased risk of death from any cause. At 7-36 months, those who had surveillance were 30% less likely to have died than those managed by surgery (hazard ratio, 0.70). After 36 months, patients were 63% less likely to have died if their tumors were managed by surveillance instead of surgery (HR, 0.37).

Dr. Huang also demonstrated that those in the surveillance group experienced a significant cardiovascular benefit as well. By the end of the study, 25% of the deaths were due to a cardiovascular event. Patients in the surveillance group had a 49% reduction in the chance of an event.

Dr. Huang said he had no relevant financial disclosures.

[email protected]

Older patients with small kidney tumors are up to 70% less likely to die from any cause when managed by watchful waiting rather than by surgery, based on findings from a large retrospective study.

Surveillance appears to be safe for these small lesions, with a kidney cancer mortality of just 3% over a 5-year period. In addition, watchful waiting seems to confer a cardiovascular benefit; these patients had a 49% lower cardiac mortality risk compared with that for patients who had kidney surgery, said lead author Dr. William C. Huang of New York University Medical Center.

The link between kidney surgery and heart problems is probably mediated by compromised kidney function, Dr. Huang said. "It’s believed that when surgery takes excess normal kidney tissue, it hastens the acceleration of kidney failure," leading to cardiovascular problems, he said.

The study findings are going to be increasingly valuable as imaging turns up more and more incidental asymptomatic kidney tumors. Last year alone, about 65,000 of these lesions were diagnosed, most of them during a work-up for other abdominal complaints.

While the trend toward surveillance of small asymptomatic lesions is growing, Dr. Huang said surgery is still the treatment mode for more than half of cases. Most procedures in the retrospective study were radical nephrectomies, with kidney removal in about half of those. "The majority of these small lesions could be removed laparoscopically, but even then you’re taking out normal kidney tissue that you might really want back someday," he said at a press briefing at the Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

"Physicians can comfortably tell an elderly patient, especially a patient who is not healthy enough to tolerate general anesthesia and surgery, that the likelihood of dying of kidney cancer is low and that kidney surgery is unlikely to extend their lives," he said. "However, since it is difficult to identify which tumors will become lethal, elderly patients who are completely healthy and have an extended life expectancy, may opt for surgery."

The study examined mortality data in the Surveillance, Epidemiology, and End Results database for 8,317 patients, aged 66 years or older, who were diagnosed from 2002 to 2007 with kidney tumors smaller than 1.5 cm. The patients were followed for a median of 59 months; 78% were managed with surgery and 22%, with surveillance. The use of surveillance increased over the course of the study, from about 25% in 2002 to almost 40% in 2007.

Over the study period, 2,078 (25%) of the patients died, including 277 (3%) who died of kidney cancer. At least one cardiovascular event occurred in 24% of the patients.

Kidney cancer mortality rates did not vary between the treatment groups. However, surgical patients had a significantly increased risk of death from any cause. At 7-36 months, those who had surveillance were 30% less likely to have died than those managed by surgery (hazard ratio, 0.70). After 36 months, patients were 63% less likely to have died if their tumors were managed by surveillance instead of surgery (HR, 0.37).

Dr. Huang also demonstrated that those in the surveillance group experienced a significant cardiovascular benefit as well. By the end of the study, 25% of the deaths were due to a cardiovascular event. Patients in the surveillance group had a 49% reduction in the chance of an event.

Dr. Huang said he had no relevant financial disclosures.

[email protected]

Older patients with small kidney tumors are up to 70% less likely to die from any cause when managed by watchful waiting rather than by surgery, based on findings from a large retrospective study.

Surveillance appears to be safe for these small lesions, with a kidney cancer mortality of just 3% over a 5-year period. In addition, watchful waiting seems to confer a cardiovascular benefit; these patients had a 49% lower cardiac mortality risk compared with that for patients who had kidney surgery, said lead author Dr. William C. Huang of New York University Medical Center.

The link between kidney surgery and heart problems is probably mediated by compromised kidney function, Dr. Huang said. "It’s believed that when surgery takes excess normal kidney tissue, it hastens the acceleration of kidney failure," leading to cardiovascular problems, he said.

The study findings are going to be increasingly valuable as imaging turns up more and more incidental asymptomatic kidney tumors. Last year alone, about 65,000 of these lesions were diagnosed, most of them during a work-up for other abdominal complaints.

While the trend toward surveillance of small asymptomatic lesions is growing, Dr. Huang said surgery is still the treatment mode for more than half of cases. Most procedures in the retrospective study were radical nephrectomies, with kidney removal in about half of those. "The majority of these small lesions could be removed laparoscopically, but even then you’re taking out normal kidney tissue that you might really want back someday," he said at a press briefing at the Genitourinary Cancers Symposium, sponsored by the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Urologic Oncology.

"Physicians can comfortably tell an elderly patient, especially a patient who is not healthy enough to tolerate general anesthesia and surgery, that the likelihood of dying of kidney cancer is low and that kidney surgery is unlikely to extend their lives," he said. "However, since it is difficult to identify which tumors will become lethal, elderly patients who are completely healthy and have an extended life expectancy, may opt for surgery."

The study examined mortality data in the Surveillance, Epidemiology, and End Results database for 8,317 patients, aged 66 years or older, who were diagnosed from 2002 to 2007 with kidney tumors smaller than 1.5 cm. The patients were followed for a median of 59 months; 78% were managed with surgery and 22%, with surveillance. The use of surveillance increased over the course of the study, from about 25% in 2002 to almost 40% in 2007.

Over the study period, 2,078 (25%) of the patients died, including 277 (3%) who died of kidney cancer. At least one cardiovascular event occurred in 24% of the patients.

Kidney cancer mortality rates did not vary between the treatment groups. However, surgical patients had a significantly increased risk of death from any cause. At 7-36 months, those who had surveillance were 30% less likely to have died than those managed by surgery (hazard ratio, 0.70). After 36 months, patients were 63% less likely to have died if their tumors were managed by surveillance instead of surgery (HR, 0.37).

Dr. Huang also demonstrated that those in the surveillance group experienced a significant cardiovascular benefit as well. By the end of the study, 25% of the deaths were due to a cardiovascular event. Patients in the surveillance group had a 49% reduction in the chance of an event.

Dr. Huang said he had no relevant financial disclosures.

[email protected]

Men who underwent radiotherapy for localized high-risk prostate cancer and had 18 months of androgen blockade did just as well as comparable men who had 3 years of androgen blockade.

The finding of nearly identical overall and disease-free survival with traditional and shortened hormone therapy is "practice changing," Dr. Bruce Roth said during a press briefing at the 2013 Genitourinary Cancers Symposium.

"I would be willing to change the way I treat my patients," based on the results of the phase III study, said Dr. Roth of Washington University, St. Louis. "The consequences of long-term androgen deprivation are often more striking than the positive aspects of prolonging it. If treatment time can be safely halved, patients will enjoy a much better quality of life."

Dr. Abdenour Nabid of the Centre Hospitalier Universitaire de Sherbrooke, Canada, headed the study. It randomized 630 men with node-negative high-risk prostate cancer to radiation therapy plus either 36 or 18 months of androgen blockade. The hormone therapy consisted of bicalutamide 50 mg/day for 1 month plus goserelin 10.8 mg given as an injection once every 3 months.

At baseline, the patients were a median of 71 years old; the median prostate specific antigen (PSA) level was 16 ng/mL, and the median Gleason score was 8. Most had T2-T3 disease.

The median follow-up period was about 77 months. At that point, 23% of patients in the extended therapy group and 24% in the abbreviated therapy group had died. Of these 147 patients, 116 (79%) had died from causes other than prostate cancer.

Fifty patients developed bone metastases, Dr. Nabid said, but there was not a significant between-group difference in this outcome. Nor were there differences in biochemical failure, regional or distant recurrence, pelvic metastases, or the need for a second course of androgen blockade.

When Dr. Nabid broke the data out by 5- and 10-year follow-up points, the survival results were similar. At 5 years, overall survival was 92% in the 36-month group and 87% in the 18-month group; disease specific survival was 98% and 96%, respectively. At 10 years, overall survival was 64% vs. 63%, and disease-specific survival was 87% in both groups.

He said the study will follow all patients through 10 years, adding "I am convinced this finding won’t change."

Decreasing the length of androgen blockade could avoid some cases of permanent castration syndrome, Dr. Roth said. "The longer the hormone therapy, the less chance that testosterone will recover when it’s finished. With 3 years of hormone therapy, you might be inducing a lifetime of hormone suppression" and a host of problems including sexual dysfunction, loss of muscle tone, and increased visceral fat. These consequences are in turn associated with significantly increased rates of metabolic syndrome, diabetes, myocardial infarction, and coronary heart disease.

"If a patient has several decades left of life and his testosterone levels are lowered to the point of castration syndrome, there is a price to pay," Dr. Roth said. "If this patient dies of a heart attack 10 years before he would have died of prostate cancer, we have not really provided good anticancer therapy."

This is the first study showing that short-term androgen blockade is both safe and effective. "Could we get by with less?" Dr. Nabid asked. "We don’t know. Previous trials have shown that 6 months of hormone treatment is inferior to 24 months, but we don’t know what the effect of 12 months would be. Still, we are excited to see this, and our hope is that this will change the standard of care for this stage of disease."

Dr. Nabid had no financial disclosures.

[email protected]

Men who underwent radiotherapy for localized high-risk prostate cancer and had 18 months of androgen blockade did just as well as comparable men who had 3 years of androgen blockade.

The finding of nearly identical overall and disease-free survival with traditional and shortened hormone therapy is "practice changing," Dr. Bruce Roth said during a press briefing at the 2013 Genitourinary Cancers Symposium.

"I would be willing to change the way I treat my patients," based on the results of the phase III study, said Dr. Roth of Washington University, St. Louis. "The consequences of long-term androgen deprivation are often more striking than the positive aspects of prolonging it. If treatment time can be safely halved, patients will enjoy a much better quality of life."

Dr. Abdenour Nabid of the Centre Hospitalier Universitaire de Sherbrooke, Canada, headed the study. It randomized 630 men with node-negative high-risk prostate cancer to radiation therapy plus either 36 or 18 months of androgen blockade. The hormone therapy consisted of bicalutamide 50 mg/day for 1 month plus goserelin 10.8 mg given as an injection once every 3 months.

At baseline, the patients were a median of 71 years old; the median prostate specific antigen (PSA) level was 16 ng/mL, and the median Gleason score was 8. Most had T2-T3 disease.

The median follow-up period was about 77 months. At that point, 23% of patients in the extended therapy group and 24% in the abbreviated therapy group had died. Of these 147 patients, 116 (79%) had died from causes other than prostate cancer.

Fifty patients developed bone metastases, Dr. Nabid said, but there was not a significant between-group difference in this outcome. Nor were there differences in biochemical failure, regional or distant recurrence, pelvic metastases, or the need for a second course of androgen blockade.

When Dr. Nabid broke the data out by 5- and 10-year follow-up points, the survival results were similar. At 5 years, overall survival was 92% in the 36-month group and 87% in the 18-month group; disease specific survival was 98% and 96%, respectively. At 10 years, overall survival was 64% vs. 63%, and disease-specific survival was 87% in both groups.

He said the study will follow all patients through 10 years, adding "I am convinced this finding won’t change."

Decreasing the length of androgen blockade could avoid some cases of permanent castration syndrome, Dr. Roth said. "The longer the hormone therapy, the less chance that testosterone will recover when it’s finished. With 3 years of hormone therapy, you might be inducing a lifetime of hormone suppression" and a host of problems including sexual dysfunction, loss of muscle tone, and increased visceral fat. These consequences are in turn associated with significantly increased rates of metabolic syndrome, diabetes, myocardial infarction, and coronary heart disease.

"If a patient has several decades left of life and his testosterone levels are lowered to the point of castration syndrome, there is a price to pay," Dr. Roth said. "If this patient dies of a heart attack 10 years before he would have died of prostate cancer, we have not really provided good anticancer therapy."

This is the first study showing that short-term androgen blockade is both safe and effective. "Could we get by with less?" Dr. Nabid asked. "We don’t know. Previous trials have shown that 6 months of hormone treatment is inferior to 24 months, but we don’t know what the effect of 12 months would be. Still, we are excited to see this, and our hope is that this will change the standard of care for this stage of disease."

Dr. Nabid had no financial disclosures.

[email protected]

Men who underwent radiotherapy for localized high-risk prostate cancer and had 18 months of androgen blockade did just as well as comparable men who had 3 years of androgen blockade.

The finding of nearly identical overall and disease-free survival with traditional and shortened hormone therapy is "practice changing," Dr. Bruce Roth said during a press briefing at the 2013 Genitourinary Cancers Symposium.

"I would be willing to change the way I treat my patients," based on the results of the phase III study, said Dr. Roth of Washington University, St. Louis. "The consequences of long-term androgen deprivation are often more striking than the positive aspects of prolonging it. If treatment time can be safely halved, patients will enjoy a much better quality of life."

Dr. Abdenour Nabid of the Centre Hospitalier Universitaire de Sherbrooke, Canada, headed the study. It randomized 630 men with node-negative high-risk prostate cancer to radiation therapy plus either 36 or 18 months of androgen blockade. The hormone therapy consisted of bicalutamide 50 mg/day for 1 month plus goserelin 10.8 mg given as an injection once every 3 months.

At baseline, the patients were a median of 71 years old; the median prostate specific antigen (PSA) level was 16 ng/mL, and the median Gleason score was 8. Most had T2-T3 disease.

The median follow-up period was about 77 months. At that point, 23% of patients in the extended therapy group and 24% in the abbreviated therapy group had died. Of these 147 patients, 116 (79%) had died from causes other than prostate cancer.

Fifty patients developed bone metastases, Dr. Nabid said, but there was not a significant between-group difference in this outcome. Nor were there differences in biochemical failure, regional or distant recurrence, pelvic metastases, or the need for a second course of androgen blockade.

When Dr. Nabid broke the data out by 5- and 10-year follow-up points, the survival results were similar. At 5 years, overall survival was 92% in the 36-month group and 87% in the 18-month group; disease specific survival was 98% and 96%, respectively. At 10 years, overall survival was 64% vs. 63%, and disease-specific survival was 87% in both groups.

He said the study will follow all patients through 10 years, adding "I am convinced this finding won’t change."

Decreasing the length of androgen blockade could avoid some cases of permanent castration syndrome, Dr. Roth said. "The longer the hormone therapy, the less chance that testosterone will recover when it’s finished. With 3 years of hormone therapy, you might be inducing a lifetime of hormone suppression" and a host of problems including sexual dysfunction, loss of muscle tone, and increased visceral fat. These consequences are in turn associated with significantly increased rates of metabolic syndrome, diabetes, myocardial infarction, and coronary heart disease.

"If a patient has several decades left of life and his testosterone levels are lowered to the point of castration syndrome, there is a price to pay," Dr. Roth said. "If this patient dies of a heart attack 10 years before he would have died of prostate cancer, we have not really provided good anticancer therapy."

This is the first study showing that short-term androgen blockade is both safe and effective. "Could we get by with less?" Dr. Nabid asked. "We don’t know. Previous trials have shown that 6 months of hormone treatment is inferior to 24 months, but we don’t know what the effect of 12 months would be. Still, we are excited to see this, and our hope is that this will change the standard of care for this stage of disease."

Dr. Nabid had no financial disclosures.

[email protected]

Prostate cancers detected during screening are much more likely to be high risk when they affect black men and men aged 75 years or older.

Men over age 74 years were nine times more likely to have high-risk disease after a positive prostate-specific antigen test, and black men of all ages were twice as likely to have high-risk disease as were white men, based on a study of 4 years of data extracted from the Surveillance, Epidemiology and End Results (SEER) database.

The findings make the case for a more personalized approach to screening, Dr. Hong Zhang said at a press briefing during the 2013 Genitourinary Cancers Symposium.

Without prostate-specific antigen (PSA) screening, "we have no other way to detect prostate cancer sufficiently early to have the best chance of helping this group of high-risk patients," said Dr. Zhang of the University of Rochester (N.Y.).

The study brings a bit of context to current PSA screening guidelines, which are "all over the map," according to session moderator Dr. Bruce Roth of Washington University, St. Louis. In 2011, the United States Preventive Services Task Force determined that routine screening harms more men that it helps.

"The American Cancer Society recommends just screening older men and the USPTF recommends that nobody get screened," Dr. Roth said. Based on these results, the presumption that older men will die first of something other than their prostate cancer is not necessarily true. "In fact, a significant number of these men present with high-risk disease. Age is not the greatest determinant of who should and should not be screened."

During 2004-2008, 70,345 men were diagnosed with T1cN0M0 prostate cancer in SEER. Of these, 48% had low-risk disease (PSA less than 10 mg/L or Gleason score of 6 or less), 36% intermediate-risk disease (PSA between 10 mg/L and 20 mg/L or Gleason score 7), and 16% high-risk disease (PSA at least 20 mg/L, or Gleason score of 8 or higher).

The median age of patients with low-risk disease was 67 years; for those with intermediate-risk disease, median age was 70 years; and for high-risk disease, it was 72 years. Men 75 years or older accounted for 12% of the population, but for 24% of intermediate-risk and 26% of high-risk disease.

In a multivariate analysis, Dr. Zhang determined that, compared with younger men, those aged 75 years and older were almost five times more likely to have intermediate-risk disease and nine times more likely to have high-risk disease.

Blacks made up 13% of the low-risk category, 16% of the intermediate-risk category, and 18% of the high-risk category. Compared with whites, blacks were 1.5 times more likely to have intermediate-risk disease and twice as likely to have high-risk disease.

Dr. Zhang and Dr. Roth had no financial disclosures.

[email protected]

Prostate cancers detected during screening are much more likely to be high risk when they affect black men and men aged 75 years or older.

Men over age 74 years were nine times more likely to have high-risk disease after a positive prostate-specific antigen test, and black men of all ages were twice as likely to have high-risk disease as were white men, based on a study of 4 years of data extracted from the Surveillance, Epidemiology and End Results (SEER) database.

The findings make the case for a more personalized approach to screening, Dr. Hong Zhang said at a press briefing during the 2013 Genitourinary Cancers Symposium.

Without prostate-specific antigen (PSA) screening, "we have no other way to detect prostate cancer sufficiently early to have the best chance of helping this group of high-risk patients," said Dr. Zhang of the University of Rochester (N.Y.).

The study brings a bit of context to current PSA screening guidelines, which are "all over the map," according to session moderator Dr. Bruce Roth of Washington University, St. Louis. In 2011, the United States Preventive Services Task Force determined that routine screening harms more men that it helps.

"The American Cancer Society recommends just screening older men and the USPTF recommends that nobody get screened," Dr. Roth said. Based on these results, the presumption that older men will die first of something other than their prostate cancer is not necessarily true. "In fact, a significant number of these men present with high-risk disease. Age is not the greatest determinant of who should and should not be screened."

During 2004-2008, 70,345 men were diagnosed with T1cN0M0 prostate cancer in SEER. Of these, 48% had low-risk disease (PSA less than 10 mg/L or Gleason score of 6 or less), 36% intermediate-risk disease (PSA between 10 mg/L and 20 mg/L or Gleason score 7), and 16% high-risk disease (PSA at least 20 mg/L, or Gleason score of 8 or higher).

The median age of patients with low-risk disease was 67 years; for those with intermediate-risk disease, median age was 70 years; and for high-risk disease, it was 72 years. Men 75 years or older accounted for 12% of the population, but for 24% of intermediate-risk and 26% of high-risk disease.

In a multivariate analysis, Dr. Zhang determined that, compared with younger men, those aged 75 years and older were almost five times more likely to have intermediate-risk disease and nine times more likely to have high-risk disease.

Blacks made up 13% of the low-risk category, 16% of the intermediate-risk category, and 18% of the high-risk category. Compared with whites, blacks were 1.5 times more likely to have intermediate-risk disease and twice as likely to have high-risk disease.

Dr. Zhang and Dr. Roth had no financial disclosures.

[email protected]

Prostate cancers detected during screening are much more likely to be high risk when they affect black men and men aged 75 years or older.

Men over age 74 years were nine times more likely to have high-risk disease after a positive prostate-specific antigen test, and black men of all ages were twice as likely to have high-risk disease as were white men, based on a study of 4 years of data extracted from the Surveillance, Epidemiology and End Results (SEER) database.

The findings make the case for a more personalized approach to screening, Dr. Hong Zhang said at a press briefing during the 2013 Genitourinary Cancers Symposium.

Without prostate-specific antigen (PSA) screening, "we have no other way to detect prostate cancer sufficiently early to have the best chance of helping this group of high-risk patients," said Dr. Zhang of the University of Rochester (N.Y.).

The study brings a bit of context to current PSA screening guidelines, which are "all over the map," according to session moderator Dr. Bruce Roth of Washington University, St. Louis. In 2011, the United States Preventive Services Task Force determined that routine screening harms more men that it helps.

"The American Cancer Society recommends just screening older men and the USPTF recommends that nobody get screened," Dr. Roth said. Based on these results, the presumption that older men will die first of something other than their prostate cancer is not necessarily true. "In fact, a significant number of these men present with high-risk disease. Age is not the greatest determinant of who should and should not be screened."

During 2004-2008, 70,345 men were diagnosed with T1cN0M0 prostate cancer in SEER. Of these, 48% had low-risk disease (PSA less than 10 mg/L or Gleason score of 6 or less), 36% intermediate-risk disease (PSA between 10 mg/L and 20 mg/L or Gleason score 7), and 16% high-risk disease (PSA at least 20 mg/L, or Gleason score of 8 or higher).

The median age of patients with low-risk disease was 67 years; for those with intermediate-risk disease, median age was 70 years; and for high-risk disease, it was 72 years. Men 75 years or older accounted for 12% of the population, but for 24% of intermediate-risk and 26% of high-risk disease.

In a multivariate analysis, Dr. Zhang determined that, compared with younger men, those aged 75 years and older were almost five times more likely to have intermediate-risk disease and nine times more likely to have high-risk disease.

Blacks made up 13% of the low-risk category, 16% of the intermediate-risk category, and 18% of the high-risk category. Compared with whites, blacks were 1.5 times more likely to have intermediate-risk disease and twice as likely to have high-risk disease.

Dr. Zhang and Dr. Roth had no financial disclosures.

[email protected]

Women who underwent lumpectomy for stage I or II breast cancer were 28% less likely to die from any cause and up to 16% less likely to die from breast cancer, compared with women who underwent mastectomy, Dr. E. Shelley Hwang and her colleagues reported Jan. 28 in the online issue of Cancer.

The 3-year disease-specific survival benefit for breast-conserving therapy (BCT) was most pronounced for chronic respiratory disease, for which lumpectomy was associated with a 54% decreased risk of death; heart disease, with a 49% decreased risk; and cerebrovascular disease, with a decreased risk of 36%.

The survival benefit varied with age, tumor size, and hormone receptor status but was significant in every subgroup, Dr. Hwang and her colleagues wrote (Cancer Jan. 28, 2013 [doi:10.1002/cncr.27795]).

"Our findings have important implications for understanding the overall benefit of BCT at the population level," wrote Dr. Hwang of the Duke University Comprehensive Cancer Center, Durham, N.C., and her coauthors. "These results provide confidence in the efficacy of BCT even among younger patients with HR-negative disease thought to be at relatively higher risk for local failure."

The team reviewed the records of 112,154 women who were treated for a new, unilateral T1/T2 stage I or II breast cancer diagnosed from 1990 to 2004. Most of these women (61,771) underwent a lumpectomy and radiation; the remainder underwent mastectomy without radiation. They were followed for a median of 10 years.

About a quarter of each group was younger than 50 years when diagnosed; another quarter was aged 70-80 years. A small portion (6%) was younger than 40 years.

Surgical approach evolved over the study period. Breast-conserving therapy increased from 37% in 1990-92 to 62% by 2002-04, while the rate of mastectomies declined.

The median tumor size was 1.5 cm; patients with larger tumors were more likely to have mastectomies. "Interestingly, the use of BCT varied by age even among tumors [smaller than and equal to] 2 cm where the youngest and oldest age groups had the lowest BCT rate. In [tumors larger than] 2 cm, BCT rate declined by age," Dr. Hwang and her associates said.

Over the follow-up period, there were 31,416 deaths; 39% of these were caused by breast cancer; 5-year overall survival was 89%.

To further explore the treatment-mortality interaction, the investigators divided the cohort into four groups according to age and tumor characteristics:

• 50 years or older, hormone receptor negative.

• 50 years or older, hormone receptor negative.

• Younger than 50 years, hormone receptor positive.

• Younger than 50 years, hormone receptor positive.

Women 50 years and older with HR-positive tumors who had BCT experienced the greatest survival benefit, compared with mastectomy patients (hazard ratio, 0.81). Women younger than 50 years with HR- positive tumors experienced the smallest benefit (HR, 0.93), but one which was still statistically significant.

The investigators also looked at 3-year overall and disease-specific survival. "Notably, BCT was associated with significantly lower 3-year mortality rates from all causes," including heart disease (HR, 0.51), chronic respiratory disease (HR, 0.46), and cerebrovascular disease (HR, 0.64).

The findings align with those of randomized trials showing the benefits of BCT, the authors noted.

"Despite this, recent studies have shown an increased rate of mastectomy for patient subgroups including younger women with early-stage tumors, many of which would have presumably been amenable to BCT," they wrote. This could be the result of a perception that women with unfavorable characteristics, like younger age and high-risk tumors, don’t do as well with BCT.

The investigators noted that some differences in disease burden at baseline could have contributed to the findings.

"Interestingly, for every cause of mortality that we evaluated, women who had mastectomy were more likely to die within 3 years of their breast cancer diagnosis than women who chose BCT. Based on these findings, it is reasonable to infer that the mastectomy group was likely to have a greater burden of nonfatal comorbidities at presentation, and that this factor may well have influenced surgical decision-making. Nevertheless, this factor alone cannot account for why women with mastectomy had lower [disease specific survival] after adjusting for age and tumor characteristics," Dr. Hwang and her associates said.

Based on the strong associations with survival, "these findings support the notion that BCT, when combined with radiation, confers at least equivalent and perhaps even superior survival to mastectomy as definitive breast cancer treatment," they said.

The National Cancer Institute funded the study. Dr. Hwang had no financial disclosures.

[email protected]

Women who underwent lumpectomy for stage I or II breast cancer were 28% less likely to die from any cause and up to 16% less likely to die from breast cancer, compared with women who underwent mastectomy, Dr. E. Shelley Hwang and her colleagues reported Jan. 28 in the online issue of Cancer.

The 3-year disease-specific survival benefit for breast-conserving therapy (BCT) was most pronounced for chronic respiratory disease, for which lumpectomy was associated with a 54% decreased risk of death; heart disease, with a 49% decreased risk; and cerebrovascular disease, with a decreased risk of 36%.

The survival benefit varied with age, tumor size, and hormone receptor status but was significant in every subgroup, Dr. Hwang and her colleagues wrote (Cancer Jan. 28, 2013 [doi:10.1002/cncr.27795]).

"Our findings have important implications for understanding the overall benefit of BCT at the population level," wrote Dr. Hwang of the Duke University Comprehensive Cancer Center, Durham, N.C., and her coauthors. "These results provide confidence in the efficacy of BCT even among younger patients with HR-negative disease thought to be at relatively higher risk for local failure."

The team reviewed the records of 112,154 women who were treated for a new, unilateral T1/T2 stage I or II breast cancer diagnosed from 1990 to 2004. Most of these women (61,771) underwent a lumpectomy and radiation; the remainder underwent mastectomy without radiation. They were followed for a median of 10 years.

About a quarter of each group was younger than 50 years when diagnosed; another quarter was aged 70-80 years. A small portion (6%) was younger than 40 years.

Surgical approach evolved over the study period. Breast-conserving therapy increased from 37% in 1990-92 to 62% by 2002-04, while the rate of mastectomies declined.

The median tumor size was 1.5 cm; patients with larger tumors were more likely to have mastectomies. "Interestingly, the use of BCT varied by age even among tumors [smaller than and equal to] 2 cm where the youngest and oldest age groups had the lowest BCT rate. In [tumors larger than] 2 cm, BCT rate declined by age," Dr. Hwang and her associates said.

Over the follow-up period, there were 31,416 deaths; 39% of these were caused by breast cancer; 5-year overall survival was 89%.

To further explore the treatment-mortality interaction, the investigators divided the cohort into four groups according to age and tumor characteristics:

• 50 years or older, hormone receptor negative.

• 50 years or older, hormone receptor negative.

• Younger than 50 years, hormone receptor positive.

• Younger than 50 years, hormone receptor positive.

Women 50 years and older with HR-positive tumors who had BCT experienced the greatest survival benefit, compared with mastectomy patients (hazard ratio, 0.81). Women younger than 50 years with HR- positive tumors experienced the smallest benefit (HR, 0.93), but one which was still statistically significant.

The investigators also looked at 3-year overall and disease-specific survival. "Notably, BCT was associated with significantly lower 3-year mortality rates from all causes," including heart disease (HR, 0.51), chronic respiratory disease (HR, 0.46), and cerebrovascular disease (HR, 0.64).

The findings align with those of randomized trials showing the benefits of BCT, the authors noted.

"Despite this, recent studies have shown an increased rate of mastectomy for patient subgroups including younger women with early-stage tumors, many of which would have presumably been amenable to BCT," they wrote. This could be the result of a perception that women with unfavorable characteristics, like younger age and high-risk tumors, don’t do as well with BCT.

The investigators noted that some differences in disease burden at baseline could have contributed to the findings.

"Interestingly, for every cause of mortality that we evaluated, women who had mastectomy were more likely to die within 3 years of their breast cancer diagnosis than women who chose BCT. Based on these findings, it is reasonable to infer that the mastectomy group was likely to have a greater burden of nonfatal comorbidities at presentation, and that this factor may well have influenced surgical decision-making. Nevertheless, this factor alone cannot account for why women with mastectomy had lower [disease specific survival] after adjusting for age and tumor characteristics," Dr. Hwang and her associates said.

Based on the strong associations with survival, "these findings support the notion that BCT, when combined with radiation, confers at least equivalent and perhaps even superior survival to mastectomy as definitive breast cancer treatment," they said.

The National Cancer Institute funded the study. Dr. Hwang had no financial disclosures.

[email protected]

Women who underwent lumpectomy for stage I or II breast cancer were 28% less likely to die from any cause and up to 16% less likely to die from breast cancer, compared with women who underwent mastectomy, Dr. E. Shelley Hwang and her colleagues reported Jan. 28 in the online issue of Cancer.

The 3-year disease-specific survival benefit for breast-conserving therapy (BCT) was most pronounced for chronic respiratory disease, for which lumpectomy was associated with a 54% decreased risk of death; heart disease, with a 49% decreased risk; and cerebrovascular disease, with a decreased risk of 36%.

The survival benefit varied with age, tumor size, and hormone receptor status but was significant in every subgroup, Dr. Hwang and her colleagues wrote (Cancer Jan. 28, 2013 [doi:10.1002/cncr.27795]).

"Our findings have important implications for understanding the overall benefit of BCT at the population level," wrote Dr. Hwang of the Duke University Comprehensive Cancer Center, Durham, N.C., and her coauthors. "These results provide confidence in the efficacy of BCT even among younger patients with HR-negative disease thought to be at relatively higher risk for local failure."

The team reviewed the records of 112,154 women who were treated for a new, unilateral T1/T2 stage I or II breast cancer diagnosed from 1990 to 2004. Most of these women (61,771) underwent a lumpectomy and radiation; the remainder underwent mastectomy without radiation. They were followed for a median of 10 years.

About a quarter of each group was younger than 50 years when diagnosed; another quarter was aged 70-80 years. A small portion (6%) was younger than 40 years.

Surgical approach evolved over the study period. Breast-conserving therapy increased from 37% in 1990-92 to 62% by 2002-04, while the rate of mastectomies declined.

The median tumor size was 1.5 cm; patients with larger tumors were more likely to have mastectomies. "Interestingly, the use of BCT varied by age even among tumors [smaller than and equal to] 2 cm where the youngest and oldest age groups had the lowest BCT rate. In [tumors larger than] 2 cm, BCT rate declined by age," Dr. Hwang and her associates said.

Over the follow-up period, there were 31,416 deaths; 39% of these were caused by breast cancer; 5-year overall survival was 89%.

To further explore the treatment-mortality interaction, the investigators divided the cohort into four groups according to age and tumor characteristics:

• 50 years or older, hormone receptor negative.

• 50 years or older, hormone receptor negative.

• Younger than 50 years, hormone receptor positive.

• Younger than 50 years, hormone receptor positive.

Women 50 years and older with HR-positive tumors who had BCT experienced the greatest survival benefit, compared with mastectomy patients (hazard ratio, 0.81). Women younger than 50 years with HR- positive tumors experienced the smallest benefit (HR, 0.93), but one which was still statistically significant.

The investigators also looked at 3-year overall and disease-specific survival. "Notably, BCT was associated with significantly lower 3-year mortality rates from all causes," including heart disease (HR, 0.51), chronic respiratory disease (HR, 0.46), and cerebrovascular disease (HR, 0.64).

The findings align with those of randomized trials showing the benefits of BCT, the authors noted.

"Despite this, recent studies have shown an increased rate of mastectomy for patient subgroups including younger women with early-stage tumors, many of which would have presumably been amenable to BCT," they wrote. This could be the result of a perception that women with unfavorable characteristics, like younger age and high-risk tumors, don’t do as well with BCT.

The investigators noted that some differences in disease burden at baseline could have contributed to the findings.

"Interestingly, for every cause of mortality that we evaluated, women who had mastectomy were more likely to die within 3 years of their breast cancer diagnosis than women who chose BCT. Based on these findings, it is reasonable to infer that the mastectomy group was likely to have a greater burden of nonfatal comorbidities at presentation, and that this factor may well have influenced surgical decision-making. Nevertheless, this factor alone cannot account for why women with mastectomy had lower [disease specific survival] after adjusting for age and tumor characteristics," Dr. Hwang and her associates said.

Based on the strong associations with survival, "these findings support the notion that BCT, when combined with radiation, confers at least equivalent and perhaps even superior survival to mastectomy as definitive breast cancer treatment," they said.

The National Cancer Institute funded the study. Dr. Hwang had no financial disclosures.

[email protected]

For genetic skin diseases, the future is nearly here.

"It seems like every other day there’s another article published based on using next-generation gene sequencing to find out what’s causing disease, and then using that information to work toward personalized gene and pharmacologic therapy," said Dr. Amy Paller, the Walter J. Hamlin Professor and chair of dermatology at Northwestern University, Chicago. "We’re talking about these things not only in the very near future, but right now."

Viral vectors have made possible enormous advances in the treatment of genetic skin disorders, but they are far from perfect, Dr. Paller said in an interview. Researchers are looking beyond them, hoping to sidestep their problems while capitalizing on the delivery of genetic material to highly targeted areas.

"The problem with viral vectors – and particularly with the ones that are out there now – is that they insert their genetic information randomly into the chromosome. If they insert it into the wrong place, it can cause oncogenesis. We know that leukemia and lymphomas have developed because of this. The next frontier is to develop other techniques" that would avoid the problem altogether, she said at the Hawaii Dermatology Seminar, sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

One of the most exciting areas of research is the topical delivery of genetic therapy, she said. Researchers are wrestling with the problem of effectively delivering molecules to target areas.

"Getting through the epidermal barrier is a major problem for topical genetic modulation therapy. What we are trying to do is conquer this barrier using physical or chemical techniques to decrease its integrity."

A number of methods are under investigation, including microneedles coated with the desired genetic material, which can be injected into very specific sites.

Topically delivering therapeutic nanoparticles is another hot area. Last summer, Dr. Paller’s team obtained some early positive results with spherical nucleic acid nanoparticle conjugates – gold cores surrounded by small interfering RNA. They used a commercially available topical emollient as the vehicle and showed that the nanoparticles penetrated almost 100% of keratinocytes in both mouse and human epidermis. The treatment induced a complete knockdown of epidermal growth factor receptor expression and, in hairless mice, decreased skin thickness by 40%.

One big benefit of this approach is that it requires no compromise of the epidermal barrier, Dr. Paller said. Treatment doesn’t appear to induce any inflammatory cytokines or lead to local or systemic toxicity.

Her lab has moved on from animal models to humans. "We’re looking at real disease now, working on skin cancers and wound healing, psoriasis, and dominant negative keratin gene disorders."

But although the field of gene therapy is rapidly progressing, the process of diagnosis seems mired in the past.

"Diagnosis of genetic disease is still made clinically," Dr. Paller said. While diagnosis can be supplemented by information on family history, extracutaneous exams, and other testing, most children in the U.S. don’t get a complete genetic work-up to pinpoint their unique problem. "In Europe, many children with genetic skin disease undergo genotype analysis, but only a minority of children in the United States does so."

Cost is probably the biggest barrier, "especially without insurance, or if insurance won’t cover the testing. For example, testing six genes for autosomal recessive congenital ichthyosis in a collodion baby can cost more than $12,000."

Some argue that the testing doesn’t provide much practical information. "There are limited genotype-phenotype correlations that predict prognosis," Dr. Paller said. "And unless the information is used for family planning purposes, it has limited value."

Fortunately, genotyping technology is improving even as the cost is coming down. Next-generation sequencing can analyze the entire genome, and even whole-exome sequences – a refinement that could identify about 85% of mutations and allows a detailed look at very small, specific regions. Experts predict that the cost of next-generation sequencing is going to decrease exponentially over the next few years, into the range of $1,000-$5,000.

Leveraging next-generation sequencing could help patients with genetic skin disorders in a number of ways, Dr. Paller said. In addition to finding low-frequency mutations in known genes, the process could identify mutations in newly associated genes and pave the way for the genotype-phenotype correlations that could help diagnosis.

Next-generation sequencing might even make it possible to predict drug response, leading to a truly individualized prescription of genetic treatment, Dr. Paller said.

"These discoveries have translated into new therapy for patients with genetic disorders and will guide innovative treatment in the future. New technology will revolutionize our knowledge of the human genome and disease, facilitating mutation-based gene and pharmacologic therapy."

SDEF and this news organization are owned by the same parent company.

*This story was updated March 1, 2013.

For genetic skin diseases, the future is nearly here.

"It seems like every other day there’s another article published based on using next-generation gene sequencing to find out what’s causing disease, and then using that information to work toward personalized gene and pharmacologic therapy," said Dr. Amy Paller, the Walter J. Hamlin Professor and chair of dermatology at Northwestern University, Chicago. "We’re talking about these things not only in the very near future, but right now."

Viral vectors have made possible enormous advances in the treatment of genetic skin disorders, but they are far from perfect, Dr. Paller said in an interview. Researchers are looking beyond them, hoping to sidestep their problems while capitalizing on the delivery of genetic material to highly targeted areas.

"The problem with viral vectors – and particularly with the ones that are out there now – is that they insert their genetic information randomly into the chromosome. If they insert it into the wrong place, it can cause oncogenesis. We know that leukemia and lymphomas have developed because of this. The next frontier is to develop other techniques" that would avoid the problem altogether, she said at the Hawaii Dermatology Seminar, sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

One of the most exciting areas of research is the topical delivery of genetic therapy, she said. Researchers are wrestling with the problem of effectively delivering molecules to target areas.

"Getting through the epidermal barrier is a major problem for topical genetic modulation therapy. What we are trying to do is conquer this barrier using physical or chemical techniques to decrease its integrity."

A number of methods are under investigation, including microneedles coated with the desired genetic material, which can be injected into very specific sites.

Topically delivering therapeutic nanoparticles is another hot area. Last summer, Dr. Paller’s team obtained some early positive results with spherical nucleic acid nanoparticle conjugates – gold cores surrounded by small interfering RNA. They used a commercially available topical emollient as the vehicle and showed that the nanoparticles penetrated almost 100% of keratinocytes in both mouse and human epidermis. The treatment induced a complete knockdown of epidermal growth factor receptor expression and, in hairless mice, decreased skin thickness by 40%.

One big benefit of this approach is that it requires no compromise of the epidermal barrier, Dr. Paller said. Treatment doesn’t appear to induce any inflammatory cytokines or lead to local or systemic toxicity.

Her lab has moved on from animal models to humans. "We’re looking at real disease now, working on skin cancers and wound healing, psoriasis, and dominant negative keratin gene disorders."

But although the field of gene therapy is rapidly progressing, the process of diagnosis seems mired in the past.

"Diagnosis of genetic disease is still made clinically," Dr. Paller said. While diagnosis can be supplemented by information on family history, extracutaneous exams, and other testing, most children in the U.S. don’t get a complete genetic work-up to pinpoint their unique problem. "In Europe, many children with genetic skin disease undergo genotype analysis, but only a minority of children in the United States does so."

Cost is probably the biggest barrier, "especially without insurance, or if insurance won’t cover the testing. For example, testing six genes for autosomal recessive congenital ichthyosis in a collodion baby can cost more than $12,000."

Some argue that the testing doesn’t provide much practical information. "There are limited genotype-phenotype correlations that predict prognosis," Dr. Paller said. "And unless the information is used for family planning purposes, it has limited value."

Fortunately, genotyping technology is improving even as the cost is coming down. Next-generation sequencing can analyze the entire genome, and even whole-exome sequences – a refinement that could identify about 85% of mutations and allows a detailed look at very small, specific regions. Experts predict that the cost of next-generation sequencing is going to decrease exponentially over the next few years, into the range of $1,000-$5,000.

Leveraging next-generation sequencing could help patients with genetic skin disorders in a number of ways, Dr. Paller said. In addition to finding low-frequency mutations in known genes, the process could identify mutations in newly associated genes and pave the way for the genotype-phenotype correlations that could help diagnosis.

Next-generation sequencing might even make it possible to predict drug response, leading to a truly individualized prescription of genetic treatment, Dr. Paller said.

"These discoveries have translated into new therapy for patients with genetic disorders and will guide innovative treatment in the future. New technology will revolutionize our knowledge of the human genome and disease, facilitating mutation-based gene and pharmacologic therapy."

SDEF and this news organization are owned by the same parent company.

*This story was updated March 1, 2013.

For genetic skin diseases, the future is nearly here.

"It seems like every other day there’s another article published based on using next-generation gene sequencing to find out what’s causing disease, and then using that information to work toward personalized gene and pharmacologic therapy," said Dr. Amy Paller, the Walter J. Hamlin Professor and chair of dermatology at Northwestern University, Chicago. "We’re talking about these things not only in the very near future, but right now."

Viral vectors have made possible enormous advances in the treatment of genetic skin disorders, but they are far from perfect, Dr. Paller said in an interview. Researchers are looking beyond them, hoping to sidestep their problems while capitalizing on the delivery of genetic material to highly targeted areas.

"The problem with viral vectors – and particularly with the ones that are out there now – is that they insert their genetic information randomly into the chromosome. If they insert it into the wrong place, it can cause oncogenesis. We know that leukemia and lymphomas have developed because of this. The next frontier is to develop other techniques" that would avoid the problem altogether, she said at the Hawaii Dermatology Seminar, sponsored by Global Academy for Medical Education/Skin Disease Education Foundation.

One of the most exciting areas of research is the topical delivery of genetic therapy, she said. Researchers are wrestling with the problem of effectively delivering molecules to target areas.

"Getting through the epidermal barrier is a major problem for topical genetic modulation therapy. What we are trying to do is conquer this barrier using physical or chemical techniques to decrease its integrity."

A number of methods are under investigation, including microneedles coated with the desired genetic material, which can be injected into very specific sites.

Topically delivering therapeutic nanoparticles is another hot area. Last summer, Dr. Paller’s team obtained some early positive results with spherical nucleic acid nanoparticle conjugates – gold cores surrounded by small interfering RNA. They used a commercially available topical emollient as the vehicle and showed that the nanoparticles penetrated almost 100% of keratinocytes in both mouse and human epidermis. The treatment induced a complete knockdown of epidermal growth factor receptor expression and, in hairless mice, decreased skin thickness by 40%.

One big benefit of this approach is that it requires no compromise of the epidermal barrier, Dr. Paller said. Treatment doesn’t appear to induce any inflammatory cytokines or lead to local or systemic toxicity.

Her lab has moved on from animal models to humans. "We’re looking at real disease now, working on skin cancers and wound healing, psoriasis, and dominant negative keratin gene disorders."

But although the field of gene therapy is rapidly progressing, the process of diagnosis seems mired in the past.

"Diagnosis of genetic disease is still made clinically," Dr. Paller said. While diagnosis can be supplemented by information on family history, extracutaneous exams, and other testing, most children in the U.S. don’t get a complete genetic work-up to pinpoint their unique problem. "In Europe, many children with genetic skin disease undergo genotype analysis, but only a minority of children in the United States does so."

Cost is probably the biggest barrier, "especially without insurance, or if insurance won’t cover the testing. For example, testing six genes for autosomal recessive congenital ichthyosis in a collodion baby can cost more than $12,000."

Some argue that the testing doesn’t provide much practical information. "There are limited genotype-phenotype correlations that predict prognosis," Dr. Paller said. "And unless the information is used for family planning purposes, it has limited value."

Fortunately, genotyping technology is improving even as the cost is coming down. Next-generation sequencing can analyze the entire genome, and even whole-exome sequences – a refinement that could identify about 85% of mutations and allows a detailed look at very small, specific regions. Experts predict that the cost of next-generation sequencing is going to decrease exponentially over the next few years, into the range of $1,000-$5,000.

Leveraging next-generation sequencing could help patients with genetic skin disorders in a number of ways, Dr. Paller said. In addition to finding low-frequency mutations in known genes, the process could identify mutations in newly associated genes and pave the way for the genotype-phenotype correlations that could help diagnosis.

Next-generation sequencing might even make it possible to predict drug response, leading to a truly individualized prescription of genetic treatment, Dr. Paller said.

"These discoveries have translated into new therapy for patients with genetic disorders and will guide innovative treatment in the future. New technology will revolutionize our knowledge of the human genome and disease, facilitating mutation-based gene and pharmacologic therapy."

SDEF and this news organization are owned by the same parent company.

*This story was updated March 1, 2013.