Printed circuit board

Researchers have found evidence suggesting that men who work in microelectronics and business machine facilities may have an increased risk of dying from certain cancers, including non-Hodgkin lymphoma (NHL).

Their study, published in the American Journal of Industrial Medicine, was designed to assess the effects chemical exposure might have on the incidence of diseases and worker mortality.

The results showed that hourly male workers, who were more likely than other employees to be exposed to the chemicals studied, had a 1.5-fold increased risk of death from NHL.

However, the investigators did not observe a significant relationship between NHL and any of the chemicals studied.

This research originated from concerns about the release of trichloroethylene (TCE), perchlorethylene (PCE), and other industrial chemicals through groundwater and air emissions from several industrial facilities in a town in upstate New York.

Previous studies suggested the chemicals were associated with increases in the incidence of kidney, lung, and testicular cancer in the community. So researchers initiated a study of current and former workers of the local microelectronics and business machine facility.

Patient population

Sharon R. Silver, of the National Institute for Occupational Safety and Health in Cincinnati, Ohio, and her colleagues examined health outcomes among 34,494 former workers employed at the facility for at least 91 days between 1969 and 2001.

Machining workers were exposed to dust, noise, solvents, and metals. And “wet” process workers were exposed to chemical solutions used in manufacturing circuit boards and their substrates. The facility also had employees in non-production roles, including sales and office support, as well as computer programming.

The researchers evaluated the relationship between health outcomes and the estimated cumulative extent of potential chemical exposures, stratified according to gender and pay code.

Of the 34,494 workers, 69.7% were male. Among males, 15,447 were hourly workers, and 8590 were salaried. Among females, 8934 were hourly workers, and 1523 were salaried.

Chemical exposure

A previous study of this population revealed the use of 6 chemical agents (fiberglass, lead, methylene chloride, methyl chloroform, PCE, and TCE), 6 chemical classes (acid-base, aromatic hydrocarbons, chlorinated hydrocarbons, other hydrocarbons, chlorofluorocarbons, and metals), and general chemicals (including unspecified).

The potential for exposure to a chemical agent or class was much more common among hourly workers than salaried workers. Among males, 65.7% of hourly workers and 20% of salaried workers were exposed to at least 1 of the chemicals studied. Among females, exposure rates were 58.5% and 13.9%, respectively.

“Other hydrocarbons” was the chemical class that male hourly workers were potentially exposed to most often (60.5%). At least one-third of workers in this group had potential exposure to chlorinated hydrocarbons, lead, and acids and bases. TCE and PCE were the least common exposure agents among male hourly workers, with 13.9% and 15.1% exposed, respectively.

Cancer mortality, incidence

The investigators used mortality rates from the US population, as well as New York State (excluding New York City), to calculate the number of expected deaths among study participants. The standardized mortality ratio (SMR) is the ratio of observed to expected deaths.

The average follow-up was 25.7 years. By the study end date, 5966 workers (17.3%) had died. Workers employed less than a year at the facility (n=8397) comprised 363 of these deaths.

Both all-cause mortality (SMR=0.67) and all-cancer mortality (SMR=0.74) showed a statistically significant deficit for the entire workforce. Most of the individual cancers and other conditions studied were not associated with an increased risk of death.

There were significant increases in death for certain cancers among males, but there was no significant increase in a specific cause of death among females belonging to either pay code.

There was an increased risk of death from NHL among male hourly workers but not salaried workers, with SMRs of 1.49 and 0.68, respectively. The same pattern occurred for rectal cancer, with SMRs of 1.71 and 0.71, respectively.

The study also revealed an elevated incidence of pleural cancers in salaried males, mesothelioma in hourly workers, and testicular cancer in salaried males.

The increase in mesothelioma and pleural cancers was seen only in workers hired before 1969, which would support a link between the cancers and asbestos exposure. However, the researchers could find no evidence that asbestos was used in manufacturing at the facility.

Similarly, the investigators found no significant link between exposure to specific chemicals and the increased mortality from NHL or rectal cancer. And there was no significant link between exposure and testicular cancer.

Although these results do not suggest a strong role for occupational chemical exposures in cancer incidence and mortality, the researchers said risks from occupational exposures cannot be ruled out due to limitations of this study and the relative youth of this patient cohort.

Printed circuit board

Researchers have found evidence suggesting that men who work in microelectronics and business machine facilities may have an increased risk of dying from certain cancers, including non-Hodgkin lymphoma (NHL).

Their study, published in the American Journal of Industrial Medicine, was designed to assess the effects chemical exposure might have on the incidence of diseases and worker mortality.

The results showed that hourly male workers, who were more likely than other employees to be exposed to the chemicals studied, had a 1.5-fold increased risk of death from NHL.

However, the investigators did not observe a significant relationship between NHL and any of the chemicals studied.

This research originated from concerns about the release of trichloroethylene (TCE), perchlorethylene (PCE), and other industrial chemicals through groundwater and air emissions from several industrial facilities in a town in upstate New York.

Previous studies suggested the chemicals were associated with increases in the incidence of kidney, lung, and testicular cancer in the community. So researchers initiated a study of current and former workers of the local microelectronics and business machine facility.

Patient population

Sharon R. Silver, of the National Institute for Occupational Safety and Health in Cincinnati, Ohio, and her colleagues examined health outcomes among 34,494 former workers employed at the facility for at least 91 days between 1969 and 2001.

Machining workers were exposed to dust, noise, solvents, and metals. And “wet” process workers were exposed to chemical solutions used in manufacturing circuit boards and their substrates. The facility also had employees in non-production roles, including sales and office support, as well as computer programming.

The researchers evaluated the relationship between health outcomes and the estimated cumulative extent of potential chemical exposures, stratified according to gender and pay code.

Of the 34,494 workers, 69.7% were male. Among males, 15,447 were hourly workers, and 8590 were salaried. Among females, 8934 were hourly workers, and 1523 were salaried.

Chemical exposure

A previous study of this population revealed the use of 6 chemical agents (fiberglass, lead, methylene chloride, methyl chloroform, PCE, and TCE), 6 chemical classes (acid-base, aromatic hydrocarbons, chlorinated hydrocarbons, other hydrocarbons, chlorofluorocarbons, and metals), and general chemicals (including unspecified).

The potential for exposure to a chemical agent or class was much more common among hourly workers than salaried workers. Among males, 65.7% of hourly workers and 20% of salaried workers were exposed to at least 1 of the chemicals studied. Among females, exposure rates were 58.5% and 13.9%, respectively.

“Other hydrocarbons” was the chemical class that male hourly workers were potentially exposed to most often (60.5%). At least one-third of workers in this group had potential exposure to chlorinated hydrocarbons, lead, and acids and bases. TCE and PCE were the least common exposure agents among male hourly workers, with 13.9% and 15.1% exposed, respectively.

Cancer mortality, incidence

The investigators used mortality rates from the US population, as well as New York State (excluding New York City), to calculate the number of expected deaths among study participants. The standardized mortality ratio (SMR) is the ratio of observed to expected deaths.

The average follow-up was 25.7 years. By the study end date, 5966 workers (17.3%) had died. Workers employed less than a year at the facility (n=8397) comprised 363 of these deaths.

Both all-cause mortality (SMR=0.67) and all-cancer mortality (SMR=0.74) showed a statistically significant deficit for the entire workforce. Most of the individual cancers and other conditions studied were not associated with an increased risk of death.

There were significant increases in death for certain cancers among males, but there was no significant increase in a specific cause of death among females belonging to either pay code.

There was an increased risk of death from NHL among male hourly workers but not salaried workers, with SMRs of 1.49 and 0.68, respectively. The same pattern occurred for rectal cancer, with SMRs of 1.71 and 0.71, respectively.

The study also revealed an elevated incidence of pleural cancers in salaried males, mesothelioma in hourly workers, and testicular cancer in salaried males.

The increase in mesothelioma and pleural cancers was seen only in workers hired before 1969, which would support a link between the cancers and asbestos exposure. However, the researchers could find no evidence that asbestos was used in manufacturing at the facility.

Similarly, the investigators found no significant link between exposure to specific chemicals and the increased mortality from NHL or rectal cancer. And there was no significant link between exposure and testicular cancer.

Although these results do not suggest a strong role for occupational chemical exposures in cancer incidence and mortality, the researchers said risks from occupational exposures cannot be ruled out due to limitations of this study and the relative youth of this patient cohort.

Printed circuit board

Researchers have found evidence suggesting that men who work in microelectronics and business machine facilities may have an increased risk of dying from certain cancers, including non-Hodgkin lymphoma (NHL).

Their study, published in the American Journal of Industrial Medicine, was designed to assess the effects chemical exposure might have on the incidence of diseases and worker mortality.

The results showed that hourly male workers, who were more likely than other employees to be exposed to the chemicals studied, had a 1.5-fold increased risk of death from NHL.

However, the investigators did not observe a significant relationship between NHL and any of the chemicals studied.

This research originated from concerns about the release of trichloroethylene (TCE), perchlorethylene (PCE), and other industrial chemicals through groundwater and air emissions from several industrial facilities in a town in upstate New York.

Previous studies suggested the chemicals were associated with increases in the incidence of kidney, lung, and testicular cancer in the community. So researchers initiated a study of current and former workers of the local microelectronics and business machine facility.

Patient population

Sharon R. Silver, of the National Institute for Occupational Safety and Health in Cincinnati, Ohio, and her colleagues examined health outcomes among 34,494 former workers employed at the facility for at least 91 days between 1969 and 2001.

Machining workers were exposed to dust, noise, solvents, and metals. And “wet” process workers were exposed to chemical solutions used in manufacturing circuit boards and their substrates. The facility also had employees in non-production roles, including sales and office support, as well as computer programming.

The researchers evaluated the relationship between health outcomes and the estimated cumulative extent of potential chemical exposures, stratified according to gender and pay code.

Of the 34,494 workers, 69.7% were male. Among males, 15,447 were hourly workers, and 8590 were salaried. Among females, 8934 were hourly workers, and 1523 were salaried.

Chemical exposure

A previous study of this population revealed the use of 6 chemical agents (fiberglass, lead, methylene chloride, methyl chloroform, PCE, and TCE), 6 chemical classes (acid-base, aromatic hydrocarbons, chlorinated hydrocarbons, other hydrocarbons, chlorofluorocarbons, and metals), and general chemicals (including unspecified).

The potential for exposure to a chemical agent or class was much more common among hourly workers than salaried workers. Among males, 65.7% of hourly workers and 20% of salaried workers were exposed to at least 1 of the chemicals studied. Among females, exposure rates were 58.5% and 13.9%, respectively.

“Other hydrocarbons” was the chemical class that male hourly workers were potentially exposed to most often (60.5%). At least one-third of workers in this group had potential exposure to chlorinated hydrocarbons, lead, and acids and bases. TCE and PCE were the least common exposure agents among male hourly workers, with 13.9% and 15.1% exposed, respectively.

Cancer mortality, incidence

The investigators used mortality rates from the US population, as well as New York State (excluding New York City), to calculate the number of expected deaths among study participants. The standardized mortality ratio (SMR) is the ratio of observed to expected deaths.

The average follow-up was 25.7 years. By the study end date, 5966 workers (17.3%) had died. Workers employed less than a year at the facility (n=8397) comprised 363 of these deaths.

Both all-cause mortality (SMR=0.67) and all-cancer mortality (SMR=0.74) showed a statistically significant deficit for the entire workforce. Most of the individual cancers and other conditions studied were not associated with an increased risk of death.

There were significant increases in death for certain cancers among males, but there was no significant increase in a specific cause of death among females belonging to either pay code.

There was an increased risk of death from NHL among male hourly workers but not salaried workers, with SMRs of 1.49 and 0.68, respectively. The same pattern occurred for rectal cancer, with SMRs of 1.71 and 0.71, respectively.

The study also revealed an elevated incidence of pleural cancers in salaried males, mesothelioma in hourly workers, and testicular cancer in salaried males.

The increase in mesothelioma and pleural cancers was seen only in workers hired before 1969, which would support a link between the cancers and asbestos exposure. However, the researchers could find no evidence that asbestos was used in manufacturing at the facility.

Similarly, the investigators found no significant link between exposure to specific chemicals and the increased mortality from NHL or rectal cancer. And there was no significant link between exposure and testicular cancer.

Although these results do not suggest a strong role for occupational chemical exposures in cancer incidence and mortality, the researchers said risks from occupational exposures cannot be ruled out due to limitations of this study and the relative youth of this patient cohort.

CT scan showing a pulmonary

embolism; Credit: Medical

College of Georgia

Incorporating age into D-dimer test results can help clinicians more accurately diagnose pulmonary embolism (PE) in older patients, according to a new study.

Adjusting the D-dimer cutoff between abnormal and normal results according to a patient’s age allowed researchers to better differentiate healthy patients from those with PE.

The method did prove ineffective in 1 patient, who was ultimately diagnosed with venous thromboembolism (VTE).

But the remaining 300 patients who had D-dimer levels above the standard cutoff and below their age-adjusted cutoff were VTE-free during follow-up.

And among patients aged 75 and older, the age-adjusted cutoff safely excluded PE in about 30% of patients, whereas the standard cutoff excluded PE in about 6%.

Marc Righini, MD, of Geneva University Hospital in Switzerland, and his colleagues conducted this research and described their results in JAMA.

Previous studies showed that D-dimer levels increase with age. So the proportion of healthy patients with abnormal test results (above 500 µg/L for most tests) increases with age, and this limits the test’s utility in older patients.

Therefore, Dr Righini and his colleagues decided to determine whether an age-adjusted D-dimer threshold could safely exclude the diagnosis of PE in older patients. The team changed the cutoff between abnormal and normal results by multiplying the patient’s age by 10 in those 50 years or older.

The study included 3324 patients with suspected PE who first underwent a clinical probability assessment using either the simplified, revised Geneva score or the 2-level Wells score for PE.

If patients had a high clinical probability of PE (n=426), they underwent computed tomography pulmonary angiography (CTPA) and received treatment according to the results.

If PE was deemed unlikely, patients had a D-dimer test. Of these 2898 patients, 817 had normal results (< 500 μg/L), 337 had D-dimer levels ≥ 500 μg/L but below their age-adjusted cutoff, and 1744 had results higher than their age-adjusted cutoff.

Those 1744 patients joined the group of 426 who underwent CTPA (n=2170), and 631 of them were diagnosed with PE.

Of the 1539 patients who were not diagnosed with PE, 1481 completed the 3-month follow-up without receiving anticoagulant therapy. During that time, 7 of those patients had a confirmed VTE.

Of the 337 patients who had D-dimer levels ≥ 500 μg/L but below their age-adjusted cutoff, 331 completed follow-up without anticoagulation. And 1 of those patients was diagnosed with a VTE during that time.

Similarly, of the 817 patients who had normal D-dimer results, 810 completed follow-up without anticoagulation, and 1 patient was diagnosed with VTE.

So the age-adjusted D-dimer test and clinical probability assessment proved largely effective in identifying those patients at risk of VTE. But it also increased the proportion of elderly patients in whom PE could be safely excluded without further imaging.

Among the 766 patients aged 75 and older, 673 did not have a high clinical probability of PE. And using the age-adjusted cutoff instead of the 500 μg/L cutoff increased the proportion of patients in whom PE could be excluded from 6.4% (43/673) to 29.7% (200/673), without any additional false-negative findings.

The researchers said future studies should assess the utility of the age-adjusted D-dimer cutoff in clinical practice. It remains to be seen whether this method can decrease costs or improve the quality of care.

CT scan showing a pulmonary

embolism; Credit: Medical

College of Georgia

Incorporating age into D-dimer test results can help clinicians more accurately diagnose pulmonary embolism (PE) in older patients, according to a new study.

Adjusting the D-dimer cutoff between abnormal and normal results according to a patient’s age allowed researchers to better differentiate healthy patients from those with PE.

The method did prove ineffective in 1 patient, who was ultimately diagnosed with venous thromboembolism (VTE).

But the remaining 300 patients who had D-dimer levels above the standard cutoff and below their age-adjusted cutoff were VTE-free during follow-up.

And among patients aged 75 and older, the age-adjusted cutoff safely excluded PE in about 30% of patients, whereas the standard cutoff excluded PE in about 6%.

Marc Righini, MD, of Geneva University Hospital in Switzerland, and his colleagues conducted this research and described their results in JAMA.

Previous studies showed that D-dimer levels increase with age. So the proportion of healthy patients with abnormal test results (above 500 µg/L for most tests) increases with age, and this limits the test’s utility in older patients.

Therefore, Dr Righini and his colleagues decided to determine whether an age-adjusted D-dimer threshold could safely exclude the diagnosis of PE in older patients. The team changed the cutoff between abnormal and normal results by multiplying the patient’s age by 10 in those 50 years or older.

The study included 3324 patients with suspected PE who first underwent a clinical probability assessment using either the simplified, revised Geneva score or the 2-level Wells score for PE.

If patients had a high clinical probability of PE (n=426), they underwent computed tomography pulmonary angiography (CTPA) and received treatment according to the results.

If PE was deemed unlikely, patients had a D-dimer test. Of these 2898 patients, 817 had normal results (< 500 μg/L), 337 had D-dimer levels ≥ 500 μg/L but below their age-adjusted cutoff, and 1744 had results higher than their age-adjusted cutoff.

Those 1744 patients joined the group of 426 who underwent CTPA (n=2170), and 631 of them were diagnosed with PE.

Of the 1539 patients who were not diagnosed with PE, 1481 completed the 3-month follow-up without receiving anticoagulant therapy. During that time, 7 of those patients had a confirmed VTE.

Of the 337 patients who had D-dimer levels ≥ 500 μg/L but below their age-adjusted cutoff, 331 completed follow-up without anticoagulation. And 1 of those patients was diagnosed with a VTE during that time.

Similarly, of the 817 patients who had normal D-dimer results, 810 completed follow-up without anticoagulation, and 1 patient was diagnosed with VTE.

So the age-adjusted D-dimer test and clinical probability assessment proved largely effective in identifying those patients at risk of VTE. But it also increased the proportion of elderly patients in whom PE could be safely excluded without further imaging.

Among the 766 patients aged 75 and older, 673 did not have a high clinical probability of PE. And using the age-adjusted cutoff instead of the 500 μg/L cutoff increased the proportion of patients in whom PE could be excluded from 6.4% (43/673) to 29.7% (200/673), without any additional false-negative findings.

The researchers said future studies should assess the utility of the age-adjusted D-dimer cutoff in clinical practice. It remains to be seen whether this method can decrease costs or improve the quality of care.

CT scan showing a pulmonary

embolism; Credit: Medical

College of Georgia

Incorporating age into D-dimer test results can help clinicians more accurately diagnose pulmonary embolism (PE) in older patients, according to a new study.

Adjusting the D-dimer cutoff between abnormal and normal results according to a patient’s age allowed researchers to better differentiate healthy patients from those with PE.

The method did prove ineffective in 1 patient, who was ultimately diagnosed with venous thromboembolism (VTE).

But the remaining 300 patients who had D-dimer levels above the standard cutoff and below their age-adjusted cutoff were VTE-free during follow-up.

And among patients aged 75 and older, the age-adjusted cutoff safely excluded PE in about 30% of patients, whereas the standard cutoff excluded PE in about 6%.

Marc Righini, MD, of Geneva University Hospital in Switzerland, and his colleagues conducted this research and described their results in JAMA.

Previous studies showed that D-dimer levels increase with age. So the proportion of healthy patients with abnormal test results (above 500 µg/L for most tests) increases with age, and this limits the test’s utility in older patients.

Therefore, Dr Righini and his colleagues decided to determine whether an age-adjusted D-dimer threshold could safely exclude the diagnosis of PE in older patients. The team changed the cutoff between abnormal and normal results by multiplying the patient’s age by 10 in those 50 years or older.

The study included 3324 patients with suspected PE who first underwent a clinical probability assessment using either the simplified, revised Geneva score or the 2-level Wells score for PE.

If patients had a high clinical probability of PE (n=426), they underwent computed tomography pulmonary angiography (CTPA) and received treatment according to the results.

If PE was deemed unlikely, patients had a D-dimer test. Of these 2898 patients, 817 had normal results (< 500 μg/L), 337 had D-dimer levels ≥ 500 μg/L but below their age-adjusted cutoff, and 1744 had results higher than their age-adjusted cutoff.

Those 1744 patients joined the group of 426 who underwent CTPA (n=2170), and 631 of them were diagnosed with PE.

Of the 1539 patients who were not diagnosed with PE, 1481 completed the 3-month follow-up without receiving anticoagulant therapy. During that time, 7 of those patients had a confirmed VTE.

Of the 337 patients who had D-dimer levels ≥ 500 μg/L but below their age-adjusted cutoff, 331 completed follow-up without anticoagulation. And 1 of those patients was diagnosed with a VTE during that time.

Similarly, of the 817 patients who had normal D-dimer results, 810 completed follow-up without anticoagulation, and 1 patient was diagnosed with VTE.

So the age-adjusted D-dimer test and clinical probability assessment proved largely effective in identifying those patients at risk of VTE. But it also increased the proportion of elderly patients in whom PE could be safely excluded without further imaging.

Among the 766 patients aged 75 and older, 673 did not have a high clinical probability of PE. And using the age-adjusted cutoff instead of the 500 μg/L cutoff increased the proportion of patients in whom PE could be excluded from 6.4% (43/673) to 29.7% (200/673), without any additional false-negative findings.

The researchers said future studies should assess the utility of the age-adjusted D-dimer cutoff in clinical practice. It remains to be seen whether this method can decrease costs or improve the quality of care.

Prescription medications

Credit: CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending against the use of lenalidomide (Revlimid) in multiple myeloma (MM) patients who have previously received bortezomib.

Based on current information, NICE has said it cannot recommend the drug for patients who have received bortezomib once and are unable to receive thalidomide or undergo hematopoietic stem cell transplant.

NICE’s previous recommendation regarding lenalidomide in MM has not changed. The drug will still be available through the National Health Service (NHS) for MM patients who have received 2 or more prior therapies.

“We are now looking specifically at how well lenalidomide works after someone has received bortezomib, and whether it provides value for money,” said Sir Andrew Dillon, NICE Chief Executive.

“However, from the information provided by the manufacturer, it was unclear if lenalidomide was as effective as re-treatment with bortezomib, and the manufacturer’s own economic model showed that the drug would not be cost effective at this stage.”

“Because of this, we are unable to recommend the drug in preliminary recommendations. We hope that the manufacturer, Celgene, will look again at their submission.”

NICE also pointed out that, since the organization recommended lenalidomide for MM in 2009, there have been no studies comparing lenalidomide to other treatments in these patients. Celgene has only provided data comparing lenalidomide to placebo.

In addition, for the 2009 guidance, Celgene submitted a patient access scheme, where they bear the costs of the drug beyond 26 cycles (normally for a period of 2 years). And this enabled NICE to recommend the drug. But Celgene has not submitted a patient access scheme for the current appraisal.

NICE considered all the cost effectiveness models Celgene submitted to be fundamentally flawed.

NICE concluded that the most plausible costs per quality-adjusted life-year for lenalidomide compared with bortezomib or standard chemotherapies were more than £30,000, whether bortezomib re-treatment was appropriate or not.

Lenalidomide is available as a 21-capsule pack. The cost per pack varies according to capsule size: £3570 (5 mg), £3780 (10 mg), £3969 (15 mg), and £4368 (25 mg). The recommended starting dose is 25 mg orally, once daily on days 1-21 of repeated 28-day cycles.

The draft guidance is open for public comment until April 4. Until a final guidance is issued, NHS bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance, it replaces local recommendations.

Prescription medications

Credit: CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending against the use of lenalidomide (Revlimid) in multiple myeloma (MM) patients who have previously received bortezomib.

Based on current information, NICE has said it cannot recommend the drug for patients who have received bortezomib once and are unable to receive thalidomide or undergo hematopoietic stem cell transplant.

NICE’s previous recommendation regarding lenalidomide in MM has not changed. The drug will still be available through the National Health Service (NHS) for MM patients who have received 2 or more prior therapies.

“We are now looking specifically at how well lenalidomide works after someone has received bortezomib, and whether it provides value for money,” said Sir Andrew Dillon, NICE Chief Executive.

“However, from the information provided by the manufacturer, it was unclear if lenalidomide was as effective as re-treatment with bortezomib, and the manufacturer’s own economic model showed that the drug would not be cost effective at this stage.”

“Because of this, we are unable to recommend the drug in preliminary recommendations. We hope that the manufacturer, Celgene, will look again at their submission.”

NICE also pointed out that, since the organization recommended lenalidomide for MM in 2009, there have been no studies comparing lenalidomide to other treatments in these patients. Celgene has only provided data comparing lenalidomide to placebo.

In addition, for the 2009 guidance, Celgene submitted a patient access scheme, where they bear the costs of the drug beyond 26 cycles (normally for a period of 2 years). And this enabled NICE to recommend the drug. But Celgene has not submitted a patient access scheme for the current appraisal.

NICE considered all the cost effectiveness models Celgene submitted to be fundamentally flawed.

NICE concluded that the most plausible costs per quality-adjusted life-year for lenalidomide compared with bortezomib or standard chemotherapies were more than £30,000, whether bortezomib re-treatment was appropriate or not.

Lenalidomide is available as a 21-capsule pack. The cost per pack varies according to capsule size: £3570 (5 mg), £3780 (10 mg), £3969 (15 mg), and £4368 (25 mg). The recommended starting dose is 25 mg orally, once daily on days 1-21 of repeated 28-day cycles.

The draft guidance is open for public comment until April 4. Until a final guidance is issued, NHS bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance, it replaces local recommendations.

Prescription medications

Credit: CDC

The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending against the use of lenalidomide (Revlimid) in multiple myeloma (MM) patients who have previously received bortezomib.

Based on current information, NICE has said it cannot recommend the drug for patients who have received bortezomib once and are unable to receive thalidomide or undergo hematopoietic stem cell transplant.

NICE’s previous recommendation regarding lenalidomide in MM has not changed. The drug will still be available through the National Health Service (NHS) for MM patients who have received 2 or more prior therapies.

“We are now looking specifically at how well lenalidomide works after someone has received bortezomib, and whether it provides value for money,” said Sir Andrew Dillon, NICE Chief Executive.

“However, from the information provided by the manufacturer, it was unclear if lenalidomide was as effective as re-treatment with bortezomib, and the manufacturer’s own economic model showed that the drug would not be cost effective at this stage.”

“Because of this, we are unable to recommend the drug in preliminary recommendations. We hope that the manufacturer, Celgene, will look again at their submission.”

NICE also pointed out that, since the organization recommended lenalidomide for MM in 2009, there have been no studies comparing lenalidomide to other treatments in these patients. Celgene has only provided data comparing lenalidomide to placebo.

In addition, for the 2009 guidance, Celgene submitted a patient access scheme, where they bear the costs of the drug beyond 26 cycles (normally for a period of 2 years). And this enabled NICE to recommend the drug. But Celgene has not submitted a patient access scheme for the current appraisal.

NICE considered all the cost effectiveness models Celgene submitted to be fundamentally flawed.

NICE concluded that the most plausible costs per quality-adjusted life-year for lenalidomide compared with bortezomib or standard chemotherapies were more than £30,000, whether bortezomib re-treatment was appropriate or not.

Lenalidomide is available as a 21-capsule pack. The cost per pack varies according to capsule size: £3570 (5 mg), £3780 (10 mg), £3969 (15 mg), and £4368 (25 mg). The recommended starting dose is 25 mg orally, once daily on days 1-21 of repeated 28-day cycles.

The draft guidance is open for public comment until April 4. Until a final guidance is issued, NHS bodies should make decisions locally on the funding of specific treatments. Once NICE issues its final guidance, it replaces local recommendations.

Hemangioma on an

infant’s stomach

The US Food and Drug Administration has approved oral propranolol hydrochloride (Hemangeol) to treat proliferating infantile hemangiomas that require systemic therapy.

The drug, which is also under review in the European Union, will be available in the US in June.

Infantile hemangioma is the most common vascular benign tumor of infancy, affecting 3% to 10% of newborns. The lesions are rarely detectable at birth and start growing noticeably in the first 4 to 6 weeks of life.

While most infantile hemangiomas do not require treatment, approximately 12% do. Depending upon their location, infantile hemangiomas might impair breathing, eating, or vision, or become life-threatening.

Propranolol has long been used in cardiology, but its use in infantile hemangiomas is relatively new. In 2007, Christine Léauté-Labreze, MD, a dermatologist at the Bordeaux University Hospital in France, discovered that propranolol could treat infantile hemangiomas.

Since then, the drug has been used for this indication off-label. And in 2009, Pierre Fabre Dermatologie began developing propranolol hydrochloride for use in infantile hemangiomas.

In a study of 32 children, propranolol slowed the growth of infantile hemangiomas in 100% of patients. Patients had received propranolol at 2 to 3 mg/kg per day for a median of 6.1 months. Side effects were “limited and mild,” according to researchers (V Sans et al. Pediatrics 2009).

Researchers also conducted a randomized, controlled trial of the drug in infants 5 weeks to 5 months old at therapy initiation. The team compared 4 propranolol treatment protocols (1 or 3 mg/kg/day for 3 or 6 months) to placebo.

Propranolol at a daily dose of 3 mg/kg for 6 months had a 60.4% success rate, compared to 3.6% in the placebo group (P<0.0001). Success was defined as complete or nearly complete resolution of the target hemangioma. However, 11.4% of patients needed to be re-treated after stopping propranolol.

The drug is contraindicated in premature infants who have a corrected age of less than 5 weeks, weight less than 2 kg, known hypersensitivity to propranolol or any of its excipients, asthma or a history of bronchospasm, pheochromocytoma, blood pressure less than 50/30 mmHg, a heart rate less than 80 beats per minute, greater than first degree heart block, or decompensated heart failure.

Propranolol hydrochloride can cause serious side effects, including hypoglycemia, bradycardia, hypotension, and bronchospasm. The drug can worsen congestive heart failure and may increase the risk of stroke in children with PHACE syndrome.

The most frequently reported adverse reactions, occurring in more than 10% of infants receiving propranolol hydrochloride, were sleep disorders, diarrhea, vomiting, and aggravated respiratory tract infections, such as bronchitis and bronchiolitis associated with cough and fever. Adverse reactions led to treatment discontinuation in fewer than 2% of treated patients.

Hemangioma on an

infant’s stomach

The US Food and Drug Administration has approved oral propranolol hydrochloride (Hemangeol) to treat proliferating infantile hemangiomas that require systemic therapy.

The drug, which is also under review in the European Union, will be available in the US in June.

Infantile hemangioma is the most common vascular benign tumor of infancy, affecting 3% to 10% of newborns. The lesions are rarely detectable at birth and start growing noticeably in the first 4 to 6 weeks of life.

While most infantile hemangiomas do not require treatment, approximately 12% do. Depending upon their location, infantile hemangiomas might impair breathing, eating, or vision, or become life-threatening.

Propranolol has long been used in cardiology, but its use in infantile hemangiomas is relatively new. In 2007, Christine Léauté-Labreze, MD, a dermatologist at the Bordeaux University Hospital in France, discovered that propranolol could treat infantile hemangiomas.

Since then, the drug has been used for this indication off-label. And in 2009, Pierre Fabre Dermatologie began developing propranolol hydrochloride for use in infantile hemangiomas.

In a study of 32 children, propranolol slowed the growth of infantile hemangiomas in 100% of patients. Patients had received propranolol at 2 to 3 mg/kg per day for a median of 6.1 months. Side effects were “limited and mild,” according to researchers (V Sans et al. Pediatrics 2009).

Researchers also conducted a randomized, controlled trial of the drug in infants 5 weeks to 5 months old at therapy initiation. The team compared 4 propranolol treatment protocols (1 or 3 mg/kg/day for 3 or 6 months) to placebo.

Propranolol at a daily dose of 3 mg/kg for 6 months had a 60.4% success rate, compared to 3.6% in the placebo group (P<0.0001). Success was defined as complete or nearly complete resolution of the target hemangioma. However, 11.4% of patients needed to be re-treated after stopping propranolol.

The drug is contraindicated in premature infants who have a corrected age of less than 5 weeks, weight less than 2 kg, known hypersensitivity to propranolol or any of its excipients, asthma or a history of bronchospasm, pheochromocytoma, blood pressure less than 50/30 mmHg, a heart rate less than 80 beats per minute, greater than first degree heart block, or decompensated heart failure.

Propranolol hydrochloride can cause serious side effects, including hypoglycemia, bradycardia, hypotension, and bronchospasm. The drug can worsen congestive heart failure and may increase the risk of stroke in children with PHACE syndrome.

The most frequently reported adverse reactions, occurring in more than 10% of infants receiving propranolol hydrochloride, were sleep disorders, diarrhea, vomiting, and aggravated respiratory tract infections, such as bronchitis and bronchiolitis associated with cough and fever. Adverse reactions led to treatment discontinuation in fewer than 2% of treated patients.

Hemangioma on an

infant’s stomach

The US Food and Drug Administration has approved oral propranolol hydrochloride (Hemangeol) to treat proliferating infantile hemangiomas that require systemic therapy.

The drug, which is also under review in the European Union, will be available in the US in June.

Infantile hemangioma is the most common vascular benign tumor of infancy, affecting 3% to 10% of newborns. The lesions are rarely detectable at birth and start growing noticeably in the first 4 to 6 weeks of life.

While most infantile hemangiomas do not require treatment, approximately 12% do. Depending upon their location, infantile hemangiomas might impair breathing, eating, or vision, or become life-threatening.

Propranolol has long been used in cardiology, but its use in infantile hemangiomas is relatively new. In 2007, Christine Léauté-Labreze, MD, a dermatologist at the Bordeaux University Hospital in France, discovered that propranolol could treat infantile hemangiomas.

Since then, the drug has been used for this indication off-label. And in 2009, Pierre Fabre Dermatologie began developing propranolol hydrochloride for use in infantile hemangiomas.

In a study of 32 children, propranolol slowed the growth of infantile hemangiomas in 100% of patients. Patients had received propranolol at 2 to 3 mg/kg per day for a median of 6.1 months. Side effects were “limited and mild,” according to researchers (V Sans et al. Pediatrics 2009).

Researchers also conducted a randomized, controlled trial of the drug in infants 5 weeks to 5 months old at therapy initiation. The team compared 4 propranolol treatment protocols (1 or 3 mg/kg/day for 3 or 6 months) to placebo.

Propranolol at a daily dose of 3 mg/kg for 6 months had a 60.4% success rate, compared to 3.6% in the placebo group (P<0.0001). Success was defined as complete or nearly complete resolution of the target hemangioma. However, 11.4% of patients needed to be re-treated after stopping propranolol.

The drug is contraindicated in premature infants who have a corrected age of less than 5 weeks, weight less than 2 kg, known hypersensitivity to propranolol or any of its excipients, asthma or a history of bronchospasm, pheochromocytoma, blood pressure less than 50/30 mmHg, a heart rate less than 80 beats per minute, greater than first degree heart block, or decompensated heart failure.

Propranolol hydrochloride can cause serious side effects, including hypoglycemia, bradycardia, hypotension, and bronchospasm. The drug can worsen congestive heart failure and may increase the risk of stroke in children with PHACE syndrome.

The most frequently reported adverse reactions, occurring in more than 10% of infants receiving propranolol hydrochloride, were sleep disorders, diarrhea, vomiting, and aggravated respiratory tract infections, such as bronchitis and bronchiolitis associated with cough and fever. Adverse reactions led to treatment discontinuation in fewer than 2% of treated patients.

MILAN – Pazopanib, which received U.S. approval in 2012 for treating advanced soft-tissue sarcomas, can be very effective for durably halting tumor progression in a significant minority of sarcoma patients but requires close monitoring for adverse effects.

"Although the overall response rate is low, some patients experience important palliation of symptoms and prolonged disease control" from treatment with pazotinib (Votrient), Dr. Ian R. Judson said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

"We see a number of adverse effects [from pazopanib treatment] that need careful monitoring, particularly fatigue, diarrhea, nausea, and weight loss," adverse effects that had previously been seen in patients with other tumor types treated with the drug, said Dr. Judson, professor of cancer pharmacology and head of the sarcoma unit at the Royal Marsden Hospital, London. Results from the phase III trial of pazopanib in patients with advanced soft-tissue sarcoma with a history of chemotherapy, also showed that the drug can cause other, previously unreported adverse effects: myocardial dysfunction, an increased risk for venous thromboembolism, and the possibility for some patients to develop pneumothorax (Lancet 2012;379:1879-86).

The upside of pazopanib treatment is that it can produce "clear and dramatic" increases in progression-free survival and "durable, stable disease" in certain patients, said Dr. Judson.

Pazopanib became the first tyrosine kinase inhibitor to receive approval from the Food and Drug Administration and other regulatory agencies for treating soft tissue sarcomas (STS), although it has not been proven effective for treating adipocyte STS and is also not indicated for gastrointestinal stromal tumors. But it remains unclear which patients with other types of STS will respond to pazopanib and which won’t. "I wish we knew what the molecular target for this drug really is," Dr. Judson said.

Mitchel L. Zoler/Frontline Medical News

A recently published analysis retrospectively pooled data from 118 STS patients enrolled in a phase II study of pazopanib and 226 patients from the phase III study PALETTE (Pazopanib for Metastatic Soft Tissue Sarcoma). The analysis showed that 36% of the entire group of patients on pazopanib were long-term responders to the drug, defined as having progression-free survival for at least 6 months following the start of pazopanib treatment, and 34% of patients on the drug were long-term survivors on the drug, defined as living for at least 18 months on treatment, noted Dr. Shreyaskumar R. Patel in a talk at the conference (Ann. Oncol. 2014;25:719-24).

During an overall median follow-up of 2.3 years in the two studies, 76 patients (22%) were both long-term responders and long-term survivors. Twelve patients remained on pazopanib treatment for more than 2 years, with a median time on treatment of 2.4 years, and 1 patient from the combined groups stayed on pazopanib for as long as 3.7 years, said Dr. Patel, professor and deputy chair of the department of sarcoma medical oncology at M.D. Anderson Cancer Center, Houston.

"Pazopanib is probably my second-line choice" for treating advanced STS, "particularly synovial sarcomas" after treatment with doxorubicin (Adriamycin) and ifosfamide (Ifex) fails, said Dr. Robert S. Benjamin, professor and chair of sarcoma medical oncology at M.D. Anderson.

The pazopanib trials were sponsored by GlaxoSmithKline, which markets pazopanib. Dr. Judson said that he has received honoraria from GlaxoSmithKline and Novartis, and research support from GlaxoSmithKline, AstraZeneca, and other companies. Dr. Patel said that he has received honoraria or consulting fees from GlaxoSmithKline, Novartis, and Johnson & Johnson, and research support from Johnson & Johnson, PharmaMar, and other companies. Dr. Benjamin said that he has received research support from Johnson & Johnson, Merck, and Pfizer.

[email protected] Twitter: @mitchelzoler

MILAN – Pazopanib, which received U.S. approval in 2012 for treating advanced soft-tissue sarcomas, can be very effective for durably halting tumor progression in a significant minority of sarcoma patients but requires close monitoring for adverse effects.

"Although the overall response rate is low, some patients experience important palliation of symptoms and prolonged disease control" from treatment with pazotinib (Votrient), Dr. Ian R. Judson said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

"We see a number of adverse effects [from pazopanib treatment] that need careful monitoring, particularly fatigue, diarrhea, nausea, and weight loss," adverse effects that had previously been seen in patients with other tumor types treated with the drug, said Dr. Judson, professor of cancer pharmacology and head of the sarcoma unit at the Royal Marsden Hospital, London. Results from the phase III trial of pazopanib in patients with advanced soft-tissue sarcoma with a history of chemotherapy, also showed that the drug can cause other, previously unreported adverse effects: myocardial dysfunction, an increased risk for venous thromboembolism, and the possibility for some patients to develop pneumothorax (Lancet 2012;379:1879-86).

The upside of pazopanib treatment is that it can produce "clear and dramatic" increases in progression-free survival and "durable, stable disease" in certain patients, said Dr. Judson.

Pazopanib became the first tyrosine kinase inhibitor to receive approval from the Food and Drug Administration and other regulatory agencies for treating soft tissue sarcomas (STS), although it has not been proven effective for treating adipocyte STS and is also not indicated for gastrointestinal stromal tumors. But it remains unclear which patients with other types of STS will respond to pazopanib and which won’t. "I wish we knew what the molecular target for this drug really is," Dr. Judson said.

Mitchel L. Zoler/Frontline Medical News

A recently published analysis retrospectively pooled data from 118 STS patients enrolled in a phase II study of pazopanib and 226 patients from the phase III study PALETTE (Pazopanib for Metastatic Soft Tissue Sarcoma). The analysis showed that 36% of the entire group of patients on pazopanib were long-term responders to the drug, defined as having progression-free survival for at least 6 months following the start of pazopanib treatment, and 34% of patients on the drug were long-term survivors on the drug, defined as living for at least 18 months on treatment, noted Dr. Shreyaskumar R. Patel in a talk at the conference (Ann. Oncol. 2014;25:719-24).

During an overall median follow-up of 2.3 years in the two studies, 76 patients (22%) were both long-term responders and long-term survivors. Twelve patients remained on pazopanib treatment for more than 2 years, with a median time on treatment of 2.4 years, and 1 patient from the combined groups stayed on pazopanib for as long as 3.7 years, said Dr. Patel, professor and deputy chair of the department of sarcoma medical oncology at M.D. Anderson Cancer Center, Houston.

"Pazopanib is probably my second-line choice" for treating advanced STS, "particularly synovial sarcomas" after treatment with doxorubicin (Adriamycin) and ifosfamide (Ifex) fails, said Dr. Robert S. Benjamin, professor and chair of sarcoma medical oncology at M.D. Anderson.

The pazopanib trials were sponsored by GlaxoSmithKline, which markets pazopanib. Dr. Judson said that he has received honoraria from GlaxoSmithKline and Novartis, and research support from GlaxoSmithKline, AstraZeneca, and other companies. Dr. Patel said that he has received honoraria or consulting fees from GlaxoSmithKline, Novartis, and Johnson & Johnson, and research support from Johnson & Johnson, PharmaMar, and other companies. Dr. Benjamin said that he has received research support from Johnson & Johnson, Merck, and Pfizer.

[email protected] Twitter: @mitchelzoler

MILAN – Pazopanib, which received U.S. approval in 2012 for treating advanced soft-tissue sarcomas, can be very effective for durably halting tumor progression in a significant minority of sarcoma patients but requires close monitoring for adverse effects.

"Although the overall response rate is low, some patients experience important palliation of symptoms and prolonged disease control" from treatment with pazotinib (Votrient), Dr. Ian R. Judson said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology.

"We see a number of adverse effects [from pazopanib treatment] that need careful monitoring, particularly fatigue, diarrhea, nausea, and weight loss," adverse effects that had previously been seen in patients with other tumor types treated with the drug, said Dr. Judson, professor of cancer pharmacology and head of the sarcoma unit at the Royal Marsden Hospital, London. Results from the phase III trial of pazopanib in patients with advanced soft-tissue sarcoma with a history of chemotherapy, also showed that the drug can cause other, previously unreported adverse effects: myocardial dysfunction, an increased risk for venous thromboembolism, and the possibility for some patients to develop pneumothorax (Lancet 2012;379:1879-86).

The upside of pazopanib treatment is that it can produce "clear and dramatic" increases in progression-free survival and "durable, stable disease" in certain patients, said Dr. Judson.

Pazopanib became the first tyrosine kinase inhibitor to receive approval from the Food and Drug Administration and other regulatory agencies for treating soft tissue sarcomas (STS), although it has not been proven effective for treating adipocyte STS and is also not indicated for gastrointestinal stromal tumors. But it remains unclear which patients with other types of STS will respond to pazopanib and which won’t. "I wish we knew what the molecular target for this drug really is," Dr. Judson said.

Mitchel L. Zoler/Frontline Medical News

A recently published analysis retrospectively pooled data from 118 STS patients enrolled in a phase II study of pazopanib and 226 patients from the phase III study PALETTE (Pazopanib for Metastatic Soft Tissue Sarcoma). The analysis showed that 36% of the entire group of patients on pazopanib were long-term responders to the drug, defined as having progression-free survival for at least 6 months following the start of pazopanib treatment, and 34% of patients on the drug were long-term survivors on the drug, defined as living for at least 18 months on treatment, noted Dr. Shreyaskumar R. Patel in a talk at the conference (Ann. Oncol. 2014;25:719-24).

During an overall median follow-up of 2.3 years in the two studies, 76 patients (22%) were both long-term responders and long-term survivors. Twelve patients remained on pazopanib treatment for more than 2 years, with a median time on treatment of 2.4 years, and 1 patient from the combined groups stayed on pazopanib for as long as 3.7 years, said Dr. Patel, professor and deputy chair of the department of sarcoma medical oncology at M.D. Anderson Cancer Center, Houston.

"Pazopanib is probably my second-line choice" for treating advanced STS, "particularly synovial sarcomas" after treatment with doxorubicin (Adriamycin) and ifosfamide (Ifex) fails, said Dr. Robert S. Benjamin, professor and chair of sarcoma medical oncology at M.D. Anderson.

The pazopanib trials were sponsored by GlaxoSmithKline, which markets pazopanib. Dr. Judson said that he has received honoraria from GlaxoSmithKline and Novartis, and research support from GlaxoSmithKline, AstraZeneca, and other companies. Dr. Patel said that he has received honoraria or consulting fees from GlaxoSmithKline, Novartis, and Johnson & Johnson, and research support from Johnson & Johnson, PharmaMar, and other companies. Dr. Benjamin said that he has received research support from Johnson & Johnson, Merck, and Pfizer.

[email protected] Twitter: @mitchelzoler

ORLANDO – The prevalence of pseudobulbar affect symptoms – that is, uncontrollable, disruptive outbursts of crying and/or laughing – is considerably greater across a range of neurologic disorders than previously appreciated, according to the largest-ever study to screen for this condition.

Pseudobulbar affect (PBA) symptoms were found in the study to be more common among neurology patients under age 65; however, the adverse impact of PBA symptoms upon quality of life was greater in the elderly, Dr. David W. Crumpacker reported at the annual meeting of the American Association for Geriatric Psychiatry.

The CNS-LS is a simple test that can be completed quickly by either the patient or caregiver. The test is well-suited for routine use in clinical practice, noted Dr. W. Crumpacker, a psychiatrist at Baylor University Medical Center, Dallas.

The overall prevalence of PBA symptoms among the 3,048 PRISM participants aged 65 years or older was 27.4%, with the highest rate seen in patients having ALS (see chart). In contrast, the prevalence of PBA symptoms among patients under age 65 years was 49.5%, with the highest rate – 56.9% – being seen in traumatic brain injury patients.

Patients or caregivers were asked to rate on a 0-10 scale the impact their primary neurologic disease has had on their quality of life. Patients 65 years and older with PBA symptoms reported a significantly greater negative impact than did those without PBA symptoms, with mean scores on the quality of life impact scale of 6.3 vs. 4.6. The quality of life difference between those with PBA symptoms and those without was significant for patients with each of the neurologic diseases except for ALS.

As another measure of the adverse impact of having PBA symptoms, 56% of affected older patients were on at least one antipsychotic or antidepressant, compared with 35% of older patients without PBA symptoms.

PBA is thought to result from injury to neurologic pathways that regulate emotional expression as a secondary consequence of a variety of neurologic disorders.

In an interview, Dr. Crumpacker said PBA is greatly underdiagnosed and often gets misdiagnosed as depression.

"The symptoms are extremely disturbing to others, and patients are acutely aware of that. I tell my friends in neurology, it’s the psychiatric pathology that causes people problems in their lives. No one gets divorced over neurologic pathology, they get divorced over psychiatric pathology. It’s not, ‘I got a divorce because he had a stroke.’ " "It’s "We got divorced because he had a stroke and it changed his personality; he was a different person and I couldn’t be around him anymore,’ " the psychiatrist said.

PBA became a diagnosable disorder with its own ICD-9 code, albeit a diagnosis that can’t be made in the absence of neurologic pathology, at the behest of the Food and Drug Administration, Dr. Crumpacker explained. The impetus was the discovery of an effective treatment, dextromethorphan HBr and quinidine sulfate (Nuedexta), which received FDA approval for PBA 3 years ago.

Nuedexta’s development as the sole medication indicated for PBA was serendipitous, according to Dr. Crumpacker.

"The drug was being tested in Alzheimer’s disease. The jury is still out on whether it helps. But families of study participants came back saying, ‘You know that stuff dad used to do – the crying, the inappropriate laughter, the anger? He doesn’t do those kinds of things anymore,’ " Dr. Crumpacker recalled.

He reported serving on a scientific advisory board for Avanir Pharmaceuticals, which markets Nuedexta.

[email protected]

ORLANDO – The prevalence of pseudobulbar affect symptoms – that is, uncontrollable, disruptive outbursts of crying and/or laughing – is considerably greater across a range of neurologic disorders than previously appreciated, according to the largest-ever study to screen for this condition.

Pseudobulbar affect (PBA) symptoms were found in the study to be more common among neurology patients under age 65; however, the adverse impact of PBA symptoms upon quality of life was greater in the elderly, Dr. David W. Crumpacker reported at the annual meeting of the American Association for Geriatric Psychiatry.

The CNS-LS is a simple test that can be completed quickly by either the patient or caregiver. The test is well-suited for routine use in clinical practice, noted Dr. W. Crumpacker, a psychiatrist at Baylor University Medical Center, Dallas.

The overall prevalence of PBA symptoms among the 3,048 PRISM participants aged 65 years or older was 27.4%, with the highest rate seen in patients having ALS (see chart). In contrast, the prevalence of PBA symptoms among patients under age 65 years was 49.5%, with the highest rate – 56.9% – being seen in traumatic brain injury patients.

Patients or caregivers were asked to rate on a 0-10 scale the impact their primary neurologic disease has had on their quality of life. Patients 65 years and older with PBA symptoms reported a significantly greater negative impact than did those without PBA symptoms, with mean scores on the quality of life impact scale of 6.3 vs. 4.6. The quality of life difference between those with PBA symptoms and those without was significant for patients with each of the neurologic diseases except for ALS.

As another measure of the adverse impact of having PBA symptoms, 56% of affected older patients were on at least one antipsychotic or antidepressant, compared with 35% of older patients without PBA symptoms.

PBA is thought to result from injury to neurologic pathways that regulate emotional expression as a secondary consequence of a variety of neurologic disorders.

In an interview, Dr. Crumpacker said PBA is greatly underdiagnosed and often gets misdiagnosed as depression.

"The symptoms are extremely disturbing to others, and patients are acutely aware of that. I tell my friends in neurology, it’s the psychiatric pathology that causes people problems in their lives. No one gets divorced over neurologic pathology, they get divorced over psychiatric pathology. It’s not, ‘I got a divorce because he had a stroke.’ " "It’s "We got divorced because he had a stroke and it changed his personality; he was a different person and I couldn’t be around him anymore,’ " the psychiatrist said.

PBA became a diagnosable disorder with its own ICD-9 code, albeit a diagnosis that can’t be made in the absence of neurologic pathology, at the behest of the Food and Drug Administration, Dr. Crumpacker explained. The impetus was the discovery of an effective treatment, dextromethorphan HBr and quinidine sulfate (Nuedexta), which received FDA approval for PBA 3 years ago.

Nuedexta’s development as the sole medication indicated for PBA was serendipitous, according to Dr. Crumpacker.

"The drug was being tested in Alzheimer’s disease. The jury is still out on whether it helps. But families of study participants came back saying, ‘You know that stuff dad used to do – the crying, the inappropriate laughter, the anger? He doesn’t do those kinds of things anymore,’ " Dr. Crumpacker recalled.

He reported serving on a scientific advisory board for Avanir Pharmaceuticals, which markets Nuedexta.

[email protected]

ORLANDO – The prevalence of pseudobulbar affect symptoms – that is, uncontrollable, disruptive outbursts of crying and/or laughing – is considerably greater across a range of neurologic disorders than previously appreciated, according to the largest-ever study to screen for this condition.

Pseudobulbar affect (PBA) symptoms were found in the study to be more common among neurology patients under age 65; however, the adverse impact of PBA symptoms upon quality of life was greater in the elderly, Dr. David W. Crumpacker reported at the annual meeting of the American Association for Geriatric Psychiatry.

The CNS-LS is a simple test that can be completed quickly by either the patient or caregiver. The test is well-suited for routine use in clinical practice, noted Dr. W. Crumpacker, a psychiatrist at Baylor University Medical Center, Dallas.

The overall prevalence of PBA symptoms among the 3,048 PRISM participants aged 65 years or older was 27.4%, with the highest rate seen in patients having ALS (see chart). In contrast, the prevalence of PBA symptoms among patients under age 65 years was 49.5%, with the highest rate – 56.9% – being seen in traumatic brain injury patients.

Patients or caregivers were asked to rate on a 0-10 scale the impact their primary neurologic disease has had on their quality of life. Patients 65 years and older with PBA symptoms reported a significantly greater negative impact than did those without PBA symptoms, with mean scores on the quality of life impact scale of 6.3 vs. 4.6. The quality of life difference between those with PBA symptoms and those without was significant for patients with each of the neurologic diseases except for ALS.

As another measure of the adverse impact of having PBA symptoms, 56% of affected older patients were on at least one antipsychotic or antidepressant, compared with 35% of older patients without PBA symptoms.

PBA is thought to result from injury to neurologic pathways that regulate emotional expression as a secondary consequence of a variety of neurologic disorders.

In an interview, Dr. Crumpacker said PBA is greatly underdiagnosed and often gets misdiagnosed as depression.

"The symptoms are extremely disturbing to others, and patients are acutely aware of that. I tell my friends in neurology, it’s the psychiatric pathology that causes people problems in their lives. No one gets divorced over neurologic pathology, they get divorced over psychiatric pathology. It’s not, ‘I got a divorce because he had a stroke.’ " "It’s "We got divorced because he had a stroke and it changed his personality; he was a different person and I couldn’t be around him anymore,’ " the psychiatrist said.

PBA became a diagnosable disorder with its own ICD-9 code, albeit a diagnosis that can’t be made in the absence of neurologic pathology, at the behest of the Food and Drug Administration, Dr. Crumpacker explained. The impetus was the discovery of an effective treatment, dextromethorphan HBr and quinidine sulfate (Nuedexta), which received FDA approval for PBA 3 years ago.

Nuedexta’s development as the sole medication indicated for PBA was serendipitous, according to Dr. Crumpacker.

"The drug was being tested in Alzheimer’s disease. The jury is still out on whether it helps. But families of study participants came back saying, ‘You know that stuff dad used to do – the crying, the inappropriate laughter, the anger? He doesn’t do those kinds of things anymore,’ " Dr. Crumpacker recalled.

He reported serving on a scientific advisory board for Avanir Pharmaceuticals, which markets Nuedexta.

[email protected]

When I moved to Maryland over a decade ago, my first job was at Kaiser Permanente, where I had a panel of office patients and occasionally rounded at the hospital. Ultimately, management gave us the option of being solely office-based and giving up hospital rounds or continuing to do both. Most of my colleagues jumped at the chance to give up the grueling 24-hour shifts – a full day in the office followed by in-house night call at our hospital. Ouch!

But a little voice inside my head told me not to give up my hospital skills, and I’m so glad I listened. Little did I know that I would soon be offered a full-time hospitalist position. What a lifestyle change! I went from working Monday through Friday with occasional weekend and night shifts, counting the months until my next vacation, to working block shifts and having "vacation" time every month. What’s more, unlike my days in private practice, when I often struggled to make ends meet, I could count on a steady paycheck.

And while many of our office-based colleagues currently thrive in primary care, the Affordable Care Act has made many rethink their future. The ACA has ushered in new payment rates and regulations that make it more challenging for some small practices to stay afloat, and impossible for others.

Since the ACA was passed in 2010, many hospitals have aggressively pursued and acquired physician practices, which allows them to reap the benefits of some incentives available under the Affordable Care Act, potentially a win-win for hospitals and struggling physicians alike. In addition, many primary care physicians have joined independent accountable care organizations to mitigate the challenges and reap the potential rewards of the ACA.

But this is only the tip of the iceberg. For instance, in its recently released 2015 budget request, the administration proposed cutting an additional $2 billion from health care through decreased payments to rural hospitals, reductions to postacute care, and reimbursements for care given to those Medicare beneficiaries whose bills go unpaid. Meanwhile, the Federation of American Hospitals, an organization representing over 1,000 providers of health care, is working on a study it hopes will help persuade lawmakers to forgo the proposed cuts.

In this seemingly never-ending flux of our new health care system, it appears that we hospitalists, for the moment, are faring quite well. And, relatively unburdened by these forces of flux, we are free to focus our energies on top-notch patient care.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.

When I moved to Maryland over a decade ago, my first job was at Kaiser Permanente, where I had a panel of office patients and occasionally rounded at the hospital. Ultimately, management gave us the option of being solely office-based and giving up hospital rounds or continuing to do both. Most of my colleagues jumped at the chance to give up the grueling 24-hour shifts – a full day in the office followed by in-house night call at our hospital. Ouch!

But a little voice inside my head told me not to give up my hospital skills, and I’m so glad I listened. Little did I know that I would soon be offered a full-time hospitalist position. What a lifestyle change! I went from working Monday through Friday with occasional weekend and night shifts, counting the months until my next vacation, to working block shifts and having "vacation" time every month. What’s more, unlike my days in private practice, when I often struggled to make ends meet, I could count on a steady paycheck.

And while many of our office-based colleagues currently thrive in primary care, the Affordable Care Act has made many rethink their future. The ACA has ushered in new payment rates and regulations that make it more challenging for some small practices to stay afloat, and impossible for others.

Since the ACA was passed in 2010, many hospitals have aggressively pursued and acquired physician practices, which allows them to reap the benefits of some incentives available under the Affordable Care Act, potentially a win-win for hospitals and struggling physicians alike. In addition, many primary care physicians have joined independent accountable care organizations to mitigate the challenges and reap the potential rewards of the ACA.

But this is only the tip of the iceberg. For instance, in its recently released 2015 budget request, the administration proposed cutting an additional $2 billion from health care through decreased payments to rural hospitals, reductions to postacute care, and reimbursements for care given to those Medicare beneficiaries whose bills go unpaid. Meanwhile, the Federation of American Hospitals, an organization representing over 1,000 providers of health care, is working on a study it hopes will help persuade lawmakers to forgo the proposed cuts.

In this seemingly never-ending flux of our new health care system, it appears that we hospitalists, for the moment, are faring quite well. And, relatively unburdened by these forces of flux, we are free to focus our energies on top-notch patient care.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.

When I moved to Maryland over a decade ago, my first job was at Kaiser Permanente, where I had a panel of office patients and occasionally rounded at the hospital. Ultimately, management gave us the option of being solely office-based and giving up hospital rounds or continuing to do both. Most of my colleagues jumped at the chance to give up the grueling 24-hour shifts – a full day in the office followed by in-house night call at our hospital. Ouch!

But a little voice inside my head told me not to give up my hospital skills, and I’m so glad I listened. Little did I know that I would soon be offered a full-time hospitalist position. What a lifestyle change! I went from working Monday through Friday with occasional weekend and night shifts, counting the months until my next vacation, to working block shifts and having "vacation" time every month. What’s more, unlike my days in private practice, when I often struggled to make ends meet, I could count on a steady paycheck.

And while many of our office-based colleagues currently thrive in primary care, the Affordable Care Act has made many rethink their future. The ACA has ushered in new payment rates and regulations that make it more challenging for some small practices to stay afloat, and impossible for others.

Since the ACA was passed in 2010, many hospitals have aggressively pursued and acquired physician practices, which allows them to reap the benefits of some incentives available under the Affordable Care Act, potentially a win-win for hospitals and struggling physicians alike. In addition, many primary care physicians have joined independent accountable care organizations to mitigate the challenges and reap the potential rewards of the ACA.

But this is only the tip of the iceberg. For instance, in its recently released 2015 budget request, the administration proposed cutting an additional $2 billion from health care through decreased payments to rural hospitals, reductions to postacute care, and reimbursements for care given to those Medicare beneficiaries whose bills go unpaid. Meanwhile, the Federation of American Hospitals, an organization representing over 1,000 providers of health care, is working on a study it hopes will help persuade lawmakers to forgo the proposed cuts.

In this seemingly never-ending flux of our new health care system, it appears that we hospitalists, for the moment, are faring quite well. And, relatively unburdened by these forces of flux, we are free to focus our energies on top-notch patient care.

Dr. Hester is a hospitalist with Baltimore-Washington Medical Center who has a passion for empowering patients to partner in their health care. She is the creator of the Patient Whiz, a patient-engagement app for iOS.

The last time I gave the talk, "Help! I’ve Been Yelped!" to physicians, there was a full house, a sometimes defiant, sometimes incredulous but always engaged full house. Most physicians don’t like Yelp and other online doctor rating sites because of the potential for negative reviews.

In past columns, I’ve written about these sites and how to respond to negative reviews and comments. Now, I’m going to share data on the use of online reviews and why they are important.

We live in a digital world that values reviews. We compare hotels on TripAdvisor.com before booking them and read reviews on Amazon.com before ordering products. We "like" or "dislike" Facebook pages and give thumbs up or thumbs down to videos on YouTube. We even rate physicians’ comments on medical question-and-answer sites such as HealthTap.com.

But how much do all of these online ratings really matter? A 2012 Nielsen report that surveyed more than 28,000 Internet users in 56 countries found that online consumer reviews are the second-most-trusted source of brand information, following only recommendations from family and friends. In other words, we trust online reviews and use them to make our own decisions.

The same is true when it comes to shopping for a doctor. According to an Internet-based survey of 2,137 adults published in the February issue of JAMA, 59% of respondents said that online doctor ratings were either "somewhat important" or "very important" when choosing a physician (2014;11:734-5).

Similarly, the "2013 Industry View Report" by Software Advice found that 62% of respondents said they read online reviews when seeking a new doctor. Although HealthGrades.com was the most commonly used site, Yelp.com was the most trusted. Forty-four percent of those respondents considered Yelp the most trustworthy review site followed by Health Grades (31%), Vitals.com (17%), and ZocDoc.com (7%).

Whether or not we trust Yelp and other online review sites, our patients do. In the JAMA survey, 35% of respondents said that they selected a physician based on good ratings, while 37% said that they avoided a physician with negative reviews. The 2013 Industry View Report also found that 45% of respondents ranked "quality of care" as the most important type of information sought about a doctor. And since many patients equate service with quality, reviews that focus on service matter.

This isn’t an entirely bad thing. If we really listen to what patients are saying, their comments can help us to improve service and communication. And, in some instances, it can lead to stronger doctor-patient relationships. Like many other industries, health care is moving toward transparency, and doctor rating sites are a key component of that.

Dr. Jeffrey Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. He has published numerous scientific articles and is a member and fellow of the American Academy of Dermatology, and a member of the Telemedicine Association and the American Medical Association, among others. He is board certified in dermatology as well as medicine and surgery in the state of California. Dr. Benabio has a special interest in the uses of social media for education and building dermatology practice. He is the founder of The Derm Blog, an educational website that has had more than 2 million unique visitors. Dr. Benabio is also a founding member and the skin care expert for Livestrong.com, a health and wellness website of Lance Armstrong’s the Livestrong Foundation. Dr. Benabio is @Dermdoc on Twitter.

The last time I gave the talk, "Help! I’ve Been Yelped!" to physicians, there was a full house, a sometimes defiant, sometimes incredulous but always engaged full house. Most physicians don’t like Yelp and other online doctor rating sites because of the potential for negative reviews.

In past columns, I’ve written about these sites and how to respond to negative reviews and comments. Now, I’m going to share data on the use of online reviews and why they are important.

We live in a digital world that values reviews. We compare hotels on TripAdvisor.com before booking them and read reviews on Amazon.com before ordering products. We "like" or "dislike" Facebook pages and give thumbs up or thumbs down to videos on YouTube. We even rate physicians’ comments on medical question-and-answer sites such as HealthTap.com.

But how much do all of these online ratings really matter? A 2012 Nielsen report that surveyed more than 28,000 Internet users in 56 countries found that online consumer reviews are the second-most-trusted source of brand information, following only recommendations from family and friends. In other words, we trust online reviews and use them to make our own decisions.

The same is true when it comes to shopping for a doctor. According to an Internet-based survey of 2,137 adults published in the February issue of JAMA, 59% of respondents said that online doctor ratings were either "somewhat important" or "very important" when choosing a physician (2014;11:734-5).

Similarly, the "2013 Industry View Report" by Software Advice found that 62% of respondents said they read online reviews when seeking a new doctor. Although HealthGrades.com was the most commonly used site, Yelp.com was the most trusted. Forty-four percent of those respondents considered Yelp the most trustworthy review site followed by Health Grades (31%), Vitals.com (17%), and ZocDoc.com (7%).

Whether or not we trust Yelp and other online review sites, our patients do. In the JAMA survey, 35% of respondents said that they selected a physician based on good ratings, while 37% said that they avoided a physician with negative reviews. The 2013 Industry View Report also found that 45% of respondents ranked "quality of care" as the most important type of information sought about a doctor. And since many patients equate service with quality, reviews that focus on service matter.

This isn’t an entirely bad thing. If we really listen to what patients are saying, their comments can help us to improve service and communication. And, in some instances, it can lead to stronger doctor-patient relationships. Like many other industries, health care is moving toward transparency, and doctor rating sites are a key component of that.

Dr. Jeffrey Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. He has published numerous scientific articles and is a member and fellow of the American Academy of Dermatology, and a member of the Telemedicine Association and the American Medical Association, among others. He is board certified in dermatology as well as medicine and surgery in the state of California. Dr. Benabio has a special interest in the uses of social media for education and building dermatology practice. He is the founder of The Derm Blog, an educational website that has had more than 2 million unique visitors. Dr. Benabio is also a founding member and the skin care expert for Livestrong.com, a health and wellness website of Lance Armstrong’s the Livestrong Foundation. Dr. Benabio is @Dermdoc on Twitter.

The last time I gave the talk, "Help! I’ve Been Yelped!" to physicians, there was a full house, a sometimes defiant, sometimes incredulous but always engaged full house. Most physicians don’t like Yelp and other online doctor rating sites because of the potential for negative reviews.

In past columns, I’ve written about these sites and how to respond to negative reviews and comments. Now, I’m going to share data on the use of online reviews and why they are important.

We live in a digital world that values reviews. We compare hotels on TripAdvisor.com before booking them and read reviews on Amazon.com before ordering products. We "like" or "dislike" Facebook pages and give thumbs up or thumbs down to videos on YouTube. We even rate physicians’ comments on medical question-and-answer sites such as HealthTap.com.

But how much do all of these online ratings really matter? A 2012 Nielsen report that surveyed more than 28,000 Internet users in 56 countries found that online consumer reviews are the second-most-trusted source of brand information, following only recommendations from family and friends. In other words, we trust online reviews and use them to make our own decisions.

The same is true when it comes to shopping for a doctor. According to an Internet-based survey of 2,137 adults published in the February issue of JAMA, 59% of respondents said that online doctor ratings were either "somewhat important" or "very important" when choosing a physician (2014;11:734-5).

Similarly, the "2013 Industry View Report" by Software Advice found that 62% of respondents said they read online reviews when seeking a new doctor. Although HealthGrades.com was the most commonly used site, Yelp.com was the most trusted. Forty-four percent of those respondents considered Yelp the most trustworthy review site followed by Health Grades (31%), Vitals.com (17%), and ZocDoc.com (7%).

Whether or not we trust Yelp and other online review sites, our patients do. In the JAMA survey, 35% of respondents said that they selected a physician based on good ratings, while 37% said that they avoided a physician with negative reviews. The 2013 Industry View Report also found that 45% of respondents ranked "quality of care" as the most important type of information sought about a doctor. And since many patients equate service with quality, reviews that focus on service matter.

This isn’t an entirely bad thing. If we really listen to what patients are saying, their comments can help us to improve service and communication. And, in some instances, it can lead to stronger doctor-patient relationships. Like many other industries, health care is moving toward transparency, and doctor rating sites are a key component of that.

Dr. Jeffrey Benabio is a partner physician in the department of dermatology of the Southern California Permanente Group in San Diego and a volunteer clinical assistant professor at the University of California, San Diego. He has published numerous scientific articles and is a member and fellow of the American Academy of Dermatology, and a member of the Telemedicine Association and the American Medical Association, among others. He is board certified in dermatology as well as medicine and surgery in the state of California. Dr. Benabio has a special interest in the uses of social media for education and building dermatology practice. He is the founder of The Derm Blog, an educational website that has had more than 2 million unique visitors. Dr. Benabio is also a founding member and the skin care expert for Livestrong.com, a health and wellness website of Lance Armstrong’s the Livestrong Foundation. Dr. Benabio is @Dermdoc on Twitter.

Numerous screening methods for cervical cancer have been proposed internationally by various professional societies, including Pap cytology alone, cytology with human papillomavirus testing as triage (HPV testing for atypical squamous cells of unknown significance [ASCUS] on cytology), cytology with HPV cotesting (cytology and HPV testing obtained together), HPV testing alone, or HPV testing followed by Pap cytology triage (cytology in patients who are positive for high-risk oncogenic subtypes of HPV). Recommendations for use of cervical cytology and HPV testing continue to vary among professional societies, with variable adoption of these guidelines by providers as well. (Am. J. Prev. Med. 2013;45:175-81).

In 2012, updated cervical cancer screening recommendations were published by ASCCP (the American Society for Colposcopy and Cervical Pathology) (Am. J. Clin. Pathol. 2012;137:516-42); the USPSTF (U.S. Preventive Services Task Force ); and ACOG (the American College of Obstetricians and Gynecologists) (Obstet. Gynecol. 2009;114:1409-20).

These most recent guidelines show a greater degree of harmony across these governing bodies than did prior guidelines. All three professional societies recommend initiating screening at age 21 years and ceasing screening at age 65 years with an adequate screening history. All groups recommend against HPV cotesting in women under 30 years of age; however, after age 30 years, ASCCP and ACOG recommend HPV cotesting every 5 years as the preferred method of cervical cancer screening, while USPSTF suggests this only as an "option." Primary HPV testing without concurrent cytology for cervical cancer screening is not currently recommended by ASCCP and USPSTF and is not addressed by ACOG.

Efficacy of screening modalities

The rationale behind these screening recommendations depends on the efficacy of both cervical cytology and HPV testing to identify preinvasive cases or invasive cervical cancer. Multiple studies have addressed the sensitivity and specificity of cytology in cervical cancer screening. Overall, the sensitivity of Pap cytology is low at approximately 51%, while specificity is high at 96%-98% (Ann. Intern. Med. 2000;132:810-9; Vaccine 2008;26 Suppl. 10:K29-41). Since the initiation of cervical cytology for cancer screening, serial annual screening has compensated for the overall poor sensitivity of the test. Two consecutive annual Pap tests can increase overall sensitivity for detection of cervical cancer to 76%, and three consecutive annual Pap tests can increase overall sensitivity to 88%.

Unlike Pap cytology, HPV testing has a high sensitivity, ranging from 81%-97% in detection of cervical cancer (N. Engl. J. Med. 2007;357:1579-88). As a result, HPV testing does not rely on serial testing for accuracy and has a high negative predictive value, making negative results very reassuring. However, HPV testing has a slightly lower specificity of 94%, which results in a higher number of false positives. Furthermore, many patients who screen positive for high-risk HPV subtypes may have transient HPV infections, which are not clinically significant, and may not cause invasive cervical cancer.

Several randomized studies have compared Pap cytology to HPV testing for use in cervical cancer screening. A Canadian study randomized more than 10,000 women to either Pap cytology or HPV testing to detect cervical intraepithelial neoplasia (CIN) 2 or higher grade cervical lesions (Int. J. Cancer. 2006;119:615-23). Findings showed a sensitivity of 55.4% for Pap cytology vs. 94.6% for HPV testing. Pap cytology had a specificity of 96.8% while HPV testing had a specificity of 94.1%. The negative predictive value of HPV testing was 100%.

Swedescreen, a Swedish study of more 12,000 women (J. Med. Virol. 2007;79:1169-75), and POBASCAM, a large Dutch study of more than 18,000 women (Lancet 2007;370:1764-72), both compared HPV testing combined with Pap cytology (cotesting) to cytology alone. Both studies found that patients screened with Pap cytology alone had more CIN2 or greater lesions in follow-up than did patients screened with cytology in combination with HPV testing (relative risk, 0.53-0.58 for CIN 2+ and RR 0.45-0.53 for CIN 3+) (J. Natl. Cancer Inst. 2009;101:88-99).

Because of the higher sensitivity of HPV testing compared with Pap cytology, some have advocated the use of HPV testing as primary screening with cytology triage rather than the reverse (cytology with HPV triage), which is more commonly used today. A Finnish study showed that primary HPV testing with cytology performed only in patients who screened positive for high risk oncogenic subtypes of HPV was more sensitive than was conventional cytology in identifying cervical dysplasia and cancer. Additionally, in women over age 35 years, HPV testing combined with Pap cytology triage was more specific than cytology alone, and decreased colposcopy referrals and follow-up tests, making this screening option cost effective (J. Natl. Cancer Inst. 2009;101:1612-23). Nowhere else in medicine is a more specific test used prior to a more sensitive test when screening for disease; the screening test is typically the more sensitive, while the confirmatory test is the more specific.

HPV vaccination and effects on screening

Currently, given that the HPV vaccines available do not protect women from all oncogenic HPV types, the ASCCP, USPSTF, and ACOG all recommend screening vaccinated women in an identical fashion to unvaccinated women. Increasing vaccination rates will likely have an impact on the efficacy of the various cervical cancer screening modalities. Vaccination will result in a reduction in the prevalence of cytologic abnormalities. As disease prevalence decreases and screening intervals increase based on current guidelines, the positive predictive value of Pap cytology also will decline, resulting in more false-positive diagnoses and possibly unnecessary procedures and patient stress (Vaccine 2013;31:5495-9). As prevalence of disease decreases, Pap cytology has the potential to become less reliable. While the positive predictive value of HPV testing also declines with decreasing disease prevalence, HPV testing is more reproducible than interpretation of Pap cytology, so the extent of increasing false-positive results may be less (Vaccine 2006;24 Suppl 3:S3/171-7).

Future directions

HPV testing as primary screening for cervical cancer is not currently recommended. However, in the post-HPV vaccination era, this may become an increasingly reasonable approach, particularly in conjunction with Pap cytology used to triage patients who test positive for high-risk HPV subtypes. HPV testing has much greater sensitivity than Pap cytology does and can better identify patients who are likely to have a cytologic abnormality. In this group of patients with greater disease prevalence, the slightly higher specificity of Pap cytology can then be used to identify precancerous lesions and guide treatment. Once this group of patients with higher lesion prevalence than the general population has been identified through HPV testing, Pap cytology can then be used and will perform better than in a lower prevalence population.

The importance of Pap cytology and HPV testing in cervical cancer screening continues to evolve, particularly in the current era of HPV vaccination. The combination of HPV testing followed by Pap cytology has potential for becoming a highly effective screening strategy; however, the optimal administration of these tests is yet to be determined. As current screening modalities improve and new technologies emerge, ongoing work is needed to identify the most effective screening method for cervical cancer.

Dr. Wysham is currently a fellow in the department of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Kim is the department of gynecologic oncology at UNC-Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at UNC-Chapel Hill.

Numerous screening methods for cervical cancer have been proposed internationally by various professional societies, including Pap cytology alone, cytology with human papillomavirus testing as triage (HPV testing for atypical squamous cells of unknown significance [ASCUS] on cytology), cytology with HPV cotesting (cytology and HPV testing obtained together), HPV testing alone, or HPV testing followed by Pap cytology triage (cytology in patients who are positive for high-risk oncogenic subtypes of HPV). Recommendations for use of cervical cytology and HPV testing continue to vary among professional societies, with variable adoption of these guidelines by providers as well. (Am. J. Prev. Med. 2013;45:175-81).

In 2012, updated cervical cancer screening recommendations were published by ASCCP (the American Society for Colposcopy and Cervical Pathology) (Am. J. Clin. Pathol. 2012;137:516-42); the USPSTF (U.S. Preventive Services Task Force ); and ACOG (the American College of Obstetricians and Gynecologists) (Obstet. Gynecol. 2009;114:1409-20).

These most recent guidelines show a greater degree of harmony across these governing bodies than did prior guidelines. All three professional societies recommend initiating screening at age 21 years and ceasing screening at age 65 years with an adequate screening history. All groups recommend against HPV cotesting in women under 30 years of age; however, after age 30 years, ASCCP and ACOG recommend HPV cotesting every 5 years as the preferred method of cervical cancer screening, while USPSTF suggests this only as an "option." Primary HPV testing without concurrent cytology for cervical cancer screening is not currently recommended by ASCCP and USPSTF and is not addressed by ACOG.

Efficacy of screening modalities

The rationale behind these screening recommendations depends on the efficacy of both cervical cytology and HPV testing to identify preinvasive cases or invasive cervical cancer. Multiple studies have addressed the sensitivity and specificity of cytology in cervical cancer screening. Overall, the sensitivity of Pap cytology is low at approximately 51%, while specificity is high at 96%-98% (Ann. Intern. Med. 2000;132:810-9; Vaccine 2008;26 Suppl. 10:K29-41). Since the initiation of cervical cytology for cancer screening, serial annual screening has compensated for the overall poor sensitivity of the test. Two consecutive annual Pap tests can increase overall sensitivity for detection of cervical cancer to 76%, and three consecutive annual Pap tests can increase overall sensitivity to 88%.

Unlike Pap cytology, HPV testing has a high sensitivity, ranging from 81%-97% in detection of cervical cancer (N. Engl. J. Med. 2007;357:1579-88). As a result, HPV testing does not rely on serial testing for accuracy and has a high negative predictive value, making negative results very reassuring. However, HPV testing has a slightly lower specificity of 94%, which results in a higher number of false positives. Furthermore, many patients who screen positive for high-risk HPV subtypes may have transient HPV infections, which are not clinically significant, and may not cause invasive cervical cancer.

Several randomized studies have compared Pap cytology to HPV testing for use in cervical cancer screening. A Canadian study randomized more than 10,000 women to either Pap cytology or HPV testing to detect cervical intraepithelial neoplasia (CIN) 2 or higher grade cervical lesions (Int. J. Cancer. 2006;119:615-23). Findings showed a sensitivity of 55.4% for Pap cytology vs. 94.6% for HPV testing. Pap cytology had a specificity of 96.8% while HPV testing had a specificity of 94.1%. The negative predictive value of HPV testing was 100%.

Swedescreen, a Swedish study of more 12,000 women (J. Med. Virol. 2007;79:1169-75), and POBASCAM, a large Dutch study of more than 18,000 women (Lancet 2007;370:1764-72), both compared HPV testing combined with Pap cytology (cotesting) to cytology alone. Both studies found that patients screened with Pap cytology alone had more CIN2 or greater lesions in follow-up than did patients screened with cytology in combination with HPV testing (relative risk, 0.53-0.58 for CIN 2+ and RR 0.45-0.53 for CIN 3+) (J. Natl. Cancer Inst. 2009;101:88-99).

Because of the higher sensitivity of HPV testing compared with Pap cytology, some have advocated the use of HPV testing as primary screening with cytology triage rather than the reverse (cytology with HPV triage), which is more commonly used today. A Finnish study showed that primary HPV testing with cytology performed only in patients who screened positive for high risk oncogenic subtypes of HPV was more sensitive than was conventional cytology in identifying cervical dysplasia and cancer. Additionally, in women over age 35 years, HPV testing combined with Pap cytology triage was more specific than cytology alone, and decreased colposcopy referrals and follow-up tests, making this screening option cost effective (J. Natl. Cancer Inst. 2009;101:1612-23). Nowhere else in medicine is a more specific test used prior to a more sensitive test when screening for disease; the screening test is typically the more sensitive, while the confirmatory test is the more specific.

HPV vaccination and effects on screening

Currently, given that the HPV vaccines available do not protect women from all oncogenic HPV types, the ASCCP, USPSTF, and ACOG all recommend screening vaccinated women in an identical fashion to unvaccinated women. Increasing vaccination rates will likely have an impact on the efficacy of the various cervical cancer screening modalities. Vaccination will result in a reduction in the prevalence of cytologic abnormalities. As disease prevalence decreases and screening intervals increase based on current guidelines, the positive predictive value of Pap cytology also will decline, resulting in more false-positive diagnoses and possibly unnecessary procedures and patient stress (Vaccine 2013;31:5495-9). As prevalence of disease decreases, Pap cytology has the potential to become less reliable. While the positive predictive value of HPV testing also declines with decreasing disease prevalence, HPV testing is more reproducible than interpretation of Pap cytology, so the extent of increasing false-positive results may be less (Vaccine 2006;24 Suppl 3:S3/171-7).

Future directions

HPV testing as primary screening for cervical cancer is not currently recommended. However, in the post-HPV vaccination era, this may become an increasingly reasonable approach, particularly in conjunction with Pap cytology used to triage patients who test positive for high-risk HPV subtypes. HPV testing has much greater sensitivity than Pap cytology does and can better identify patients who are likely to have a cytologic abnormality. In this group of patients with greater disease prevalence, the slightly higher specificity of Pap cytology can then be used to identify precancerous lesions and guide treatment. Once this group of patients with higher lesion prevalence than the general population has been identified through HPV testing, Pap cytology can then be used and will perform better than in a lower prevalence population.

The importance of Pap cytology and HPV testing in cervical cancer screening continues to evolve, particularly in the current era of HPV vaccination. The combination of HPV testing followed by Pap cytology has potential for becoming a highly effective screening strategy; however, the optimal administration of these tests is yet to be determined. As current screening modalities improve and new technologies emerge, ongoing work is needed to identify the most effective screening method for cervical cancer.

Dr. Wysham is currently a fellow in the department of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Kim is the department of gynecologic oncology at UNC-Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at UNC-Chapel Hill.

Numerous screening methods for cervical cancer have been proposed internationally by various professional societies, including Pap cytology alone, cytology with human papillomavirus testing as triage (HPV testing for atypical squamous cells of unknown significance [ASCUS] on cytology), cytology with HPV cotesting (cytology and HPV testing obtained together), HPV testing alone, or HPV testing followed by Pap cytology triage (cytology in patients who are positive for high-risk oncogenic subtypes of HPV). Recommendations for use of cervical cytology and HPV testing continue to vary among professional societies, with variable adoption of these guidelines by providers as well. (Am. J. Prev. Med. 2013;45:175-81).

In 2012, updated cervical cancer screening recommendations were published by ASCCP (the American Society for Colposcopy and Cervical Pathology) (Am. J. Clin. Pathol. 2012;137:516-42); the USPSTF (U.S. Preventive Services Task Force ); and ACOG (the American College of Obstetricians and Gynecologists) (Obstet. Gynecol. 2009;114:1409-20).

These most recent guidelines show a greater degree of harmony across these governing bodies than did prior guidelines. All three professional societies recommend initiating screening at age 21 years and ceasing screening at age 65 years with an adequate screening history. All groups recommend against HPV cotesting in women under 30 years of age; however, after age 30 years, ASCCP and ACOG recommend HPV cotesting every 5 years as the preferred method of cervical cancer screening, while USPSTF suggests this only as an "option." Primary HPV testing without concurrent cytology for cervical cancer screening is not currently recommended by ASCCP and USPSTF and is not addressed by ACOG.

Efficacy of screening modalities

The rationale behind these screening recommendations depends on the efficacy of both cervical cytology and HPV testing to identify preinvasive cases or invasive cervical cancer. Multiple studies have addressed the sensitivity and specificity of cytology in cervical cancer screening. Overall, the sensitivity of Pap cytology is low at approximately 51%, while specificity is high at 96%-98% (Ann. Intern. Med. 2000;132:810-9; Vaccine 2008;26 Suppl. 10:K29-41). Since the initiation of cervical cytology for cancer screening, serial annual screening has compensated for the overall poor sensitivity of the test. Two consecutive annual Pap tests can increase overall sensitivity for detection of cervical cancer to 76%, and three consecutive annual Pap tests can increase overall sensitivity to 88%.

Unlike Pap cytology, HPV testing has a high sensitivity, ranging from 81%-97% in detection of cervical cancer (N. Engl. J. Med. 2007;357:1579-88). As a result, HPV testing does not rely on serial testing for accuracy and has a high negative predictive value, making negative results very reassuring. However, HPV testing has a slightly lower specificity of 94%, which results in a higher number of false positives. Furthermore, many patients who screen positive for high-risk HPV subtypes may have transient HPV infections, which are not clinically significant, and may not cause invasive cervical cancer.

Several randomized studies have compared Pap cytology to HPV testing for use in cervical cancer screening. A Canadian study randomized more than 10,000 women to either Pap cytology or HPV testing to detect cervical intraepithelial neoplasia (CIN) 2 or higher grade cervical lesions (Int. J. Cancer. 2006;119:615-23). Findings showed a sensitivity of 55.4% for Pap cytology vs. 94.6% for HPV testing. Pap cytology had a specificity of 96.8% while HPV testing had a specificity of 94.1%. The negative predictive value of HPV testing was 100%.

Swedescreen, a Swedish study of more 12,000 women (J. Med. Virol. 2007;79:1169-75), and POBASCAM, a large Dutch study of more than 18,000 women (Lancet 2007;370:1764-72), both compared HPV testing combined with Pap cytology (cotesting) to cytology alone. Both studies found that patients screened with Pap cytology alone had more CIN2 or greater lesions in follow-up than did patients screened with cytology in combination with HPV testing (relative risk, 0.53-0.58 for CIN 2+ and RR 0.45-0.53 for CIN 3+) (J. Natl. Cancer Inst. 2009;101:88-99).

Because of the higher sensitivity of HPV testing compared with Pap cytology, some have advocated the use of HPV testing as primary screening with cytology triage rather than the reverse (cytology with HPV triage), which is more commonly used today. A Finnish study showed that primary HPV testing with cytology performed only in patients who screened positive for high risk oncogenic subtypes of HPV was more sensitive than was conventional cytology in identifying cervical dysplasia and cancer. Additionally, in women over age 35 years, HPV testing combined with Pap cytology triage was more specific than cytology alone, and decreased colposcopy referrals and follow-up tests, making this screening option cost effective (J. Natl. Cancer Inst. 2009;101:1612-23). Nowhere else in medicine is a more specific test used prior to a more sensitive test when screening for disease; the screening test is typically the more sensitive, while the confirmatory test is the more specific.

HPV vaccination and effects on screening

Currently, given that the HPV vaccines available do not protect women from all oncogenic HPV types, the ASCCP, USPSTF, and ACOG all recommend screening vaccinated women in an identical fashion to unvaccinated women. Increasing vaccination rates will likely have an impact on the efficacy of the various cervical cancer screening modalities. Vaccination will result in a reduction in the prevalence of cytologic abnormalities. As disease prevalence decreases and screening intervals increase based on current guidelines, the positive predictive value of Pap cytology also will decline, resulting in more false-positive diagnoses and possibly unnecessary procedures and patient stress (Vaccine 2013;31:5495-9). As prevalence of disease decreases, Pap cytology has the potential to become less reliable. While the positive predictive value of HPV testing also declines with decreasing disease prevalence, HPV testing is more reproducible than interpretation of Pap cytology, so the extent of increasing false-positive results may be less (Vaccine 2006;24 Suppl 3:S3/171-7).

Future directions

HPV testing as primary screening for cervical cancer is not currently recommended. However, in the post-HPV vaccination era, this may become an increasingly reasonable approach, particularly in conjunction with Pap cytology used to triage patients who test positive for high-risk HPV subtypes. HPV testing has much greater sensitivity than Pap cytology does and can better identify patients who are likely to have a cytologic abnormality. In this group of patients with greater disease prevalence, the slightly higher specificity of Pap cytology can then be used to identify precancerous lesions and guide treatment. Once this group of patients with higher lesion prevalence than the general population has been identified through HPV testing, Pap cytology can then be used and will perform better than in a lower prevalence population.

The importance of Pap cytology and HPV testing in cervical cancer screening continues to evolve, particularly in the current era of HPV vaccination. The combination of HPV testing followed by Pap cytology has potential for becoming a highly effective screening strategy; however, the optimal administration of these tests is yet to be determined. As current screening modalities improve and new technologies emerge, ongoing work is needed to identify the most effective screening method for cervical cancer.

Dr. Wysham is currently a fellow in the department of gynecologic oncology at the University of North Carolina at Chapel Hill. Dr. Kim is the department of gynecologic oncology at UNC-Chapel Hill. Dr. Gehrig is professor and director of gynecologic oncology at UNC-Chapel Hill.