Elizabeth Mechcatie

A low vitamin B₁₂ blood level was an independent and significant risk factor for having a pregnancy affected by a neural tube defect in a study of Irish women, in what the authors say is the first study to examine the risk of the birth defect associated with maternal B₁₂ concentration.

Their results have public health implications in terms of possible fortification of grains with B₁₂, although more studies are needed to learn more about the safety of this approach and the optimal protective dose of B₁₂ in food, according to Anne M. Molloy, Ph.D., of Trinity College, Dublin and her associates.

The data indicated that most of the neural tube defect (NTD) risk was limited to maternal B₁₂ levels at approximately 250 ng/L or less, although the data suggested that the risk could be further lowered if the B₁₂ level was above 320–350 ng/L. Based on this, they recommended that women have a vitamin B₁₂ level above 300 ng/L before conceiving.

The other authors were from the Child Health Epidemiology Unit at the Health Research Board in Dublin; and the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health and the National Human Genome Institute at NIH (Pediatrics 2009;123:917–23). Because the neural tube defect rate in Ireland is high, NIH and Irish researchers have worked together on NTD studies.

The study compared B₁₂ levels in stored blood samples of three groups of Irish women, at a median 15 weeks' gestation, obtained between 1983 and 1990, before food was fortified with folic acid and when vitamin supplementation during pregnancy in Ireland was not common. Mandatory folic acid fortification of grains in the United States has been reported to have reduced the incidence of NTDs by as much as 78%. But folic acid cannot prevent all NTDs and low maternal B₁₂ has previously been associated with a risk of NTDs, the authors wrote.

The three groups were composed as follows: 95 women with a pregnancy affected by a NTD (mean age 27 years) and 265 controls with a normal pregnancy (mean age 28 years); 107 women who had had a previous pregnancy affected by an NTD but were pregnant again with an unaffected pregnancy (mean age 32 years) and 414 controls (mean age 28 years); 76 women during an affected pregnancy (mean age 27 years); and 222 controls (mean age 28 years).

When compared with controls, the B₁₂ levels were significantly lower among the women who had a pregnancy affected by a NTD, with levels below 250 ng/L associated with the greatest risk. The risk of having a pregnancy affected by an NTD was three times greater among women with B₁₂ concentrations below 200 ng/L, compared with those whose levels were above 400 ng/L. The median B₁₂ concentrations among the affected women in all three groups were 13%-19% lower than those with unaffected pregnancies, a significant difference.

Since B₁₂ values were obtained at a median 15 weeks' gestation, at which time the level naturally would have dropped by about 20%-25%, “our data indicate that women should aim to enter pregnancy” with serum B₁₂ concentrations above 300 ng/L,” the authors concluded, adding that concentrations above 400 ng/L “might be desirable, although we found no statistically significant benefit,” for that value.

The researchers did an analysis to determine if the effects of B₁₂ and folate on NTD risk were independent, which found “little interaction between B₁₂ and folate,” they said. Mandatory fortification of grain products in the United States with folic acid, the synthetic version of the vitamin folate, has been reported to reduce NTD incidence by as much as 78%. But, “it is generally agreed that not all NTDs are preventable by folic acid.”

In a statement issued by NICHD, Dr. James Mills, one of the authors and a senior investigator in the NICHD's division of epidemiology, statistics, and prevention research, pointed out that since dietary B₁₂ is contained in milk, poultry, and other animal sources, women who are on a strict vegan diet may be at an increased risk of an NTD. He also advised that women with intestinal disorders who may not absorb an adequate amount of B₁₂ should consult with physicians before pregnancy, to ensure that they are getting enough of this vitamin.

The authors had no relevant disclosures.

A low vitamin B₁₂ blood level was an independent and significant risk factor for having a pregnancy affected by a neural tube defect in a study of Irish women, in what the authors say is the first study to examine the risk of the birth defect associated with maternal B₁₂ concentration.

Their results have public health implications in terms of possible fortification of grains with B₁₂, although more studies are needed to learn more about the safety of this approach and the optimal protective dose of B₁₂ in food, according to Anne M. Molloy, Ph.D., of Trinity College, Dublin and her associates.

The data indicated that most of the neural tube defect (NTD) risk was limited to maternal B₁₂ levels at approximately 250 ng/L or less, although the data suggested that the risk could be further lowered if the B₁₂ level was above 320–350 ng/L. Based on this, they recommended that women have a vitamin B₁₂ level above 300 ng/L before conceiving.

The other authors were from the Child Health Epidemiology Unit at the Health Research Board in Dublin; and the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health and the National Human Genome Institute at NIH (Pediatrics 2009;123:917–23). Because the neural tube defect rate in Ireland is high, NIH and Irish researchers have worked together on NTD studies.

The study compared B₁₂ levels in stored blood samples of three groups of Irish women, at a median 15 weeks' gestation, obtained between 1983 and 1990, before food was fortified with folic acid and when vitamin supplementation during pregnancy in Ireland was not common. Mandatory folic acid fortification of grains in the United States has been reported to have reduced the incidence of NTDs by as much as 78%. But folic acid cannot prevent all NTDs and low maternal B₁₂ has previously been associated with a risk of NTDs, the authors wrote.

The three groups were composed as follows: 95 women with a pregnancy affected by a NTD (mean age 27 years) and 265 controls with a normal pregnancy (mean age 28 years); 107 women who had had a previous pregnancy affected by an NTD but were pregnant again with an unaffected pregnancy (mean age 32 years) and 414 controls (mean age 28 years); 76 women during an affected pregnancy (mean age 27 years); and 222 controls (mean age 28 years).

When compared with controls, the B₁₂ levels were significantly lower among the women who had a pregnancy affected by a NTD, with levels below 250 ng/L associated with the greatest risk. The risk of having a pregnancy affected by an NTD was three times greater among women with B₁₂ concentrations below 200 ng/L, compared with those whose levels were above 400 ng/L. The median B₁₂ concentrations among the affected women in all three groups were 13%-19% lower than those with unaffected pregnancies, a significant difference.

Since B₁₂ values were obtained at a median 15 weeks' gestation, at which time the level naturally would have dropped by about 20%-25%, “our data indicate that women should aim to enter pregnancy” with serum B₁₂ concentrations above 300 ng/L,” the authors concluded, adding that concentrations above 400 ng/L “might be desirable, although we found no statistically significant benefit,” for that value.

The researchers did an analysis to determine if the effects of B₁₂ and folate on NTD risk were independent, which found “little interaction between B₁₂ and folate,” they said. Mandatory fortification of grain products in the United States with folic acid, the synthetic version of the vitamin folate, has been reported to reduce NTD incidence by as much as 78%. But, “it is generally agreed that not all NTDs are preventable by folic acid.”

In a statement issued by NICHD, Dr. James Mills, one of the authors and a senior investigator in the NICHD's division of epidemiology, statistics, and prevention research, pointed out that since dietary B₁₂ is contained in milk, poultry, and other animal sources, women who are on a strict vegan diet may be at an increased risk of an NTD. He also advised that women with intestinal disorders who may not absorb an adequate amount of B₁₂ should consult with physicians before pregnancy, to ensure that they are getting enough of this vitamin.

The authors had no relevant disclosures.

A low vitamin B₁₂ blood level was an independent and significant risk factor for having a pregnancy affected by a neural tube defect in a study of Irish women, in what the authors say is the first study to examine the risk of the birth defect associated with maternal B₁₂ concentration.

Their results have public health implications in terms of possible fortification of grains with B₁₂, although more studies are needed to learn more about the safety of this approach and the optimal protective dose of B₁₂ in food, according to Anne M. Molloy, Ph.D., of Trinity College, Dublin and her associates.

The data indicated that most of the neural tube defect (NTD) risk was limited to maternal B₁₂ levels at approximately 250 ng/L or less, although the data suggested that the risk could be further lowered if the B₁₂ level was above 320–350 ng/L. Based on this, they recommended that women have a vitamin B₁₂ level above 300 ng/L before conceiving.

The other authors were from the Child Health Epidemiology Unit at the Health Research Board in Dublin; and the Eunice Kennedy Shriver National Institute of Child Health and Human Development at the National Institutes of Health and the National Human Genome Institute at NIH (Pediatrics 2009;123:917–23). Because the neural tube defect rate in Ireland is high, NIH and Irish researchers have worked together on NTD studies.

The study compared B₁₂ levels in stored blood samples of three groups of Irish women, at a median 15 weeks' gestation, obtained between 1983 and 1990, before food was fortified with folic acid and when vitamin supplementation during pregnancy in Ireland was not common. Mandatory folic acid fortification of grains in the United States has been reported to have reduced the incidence of NTDs by as much as 78%. But folic acid cannot prevent all NTDs and low maternal B₁₂ has previously been associated with a risk of NTDs, the authors wrote.

The three groups were composed as follows: 95 women with a pregnancy affected by a NTD (mean age 27 years) and 265 controls with a normal pregnancy (mean age 28 years); 107 women who had had a previous pregnancy affected by an NTD but were pregnant again with an unaffected pregnancy (mean age 32 years) and 414 controls (mean age 28 years); 76 women during an affected pregnancy (mean age 27 years); and 222 controls (mean age 28 years).

When compared with controls, the B₁₂ levels were significantly lower among the women who had a pregnancy affected by a NTD, with levels below 250 ng/L associated with the greatest risk. The risk of having a pregnancy affected by an NTD was three times greater among women with B₁₂ concentrations below 200 ng/L, compared with those whose levels were above 400 ng/L. The median B₁₂ concentrations among the affected women in all three groups were 13%-19% lower than those with unaffected pregnancies, a significant difference.

Since B₁₂ values were obtained at a median 15 weeks' gestation, at which time the level naturally would have dropped by about 20%-25%, “our data indicate that women should aim to enter pregnancy” with serum B₁₂ concentrations above 300 ng/L,” the authors concluded, adding that concentrations above 400 ng/L “might be desirable, although we found no statistically significant benefit,” for that value.

The researchers did an analysis to determine if the effects of B₁₂ and folate on NTD risk were independent, which found “little interaction between B₁₂ and folate,” they said. Mandatory fortification of grain products in the United States with folic acid, the synthetic version of the vitamin folate, has been reported to reduce NTD incidence by as much as 78%. But, “it is generally agreed that not all NTDs are preventable by folic acid.”

In a statement issued by NICHD, Dr. James Mills, one of the authors and a senior investigator in the NICHD's division of epidemiology, statistics, and prevention research, pointed out that since dietary B₁₂ is contained in milk, poultry, and other animal sources, women who are on a strict vegan diet may be at an increased risk of an NTD. He also advised that women with intestinal disorders who may not absorb an adequate amount of B₁₂ should consult with physicians before pregnancy, to ensure that they are getting enough of this vitamin.

The authors had no relevant disclosures.

A link to the advisory is available at: www.fda.gov/medwatch/safety/2009/safety09.htm#Transdermal

To eliminate any risk of skin burns, transdermal medication patches should be removed before patients undergo magnetic resonance imaging scans, the Food and Drug Administration advises.

The FDA's public health advisory was prompted by fewer than half a dozen reports of burns associated with medication patches that contain trace amounts of aluminum or other metals, which can heat up just enough during an MRI scan to cause a burn.

The reported cases have been in nicotine patches, Dr. Sandra Kweder, deputy director of the FDA's Office of New Drugs, said during an FDA telebriefing.

About 60 medicated patches are on the market, and include both over-the-counter and prescription products. Uses include smoking cessation, contraception, hormone therapy, and pain treatment. More than 25% of patches contain metal, Dr. Kweder said. Even transparent patches may contain metals.

Clinicians should instruct the patient about when to remove the patch before the procedure and about replacing it after the procedure, the advisory said.

The FDA is currently reviewing the labeling and composition of all transdermal medication patches, and is working with manufacturers to improve labeling, which could include some type of warning on the patch.

A link to the advisory is available at: www.fda.gov/medwatch/safety/2009/safety09.htm#Transdermal

To eliminate any risk of skin burns, transdermal medication patches should be removed before patients undergo magnetic resonance imaging scans, the Food and Drug Administration advises.

The FDA's public health advisory was prompted by fewer than half a dozen reports of burns associated with medication patches that contain trace amounts of aluminum or other metals, which can heat up just enough during an MRI scan to cause a burn.

The reported cases have been in nicotine patches, Dr. Sandra Kweder, deputy director of the FDA's Office of New Drugs, said during an FDA telebriefing.

About 60 medicated patches are on the market, and include both over-the-counter and prescription products. Uses include smoking cessation, contraception, hormone therapy, and pain treatment. More than 25% of patches contain metal, Dr. Kweder said. Even transparent patches may contain metals.

Clinicians should instruct the patient about when to remove the patch before the procedure and about replacing it after the procedure, the advisory said.

The FDA is currently reviewing the labeling and composition of all transdermal medication patches, and is working with manufacturers to improve labeling, which could include some type of warning on the patch.

A link to the advisory is available at: www.fda.gov/medwatch/safety/2009/safety09.htm#Transdermal

To eliminate any risk of skin burns, transdermal medication patches should be removed before patients undergo magnetic resonance imaging scans, the Food and Drug Administration advises.

The FDA's public health advisory was prompted by fewer than half a dozen reports of burns associated with medication patches that contain trace amounts of aluminum or other metals, which can heat up just enough during an MRI scan to cause a burn.

The reported cases have been in nicotine patches, Dr. Sandra Kweder, deputy director of the FDA's Office of New Drugs, said during an FDA telebriefing.

About 60 medicated patches are on the market, and include both over-the-counter and prescription products. Uses include smoking cessation, contraception, hormone therapy, and pain treatment. More than 25% of patches contain metal, Dr. Kweder said. Even transparent patches may contain metals.

Clinicians should instruct the patient about when to remove the patch before the procedure and about replacing it after the procedure, the advisory said.

The FDA is currently reviewing the labeling and composition of all transdermal medication patches, and is working with manufacturers to improve labeling, which could include some type of warning on the patch.

To eliminate any risk of skin burns, transdermal medication patches should be removed before patients undergo magnetic resonance imaging scans, the Food and Drug Administration advises.

Prompted by less than half a dozen reports of burns associated with patches that contain trace amounts of aluminum or other metals, the FDA issued a public health advisory in March. The burns, reported in nicotine patches, have been described as similar to a “serious sunburn,” Dr. Sandra Kweder, deputy director of the FDA's Office of New Drugs, said during a telebriefing.

The advisory applies to all patches, even those without metals, because not all patches carry a warning about the risk, and metal may not be visible. Clinicians should instruct patients about when to remove patches before procedures and about replacing them afterward, the advisory said.

About 60 medicated patches are on the market. Uses include smoking cessation, contraception, hormone therapy, and pain treatment.

More than 25% of them contain metal, Dr. Kweder said. Even transparent patches may contain metals.

The FDA is reviewing the labeling and composition of all transdermal medication patches, and is working with manufacturers to improve labeling, which could include some type of warning on the patch.

The advisory is available online at www.fda.gov/medwatch/safety/2009/safety09.htm#Transdermal

To eliminate any risk of skin burns, transdermal medication patches should be removed before patients undergo magnetic resonance imaging scans, the Food and Drug Administration advises.

Prompted by less than half a dozen reports of burns associated with patches that contain trace amounts of aluminum or other metals, the FDA issued a public health advisory in March. The burns, reported in nicotine patches, have been described as similar to a “serious sunburn,” Dr. Sandra Kweder, deputy director of the FDA's Office of New Drugs, said during a telebriefing.

The advisory applies to all patches, even those without metals, because not all patches carry a warning about the risk, and metal may not be visible. Clinicians should instruct patients about when to remove patches before procedures and about replacing them afterward, the advisory said.

About 60 medicated patches are on the market. Uses include smoking cessation, contraception, hormone therapy, and pain treatment.

More than 25% of them contain metal, Dr. Kweder said. Even transparent patches may contain metals.

The FDA is reviewing the labeling and composition of all transdermal medication patches, and is working with manufacturers to improve labeling, which could include some type of warning on the patch.

The advisory is available online at www.fda.gov/medwatch/safety/2009/safety09.htm#Transdermal

To eliminate any risk of skin burns, transdermal medication patches should be removed before patients undergo magnetic resonance imaging scans, the Food and Drug Administration advises.

Prompted by less than half a dozen reports of burns associated with patches that contain trace amounts of aluminum or other metals, the FDA issued a public health advisory in March. The burns, reported in nicotine patches, have been described as similar to a “serious sunburn,” Dr. Sandra Kweder, deputy director of the FDA's Office of New Drugs, said during a telebriefing.

The advisory applies to all patches, even those without metals, because not all patches carry a warning about the risk, and metal may not be visible. Clinicians should instruct patients about when to remove patches before procedures and about replacing them afterward, the advisory said.

About 60 medicated patches are on the market. Uses include smoking cessation, contraception, hormone therapy, and pain treatment.

More than 25% of them contain metal, Dr. Kweder said. Even transparent patches may contain metals.

The FDA is reviewing the labeling and composition of all transdermal medication patches, and is working with manufacturers to improve labeling, which could include some type of warning on the patch.

The advisory is available online at www.fda.gov/medwatch/safety/2009/safety09.htm#Transdermal

SILVER SPRING, MD. — With unanimous support by an expert panel of prasugrel, the Food and Drug Administration is poised to approve the antiplatelet drug for treating patients with acute coronary syndrome who present with unstable angina, non-ST-segment elevation myocardial infarction, or ST-elevation MI.

All nine voting members of the FDA's Cardiovascular and Renal Drugs Advisory Committee agreed that prasugrel, a thienopyridine developed by Eli Lilly & Co. and Daiichi Sankyo Inc., has a favorable benefit-to-risk profile, based on clinical trial data.

Prasugrel, given as a 60-mg loading dose followed by 10 mg/day, was compared with clopidogrel, administered at a 300-mg loading dose followed by 75 mg/day, in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38), an international double-blind study of 13,608 patients with moderate to high-risk ACS, scheduled to have percutaneous coronary intervention. They had unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), or STEMI. All patients were on aspirin.

Over a mean of 12 months, the primary end point—a composite of cardiovascular death, MI, or nonfatal stroke—occurred in 12.1% of patients on clopidogrel and 9.9% of those on prasugrel, a significant reduction.

The rate of strokes in both groups was 0.9%. The overall risk of cardiovascular death was also not significantly different between the two groups.

The main risk was bleeding. The rate of major bleeding was 2.2% in those on prasugrel, compared with 1.7% in those on clopidogrel; the rates were 1.3% and 0.8% for life-threatening bleeding, including fatalities; 0.3% and 0.1% for fatal bleeding; and 0.3% and 0.2% for intracranial hemorrhage.

An FDA analysis showed that for every 1,000 patients with ACS treated with prasugrel, the treatment prevents 21 nonfatal MIs and 3 cardiovascular deaths, with no strokes, but at a cost of 2 fatal hemorrhages, 3 nonfatal major hemorrhages, 5 minor hemorrhages, and 19 minimal hemorrhages.

All panelists agreed that labeling should discourage physicians from prescribing prasugrel to treat patients with a history of stroke or TIA.

Among patients over age 70 years, bleeding was not more common with prasugrel, but the sequelae were more serious. The company has proposed that a lower dose be used in patients over age 75 years, and in people who weigh less than 60 kg, who also were at a greater risk of hemorrhage.

The panel recommended that the drug not be taken around the time of CABG.

The FDA usually follows the recommendations of its advisory committee. If approved, prasugrel will be marketed as Effient.

SILVER SPRING, MD. — With unanimous support by an expert panel of prasugrel, the Food and Drug Administration is poised to approve the antiplatelet drug for treating patients with acute coronary syndrome who present with unstable angina, non-ST-segment elevation myocardial infarction, or ST-elevation MI.

All nine voting members of the FDA's Cardiovascular and Renal Drugs Advisory Committee agreed that prasugrel, a thienopyridine developed by Eli Lilly & Co. and Daiichi Sankyo Inc., has a favorable benefit-to-risk profile, based on clinical trial data.

Prasugrel, given as a 60-mg loading dose followed by 10 mg/day, was compared with clopidogrel, administered at a 300-mg loading dose followed by 75 mg/day, in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38), an international double-blind study of 13,608 patients with moderate to high-risk ACS, scheduled to have percutaneous coronary intervention. They had unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), or STEMI. All patients were on aspirin.

Over a mean of 12 months, the primary end point—a composite of cardiovascular death, MI, or nonfatal stroke—occurred in 12.1% of patients on clopidogrel and 9.9% of those on prasugrel, a significant reduction.

The rate of strokes in both groups was 0.9%. The overall risk of cardiovascular death was also not significantly different between the two groups.

The main risk was bleeding. The rate of major bleeding was 2.2% in those on prasugrel, compared with 1.7% in those on clopidogrel; the rates were 1.3% and 0.8% for life-threatening bleeding, including fatalities; 0.3% and 0.1% for fatal bleeding; and 0.3% and 0.2% for intracranial hemorrhage.

An FDA analysis showed that for every 1,000 patients with ACS treated with prasugrel, the treatment prevents 21 nonfatal MIs and 3 cardiovascular deaths, with no strokes, but at a cost of 2 fatal hemorrhages, 3 nonfatal major hemorrhages, 5 minor hemorrhages, and 19 minimal hemorrhages.

All panelists agreed that labeling should discourage physicians from prescribing prasugrel to treat patients with a history of stroke or TIA.

Among patients over age 70 years, bleeding was not more common with prasugrel, but the sequelae were more serious. The company has proposed that a lower dose be used in patients over age 75 years, and in people who weigh less than 60 kg, who also were at a greater risk of hemorrhage.

The panel recommended that the drug not be taken around the time of CABG.

The FDA usually follows the recommendations of its advisory committee. If approved, prasugrel will be marketed as Effient.

SILVER SPRING, MD. — With unanimous support by an expert panel of prasugrel, the Food and Drug Administration is poised to approve the antiplatelet drug for treating patients with acute coronary syndrome who present with unstable angina, non-ST-segment elevation myocardial infarction, or ST-elevation MI.

All nine voting members of the FDA's Cardiovascular and Renal Drugs Advisory Committee agreed that prasugrel, a thienopyridine developed by Eli Lilly & Co. and Daiichi Sankyo Inc., has a favorable benefit-to-risk profile, based on clinical trial data.

Prasugrel, given as a 60-mg loading dose followed by 10 mg/day, was compared with clopidogrel, administered at a 300-mg loading dose followed by 75 mg/day, in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI 38), an international double-blind study of 13,608 patients with moderate to high-risk ACS, scheduled to have percutaneous coronary intervention. They had unstable angina, non-ST-segment elevation myocardial infarction (NSTEMI), or STEMI. All patients were on aspirin.

Over a mean of 12 months, the primary end point—a composite of cardiovascular death, MI, or nonfatal stroke—occurred in 12.1% of patients on clopidogrel and 9.9% of those on prasugrel, a significant reduction.

The rate of strokes in both groups was 0.9%. The overall risk of cardiovascular death was also not significantly different between the two groups.

The main risk was bleeding. The rate of major bleeding was 2.2% in those on prasugrel, compared with 1.7% in those on clopidogrel; the rates were 1.3% and 0.8% for life-threatening bleeding, including fatalities; 0.3% and 0.1% for fatal bleeding; and 0.3% and 0.2% for intracranial hemorrhage.

An FDA analysis showed that for every 1,000 patients with ACS treated with prasugrel, the treatment prevents 21 nonfatal MIs and 3 cardiovascular deaths, with no strokes, but at a cost of 2 fatal hemorrhages, 3 nonfatal major hemorrhages, 5 minor hemorrhages, and 19 minimal hemorrhages.

All panelists agreed that labeling should discourage physicians from prescribing prasugrel to treat patients with a history of stroke or TIA.

Among patients over age 70 years, bleeding was not more common with prasugrel, but the sequelae were more serious. The company has proposed that a lower dose be used in patients over age 75 years, and in people who weigh less than 60 kg, who also were at a greater risk of hemorrhage.

The panel recommended that the drug not be taken around the time of CABG.

The FDA usually follows the recommendations of its advisory committee. If approved, prasugrel will be marketed as Effient.

ADELPHI, MD. — A federal panel agreed that data on the oral anticoagulant rivaroxaban indicate that the drug's benefits in preventing venous thromboembolic events after hip and knee replacement surgery outweigh its potential risks of excess bleeding and potential risk of severe hepatotoxicity.

The Food and Drug Administration's Cardiovascular and Renal Drugs Advisory Committee voted 15–2 that data from four clinical trials showed that rivaroxaban has a favorable risk-benefit profile for the proposed indication—prophylaxis of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery. The recommended dosage schedule is 10 mg once daily, for 35 days after hip surgery or 14 days after knee replacement.

Most panelists agreed that potential hepatoxicity should not preclude approval, although long-term data on hepatoxicity are critically needed. Panelists, who were concerned about off-label use of the drug, emphasized the importance of advising clinicians to avoid prescribing the drug for longer periods and for other uses, and of continuing to follow patients on rivaroxaban in clinical trials and clinical practice for hepatoxicity.

If approved, rivaroxaban, an oral, direct Factor Xa inhibitor made by Johnson & Johnson Pharmaceutical Research & Development LLC, would be marketed as Xarelto. It would be the first oral anticoagulant approved for these indications, as well as the first oral anticoagulant approved since warfarin. The drug works by inhibiting direct Factor Xa, which lowers thrombin production and prolongs prothrombin time. The FDA usually follows the recommendations of its advisory panels.

The proposed regimen was compared with enoxaparin in four international studies of more than 12,000 patients (6,183 patients on rivaroxaban) after total hip or knee replacement surgery. Patients with significant liver disease were excluded. The composite end point of venographic evidence of deep vein thrombosis (DVT), nonfatal pulmonary embolus (PE), or death was significantly lower in those treated with rivaroxaban, but patients on the drug had a higher rate of bleeding. The major bleeding rate was 0.4% in those on rivaroxaban and 0.2% in those on enoxaparin. The one bleeding-related death in the studies was in a patient on rivaroxaban.

Serious ALT elevations were more common with rivaroxaban (0.3% vs. 0.2%), as was a composite marker of liver injury (an ALT greater than three times the upper limit of normal with a total bilirubin greater than two times the upper limit of normal, in 0.15% vs. 0.11%), but these were not significant differences.

The consumer representative on the panel was Dr. Sidney Wolfe, director of the Public Citizen Health Research Group. He voted no on the risk-benefit question and said he was concerned about the bleeding risk and was “very uncomfortable about the certainty of long-term use and the absence of long-term safety data on hepatoxicity.” Because there is no need for a regular blood test, as there is with warfarin, he expects it will be used “massively” for off-label indications for which there are no data.

The panel chair, Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic Foundation, who was among the majority in favor of the risk-benefit profile, said that “the liver issue is not completely resolved, but I believe the signal for liver injury is very weak” but should be followed.

Rivaroxaban is also being studied for other indications in ongoing trials, including acute coronary syndromes, secondary prevention and long-term treatment of patients who have had a DVT or PE, and prevention of stroke and noncentral nervous system embolism in patients with nonvalvular atrial fibrillation.

ADELPHI, MD. — A federal panel agreed that data on the oral anticoagulant rivaroxaban indicate that the drug's benefits in preventing venous thromboembolic events after hip and knee replacement surgery outweigh its potential risks of excess bleeding and potential risk of severe hepatotoxicity.

The Food and Drug Administration's Cardiovascular and Renal Drugs Advisory Committee voted 15–2 that data from four clinical trials showed that rivaroxaban has a favorable risk-benefit profile for the proposed indication—prophylaxis of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery. The recommended dosage schedule is 10 mg once daily, for 35 days after hip surgery or 14 days after knee replacement.

Most panelists agreed that potential hepatoxicity should not preclude approval, although long-term data on hepatoxicity are critically needed. Panelists, who were concerned about off-label use of the drug, emphasized the importance of advising clinicians to avoid prescribing the drug for longer periods and for other uses, and of continuing to follow patients on rivaroxaban in clinical trials and clinical practice for hepatoxicity.

If approved, rivaroxaban, an oral, direct Factor Xa inhibitor made by Johnson & Johnson Pharmaceutical Research & Development LLC, would be marketed as Xarelto. It would be the first oral anticoagulant approved for these indications, as well as the first oral anticoagulant approved since warfarin. The drug works by inhibiting direct Factor Xa, which lowers thrombin production and prolongs prothrombin time. The FDA usually follows the recommendations of its advisory panels.

The proposed regimen was compared with enoxaparin in four international studies of more than 12,000 patients (6,183 patients on rivaroxaban) after total hip or knee replacement surgery. Patients with significant liver disease were excluded. The composite end point of venographic evidence of deep vein thrombosis (DVT), nonfatal pulmonary embolus (PE), or death was significantly lower in those treated with rivaroxaban, but patients on the drug had a higher rate of bleeding. The major bleeding rate was 0.4% in those on rivaroxaban and 0.2% in those on enoxaparin. The one bleeding-related death in the studies was in a patient on rivaroxaban.

Serious ALT elevations were more common with rivaroxaban (0.3% vs. 0.2%), as was a composite marker of liver injury (an ALT greater than three times the upper limit of normal with a total bilirubin greater than two times the upper limit of normal, in 0.15% vs. 0.11%), but these were not significant differences.

The consumer representative on the panel was Dr. Sidney Wolfe, director of the Public Citizen Health Research Group. He voted no on the risk-benefit question and said he was concerned about the bleeding risk and was “very uncomfortable about the certainty of long-term use and the absence of long-term safety data on hepatoxicity.” Because there is no need for a regular blood test, as there is with warfarin, he expects it will be used “massively” for off-label indications for which there are no data.

The panel chair, Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic Foundation, who was among the majority in favor of the risk-benefit profile, said that “the liver issue is not completely resolved, but I believe the signal for liver injury is very weak” but should be followed.

Rivaroxaban is also being studied for other indications in ongoing trials, including acute coronary syndromes, secondary prevention and long-term treatment of patients who have had a DVT or PE, and prevention of stroke and noncentral nervous system embolism in patients with nonvalvular atrial fibrillation.

ADELPHI, MD. — A federal panel agreed that data on the oral anticoagulant rivaroxaban indicate that the drug's benefits in preventing venous thromboembolic events after hip and knee replacement surgery outweigh its potential risks of excess bleeding and potential risk of severe hepatotoxicity.

The Food and Drug Administration's Cardiovascular and Renal Drugs Advisory Committee voted 15–2 that data from four clinical trials showed that rivaroxaban has a favorable risk-benefit profile for the proposed indication—prophylaxis of venous thromboembolism (VTE) in patients undergoing hip or knee replacement surgery. The recommended dosage schedule is 10 mg once daily, for 35 days after hip surgery or 14 days after knee replacement.

Most panelists agreed that potential hepatoxicity should not preclude approval, although long-term data on hepatoxicity are critically needed. Panelists, who were concerned about off-label use of the drug, emphasized the importance of advising clinicians to avoid prescribing the drug for longer periods and for other uses, and of continuing to follow patients on rivaroxaban in clinical trials and clinical practice for hepatoxicity.

If approved, rivaroxaban, an oral, direct Factor Xa inhibitor made by Johnson & Johnson Pharmaceutical Research & Development LLC, would be marketed as Xarelto. It would be the first oral anticoagulant approved for these indications, as well as the first oral anticoagulant approved since warfarin. The drug works by inhibiting direct Factor Xa, which lowers thrombin production and prolongs prothrombin time. The FDA usually follows the recommendations of its advisory panels.

The proposed regimen was compared with enoxaparin in four international studies of more than 12,000 patients (6,183 patients on rivaroxaban) after total hip or knee replacement surgery. Patients with significant liver disease were excluded. The composite end point of venographic evidence of deep vein thrombosis (DVT), nonfatal pulmonary embolus (PE), or death was significantly lower in those treated with rivaroxaban, but patients on the drug had a higher rate of bleeding. The major bleeding rate was 0.4% in those on rivaroxaban and 0.2% in those on enoxaparin. The one bleeding-related death in the studies was in a patient on rivaroxaban.

Serious ALT elevations were more common with rivaroxaban (0.3% vs. 0.2%), as was a composite marker of liver injury (an ALT greater than three times the upper limit of normal with a total bilirubin greater than two times the upper limit of normal, in 0.15% vs. 0.11%), but these were not significant differences.

The consumer representative on the panel was Dr. Sidney Wolfe, director of the Public Citizen Health Research Group. He voted no on the risk-benefit question and said he was concerned about the bleeding risk and was “very uncomfortable about the certainty of long-term use and the absence of long-term safety data on hepatoxicity.” Because there is no need for a regular blood test, as there is with warfarin, he expects it will be used “massively” for off-label indications for which there are no data.

The panel chair, Dr. A. Michael Lincoff, professor of medicine at the Cleveland Clinic Foundation, who was among the majority in favor of the risk-benefit profile, said that “the liver issue is not completely resolved, but I believe the signal for liver injury is very weak” but should be followed.

Rivaroxaban is also being studied for other indications in ongoing trials, including acute coronary syndromes, secondary prevention and long-term treatment of patients who have had a DVT or PE, and prevention of stroke and noncentral nervous system embolism in patients with nonvalvular atrial fibrillation.

SILVER SPRING, MD. — The idea of adding a second influenza type B strain to the seasonal influenza vaccine was met with generally positive responses by vaccine experts who discussed the utility of a quadrivalent vaccine at a meeting convened by the Food and Drug Administration.

The FDA's Vaccines and Related Biological Products Advisory Committee discussed the pros and cons of adding a second B component to the vaccine, but it did not vote on the issue or make any formal recommendations to the FDA.

Since 2000, the two cocirculating lineages of influenza B viruses (B/Yamaguchi and B/Victoria) have become more antigenically distinct, raising the issue of whether adding a second B strain to the seasonal flu vaccine would have a positive public health benefit, Rakesh Pandey, Ph.D., of the FDA's Division of Vaccines and Related Products Applications, said at the meeting.

Cocirculation of the two B lineages means that “some degree of mismatch between a vaccine and circulating strain is inevitable,” which can reduce the effectiveness of the trivalent vaccine as well as public confidence in the vaccine, pointed out Carrie Reed, D.Sc., of the Centers for Disease Control and Prevention, who also spoke at the meeting.

The current trivalent seasonal flu vaccine includes two influenza A strains (H1N1 and H3N2) and a B strain.

Among the issues that need to be considered before a second B strain is added include the clinical data needed to establish the safety and immunogenicity of a vaccine with two B strains; the public health impact and cost; and whether better coverage of influenza B would make up for potential delays in manufacturing and vaccine availability, according to Dr. Pandey. Another issue is whether the quadrivalent vaccine could be targeted to subpopulations, such as children and the elderly.

B strains are harder to grow than A strains, which could delay the availability of the influenza vaccine. However, the manufacturing capacity of influenza vaccine has markedly increased over the past 4–5 years, so manufacturers may be able to adjust to adding another component to the vaccine, Dr. Pandey noted.

Dr. Reed presented the results of a CDC analysis, conducted at the request of the FDA, on the impact that a second B strain would have had on the last 10 flu seasons in the United States. The analysis used a model that averaged all ages, and calculated the burden of influenza during each season by type, subtype, and lineage. The model did not include cost estimates.

Considering that B viruses do not grow as well as A viruses, about 25% less vaccine would be produced if a second B component were added to the vaccine, she said. This could have a negative impact on seasons in which supply of the influenza vaccine is similar to the demand, but for seasons in which supply exceeds the demand, the amount of quadrivalent vaccine available would still exceed the amount of vaccine administered, she pointed out.

For example, during the 2007–2008 influenza season, type B strains accounted for 29% of the virus tested, and 98% of the B strains tested were not the lineage included in that season's vaccine. Based on these data, the CDC analysis estimated that there would have been more than 1 million fewer cases of influenza, almost 7,500 fewer influenza-related hospitalizations, and about 320 fewer deaths if a quadrivalent vaccine had been available, Dr. Reed said. There was an excess supply of vaccine that season, so the lower number of vaccine produced would not have had a negative impact on coverage, she added.

During 2005–2006, about 20% of the circulating strains were influenza B viruses, and 78% of the strains were not the lineage in the vaccine. There would have been fewer doses of a quadrivalent vaccine, so an estimated 8% fewer people would have been vaccinated. Because of a better match provided by a quadrivalent vaccine, there would be an estimated 440,841 fewer cases because of the better match, but 298,204 more cases because of less coverage—a net benefit of 142,637 fewer cases, she said.

But for a season like 2004–2005, when there were problems with manufacturing that affected the supply and when the supply was similar to the demand, an estimated 15% fewer people would have been vaccinated if the vaccine had been a quadrivalent one. That season, 25% of the circulating strains were type B, and 26% of those B strains were the lineage not included in the vaccine. Considering these data and the supply issue, there would have been an estimated net increase of 151,566 cases of influenza if a quadrivalent vaccine had been used, according to Dr. Reed.

Several panelists said that information on the cost-benefit of a quadrivalent vaccine was crucial, because increased cost could affect immunization rates. Dr. Reed acknowledged the limitations of the model used in the CDC's analysis, which focused on the public health impact of a quadrivalent vaccine and did not include an analysis on the cost-benefit, did not consider potential adverse events associated with adding a second B component, and did not analyze different age groups separately, data that other panelists agreed were needed.

Several panelists also referred to the limited data on the effectiveness of the B component of the influenza vaccine. Because there are “very, very few pure” influenza B years, “we get used to equating influenza B effectiveness with what we know about influenza A effectiveness … but that may be totally erroneous,” said panelist Dr. Theodore Eickhoff, professor emeritus in the division of infectious diseases, University of Colorado Health Sciences Center, Aurora.

Referring to the two cocirculating B virus lineages over the past few seasons, Dr. Roland Levandowski, an infectious disease specialist in Bethesda, Md., remarked, “If we go to the trouble of immunizing against” two influenza A strains, “then we should have a vaccine with coverage against both B strains.”

At the close of the meeting, the panel chair, Dr. John Modlin, professor of pediatrics at Dartmouth-Hitchcock Medical Center, Lebanon, N.H., summarized the attitude of the panel regarding the prospect of a quadrivalent vaccine as “a qualified thumbs-up.”

A model that incorporates age-specific influenza rates, morbidity, and other factors for determining the public health impact of a quadrivalent vaccine is clearly needed, Dr. Modlin said. “Hopefully, the committee has sent the message it would like to see the CDC model work continued,” he added.

SILVER SPRING, MD. — The idea of adding a second influenza type B strain to the seasonal influenza vaccine was met with generally positive responses by vaccine experts who discussed the utility of a quadrivalent vaccine at a meeting convened by the Food and Drug Administration.

The FDA's Vaccines and Related Biological Products Advisory Committee discussed the pros and cons of adding a second B component to the vaccine, but it did not vote on the issue or make any formal recommendations to the FDA.

Since 2000, the two cocirculating lineages of influenza B viruses (B/Yamaguchi and B/Victoria) have become more antigenically distinct, raising the issue of whether adding a second B strain to the seasonal flu vaccine would have a positive public health benefit, Rakesh Pandey, Ph.D., of the FDA's Division of Vaccines and Related Products Applications, said at the meeting.

Cocirculation of the two B lineages means that “some degree of mismatch between a vaccine and circulating strain is inevitable,” which can reduce the effectiveness of the trivalent vaccine as well as public confidence in the vaccine, pointed out Carrie Reed, D.Sc., of the Centers for Disease Control and Prevention, who also spoke at the meeting.

The current trivalent seasonal flu vaccine includes two influenza A strains (H1N1 and H3N2) and a B strain.

Among the issues that need to be considered before a second B strain is added include the clinical data needed to establish the safety and immunogenicity of a vaccine with two B strains; the public health impact and cost; and whether better coverage of influenza B would make up for potential delays in manufacturing and vaccine availability, according to Dr. Pandey. Another issue is whether the quadrivalent vaccine could be targeted to subpopulations, such as children and the elderly.

B strains are harder to grow than A strains, which could delay the availability of the influenza vaccine. However, the manufacturing capacity of influenza vaccine has markedly increased over the past 4–5 years, so manufacturers may be able to adjust to adding another component to the vaccine, Dr. Pandey noted.

Dr. Reed presented the results of a CDC analysis, conducted at the request of the FDA, on the impact that a second B strain would have had on the last 10 flu seasons in the United States. The analysis used a model that averaged all ages, and calculated the burden of influenza during each season by type, subtype, and lineage. The model did not include cost estimates.

Considering that B viruses do not grow as well as A viruses, about 25% less vaccine would be produced if a second B component were added to the vaccine, she said. This could have a negative impact on seasons in which supply of the influenza vaccine is similar to the demand, but for seasons in which supply exceeds the demand, the amount of quadrivalent vaccine available would still exceed the amount of vaccine administered, she pointed out.

For example, during the 2007–2008 influenza season, type B strains accounted for 29% of the virus tested, and 98% of the B strains tested were not the lineage included in that season's vaccine. Based on these data, the CDC analysis estimated that there would have been more than 1 million fewer cases of influenza, almost 7,500 fewer influenza-related hospitalizations, and about 320 fewer deaths if a quadrivalent vaccine had been available, Dr. Reed said. There was an excess supply of vaccine that season, so the lower number of vaccine produced would not have had a negative impact on coverage, she added.

During 2005–2006, about 20% of the circulating strains were influenza B viruses, and 78% of the strains were not the lineage in the vaccine. There would have been fewer doses of a quadrivalent vaccine, so an estimated 8% fewer people would have been vaccinated. Because of a better match provided by a quadrivalent vaccine, there would be an estimated 440,841 fewer cases because of the better match, but 298,204 more cases because of less coverage—a net benefit of 142,637 fewer cases, she said.

But for a season like 2004–2005, when there were problems with manufacturing that affected the supply and when the supply was similar to the demand, an estimated 15% fewer people would have been vaccinated if the vaccine had been a quadrivalent one. That season, 25% of the circulating strains were type B, and 26% of those B strains were the lineage not included in the vaccine. Considering these data and the supply issue, there would have been an estimated net increase of 151,566 cases of influenza if a quadrivalent vaccine had been used, according to Dr. Reed.

Several panelists said that information on the cost-benefit of a quadrivalent vaccine was crucial, because increased cost could affect immunization rates. Dr. Reed acknowledged the limitations of the model used in the CDC's analysis, which focused on the public health impact of a quadrivalent vaccine and did not include an analysis on the cost-benefit, did not consider potential adverse events associated with adding a second B component, and did not analyze different age groups separately, data that other panelists agreed were needed.

Several panelists also referred to the limited data on the effectiveness of the B component of the influenza vaccine. Because there are “very, very few pure” influenza B years, “we get used to equating influenza B effectiveness with what we know about influenza A effectiveness … but that may be totally erroneous,” said panelist Dr. Theodore Eickhoff, professor emeritus in the division of infectious diseases, University of Colorado Health Sciences Center, Aurora.

Referring to the two cocirculating B virus lineages over the past few seasons, Dr. Roland Levandowski, an infectious disease specialist in Bethesda, Md., remarked, “If we go to the trouble of immunizing against” two influenza A strains, “then we should have a vaccine with coverage against both B strains.”

At the close of the meeting, the panel chair, Dr. John Modlin, professor of pediatrics at Dartmouth-Hitchcock Medical Center, Lebanon, N.H., summarized the attitude of the panel regarding the prospect of a quadrivalent vaccine as “a qualified thumbs-up.”

A model that incorporates age-specific influenza rates, morbidity, and other factors for determining the public health impact of a quadrivalent vaccine is clearly needed, Dr. Modlin said. “Hopefully, the committee has sent the message it would like to see the CDC model work continued,” he added.

SILVER SPRING, MD. — The idea of adding a second influenza type B strain to the seasonal influenza vaccine was met with generally positive responses by vaccine experts who discussed the utility of a quadrivalent vaccine at a meeting convened by the Food and Drug Administration.

The FDA's Vaccines and Related Biological Products Advisory Committee discussed the pros and cons of adding a second B component to the vaccine, but it did not vote on the issue or make any formal recommendations to the FDA.

Since 2000, the two cocirculating lineages of influenza B viruses (B/Yamaguchi and B/Victoria) have become more antigenically distinct, raising the issue of whether adding a second B strain to the seasonal flu vaccine would have a positive public health benefit, Rakesh Pandey, Ph.D., of the FDA's Division of Vaccines and Related Products Applications, said at the meeting.

Cocirculation of the two B lineages means that “some degree of mismatch between a vaccine and circulating strain is inevitable,” which can reduce the effectiveness of the trivalent vaccine as well as public confidence in the vaccine, pointed out Carrie Reed, D.Sc., of the Centers for Disease Control and Prevention, who also spoke at the meeting.

The current trivalent seasonal flu vaccine includes two influenza A strains (H1N1 and H3N2) and a B strain.

Among the issues that need to be considered before a second B strain is added include the clinical data needed to establish the safety and immunogenicity of a vaccine with two B strains; the public health impact and cost; and whether better coverage of influenza B would make up for potential delays in manufacturing and vaccine availability, according to Dr. Pandey. Another issue is whether the quadrivalent vaccine could be targeted to subpopulations, such as children and the elderly.

B strains are harder to grow than A strains, which could delay the availability of the influenza vaccine. However, the manufacturing capacity of influenza vaccine has markedly increased over the past 4–5 years, so manufacturers may be able to adjust to adding another component to the vaccine, Dr. Pandey noted.

Dr. Reed presented the results of a CDC analysis, conducted at the request of the FDA, on the impact that a second B strain would have had on the last 10 flu seasons in the United States. The analysis used a model that averaged all ages, and calculated the burden of influenza during each season by type, subtype, and lineage. The model did not include cost estimates.

Considering that B viruses do not grow as well as A viruses, about 25% less vaccine would be produced if a second B component were added to the vaccine, she said. This could have a negative impact on seasons in which supply of the influenza vaccine is similar to the demand, but for seasons in which supply exceeds the demand, the amount of quadrivalent vaccine available would still exceed the amount of vaccine administered, she pointed out.

For example, during the 2007–2008 influenza season, type B strains accounted for 29% of the virus tested, and 98% of the B strains tested were not the lineage included in that season's vaccine. Based on these data, the CDC analysis estimated that there would have been more than 1 million fewer cases of influenza, almost 7,500 fewer influenza-related hospitalizations, and about 320 fewer deaths if a quadrivalent vaccine had been available, Dr. Reed said. There was an excess supply of vaccine that season, so the lower number of vaccine produced would not have had a negative impact on coverage, she added.

During 2005–2006, about 20% of the circulating strains were influenza B viruses, and 78% of the strains were not the lineage in the vaccine. There would have been fewer doses of a quadrivalent vaccine, so an estimated 8% fewer people would have been vaccinated. Because of a better match provided by a quadrivalent vaccine, there would be an estimated 440,841 fewer cases because of the better match, but 298,204 more cases because of less coverage—a net benefit of 142,637 fewer cases, she said.

But for a season like 2004–2005, when there were problems with manufacturing that affected the supply and when the supply was similar to the demand, an estimated 15% fewer people would have been vaccinated if the vaccine had been a quadrivalent one. That season, 25% of the circulating strains were type B, and 26% of those B strains were the lineage not included in the vaccine. Considering these data and the supply issue, there would have been an estimated net increase of 151,566 cases of influenza if a quadrivalent vaccine had been used, according to Dr. Reed.

Several panelists said that information on the cost-benefit of a quadrivalent vaccine was crucial, because increased cost could affect immunization rates. Dr. Reed acknowledged the limitations of the model used in the CDC's analysis, which focused on the public health impact of a quadrivalent vaccine and did not include an analysis on the cost-benefit, did not consider potential adverse events associated with adding a second B component, and did not analyze different age groups separately, data that other panelists agreed were needed.

Several panelists also referred to the limited data on the effectiveness of the B component of the influenza vaccine. Because there are “very, very few pure” influenza B years, “we get used to equating influenza B effectiveness with what we know about influenza A effectiveness … but that may be totally erroneous,” said panelist Dr. Theodore Eickhoff, professor emeritus in the division of infectious diseases, University of Colorado Health Sciences Center, Aurora.

Referring to the two cocirculating B virus lineages over the past few seasons, Dr. Roland Levandowski, an infectious disease specialist in Bethesda, Md., remarked, “If we go to the trouble of immunizing against” two influenza A strains, “then we should have a vaccine with coverage against both B strains.”

At the close of the meeting, the panel chair, Dr. John Modlin, professor of pediatrics at Dartmouth-Hitchcock Medical Center, Lebanon, N.H., summarized the attitude of the panel regarding the prospect of a quadrivalent vaccine as “a qualified thumbs-up.”

A model that incorporates age-specific influenza rates, morbidity, and other factors for determining the public health impact of a quadrivalent vaccine is clearly needed, Dr. Modlin said. “Hopefully, the committee has sent the message it would like to see the CDC model work continued,” he added.

Sherry Boschert contributed to this story.

Healthy men with a prostate-specific antigen score of 3.0 or lower should consider taking a 5-alpha reductase inhibitor to prevent prostate cancer, according to newly released clinical practice guidelines.

The guidelines, issued by the American Urological Association and the American Society of Clinical Oncology, apply to men who plan to get yearly PSA tests or regular prostate cancer screening and who have no signs of prostate cancer. In addition, for men who already are taking the drugs (to treat benign prostatic hyperplasia or male-pattern baldness, for example), physicians should discuss continuing the drug specifically to prevent prostate cancer (J. Urol. 2009;181:1642–57; J. Clin Oncol. 2009 Feb. 24 [doi:10.1200/JCO.2008.16.9599]; www.asco.org/guidelines

The guidelines are based on evidence from nine randomized, controlled clinical trials, including the Prostate Cancer Prevention Trial (PCPT). “That body of evidence provided proof” that the 5-alpha reductase inhibitors will decrease the risk of prostate cancer in men being regularly screened for the disease, Dr. Barnett S. Kramer said at a press conference held in conjunction with a symposium on genitourinary cancers.

All nine trials have enrolled men undergoing regular screening for prostate cancer. This fact is important, because it has been well-established that screening doubles the risk of being diagnosed with prostate cancer, added Dr. Kramer, cochair of the panel that produced the guidelines.

The PCPT found an overall 25% relative risk reduction for prostate cancer in men who took the 5-alpha reductase inhibitor finasteride for 1–7 years. Because most of the men in this study were white, the results “principally apply only to white men,” he noted, adding that subanalyses found no substantive differences among racial or ethnic groups.

It's not clear whether preventive treatment will affect mortality from prostate cancer or whether doses lower than those currently used would be effective in prevention, said Dr. Kramer, associate director of disease prevention at the National Institutes of Health. In addition, “we can't be confident of its effect in men who choose not to be screened.”

The 5-alpha reductase inhibitors are known to lower levels of dihydrotestosterone, which can contribute to prostate cancer growth. Their most common side effects include erectile dysfunction, decreased libido, and ejaculatory dysfunction, with rarer cases of gynecomastia.

When the PCPT was published, there was concern over what appeared to be an increase in the rate of high-grade tumors diagnosed among those randomized to finasteride (37% of the prostate cancers in the finasteride arm were high grade, vs. 22% of those in the placebo arm). But a subsequent analysis determined this increase was likely to be spurious, Dr. Kramer said, adding that his comments represented those of ASCO and the AUA, not the U.S. government or NIH.

Although Dr. Kramer said he believed that cost needs to be part of this discussion, the available data were not strong enough to calculate cost-effectiveness.

Currently, approximately one in six U.S. men gets diagnosed with prostate cancer, the second-leading cause of death from cancer in men and, after skin cancer, the most common cancer diagnosed in men in the United States.

He pointed out that prostate cancer rates in the United States are among the highest in the world. In addition, since the principal driver of prostate cancer risk is age, the recommendations target “healthy men who fulfill risk criteria by virtue of age.”

The guidelines could apply to millions of men. During the briefing, Dr. Howard Sandler, a prostate cancer specialist at Cedars-Sinai Medical Center in Los Angeles, said he expects there will be many different attitudes about taking a pill every day “for preventing a condition that may not occur.”

He said he personally might consider a trial of over a month, and if he developed side effects to the drug, it would not be worth the potential benefits. But if he did not develop adverse effects, “ultimately, I would become reassured that taking one pill per day … might decrease my risk for prostate cancer,” he said, adding that he had not yet decided whether to pursue such preventive treatment.

The ASCO Web site offers physicians a “Decision Aid Tool,” composed of charts and diagrams to help explain the risks and benefits of 5-alpha reductase inhibitors to patients and their families. ASCO also has produced a corresponding patient guide, which is available at www.cancer.net

Dr. Schellhammer has received research funds or support from GlaxoSmithKline, which markets the 5-alpha reductase inhibitor dutasteride, and from other pharmaceutical companies. Dr. Kramer has no conflicts of interest related to the guidelines.

The annual Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology, and Society of Urologic Oncology.

Sherry Boschert contributed to this story.

Healthy men with a prostate-specific antigen score of 3.0 or lower should consider taking a 5-alpha reductase inhibitor to prevent prostate cancer, according to newly released clinical practice guidelines.

The guidelines, issued by the American Urological Association and the American Society of Clinical Oncology, apply to men who plan to get yearly PSA tests or regular prostate cancer screening and who have no signs of prostate cancer. In addition, for men who already are taking the drugs (to treat benign prostatic hyperplasia or male-pattern baldness, for example), physicians should discuss continuing the drug specifically to prevent prostate cancer (J. Urol. 2009;181:1642–57; J. Clin Oncol. 2009 Feb. 24 [doi:10.1200/JCO.2008.16.9599]; www.asco.org/guidelines

The guidelines are based on evidence from nine randomized, controlled clinical trials, including the Prostate Cancer Prevention Trial (PCPT). “That body of evidence provided proof” that the 5-alpha reductase inhibitors will decrease the risk of prostate cancer in men being regularly screened for the disease, Dr. Barnett S. Kramer said at a press conference held in conjunction with a symposium on genitourinary cancers.

All nine trials have enrolled men undergoing regular screening for prostate cancer. This fact is important, because it has been well-established that screening doubles the risk of being diagnosed with prostate cancer, added Dr. Kramer, cochair of the panel that produced the guidelines.

The PCPT found an overall 25% relative risk reduction for prostate cancer in men who took the 5-alpha reductase inhibitor finasteride for 1–7 years. Because most of the men in this study were white, the results “principally apply only to white men,” he noted, adding that subanalyses found no substantive differences among racial or ethnic groups.

It's not clear whether preventive treatment will affect mortality from prostate cancer or whether doses lower than those currently used would be effective in prevention, said Dr. Kramer, associate director of disease prevention at the National Institutes of Health. In addition, “we can't be confident of its effect in men who choose not to be screened.”

The 5-alpha reductase inhibitors are known to lower levels of dihydrotestosterone, which can contribute to prostate cancer growth. Their most common side effects include erectile dysfunction, decreased libido, and ejaculatory dysfunction, with rarer cases of gynecomastia.

When the PCPT was published, there was concern over what appeared to be an increase in the rate of high-grade tumors diagnosed among those randomized to finasteride (37% of the prostate cancers in the finasteride arm were high grade, vs. 22% of those in the placebo arm). But a subsequent analysis determined this increase was likely to be spurious, Dr. Kramer said, adding that his comments represented those of ASCO and the AUA, not the U.S. government or NIH.

Although Dr. Kramer said he believed that cost needs to be part of this discussion, the available data were not strong enough to calculate cost-effectiveness.

Currently, approximately one in six U.S. men gets diagnosed with prostate cancer, the second-leading cause of death from cancer in men and, after skin cancer, the most common cancer diagnosed in men in the United States.

He pointed out that prostate cancer rates in the United States are among the highest in the world. In addition, since the principal driver of prostate cancer risk is age, the recommendations target “healthy men who fulfill risk criteria by virtue of age.”

The guidelines could apply to millions of men. During the briefing, Dr. Howard Sandler, a prostate cancer specialist at Cedars-Sinai Medical Center in Los Angeles, said he expects there will be many different attitudes about taking a pill every day “for preventing a condition that may not occur.”

He said he personally might consider a trial of over a month, and if he developed side effects to the drug, it would not be worth the potential benefits. But if he did not develop adverse effects, “ultimately, I would become reassured that taking one pill per day … might decrease my risk for prostate cancer,” he said, adding that he had not yet decided whether to pursue such preventive treatment.

The ASCO Web site offers physicians a “Decision Aid Tool,” composed of charts and diagrams to help explain the risks and benefits of 5-alpha reductase inhibitors to patients and their families. ASCO also has produced a corresponding patient guide, which is available at www.cancer.net

Dr. Schellhammer has received research funds or support from GlaxoSmithKline, which markets the 5-alpha reductase inhibitor dutasteride, and from other pharmaceutical companies. Dr. Kramer has no conflicts of interest related to the guidelines.

The annual Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology, and Society of Urologic Oncology.

Sherry Boschert contributed to this story.

Healthy men with a prostate-specific antigen score of 3.0 or lower should consider taking a 5-alpha reductase inhibitor to prevent prostate cancer, according to newly released clinical practice guidelines.

The guidelines, issued by the American Urological Association and the American Society of Clinical Oncology, apply to men who plan to get yearly PSA tests or regular prostate cancer screening and who have no signs of prostate cancer. In addition, for men who already are taking the drugs (to treat benign prostatic hyperplasia or male-pattern baldness, for example), physicians should discuss continuing the drug specifically to prevent prostate cancer (J. Urol. 2009;181:1642–57; J. Clin Oncol. 2009 Feb. 24 [doi:10.1200/JCO.2008.16.9599]; www.asco.org/guidelines

The guidelines are based on evidence from nine randomized, controlled clinical trials, including the Prostate Cancer Prevention Trial (PCPT). “That body of evidence provided proof” that the 5-alpha reductase inhibitors will decrease the risk of prostate cancer in men being regularly screened for the disease, Dr. Barnett S. Kramer said at a press conference held in conjunction with a symposium on genitourinary cancers.

All nine trials have enrolled men undergoing regular screening for prostate cancer. This fact is important, because it has been well-established that screening doubles the risk of being diagnosed with prostate cancer, added Dr. Kramer, cochair of the panel that produced the guidelines.

The PCPT found an overall 25% relative risk reduction for prostate cancer in men who took the 5-alpha reductase inhibitor finasteride for 1–7 years. Because most of the men in this study were white, the results “principally apply only to white men,” he noted, adding that subanalyses found no substantive differences among racial or ethnic groups.

It's not clear whether preventive treatment will affect mortality from prostate cancer or whether doses lower than those currently used would be effective in prevention, said Dr. Kramer, associate director of disease prevention at the National Institutes of Health. In addition, “we can't be confident of its effect in men who choose not to be screened.”

The 5-alpha reductase inhibitors are known to lower levels of dihydrotestosterone, which can contribute to prostate cancer growth. Their most common side effects include erectile dysfunction, decreased libido, and ejaculatory dysfunction, with rarer cases of gynecomastia.

When the PCPT was published, there was concern over what appeared to be an increase in the rate of high-grade tumors diagnosed among those randomized to finasteride (37% of the prostate cancers in the finasteride arm were high grade, vs. 22% of those in the placebo arm). But a subsequent analysis determined this increase was likely to be spurious, Dr. Kramer said, adding that his comments represented those of ASCO and the AUA, not the U.S. government or NIH.

Although Dr. Kramer said he believed that cost needs to be part of this discussion, the available data were not strong enough to calculate cost-effectiveness.

Currently, approximately one in six U.S. men gets diagnosed with prostate cancer, the second-leading cause of death from cancer in men and, after skin cancer, the most common cancer diagnosed in men in the United States.

He pointed out that prostate cancer rates in the United States are among the highest in the world. In addition, since the principal driver of prostate cancer risk is age, the recommendations target “healthy men who fulfill risk criteria by virtue of age.”

The guidelines could apply to millions of men. During the briefing, Dr. Howard Sandler, a prostate cancer specialist at Cedars-Sinai Medical Center in Los Angeles, said he expects there will be many different attitudes about taking a pill every day “for preventing a condition that may not occur.”

He said he personally might consider a trial of over a month, and if he developed side effects to the drug, it would not be worth the potential benefits. But if he did not develop adverse effects, “ultimately, I would become reassured that taking one pill per day … might decrease my risk for prostate cancer,” he said, adding that he had not yet decided whether to pursue such preventive treatment.

The ASCO Web site offers physicians a “Decision Aid Tool,” composed of charts and diagrams to help explain the risks and benefits of 5-alpha reductase inhibitors to patients and their families. ASCO also has produced a corresponding patient guide, which is available at www.cancer.net

Dr. Schellhammer has received research funds or support from GlaxoSmithKline, which markets the 5-alpha reductase inhibitor dutasteride, and from other pharmaceutical companies. Dr. Kramer has no conflicts of interest related to the guidelines.

The annual Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology, and Society of Urologic Oncology.

A molecular urine test that detects the fusion of two genes associated with more aggressive prostate cancers was highly specific for prostate cancer in a study in men undergoing prostate biopsies, investigators report based on an interim review.

The test, which is not available commercially, detects fusions between TMPRSS2 (T2), an androgen-responsive gene, and the oncogenic transcription factor ERG. This fusion is found in about half of all prostate tumors, and has been associated with adverse clinical outcomes.

Initially reported at the end of 2005, this fusion was the first specific chromosomal rearrangement identified in prostate tumors, and appears to be “an ideal target for a diagnostic test because of the high specificity for prostate cancer,” according to Jack Groskopf, Ph.D., director of research and development in the cancer diagnostics division of Gen-Probe Inc., the San Diego-based company developing the test.

The test, known as the T2:ERG test, may eventually be useful in determining prognosis and selecting treatment in men diagnosed with prostate cancer, Dr. Groskopf said at a press briefing in advance of the study's presentation at a symposium on genitourinary cancers. He cited the need for a test that can help determine which prostate cancers require aggressive treatment and which could be managed conservatively.

To date, the test has been used on urine specimens collected in 556 men at three medical centers following a digital rectal exam and before prostate biopsy. The test predicted the presence of prostate cancer on biopsy with a specificity of 84%, compared with a specificity of 27% for serum prostate-specific antigen (PSA), with similar results at all three sites, he said.

The gene fusion has been present in about 42% of all positive biopsies to date, an indication that the test is “doing pretty well” in terms of sensitivity, as this correlates to the prevalence of the gene fusion in about half of all prostate cancers, he noted.

In addition, there have been significant correlations between a positive test and indicators of cancer aggressiveness, Gleason score, percent of prostate cancer involvement, and percent positive core, providing preliminary evidence indicating that T2:ERG status correlates with the criteria for aggressive cancers, he said.

The next step is to follow up and confirm these findings, and “perhaps more importantly,” to start studying the correlation between the urine test and pathologic features in prostatectomy tissue, such as tumor volume, stage, and grade, Dr. Groskopf said.

Describing this work as an “important first step,” Dr. Howard Sandler, moderator of the briefing, remarked that it represents “an amazingly short interval between the basic fundamental discovery and potential clinical utility of a diagnostic test.”

If it turns out that gene fusion is related to progression of prostate cancer in half of all men who develop prostate cancer, the molecular change will have major implications for diagnosis and possibly treatment as well, because it may also be a therapeutic target, said Dr. Sandler, chairman of radiation oncology at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles. “There is interest in targeting our diagnostic strategies towards patients who will have cancers that really need to be treated, not those that are overdiagnosed and are never destined to cause clinical harm,” he added.

The annual Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology, and Society of Urologic Oncology.

A molecular urine test that detects the fusion of two genes associated with more aggressive prostate cancers was highly specific for prostate cancer in a study in men undergoing prostate biopsies, investigators report based on an interim review.

The test, which is not available commercially, detects fusions between TMPRSS2 (T2), an androgen-responsive gene, and the oncogenic transcription factor ERG. This fusion is found in about half of all prostate tumors, and has been associated with adverse clinical outcomes.

Initially reported at the end of 2005, this fusion was the first specific chromosomal rearrangement identified in prostate tumors, and appears to be “an ideal target for a diagnostic test because of the high specificity for prostate cancer,” according to Jack Groskopf, Ph.D., director of research and development in the cancer diagnostics division of Gen-Probe Inc., the San Diego-based company developing the test.

The test, known as the T2:ERG test, may eventually be useful in determining prognosis and selecting treatment in men diagnosed with prostate cancer, Dr. Groskopf said at a press briefing in advance of the study's presentation at a symposium on genitourinary cancers. He cited the need for a test that can help determine which prostate cancers require aggressive treatment and which could be managed conservatively.

To date, the test has been used on urine specimens collected in 556 men at three medical centers following a digital rectal exam and before prostate biopsy. The test predicted the presence of prostate cancer on biopsy with a specificity of 84%, compared with a specificity of 27% for serum prostate-specific antigen (PSA), with similar results at all three sites, he said.

The gene fusion has been present in about 42% of all positive biopsies to date, an indication that the test is “doing pretty well” in terms of sensitivity, as this correlates to the prevalence of the gene fusion in about half of all prostate cancers, he noted.

In addition, there have been significant correlations between a positive test and indicators of cancer aggressiveness, Gleason score, percent of prostate cancer involvement, and percent positive core, providing preliminary evidence indicating that T2:ERG status correlates with the criteria for aggressive cancers, he said.

The next step is to follow up and confirm these findings, and “perhaps more importantly,” to start studying the correlation between the urine test and pathologic features in prostatectomy tissue, such as tumor volume, stage, and grade, Dr. Groskopf said.

Describing this work as an “important first step,” Dr. Howard Sandler, moderator of the briefing, remarked that it represents “an amazingly short interval between the basic fundamental discovery and potential clinical utility of a diagnostic test.”

If it turns out that gene fusion is related to progression of prostate cancer in half of all men who develop prostate cancer, the molecular change will have major implications for diagnosis and possibly treatment as well, because it may also be a therapeutic target, said Dr. Sandler, chairman of radiation oncology at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles. “There is interest in targeting our diagnostic strategies towards patients who will have cancers that really need to be treated, not those that are overdiagnosed and are never destined to cause clinical harm,” he added.

The annual Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology, and Society of Urologic Oncology.

A molecular urine test that detects the fusion of two genes associated with more aggressive prostate cancers was highly specific for prostate cancer in a study in men undergoing prostate biopsies, investigators report based on an interim review.

The test, which is not available commercially, detects fusions between TMPRSS2 (T2), an androgen-responsive gene, and the oncogenic transcription factor ERG. This fusion is found in about half of all prostate tumors, and has been associated with adverse clinical outcomes.

Initially reported at the end of 2005, this fusion was the first specific chromosomal rearrangement identified in prostate tumors, and appears to be “an ideal target for a diagnostic test because of the high specificity for prostate cancer,” according to Jack Groskopf, Ph.D., director of research and development in the cancer diagnostics division of Gen-Probe Inc., the San Diego-based company developing the test.

The test, known as the T2:ERG test, may eventually be useful in determining prognosis and selecting treatment in men diagnosed with prostate cancer, Dr. Groskopf said at a press briefing in advance of the study's presentation at a symposium on genitourinary cancers. He cited the need for a test that can help determine which prostate cancers require aggressive treatment and which could be managed conservatively.

To date, the test has been used on urine specimens collected in 556 men at three medical centers following a digital rectal exam and before prostate biopsy. The test predicted the presence of prostate cancer on biopsy with a specificity of 84%, compared with a specificity of 27% for serum prostate-specific antigen (PSA), with similar results at all three sites, he said.

The gene fusion has been present in about 42% of all positive biopsies to date, an indication that the test is “doing pretty well” in terms of sensitivity, as this correlates to the prevalence of the gene fusion in about half of all prostate cancers, he noted.

In addition, there have been significant correlations between a positive test and indicators of cancer aggressiveness, Gleason score, percent of prostate cancer involvement, and percent positive core, providing preliminary evidence indicating that T2:ERG status correlates with the criteria for aggressive cancers, he said.

The next step is to follow up and confirm these findings, and “perhaps more importantly,” to start studying the correlation between the urine test and pathologic features in prostatectomy tissue, such as tumor volume, stage, and grade, Dr. Groskopf said.

Describing this work as an “important first step,” Dr. Howard Sandler, moderator of the briefing, remarked that it represents “an amazingly short interval between the basic fundamental discovery and potential clinical utility of a diagnostic test.”

If it turns out that gene fusion is related to progression of prostate cancer in half of all men who develop prostate cancer, the molecular change will have major implications for diagnosis and possibly treatment as well, because it may also be a therapeutic target, said Dr. Sandler, chairman of radiation oncology at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles. “There is interest in targeting our diagnostic strategies towards patients who will have cancers that really need to be treated, not those that are overdiagnosed and are never destined to cause clinical harm,” he added.

The annual Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology, and Society of Urologic Oncology.

A low vitamin B₁₂ blood level was an independent and significant risk factor for having a pregnancy affected by a neural tube defect in a study of Irish women, in what the authors say is the first study to examine the risk of the birth defect associated with maternal B₁₂ concentration.

Their results have public health implications in terms of possible fortification of grains with B₁₂, although studies are needed to learn more about the safety of this approach and the optimal protective dose of B₁₂ in food, according to Anne M. Molloy, Ph.D., of Trinity College, Dublin and her associates.

The data indicated that most of neural tube defect (NTD) risk was limited to maternal B₁₂ levels of approximately 250 ng/L or less, with the possibility that the risk could be further lowered if the B₁₂ level was above 320-350 ng/L, the authors noted. Based on these findings, they recommended that women have a vitamin B₁₂ level above 300 ng/L before conceiving (Pediatrics 2009;123:917-23).

The other investigators were from the Health Research Board in Dublin and the National Institutes of Health. Because the neural tube defect rate in Ireland is high, NIH and Irish researchers have worked together on NTD studies.

The study compared B₁₂ levels in stored blood samples of three groups of Irish women, at a median 15 weeks' gestation, obtained between 1983 and 1990, before food was fortified with folic acid and when vitamin supplementation during pregnancy in Ireland was not common. Mandatory folic acid fortification of grains in the United States has reportedly reduced the incidence of NTDs by as much as 78%. But folic acid cannot prevent all NTDs and low maternal B₁₂ has previously been associated with a risk of NTDs, the authors wrote.

The three groups were composed as follows: 95 women with a pregnancy affected by a NTD (mean age 27 years) and 265 controls with a normal pregnancy (mean age 28 years); 107 women who had had a previous pregnancy affected by an NTD but were pregnant again with an unaffected pregnancy (mean age 32 years) and 414 controls (mean age 28 years); and 76 women during an affected pregnancy (mean age 27 years) and 222 controls (mean age 28 years).

When compared with controls, the B₁₂ levels were significantly lower among the women who had a pregnancy affected by a NTD, with levels below 250 ng/L associated with the greatest risk. The risk of having a pregnancy affected by an NTD was three times greater among women with B₁₂ concentrations below 200 ng/L, compared with those whose levels were above 400 ng/L.

Median B₁₂ concentrations among the affected women in all groups were 13%-19% lower than those with unaffected pregnancies, a significant difference.

Since B₁₂values were obtained at a median 15 weeks' gestation, at which time the level naturally would have dropped by about 20%-25%, “our data indicate that women should aim to enter pregnancy” with serum B₁₂ concentrations above 300 ng/L,” the authors concluded, adding that concentrations above 400 ng/L “might be desirable, although we found no statistically significant benefit,” for that value.

The researchers did an analysis to determine if the effects of B₁₂ and folate on NTD risk were independent, which found “little interaction between B₁₂ and folate,” they said. Mandatory fortification of grain products in the United States with folic acid, the synthetic version of the vitamin folate, has been reported to reduce NTD incidence by as much as 78%. But, “it is generally agreed that not all NTDs are preventable by folic acid,” according to the investigators, who had no relevant disclosures.

A low vitamin B₁₂ blood level was an independent and significant risk factor for having a pregnancy affected by a neural tube defect in a study of Irish women, in what the authors say is the first study to examine the risk of the birth defect associated with maternal B₁₂ concentration.

Their results have public health implications in terms of possible fortification of grains with B₁₂, although studies are needed to learn more about the safety of this approach and the optimal protective dose of B₁₂ in food, according to Anne M. Molloy, Ph.D., of Trinity College, Dublin and her associates.

The data indicated that most of neural tube defect (NTD) risk was limited to maternal B₁₂ levels of approximately 250 ng/L or less, with the possibility that the risk could be further lowered if the B₁₂ level was above 320-350 ng/L, the authors noted. Based on these findings, they recommended that women have a vitamin B₁₂ level above 300 ng/L before conceiving (Pediatrics 2009;123:917-23).

The other investigators were from the Health Research Board in Dublin and the National Institutes of Health. Because the neural tube defect rate in Ireland is high, NIH and Irish researchers have worked together on NTD studies.

The study compared B₁₂ levels in stored blood samples of three groups of Irish women, at a median 15 weeks' gestation, obtained between 1983 and 1990, before food was fortified with folic acid and when vitamin supplementation during pregnancy in Ireland was not common. Mandatory folic acid fortification of grains in the United States has reportedly reduced the incidence of NTDs by as much as 78%. But folic acid cannot prevent all NTDs and low maternal B₁₂ has previously been associated with a risk of NTDs, the authors wrote.

The three groups were composed as follows: 95 women with a pregnancy affected by a NTD (mean age 27 years) and 265 controls with a normal pregnancy (mean age 28 years); 107 women who had had a previous pregnancy affected by an NTD but were pregnant again with an unaffected pregnancy (mean age 32 years) and 414 controls (mean age 28 years); and 76 women during an affected pregnancy (mean age 27 years) and 222 controls (mean age 28 years).

When compared with controls, the B₁₂ levels were significantly lower among the women who had a pregnancy affected by a NTD, with levels below 250 ng/L associated with the greatest risk. The risk of having a pregnancy affected by an NTD was three times greater among women with B₁₂ concentrations below 200 ng/L, compared with those whose levels were above 400 ng/L.

Median B₁₂ concentrations among the affected women in all groups were 13%-19% lower than those with unaffected pregnancies, a significant difference.

Since B₁₂values were obtained at a median 15 weeks' gestation, at which time the level naturally would have dropped by about 20%-25%, “our data indicate that women should aim to enter pregnancy” with serum B₁₂ concentrations above 300 ng/L,” the authors concluded, adding that concentrations above 400 ng/L “might be desirable, although we found no statistically significant benefit,” for that value.

The researchers did an analysis to determine if the effects of B₁₂ and folate on NTD risk were independent, which found “little interaction between B₁₂ and folate,” they said. Mandatory fortification of grain products in the United States with folic acid, the synthetic version of the vitamin folate, has been reported to reduce NTD incidence by as much as 78%. But, “it is generally agreed that not all NTDs are preventable by folic acid,” according to the investigators, who had no relevant disclosures.

A low vitamin B₁₂ blood level was an independent and significant risk factor for having a pregnancy affected by a neural tube defect in a study of Irish women, in what the authors say is the first study to examine the risk of the birth defect associated with maternal B₁₂ concentration.

Their results have public health implications in terms of possible fortification of grains with B₁₂, although studies are needed to learn more about the safety of this approach and the optimal protective dose of B₁₂ in food, according to Anne M. Molloy, Ph.D., of Trinity College, Dublin and her associates.

The data indicated that most of neural tube defect (NTD) risk was limited to maternal B₁₂ levels of approximately 250 ng/L or less, with the possibility that the risk could be further lowered if the B₁₂ level was above 320-350 ng/L, the authors noted. Based on these findings, they recommended that women have a vitamin B₁₂ level above 300 ng/L before conceiving (Pediatrics 2009;123:917-23).

The other investigators were from the Health Research Board in Dublin and the National Institutes of Health. Because the neural tube defect rate in Ireland is high, NIH and Irish researchers have worked together on NTD studies.

The study compared B₁₂ levels in stored blood samples of three groups of Irish women, at a median 15 weeks' gestation, obtained between 1983 and 1990, before food was fortified with folic acid and when vitamin supplementation during pregnancy in Ireland was not common. Mandatory folic acid fortification of grains in the United States has reportedly reduced the incidence of NTDs by as much as 78%. But folic acid cannot prevent all NTDs and low maternal B₁₂ has previously been associated with a risk of NTDs, the authors wrote.

The three groups were composed as follows: 95 women with a pregnancy affected by a NTD (mean age 27 years) and 265 controls with a normal pregnancy (mean age 28 years); 107 women who had had a previous pregnancy affected by an NTD but were pregnant again with an unaffected pregnancy (mean age 32 years) and 414 controls (mean age 28 years); and 76 women during an affected pregnancy (mean age 27 years) and 222 controls (mean age 28 years).

When compared with controls, the B₁₂ levels were significantly lower among the women who had a pregnancy affected by a NTD, with levels below 250 ng/L associated with the greatest risk. The risk of having a pregnancy affected by an NTD was three times greater among women with B₁₂ concentrations below 200 ng/L, compared with those whose levels were above 400 ng/L.

Median B₁₂ concentrations among the affected women in all groups were 13%-19% lower than those with unaffected pregnancies, a significant difference.

Since B₁₂values were obtained at a median 15 weeks' gestation, at which time the level naturally would have dropped by about 20%-25%, “our data indicate that women should aim to enter pregnancy” with serum B₁₂ concentrations above 300 ng/L,” the authors concluded, adding that concentrations above 400 ng/L “might be desirable, although we found no statistically significant benefit,” for that value.

The researchers did an analysis to determine if the effects of B₁₂ and folate on NTD risk were independent, which found “little interaction between B₁₂ and folate,” they said. Mandatory fortification of grain products in the United States with folic acid, the synthetic version of the vitamin folate, has been reported to reduce NTD incidence by as much as 78%. But, “it is generally agreed that not all NTDs are preventable by folic acid,” according to the investigators, who had no relevant disclosures.

A Dutch study of 5,176 men found four factors to be helpful in predicting a man's risk of developing prostate cancer: serum prostate-specific antigen, a previous negative biopsy of the prostate, family history of prostate cancer, and prostate volume.

“PSA assessments combined with the other common predictive factors may offer a personalized assessment of a man's risk of future prostate cancer,” coauthor Monique J. Roobol, Ph.D., said at a briefing before the study's presentation at a symposium on genitourinary cancers.

The men, aged 55–75 years at baseline, were from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. They were screened every 4 years for prostate cancer.

Using multivariate modeling, with data on factors at baseline and prostate cancer 4 years later, the investigators determined that PSA “is still the most significant predictor … but there are other factors that also contribute to risk estimation,” said Dr. Roobol, an epidemiologist in urologic oncology at Erasmus Medical Center, Rotterdam, the Netherlands.

The average risk of developing biopsy-detectable prostate cancer over 4 years was 5.1% at an average PSA level of 1.5 ng/mL in the study, so men with a serum PSA level above 1.5 ng/mL are at an above-average risk of developing prostate cancer over 4 years—and are at a sevenfold greater risk than are those with levels below this level, Dr. Roobol said.

Other risk factors were found to modify this threshold level: The risk of prostate cancer increases if there is a positive family history of prostate cancer, but decreases with an increasing prostate volume at the same PSA level. Risk also decreases if a man ever had a negative prostate biopsy, she said.

For example, a man with a high serum PSA, a positive family history, a small prostate, and no previous negative biopsy was at a higher than average risk, while a man with a low serum PSA and no additional risk factors was at a very low risk, which increased if he had a positive family history, she explained.

To illustrate the effect of prostate volume on PSA level (with a volume under 40 cc considered a small prostate), she said a man with a high PSA, no previous negative biopsy, and a small prostate was at a higher than average risk, which would decrease if he had a larger prostate.

Based on these findings, she and her associates concluded that a man with a PSA of 1.3 ng/mL, with no previous negative biopsy, a positive family history, and a prostate volume under 40 cc has a 5% risk of developing prostate cancer within 4 years. However, a man with a previous negative biopsy, no family history, and a large prostate can have a PSA up to 4 ng/mL “before reaching the similar threshold of a 5% risk of prostate cancer within 4 years,” Dr. Roobol added.

Using these individualized predictive factors to identify men above certain risk thresholds could make it possible to identify men who “may warrant more frequent screening and vice versa,” she said, adding that “active risk-reduction strategies can be applied, if available.”

The moderator of the press briefing, Dr. Howard Sandler, chairman of radiation oncology at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, described this approach as “a very sensible method of integrating other factors besides PSA into the complex problem of prostate cancer screening and detection.”

The study is in press at the Journal of Urology. Dr. Roobol had no disclosures to report. The annual Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology, and Society of Urologic Oncology.

A Dutch study of 5,176 men found four factors to be helpful in predicting a man's risk of developing prostate cancer: serum prostate-specific antigen, a previous negative biopsy of the prostate, family history of prostate cancer, and prostate volume.

“PSA assessments combined with the other common predictive factors may offer a personalized assessment of a man's risk of future prostate cancer,” coauthor Monique J. Roobol, Ph.D., said at a briefing before the study's presentation at a symposium on genitourinary cancers.

The men, aged 55–75 years at baseline, were from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. They were screened every 4 years for prostate cancer.

Using multivariate modeling, with data on factors at baseline and prostate cancer 4 years later, the investigators determined that PSA “is still the most significant predictor … but there are other factors that also contribute to risk estimation,” said Dr. Roobol, an epidemiologist in urologic oncology at Erasmus Medical Center, Rotterdam, the Netherlands.

The average risk of developing biopsy-detectable prostate cancer over 4 years was 5.1% at an average PSA level of 1.5 ng/mL in the study, so men with a serum PSA level above 1.5 ng/mL are at an above-average risk of developing prostate cancer over 4 years—and are at a sevenfold greater risk than are those with levels below this level, Dr. Roobol said.

Other risk factors were found to modify this threshold level: The risk of prostate cancer increases if there is a positive family history of prostate cancer, but decreases with an increasing prostate volume at the same PSA level. Risk also decreases if a man ever had a negative prostate biopsy, she said.

For example, a man with a high serum PSA, a positive family history, a small prostate, and no previous negative biopsy was at a higher than average risk, while a man with a low serum PSA and no additional risk factors was at a very low risk, which increased if he had a positive family history, she explained.

To illustrate the effect of prostate volume on PSA level (with a volume under 40 cc considered a small prostate), she said a man with a high PSA, no previous negative biopsy, and a small prostate was at a higher than average risk, which would decrease if he had a larger prostate.

Based on these findings, she and her associates concluded that a man with a PSA of 1.3 ng/mL, with no previous negative biopsy, a positive family history, and a prostate volume under 40 cc has a 5% risk of developing prostate cancer within 4 years. However, a man with a previous negative biopsy, no family history, and a large prostate can have a PSA up to 4 ng/mL “before reaching the similar threshold of a 5% risk of prostate cancer within 4 years,” Dr. Roobol added.

Using these individualized predictive factors to identify men above certain risk thresholds could make it possible to identify men who “may warrant more frequent screening and vice versa,” she said, adding that “active risk-reduction strategies can be applied, if available.”

The moderator of the press briefing, Dr. Howard Sandler, chairman of radiation oncology at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, described this approach as “a very sensible method of integrating other factors besides PSA into the complex problem of prostate cancer screening and detection.”

The study is in press at the Journal of Urology. Dr. Roobol had no disclosures to report. The annual Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology, and Society of Urologic Oncology.

A Dutch study of 5,176 men found four factors to be helpful in predicting a man's risk of developing prostate cancer: serum prostate-specific antigen, a previous negative biopsy of the prostate, family history of prostate cancer, and prostate volume.

“PSA assessments combined with the other common predictive factors may offer a personalized assessment of a man's risk of future prostate cancer,” coauthor Monique J. Roobol, Ph.D., said at a briefing before the study's presentation at a symposium on genitourinary cancers.

The men, aged 55–75 years at baseline, were from the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer. They were screened every 4 years for prostate cancer.

Using multivariate modeling, with data on factors at baseline and prostate cancer 4 years later, the investigators determined that PSA “is still the most significant predictor … but there are other factors that also contribute to risk estimation,” said Dr. Roobol, an epidemiologist in urologic oncology at Erasmus Medical Center, Rotterdam, the Netherlands.

The average risk of developing biopsy-detectable prostate cancer over 4 years was 5.1% at an average PSA level of 1.5 ng/mL in the study, so men with a serum PSA level above 1.5 ng/mL are at an above-average risk of developing prostate cancer over 4 years—and are at a sevenfold greater risk than are those with levels below this level, Dr. Roobol said.

Other risk factors were found to modify this threshold level: The risk of prostate cancer increases if there is a positive family history of prostate cancer, but decreases with an increasing prostate volume at the same PSA level. Risk also decreases if a man ever had a negative prostate biopsy, she said.

For example, a man with a high serum PSA, a positive family history, a small prostate, and no previous negative biopsy was at a higher than average risk, while a man with a low serum PSA and no additional risk factors was at a very low risk, which increased if he had a positive family history, she explained.

To illustrate the effect of prostate volume on PSA level (with a volume under 40 cc considered a small prostate), she said a man with a high PSA, no previous negative biopsy, and a small prostate was at a higher than average risk, which would decrease if he had a larger prostate.

Based on these findings, she and her associates concluded that a man with a PSA of 1.3 ng/mL, with no previous negative biopsy, a positive family history, and a prostate volume under 40 cc has a 5% risk of developing prostate cancer within 4 years. However, a man with a previous negative biopsy, no family history, and a large prostate can have a PSA up to 4 ng/mL “before reaching the similar threshold of a 5% risk of prostate cancer within 4 years,” Dr. Roobol added.

Using these individualized predictive factors to identify men above certain risk thresholds could make it possible to identify men who “may warrant more frequent screening and vice versa,” she said, adding that “active risk-reduction strategies can be applied, if available.”

The moderator of the press briefing, Dr. Howard Sandler, chairman of radiation oncology at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, described this approach as “a very sensible method of integrating other factors besides PSA into the complex problem of prostate cancer screening and detection.”

The study is in press at the Journal of Urology. Dr. Roobol had no disclosures to report. The annual Genitourinary Cancers Symposium is sponsored by the American Society of Clinical Oncology, American Society for Therapeutic Radiology and Oncology, and Society of Urologic Oncology.