Sharon Worcester

ORLANDO – The American Association for Cancer Research is rallying support for an outcry against proposed budget cuts by Congress that could cut funding to the National Institutes of Health by up to $1.6 billion.

The AACR is asking its membership of approximately 33,000 cancer physicians and researchers – as well as numerous other groups and the community in general – to voice their concerns on April 6 at 2 p.m. Eastern Time.

Cuts to the National Cancer Institute amounting to about $300 million would drastically affect research grant funding and would stymie the current unprecedented level of progress and innovation in cancer research, Dr. Jon Retzlaff said at a press conference during the AACR's annual meeting. Dr. Retzlaff is managing director of the AACR's Office of Science Policy and Government Affairs in Washington, D.C.

The organization is asking that at the designated time, "every single patient, every cancer researcher call or e-mail members of Congress ... so they hear that it is crazy to go down this path," Dr. Retzlaff said.

"We have to make our voice heard in ways we've never done before," he said, noting that the AACR has sent numerous alerts to members, and is working with various other groups to enlist their support in this effort.

The $1.6 billion in cuts to the NIH is part of the $61 billion in proposed cuts by the U.S. House of Representatives. The Senate has proposed $33 billion in budget cuts. As Congress grapples with the budget as well as the possibility that the government will be shut down in the coming days if a compromise is not reached, cancer researchers are left wondering if all their current research projects are in jeopardy.

"It's all about patients – about finding cures, and improving health," Dr. Retzlaff said, adding that there is an important economic development component that must also be considered: The investments in the NIH contribute greatly to economic development and innovation, which are priorities for the country – and which are imperative for its success in the future, he said.

The proposed cuts would likely mean reduced funding for major research programs and for cancer centers across the country, as well as the discontinuation of many grant programs that scientists rely on to pursue their research.

"We completely agree there have to be some tough choices, but ... let's not put our deficit on the backs of patients who are looking for hope and researchers who think they have wonderful opportunities to make a difference," he said.

ORLANDO – The American Association for Cancer Research is rallying support for an outcry against proposed budget cuts by Congress that could cut funding to the National Institutes of Health by up to $1.6 billion.

The AACR is asking its membership of approximately 33,000 cancer physicians and researchers – as well as numerous other groups and the community in general – to voice their concerns on April 6 at 2 p.m. Eastern Time.

Cuts to the National Cancer Institute amounting to about $300 million would drastically affect research grant funding and would stymie the current unprecedented level of progress and innovation in cancer research, Dr. Jon Retzlaff said at a press conference during the AACR's annual meeting. Dr. Retzlaff is managing director of the AACR's Office of Science Policy and Government Affairs in Washington, D.C.

The organization is asking that at the designated time, "every single patient, every cancer researcher call or e-mail members of Congress ... so they hear that it is crazy to go down this path," Dr. Retzlaff said.

"We have to make our voice heard in ways we've never done before," he said, noting that the AACR has sent numerous alerts to members, and is working with various other groups to enlist their support in this effort.

The $1.6 billion in cuts to the NIH is part of the $61 billion in proposed cuts by the U.S. House of Representatives. The Senate has proposed $33 billion in budget cuts. As Congress grapples with the budget as well as the possibility that the government will be shut down in the coming days if a compromise is not reached, cancer researchers are left wondering if all their current research projects are in jeopardy.

"It's all about patients – about finding cures, and improving health," Dr. Retzlaff said, adding that there is an important economic development component that must also be considered: The investments in the NIH contribute greatly to economic development and innovation, which are priorities for the country – and which are imperative for its success in the future, he said.

The proposed cuts would likely mean reduced funding for major research programs and for cancer centers across the country, as well as the discontinuation of many grant programs that scientists rely on to pursue their research.

"We completely agree there have to be some tough choices, but ... let's not put our deficit on the backs of patients who are looking for hope and researchers who think they have wonderful opportunities to make a difference," he said.

ORLANDO – The American Association for Cancer Research is rallying support for an outcry against proposed budget cuts by Congress that could cut funding to the National Institutes of Health by up to $1.6 billion.

The AACR is asking its membership of approximately 33,000 cancer physicians and researchers – as well as numerous other groups and the community in general – to voice their concerns on April 6 at 2 p.m. Eastern Time.

Cuts to the National Cancer Institute amounting to about $300 million would drastically affect research grant funding and would stymie the current unprecedented level of progress and innovation in cancer research, Dr. Jon Retzlaff said at a press conference during the AACR's annual meeting. Dr. Retzlaff is managing director of the AACR's Office of Science Policy and Government Affairs in Washington, D.C.

The organization is asking that at the designated time, "every single patient, every cancer researcher call or e-mail members of Congress ... so they hear that it is crazy to go down this path," Dr. Retzlaff said.

"We have to make our voice heard in ways we've never done before," he said, noting that the AACR has sent numerous alerts to members, and is working with various other groups to enlist their support in this effort.

The $1.6 billion in cuts to the NIH is part of the $61 billion in proposed cuts by the U.S. House of Representatives. The Senate has proposed $33 billion in budget cuts. As Congress grapples with the budget as well as the possibility that the government will be shut down in the coming days if a compromise is not reached, cancer researchers are left wondering if all their current research projects are in jeopardy.

"It's all about patients – about finding cures, and improving health," Dr. Retzlaff said, adding that there is an important economic development component that must also be considered: The investments in the NIH contribute greatly to economic development and innovation, which are priorities for the country – and which are imperative for its success in the future, he said.

The proposed cuts would likely mean reduced funding for major research programs and for cancer centers across the country, as well as the discontinuation of many grant programs that scientists rely on to pursue their research.

"We completely agree there have to be some tough choices, but ... let's not put our deficit on the backs of patients who are looking for hope and researchers who think they have wonderful opportunities to make a difference," he said.

ORLANDO – The American Association for Cancer Research is rallying support for an outcry against proposed budget cuts by Congress that could cut funding to the National Institutes of Health by up to $1.6 billion.

The AACR is asking its membership of approximately 33,000 cancer physicians and researchers – as well as numerous other groups and the community in general – to voice their concerns on April 6 at 2 p.m. Eastern Time.

Cuts to the National Cancer Institute amounting to about $300 million would drastically affect research grant funding and would stymie the current unprecedented level of progress and innovation in cancer research, Dr. Jon Retzlaff said at a press conference during the AACR’s annual meeting. Dr. Retzlaff is managing director of the AACR’s Office of Science Policy and Government Affairs in Washington, D.C.

The organization is asking that at the designated time, "every single patient, every cancer researcher call or e-mail members of Congress ... so they hear that it is crazy to go down this path," Dr. Retzlaff said.

"We have to make our voice heard in ways we’ve never done before," he said, noting that the AACR has sent numerous alerts to members, and is working with various other groups to enlist their support in this effort.

The $1.6 billion in cuts to the NIH is part of the $61 billion in proposed cuts by the U.S. House of Representatives. The Senate has proposed $33 billion in budget cuts. As Congress grapples with the budget as well as the possibility that the government will be shut down in the coming days if a compromise is not reached, cancer researchers are left wondering if all their current research projects are in jeopardy.

"It’s all about patients – about finding cures, and improving health," Dr. Retzlaff said, adding that there is an important economic development component that must also be considered: The investments in the NIH contribute greatly to economic development and innovation, which are priorities for the country – and which are imperative for its success in the future, he said.

The proposed cuts would likely mean reduced funding for major research programs and for cancer centers across the country, as well as the discontinuation of many grant programs that scientists rely on to pursue their research.

"We completely agree there have to be some tough choices, but ... let’s not put our deficit on the backs of patients who are looking for hope and researchers who think they have wonderful opportunities to make a difference," he said.

ORLANDO – The American Association for Cancer Research is rallying support for an outcry against proposed budget cuts by Congress that could cut funding to the National Institutes of Health by up to $1.6 billion.

The AACR is asking its membership of approximately 33,000 cancer physicians and researchers – as well as numerous other groups and the community in general – to voice their concerns on April 6 at 2 p.m. Eastern Time.

Cuts to the National Cancer Institute amounting to about $300 million would drastically affect research grant funding and would stymie the current unprecedented level of progress and innovation in cancer research, Dr. Jon Retzlaff said at a press conference during the AACR’s annual meeting. Dr. Retzlaff is managing director of the AACR’s Office of Science Policy and Government Affairs in Washington, D.C.

The organization is asking that at the designated time, "every single patient, every cancer researcher call or e-mail members of Congress ... so they hear that it is crazy to go down this path," Dr. Retzlaff said.

"We have to make our voice heard in ways we’ve never done before," he said, noting that the AACR has sent numerous alerts to members, and is working with various other groups to enlist their support in this effort.

The $1.6 billion in cuts to the NIH is part of the $61 billion in proposed cuts by the U.S. House of Representatives. The Senate has proposed $33 billion in budget cuts. As Congress grapples with the budget as well as the possibility that the government will be shut down in the coming days if a compromise is not reached, cancer researchers are left wondering if all their current research projects are in jeopardy.

"It’s all about patients – about finding cures, and improving health," Dr. Retzlaff said, adding that there is an important economic development component that must also be considered: The investments in the NIH contribute greatly to economic development and innovation, which are priorities for the country – and which are imperative for its success in the future, he said.

The proposed cuts would likely mean reduced funding for major research programs and for cancer centers across the country, as well as the discontinuation of many grant programs that scientists rely on to pursue their research.

"We completely agree there have to be some tough choices, but ... let’s not put our deficit on the backs of patients who are looking for hope and researchers who think they have wonderful opportunities to make a difference," he said.

ORLANDO – The American Association for Cancer Research is rallying support for an outcry against proposed budget cuts by Congress that could cut funding to the National Institutes of Health by up to $1.6 billion.

The AACR is asking its membership of approximately 33,000 cancer physicians and researchers – as well as numerous other groups and the community in general – to voice their concerns on April 6 at 2 p.m. Eastern Time.

Cuts to the National Cancer Institute amounting to about $300 million would drastically affect research grant funding and would stymie the current unprecedented level of progress and innovation in cancer research, Dr. Jon Retzlaff said at a press conference during the AACR’s annual meeting. Dr. Retzlaff is managing director of the AACR’s Office of Science Policy and Government Affairs in Washington, D.C.

The organization is asking that at the designated time, "every single patient, every cancer researcher call or e-mail members of Congress ... so they hear that it is crazy to go down this path," Dr. Retzlaff said.

"We have to make our voice heard in ways we’ve never done before," he said, noting that the AACR has sent numerous alerts to members, and is working with various other groups to enlist their support in this effort.

The $1.6 billion in cuts to the NIH is part of the $61 billion in proposed cuts by the U.S. House of Representatives. The Senate has proposed $33 billion in budget cuts. As Congress grapples with the budget as well as the possibility that the government will be shut down in the coming days if a compromise is not reached, cancer researchers are left wondering if all their current research projects are in jeopardy.

"It’s all about patients – about finding cures, and improving health," Dr. Retzlaff said, adding that there is an important economic development component that must also be considered: The investments in the NIH contribute greatly to economic development and innovation, which are priorities for the country – and which are imperative for its success in the future, he said.

The proposed cuts would likely mean reduced funding for major research programs and for cancer centers across the country, as well as the discontinuation of many grant programs that scientists rely on to pursue their research.

"We completely agree there have to be some tough choices, but ... let’s not put our deficit on the backs of patients who are looking for hope and researchers who think they have wonderful opportunities to make a difference," he said.

ORLANDO – The American Association for Cancer Research is rallying support for an outcry against proposed budget cuts by Congress that could cut funding to the National Institutes of Health by up to $1.6 billion.

The AACR is asking its membership of approximately 33,000 cancer physicians and researchers – as well as numerous other groups and the community in general – to voice their concerns on April 6 at 2 p.m. Eastern Time.

Cuts to the National Cancer Institute amounting to about $300 million would drastically affect research grant funding and would stymie the current unprecedented level of progress and innovation in cancer research, Dr. Jon Retzlaff said at a press conference during the AACR’s annual meeting. Dr. Retzlaff is managing director of the AACR’s Office of Science Policy and Government Affairs in Washington, D.C.

The organization is asking that at the designated time, "every single patient, every cancer researcher call or e-mail members of Congress ... so they hear that it is crazy to go down this path," Dr. Retzlaff said.

"We have to make our voice heard in ways we’ve never done before," he said, noting that the AACR has sent numerous alerts to members, and is working with various other groups to enlist their support in this effort.

The $1.6 billion in cuts to the NIH is part of the $61 billion in proposed cuts by the U.S. House of Representatives. The Senate has proposed $33 billion in budget cuts. As Congress grapples with the budget as well as the possibility that the government will be shut down in the coming days if a compromise is not reached, cancer researchers are left wondering if all their current research projects are in jeopardy.

"It’s all about patients – about finding cures, and improving health," Dr. Retzlaff said, adding that there is an important economic development component that must also be considered: The investments in the NIH contribute greatly to economic development and innovation, which are priorities for the country – and which are imperative for its success in the future, he said.

The proposed cuts would likely mean reduced funding for major research programs and for cancer centers across the country, as well as the discontinuation of many grant programs that scientists rely on to pursue their research.

"We completely agree there have to be some tough choices, but ... let’s not put our deficit on the backs of patients who are looking for hope and researchers who think they have wonderful opportunities to make a difference," he said.

ORLANDO – The American Association for Cancer Research is rallying support for an outcry against proposed budget cuts by Congress that could cut funding to the National Institutes of Health by up to $1.6 billion.

The AACR is asking its membership of approximately 33,000 cancer physicians and researchers – as well as numerous other groups and the community in general – to voice their concerns on April 6 at 2 p.m. Eastern Time.

Cuts to the National Cancer Institute amounting to about $300 million would drastically affect research grant funding and would stymie the current unprecedented level of progress and innovation in cancer research, Dr. Jon Retzlaff said at a press conference during the AACR’s annual meeting. Dr. Retzlaff is managing director of the AACR’s Office of Science Policy and Government Affairs in Washington, D.C.

The organization is asking that at the designated time, "every single patient, every cancer researcher call or e-mail members of Congress ... so they hear that it is crazy to go down this path," Dr. Retzlaff said.

"We have to make our voice heard in ways we’ve never done before," he said, noting that the AACR has sent numerous alerts to members, and is working with various other groups to enlist their support in this effort.

The $1.6 billion in cuts to the NIH is part of the $61 billion in proposed cuts by the U.S. House of Representatives. The Senate has proposed $33 billion in budget cuts. As Congress grapples with the budget as well as the possibility that the government will be shut down in the coming days if a compromise is not reached, cancer researchers are left wondering if all their current research projects are in jeopardy.

"It’s all about patients – about finding cures, and improving health," Dr. Retzlaff said, adding that there is an important economic development component that must also be considered: The investments in the NIH contribute greatly to economic development and innovation, which are priorities for the country – and which are imperative for its success in the future, he said.

The proposed cuts would likely mean reduced funding for major research programs and for cancer centers across the country, as well as the discontinuation of many grant programs that scientists rely on to pursue their research.

"We completely agree there have to be some tough choices, but ... let’s not put our deficit on the backs of patients who are looking for hope and researchers who think they have wonderful opportunities to make a difference," he said.

ORLANDO – The American Association for Cancer Research is rallying support for an outcry against proposed budget cuts by Congress that could cut funding to the National Institutes of Health by up to $1.6 billion.

The AACR is asking its membership of approximately 33,000 cancer physicians and researchers – as well as numerous other groups and the community in general – to voice their concerns on April 6 at 2 p.m. Eastern Time.

Cuts to the National Cancer Institute amounting to about $300 million would drastically affect research grant funding and would stymie the current unprecedented level of progress and innovation in cancer research, Dr. Jon Retzlaff said at a press conference during the AACR’s annual meeting. Dr. Retzlaff is managing director of the AACR’s Office of Science Policy and Government Affairs in Washington, D.C.

The organization is asking that at the designated time, "every single patient, every cancer researcher call or e-mail members of Congress ... so they hear that it is crazy to go down this path," Dr. Retzlaff said.

"We have to make our voice heard in ways we’ve never done before," he said, noting that the AACR has sent numerous alerts to members, and is working with various other groups to enlist their support in this effort.

The $1.6 billion in cuts to the NIH is part of the $61 billion in proposed cuts by the U.S. House of Representatives. The Senate has proposed $33 billion in budget cuts. As Congress grapples with the budget as well as the possibility that the government will be shut down in the coming days if a compromise is not reached, cancer researchers are left wondering if all their current research projects are in jeopardy.

"It’s all about patients – about finding cures, and improving health," Dr. Retzlaff said, adding that there is an important economic development component that must also be considered: The investments in the NIH contribute greatly to economic development and innovation, which are priorities for the country – and which are imperative for its success in the future, he said.

The proposed cuts would likely mean reduced funding for major research programs and for cancer centers across the country, as well as the discontinuation of many grant programs that scientists rely on to pursue their research.

"We completely agree there have to be some tough choices, but ... let’s not put our deficit on the backs of patients who are looking for hope and researchers who think they have wonderful opportunities to make a difference," he said.

ORLANDO – A set of epithelial-to-mesenchymal transition genes and a novel five-gene expression signature appear to predict disease control with erlotinib in refractory non–small cell lung cancer patients whether they have endothelial growth factor receptor mutations or not.

These candidate biomarkers have potentially broad impact, as they could help identify erlotinib (Tarceva) sensitivity in the 88% of patients with wild-type endothelial growth factor receptor (EGFR), Dr. John V. Heymach said at the annual meeting of the American Association for Cancer Research.

Dr. Heymach described the two gene profiles in an update of the phase II Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) 1 trial. They were identified retrospectively from gene expression profiling of pretreatment core needle biopsies in 101 BATTLE trial patients and by studying 54 non–small cell lung cancer lines to find genes involved in the epithelial-to-mesenchymal transition (EMT).

Currently, the treatment benefit of erlotinib – a tyrosine kinase inhibitor that acts on EGFR and is approved for the treatment of non–small cell lung cancer (NSCLC) and pancreatic cancer - can be predicted in only about 12% of patients who have certain mutations and amplifications of EGFR, said Dr. Heymach of the University of Texas M.D. Anderson Cancer Center, Houston.

Previously reported results from the BATTLE 1 trial, which were presented at the 2010 AACR annual meeting, focused on prespecified markers as predictors of response to EGFR inhibition; these updated findings focused on novel gene markers that were not prespecified, but were discovered retrospectively from the biopsies taken as part of the earlier BATTLE trial work.

The investigators found a five-gene expression signature, including Lipocalin-2 (LCN2), NPR3, OGG1, TRIM72, and a gene of unknown function called C5orf23, which was predictive of disease control in patients treated with erlotinib who lacked EGFR mutations. Disease control occurred by 8 weeks in 83% of those with the signature, compared with 0% of patients who lacked the signature (P less than .001).

They also found that LCN2 was involved in the EGFR pathway, and was associated with epithelial-type tumor cells. The findings suggest it is a promising potential target for therapy.

The EMT genes that were found to predict disease control in this study did so by a different measure: Disease control by 8 weeks occurred in 64% of those with cells that were still epithelial type, while disease control occurred in only 10% of those with mesenchymal type (P = .02). A gene called Axl, which is a tyrosine kinase receptor, was found to be associated with mesenchymal-type cells, and could also be a potential therapeutic target, Dr. Heymach said.

The predictive value of both the five-gene expression signature and the EMT signature will be tested prospectively in the upcoming BATTLE II trial, which will also test markers from the P13K-AKT pathway, EGFR signatures, and KRAS mutations. The trial will have four treatment arms, including erlotinib, sorafenib (Nexavar), erlotinib plus an AKT inhibitor, and the AKT inhibitor with an MEK inhibitor.

Dr. Thomas J. Lynch Jr., the discussant following Dr. Heymach’s presentation of his findings during a late-breaking abstract session at the AACR meeting, praised the "mining of data" from the landmark BATTLE 1 trial, which resulted in these findings.

While the finding are important, perhaps their greatest value is in "elucidating new targets in non–small cell lung cancer more than necessarily determining who benefits from marginally active therapy," said Dr. Lynch, director of the Yale Cancer Center and physician-in-chief at Smilow Cancer Hospital at Yale-New Haven (Conn.).

The BATTLE 1 trial, conducted by a team of researchers at M.D. Anderson, is the first completed prospective, adaptively randomized study in heavily pretreated non–small cell lung cancer patients that mandated tumor profiling with real-time core needle biopsies. The results of the trial demonstrate the feasibility of this approach, and create a new paradigm for translational research, and they represent a substantial step toward realizing personalized lung cancer therapy, according to the investigators. The findings are published in the inaugural issue of Cancer Discovery, which debuted at the 2011 AACR conference (Cancer Discovery 2011;1:OF42-9).

This study was funded by the U.S. Department of Defense, the M.D. Anderson and University of Texas Southwestern Lung Cancer Specialized Program in Research Excellence, and M.D. Anderson’s Cancer Center Support Grant from the National Cancer Institute. Dr. Heymach disclosed that he has received research support from AstraZeneca and Bayer, and has served on advisory boards for AstraZeneca, Genentech, and Bayer.

ORLANDO – A set of epithelial-to-mesenchymal transition genes and a novel five-gene expression signature appear to predict disease control with erlotinib in refractory non–small cell lung cancer patients whether they have endothelial growth factor receptor mutations or not.

These candidate biomarkers have potentially broad impact, as they could help identify erlotinib (Tarceva) sensitivity in the 88% of patients with wild-type endothelial growth factor receptor (EGFR), Dr. John V. Heymach said at the annual meeting of the American Association for Cancer Research.

Dr. Heymach described the two gene profiles in an update of the phase II Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) 1 trial. They were identified retrospectively from gene expression profiling of pretreatment core needle biopsies in 101 BATTLE trial patients and by studying 54 non–small cell lung cancer lines to find genes involved in the epithelial-to-mesenchymal transition (EMT).

Currently, the treatment benefit of erlotinib – a tyrosine kinase inhibitor that acts on EGFR and is approved for the treatment of non–small cell lung cancer (NSCLC) and pancreatic cancer - can be predicted in only about 12% of patients who have certain mutations and amplifications of EGFR, said Dr. Heymach of the University of Texas M.D. Anderson Cancer Center, Houston.

Previously reported results from the BATTLE 1 trial, which were presented at the 2010 AACR annual meeting, focused on prespecified markers as predictors of response to EGFR inhibition; these updated findings focused on novel gene markers that were not prespecified, but were discovered retrospectively from the biopsies taken as part of the earlier BATTLE trial work.

The investigators found a five-gene expression signature, including Lipocalin-2 (LCN2), NPR3, OGG1, TRIM72, and a gene of unknown function called C5orf23, which was predictive of disease control in patients treated with erlotinib who lacked EGFR mutations. Disease control occurred by 8 weeks in 83% of those with the signature, compared with 0% of patients who lacked the signature (P less than .001).

They also found that LCN2 was involved in the EGFR pathway, and was associated with epithelial-type tumor cells. The findings suggest it is a promising potential target for therapy.

The EMT genes that were found to predict disease control in this study did so by a different measure: Disease control by 8 weeks occurred in 64% of those with cells that were still epithelial type, while disease control occurred in only 10% of those with mesenchymal type (P = .02). A gene called Axl, which is a tyrosine kinase receptor, was found to be associated with mesenchymal-type cells, and could also be a potential therapeutic target, Dr. Heymach said.

The predictive value of both the five-gene expression signature and the EMT signature will be tested prospectively in the upcoming BATTLE II trial, which will also test markers from the P13K-AKT pathway, EGFR signatures, and KRAS mutations. The trial will have four treatment arms, including erlotinib, sorafenib (Nexavar), erlotinib plus an AKT inhibitor, and the AKT inhibitor with an MEK inhibitor.

Dr. Thomas J. Lynch Jr., the discussant following Dr. Heymach’s presentation of his findings during a late-breaking abstract session at the AACR meeting, praised the "mining of data" from the landmark BATTLE 1 trial, which resulted in these findings.

While the finding are important, perhaps their greatest value is in "elucidating new targets in non–small cell lung cancer more than necessarily determining who benefits from marginally active therapy," said Dr. Lynch, director of the Yale Cancer Center and physician-in-chief at Smilow Cancer Hospital at Yale-New Haven (Conn.).

The BATTLE 1 trial, conducted by a team of researchers at M.D. Anderson, is the first completed prospective, adaptively randomized study in heavily pretreated non–small cell lung cancer patients that mandated tumor profiling with real-time core needle biopsies. The results of the trial demonstrate the feasibility of this approach, and create a new paradigm for translational research, and they represent a substantial step toward realizing personalized lung cancer therapy, according to the investigators. The findings are published in the inaugural issue of Cancer Discovery, which debuted at the 2011 AACR conference (Cancer Discovery 2011;1:OF42-9).

This study was funded by the U.S. Department of Defense, the M.D. Anderson and University of Texas Southwestern Lung Cancer Specialized Program in Research Excellence, and M.D. Anderson’s Cancer Center Support Grant from the National Cancer Institute. Dr. Heymach disclosed that he has received research support from AstraZeneca and Bayer, and has served on advisory boards for AstraZeneca, Genentech, and Bayer.

ORLANDO – A set of epithelial-to-mesenchymal transition genes and a novel five-gene expression signature appear to predict disease control with erlotinib in refractory non–small cell lung cancer patients whether they have endothelial growth factor receptor mutations or not.

These candidate biomarkers have potentially broad impact, as they could help identify erlotinib (Tarceva) sensitivity in the 88% of patients with wild-type endothelial growth factor receptor (EGFR), Dr. John V. Heymach said at the annual meeting of the American Association for Cancer Research.

Dr. Heymach described the two gene profiles in an update of the phase II Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) 1 trial. They were identified retrospectively from gene expression profiling of pretreatment core needle biopsies in 101 BATTLE trial patients and by studying 54 non–small cell lung cancer lines to find genes involved in the epithelial-to-mesenchymal transition (EMT).

Currently, the treatment benefit of erlotinib – a tyrosine kinase inhibitor that acts on EGFR and is approved for the treatment of non–small cell lung cancer (NSCLC) and pancreatic cancer - can be predicted in only about 12% of patients who have certain mutations and amplifications of EGFR, said Dr. Heymach of the University of Texas M.D. Anderson Cancer Center, Houston.

Previously reported results from the BATTLE 1 trial, which were presented at the 2010 AACR annual meeting, focused on prespecified markers as predictors of response to EGFR inhibition; these updated findings focused on novel gene markers that were not prespecified, but were discovered retrospectively from the biopsies taken as part of the earlier BATTLE trial work.

The investigators found a five-gene expression signature, including Lipocalin-2 (LCN2), NPR3, OGG1, TRIM72, and a gene of unknown function called C5orf23, which was predictive of disease control in patients treated with erlotinib who lacked EGFR mutations. Disease control occurred by 8 weeks in 83% of those with the signature, compared with 0% of patients who lacked the signature (P less than .001).

They also found that LCN2 was involved in the EGFR pathway, and was associated with epithelial-type tumor cells. The findings suggest it is a promising potential target for therapy.

The EMT genes that were found to predict disease control in this study did so by a different measure: Disease control by 8 weeks occurred in 64% of those with cells that were still epithelial type, while disease control occurred in only 10% of those with mesenchymal type (P = .02). A gene called Axl, which is a tyrosine kinase receptor, was found to be associated with mesenchymal-type cells, and could also be a potential therapeutic target, Dr. Heymach said.

The predictive value of both the five-gene expression signature and the EMT signature will be tested prospectively in the upcoming BATTLE II trial, which will also test markers from the P13K-AKT pathway, EGFR signatures, and KRAS mutations. The trial will have four treatment arms, including erlotinib, sorafenib (Nexavar), erlotinib plus an AKT inhibitor, and the AKT inhibitor with an MEK inhibitor.

Dr. Thomas J. Lynch Jr., the discussant following Dr. Heymach’s presentation of his findings during a late-breaking abstract session at the AACR meeting, praised the "mining of data" from the landmark BATTLE 1 trial, which resulted in these findings.

While the finding are important, perhaps their greatest value is in "elucidating new targets in non–small cell lung cancer more than necessarily determining who benefits from marginally active therapy," said Dr. Lynch, director of the Yale Cancer Center and physician-in-chief at Smilow Cancer Hospital at Yale-New Haven (Conn.).

The BATTLE 1 trial, conducted by a team of researchers at M.D. Anderson, is the first completed prospective, adaptively randomized study in heavily pretreated non–small cell lung cancer patients that mandated tumor profiling with real-time core needle biopsies. The results of the trial demonstrate the feasibility of this approach, and create a new paradigm for translational research, and they represent a substantial step toward realizing personalized lung cancer therapy, according to the investigators. The findings are published in the inaugural issue of Cancer Discovery, which debuted at the 2011 AACR conference (Cancer Discovery 2011;1:OF42-9).

This study was funded by the U.S. Department of Defense, the M.D. Anderson and University of Texas Southwestern Lung Cancer Specialized Program in Research Excellence, and M.D. Anderson’s Cancer Center Support Grant from the National Cancer Institute. Dr. Heymach disclosed that he has received research support from AstraZeneca and Bayer, and has served on advisory boards for AstraZeneca, Genentech, and Bayer.

ORLANDO – A set of epithelial-to-mesenchymal transition genes and a novel five-gene expression signature appear to predict disease control with erlotinib in refractory non–small cell lung cancer patients whether they have endothelial growth factor receptor mutations or not.

These candidate biomarkers have potentially broad impact, as they could help identify erlotinib (Tarceva) sensitivity in the 88% of patients with wild-type endothelial growth factor receptor (EGFR), Dr. John V. Heymach said at the annual meeting of the American Association for Cancer Research.

Dr. Heymach described the two gene profiles in an update of the phase II Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) 1 trial. They were identified retrospectively from gene expression profiling of pretreatment core needle biopsies in 101 BATTLE trial patients and by studying 54 non–small cell lung cancer lines to find genes involved in the epithelial-to-mesenchymal transition (EMT).

Currently, the treatment benefit of erlotinib – a tyrosine kinase inhibitor that acts on EGFR and is approved for the treatment of non–small cell lung cancer (NSCLC) and pancreatic cancer - can be predicted in only about 12% of patients who have certain mutations and amplifications of EGFR, said Dr. Heymach of the University of Texas M.D. Anderson Cancer Center, Houston.

Previously reported results from the BATTLE 1 trial, which were presented at the 2010 AACR annual meeting, focused on prespecified markers as predictors of response to EGFR inhibition; these updated findings focused on novel gene markers that were not prespecified, but were discovered retrospectively from the biopsies taken as part of the earlier BATTLE trial work.

The investigators found a five-gene expression signature, including Lipocalin-2 (LCN2), NPR3, OGG1, TRIM72, and a gene of unknown function called C5orf23, which was predictive of disease control in patients treated with erlotinib who lacked EGFR mutations. Disease control occurred by 8 weeks in 83% of those with the signature, compared with 0% of patients who lacked the signature (P less than .001).

They also found that LCN2 was involved in the EGFR pathway, and was associated with epithelial-type tumor cells. The findings suggest it is a promising potential target for therapy.

The EMT genes that were found to predict disease control in this study did so by a different measure: Disease control by 8 weeks occurred in 64% of those with cells that were still epithelial type, while disease control occurred in only 10% of those with mesenchymal type (P = .02). A gene called Axl, which is a tyrosine kinase receptor, was found to be associated with mesenchymal-type cells, and could also be a potential therapeutic target, Dr. Heymach said.

The predictive value of both the five-gene expression signature and the EMT signature will be tested prospectively in the upcoming BATTLE II trial, which will also test markers from the P13K-AKT pathway, EGFR signatures, and KRAS mutations. The trial will have four treatment arms, including erlotinib, sorafenib (Nexavar), erlotinib plus an AKT inhibitor, and the AKT inhibitor with an MEK inhibitor.

Dr. Thomas J. Lynch Jr., the discussant following Dr. Heymach’s presentation of his findings during a late-breaking abstract session at the AACR meeting, praised the "mining of data" from the landmark BATTLE 1 trial, which resulted in these findings.

While the finding are important, perhaps their greatest value is in "elucidating new targets in non–small cell lung cancer more than necessarily determining who benefits from marginally active therapy," said Dr. Lynch, director of the Yale Cancer Center and physician-in-chief at Smilow Cancer Hospital at Yale-New Haven (Conn.).

The BATTLE 1 trial, conducted by a team of researchers at M.D. Anderson, is the first completed prospective, adaptively randomized study in heavily pretreated non–small cell lung cancer patients that mandated tumor profiling with real-time core needle biopsies. The results of the trial demonstrate the feasibility of this approach, and create a new paradigm for translational research, and they represent a substantial step toward realizing personalized lung cancer therapy, according to the investigators. The findings are published in the inaugural issue of Cancer Discovery, which debuted at the 2011 AACR conference (Cancer Discovery 2011;1:OF42-9).

This study was funded by the U.S. Department of Defense, the M.D. Anderson and University of Texas Southwestern Lung Cancer Specialized Program in Research Excellence, and M.D. Anderson’s Cancer Center Support Grant from the National Cancer Institute. Dr. Heymach disclosed that he has received research support from AstraZeneca and Bayer, and has served on advisory boards for AstraZeneca, Genentech, and Bayer.

ORLANDO – A set of epithelial-to-mesenchymal transition genes and a novel five-gene expression signature appear to predict disease control with erlotinib in refractory non–small cell lung cancer patients whether they have endothelial growth factor receptor mutations or not.

These candidate biomarkers have potentially broad impact, as they could help identify erlotinib (Tarceva) sensitivity in the 88% of patients with wild-type endothelial growth factor receptor (EGFR), Dr. John V. Heymach said at the annual meeting of the American Association for Cancer Research.

Dr. Heymach described the two gene profiles in an update of the phase II Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) 1 trial. They were identified retrospectively from gene expression profiling of pretreatment core needle biopsies in 101 BATTLE trial patients and by studying 54 non–small cell lung cancer lines to find genes involved in the epithelial-to-mesenchymal transition (EMT).

Currently, the treatment benefit of erlotinib – a tyrosine kinase inhibitor that acts on EGFR and is approved for the treatment of non–small cell lung cancer (NSCLC) and pancreatic cancer - can be predicted in only about 12% of patients who have certain mutations and amplifications of EGFR, said Dr. Heymach of the University of Texas M.D. Anderson Cancer Center, Houston.

Previously reported results from the BATTLE 1 trial, which were presented at the 2010 AACR annual meeting, focused on prespecified markers as predictors of response to EGFR inhibition; these updated findings focused on novel gene markers that were not prespecified, but were discovered retrospectively from the biopsies taken as part of the earlier BATTLE trial work.

The investigators found a five-gene expression signature, including Lipocalin-2 (LCN2), NPR3, OGG1, TRIM72, and a gene of unknown function called C5orf23, which was predictive of disease control in patients treated with erlotinib who lacked EGFR mutations. Disease control occurred by 8 weeks in 83% of those with the signature, compared with 0% of patients who lacked the signature (P less than .001).

They also found that LCN2 was involved in the EGFR pathway, and was associated with epithelial-type tumor cells. The findings suggest it is a promising potential target for therapy.

The EMT genes that were found to predict disease control in this study did so by a different measure: Disease control by 8 weeks occurred in 64% of those with cells that were still epithelial type, while disease control occurred in only 10% of those with mesenchymal type (P = .02). A gene called Axl, which is a tyrosine kinase receptor, was found to be associated with mesenchymal-type cells, and could also be a potential therapeutic target, Dr. Heymach said.

The predictive value of both the five-gene expression signature and the EMT signature will be tested prospectively in the upcoming BATTLE II trial, which will also test markers from the P13K-AKT pathway, EGFR signatures, and KRAS mutations. The trial will have four treatment arms, including erlotinib, sorafenib (Nexavar), erlotinib plus an AKT inhibitor, and the AKT inhibitor with an MEK inhibitor.

Dr. Thomas J. Lynch Jr., the discussant following Dr. Heymach’s presentation of his findings during a late-breaking abstract session at the AACR meeting, praised the "mining of data" from the landmark BATTLE 1 trial, which resulted in these findings.

While the finding are important, perhaps their greatest value is in "elucidating new targets in non–small cell lung cancer more than necessarily determining who benefits from marginally active therapy," said Dr. Lynch, director of the Yale Cancer Center and physician-in-chief at Smilow Cancer Hospital at Yale-New Haven (Conn.).

The BATTLE 1 trial, conducted by a team of researchers at M.D. Anderson, is the first completed prospective, adaptively randomized study in heavily pretreated non–small cell lung cancer patients that mandated tumor profiling with real-time core needle biopsies. The results of the trial demonstrate the feasibility of this approach, and create a new paradigm for translational research, and they represent a substantial step toward realizing personalized lung cancer therapy, according to the investigators. The findings are published in the inaugural issue of Cancer Discovery, which debuted at the 2011 AACR conference (Cancer Discovery 2011;1:OF42-9).

This study was funded by the U.S. Department of Defense, the M.D. Anderson and University of Texas Southwestern Lung Cancer Specialized Program in Research Excellence, and M.D. Anderson’s Cancer Center Support Grant from the National Cancer Institute. Dr. Heymach disclosed that he has received research support from AstraZeneca and Bayer, and has served on advisory boards for AstraZeneca, Genentech, and Bayer.

ORLANDO – A set of epithelial-to-mesenchymal transition genes and a novel five-gene expression signature appear to predict disease control with erlotinib in refractory non–small cell lung cancer patients whether they have endothelial growth factor receptor mutations or not.

These candidate biomarkers have potentially broad impact, as they could help identify erlotinib (Tarceva) sensitivity in the 88% of patients with wild-type endothelial growth factor receptor (EGFR), Dr. John V. Heymach said at the annual meeting of the American Association for Cancer Research.

Dr. Heymach described the two gene profiles in an update of the phase II Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) 1 trial. They were identified retrospectively from gene expression profiling of pretreatment core needle biopsies in 101 BATTLE trial patients and by studying 54 non–small cell lung cancer lines to find genes involved in the epithelial-to-mesenchymal transition (EMT).

Currently, the treatment benefit of erlotinib – a tyrosine kinase inhibitor that acts on EGFR and is approved for the treatment of non–small cell lung cancer (NSCLC) and pancreatic cancer - can be predicted in only about 12% of patients who have certain mutations and amplifications of EGFR, said Dr. Heymach of the University of Texas M.D. Anderson Cancer Center, Houston.

Previously reported results from the BATTLE 1 trial, which were presented at the 2010 AACR annual meeting, focused on prespecified markers as predictors of response to EGFR inhibition; these updated findings focused on novel gene markers that were not prespecified, but were discovered retrospectively from the biopsies taken as part of the earlier BATTLE trial work.

The investigators found a five-gene expression signature, including Lipocalin-2 (LCN2), NPR3, OGG1, TRIM72, and a gene of unknown function called C5orf23, which was predictive of disease control in patients treated with erlotinib who lacked EGFR mutations. Disease control occurred by 8 weeks in 83% of those with the signature, compared with 0% of patients who lacked the signature (P less than .001).

They also found that LCN2 was involved in the EGFR pathway, and was associated with epithelial-type tumor cells. The findings suggest it is a promising potential target for therapy.

The EMT genes that were found to predict disease control in this study did so by a different measure: Disease control by 8 weeks occurred in 64% of those with cells that were still epithelial type, while disease control occurred in only 10% of those with mesenchymal type (P = .02). A gene called Axl, which is a tyrosine kinase receptor, was found to be associated with mesenchymal-type cells, and could also be a potential therapeutic target, Dr. Heymach said.

The predictive value of both the five-gene expression signature and the EMT signature will be tested prospectively in the upcoming BATTLE II trial, which will also test markers from the P13K-AKT pathway, EGFR signatures, and KRAS mutations. The trial will have four treatment arms, including erlotinib, sorafenib (Nexavar), erlotinib plus an AKT inhibitor, and the AKT inhibitor with an MEK inhibitor.

Dr. Thomas J. Lynch Jr., the discussant following Dr. Heymach’s presentation of his findings during a late-breaking abstract session at the AACR meeting, praised the "mining of data" from the landmark BATTLE 1 trial, which resulted in these findings.

While the finding are important, perhaps their greatest value is in "elucidating new targets in non–small cell lung cancer more than necessarily determining who benefits from marginally active therapy," said Dr. Lynch, director of the Yale Cancer Center and physician-in-chief at Smilow Cancer Hospital at Yale-New Haven (Conn.).

The BATTLE 1 trial, conducted by a team of researchers at M.D. Anderson, is the first completed prospective, adaptively randomized study in heavily pretreated non–small cell lung cancer patients that mandated tumor profiling with real-time core needle biopsies. The results of the trial demonstrate the feasibility of this approach, and create a new paradigm for translational research, and they represent a substantial step toward realizing personalized lung cancer therapy, according to the investigators. The findings are published in the inaugural issue of Cancer Discovery, which debuted at the 2011 AACR conference (Cancer Discovery 2011;1:OF42-9).

This study was funded by the U.S. Department of Defense, the M.D. Anderson and University of Texas Southwestern Lung Cancer Specialized Program in Research Excellence, and M.D. Anderson’s Cancer Center Support Grant from the National Cancer Institute. Dr. Heymach disclosed that he has received research support from AstraZeneca and Bayer, and has served on advisory boards for AstraZeneca, Genentech, and Bayer.

Outcomes out to 5 years in the ACCORD trial are consistent with those that brought the study to a halt after a mean of 3.7 years of intensive glucose-lowering therapy reduced the risk of nonfatal myocardial infarction in patients with advanced type 2 diabetes and a high risk of cardiovascular disease, but increased the risk of death.

Thus, a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be recommend in this population, Dr. Hertzel C. Gerstein of McMaster University, Hamilton, Ont., and colleagues from the Action to Control Cardiovascular Risk in Diabetes Study Group reported.

ACCORD participants were 10,108 type 2 diabetes patients with cardiovascular disease who were randomly assigned to receive intensive glucose-lowering therapy to a target hemoglobin A_1c below 6.0% or to standard therapy with a target HbA_1c of 7.0%–7.9%. The intensive therapy was terminated after a mean of 3.5 years because of higher mortality in the intensive treatment group, and patients from that group began receiving standard therapy. The current findings reflect an additional 0.2 months of intensive therapy not previously reported, and up to 17 months of additional follow-up.

Prior to the transition, the incidence of the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes) was 2.0% per year in the intensive therapy group, and 2.2% per year in the standard therapy group (hazard ratio 0.90).

Although the intensive therapy did lower the rate of nonfatal MI (1.08% vs. 1.35%, HR 0.79), it was also associated with a nonsignificant increased rate of death from cardiovascular causes (0.71% vs. 0.55%, HR 1.27).

“These divergent effects were retained at the end of the study, with a rate of nonfatal MI in the intensive-therapy groups that was lower than in the standard-therapy group (1.18 vs. 1.42; hazard ratio 0.82) … and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio 1.29),” they found (N. Engl. J. Med. 2011;364:818-28).

At the time of transition, the death rate from any cause was a significant 21% higher in the intensive therapy group (1.42 vs. 1.16), and it remained higher – by 19% – at the end of the study (1.53 vs. 1.27).

The findings indicate that 3.7 years of intensive therapy to target normal HbA_1c in a high-risk population does not significantly lower the number of major cardiovascular events after 5 years, compared with therapy that targets “levels that are more typically achieved in person in the United States and Canada (i.e., 7–7.9%),” and indeed, the intensive approach was associated with more deaths, they said.

ACCORD was supported by the National Institutes of Health and the Centers for Disease Control and Prevention. Study medication, equipment, or supplies were provided by numerous pharmaceutical companies. Dr. Gerstein has received consulting fees, institutional grant support, and/or lecture fees from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, and several other drug companies. Individual ACCORD Study Group members' disclosures are available with the full text of the article at www.nejm.com

HbA_1c levels below 6% should be avoided, said Dr. Hertzel C. Gerstein.

Source Courtesy McMaster University

Outcomes out to 5 years in the ACCORD trial are consistent with those that brought the study to a halt after a mean of 3.7 years of intensive glucose-lowering therapy reduced the risk of nonfatal myocardial infarction in patients with advanced type 2 diabetes and a high risk of cardiovascular disease, but increased the risk of death.

Thus, a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be recommend in this population, Dr. Hertzel C. Gerstein of McMaster University, Hamilton, Ont., and colleagues from the Action to Control Cardiovascular Risk in Diabetes Study Group reported.

ACCORD participants were 10,108 type 2 diabetes patients with cardiovascular disease who were randomly assigned to receive intensive glucose-lowering therapy to a target hemoglobin A_1c below 6.0% or to standard therapy with a target HbA_1c of 7.0%–7.9%. The intensive therapy was terminated after a mean of 3.5 years because of higher mortality in the intensive treatment group, and patients from that group began receiving standard therapy. The current findings reflect an additional 0.2 months of intensive therapy not previously reported, and up to 17 months of additional follow-up.

Prior to the transition, the incidence of the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes) was 2.0% per year in the intensive therapy group, and 2.2% per year in the standard therapy group (hazard ratio 0.90).

Although the intensive therapy did lower the rate of nonfatal MI (1.08% vs. 1.35%, HR 0.79), it was also associated with a nonsignificant increased rate of death from cardiovascular causes (0.71% vs. 0.55%, HR 1.27).

“These divergent effects were retained at the end of the study, with a rate of nonfatal MI in the intensive-therapy groups that was lower than in the standard-therapy group (1.18 vs. 1.42; hazard ratio 0.82) … and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio 1.29),” they found (N. Engl. J. Med. 2011;364:818-28).

At the time of transition, the death rate from any cause was a significant 21% higher in the intensive therapy group (1.42 vs. 1.16), and it remained higher – by 19% – at the end of the study (1.53 vs. 1.27).

The findings indicate that 3.7 years of intensive therapy to target normal HbA_1c in a high-risk population does not significantly lower the number of major cardiovascular events after 5 years, compared with therapy that targets “levels that are more typically achieved in person in the United States and Canada (i.e., 7–7.9%),” and indeed, the intensive approach was associated with more deaths, they said.

ACCORD was supported by the National Institutes of Health and the Centers for Disease Control and Prevention. Study medication, equipment, or supplies were provided by numerous pharmaceutical companies. Dr. Gerstein has received consulting fees, institutional grant support, and/or lecture fees from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, and several other drug companies. Individual ACCORD Study Group members' disclosures are available with the full text of the article at www.nejm.com

HbA_1c levels below 6% should be avoided, said Dr. Hertzel C. Gerstein.

Source Courtesy McMaster University

Outcomes out to 5 years in the ACCORD trial are consistent with those that brought the study to a halt after a mean of 3.7 years of intensive glucose-lowering therapy reduced the risk of nonfatal myocardial infarction in patients with advanced type 2 diabetes and a high risk of cardiovascular disease, but increased the risk of death.

Thus, a therapeutic approach that targets glycated hemoglobin levels below 6% cannot be recommend in this population, Dr. Hertzel C. Gerstein of McMaster University, Hamilton, Ont., and colleagues from the Action to Control Cardiovascular Risk in Diabetes Study Group reported.

ACCORD participants were 10,108 type 2 diabetes patients with cardiovascular disease who were randomly assigned to receive intensive glucose-lowering therapy to a target hemoglobin A_1c below 6.0% or to standard therapy with a target HbA_1c of 7.0%–7.9%. The intensive therapy was terminated after a mean of 3.5 years because of higher mortality in the intensive treatment group, and patients from that group began receiving standard therapy. The current findings reflect an additional 0.2 months of intensive therapy not previously reported, and up to 17 months of additional follow-up.

Prior to the transition, the incidence of the primary outcome (a composite of nonfatal MI, nonfatal stroke, or death from cardiovascular causes) was 2.0% per year in the intensive therapy group, and 2.2% per year in the standard therapy group (hazard ratio 0.90).

Although the intensive therapy did lower the rate of nonfatal MI (1.08% vs. 1.35%, HR 0.79), it was also associated with a nonsignificant increased rate of death from cardiovascular causes (0.71% vs. 0.55%, HR 1.27).

“These divergent effects were retained at the end of the study, with a rate of nonfatal MI in the intensive-therapy groups that was lower than in the standard-therapy group (1.18 vs. 1.42; hazard ratio 0.82) … and a rate of death from cardiovascular causes that was higher (0.74 vs. 0.57; hazard ratio 1.29),” they found (N. Engl. J. Med. 2011;364:818-28).

At the time of transition, the death rate from any cause was a significant 21% higher in the intensive therapy group (1.42 vs. 1.16), and it remained higher – by 19% – at the end of the study (1.53 vs. 1.27).

The findings indicate that 3.7 years of intensive therapy to target normal HbA_1c in a high-risk population does not significantly lower the number of major cardiovascular events after 5 years, compared with therapy that targets “levels that are more typically achieved in person in the United States and Canada (i.e., 7–7.9%),” and indeed, the intensive approach was associated with more deaths, they said.

ACCORD was supported by the National Institutes of Health and the Centers for Disease Control and Prevention. Study medication, equipment, or supplies were provided by numerous pharmaceutical companies. Dr. Gerstein has received consulting fees, institutional grant support, and/or lecture fees from Sanofi-Aventis, GlaxoSmithKline, Novo Nordisk, and several other drug companies. Individual ACCORD Study Group members' disclosures are available with the full text of the article at www.nejm.com

HbA_1c levels below 6% should be avoided, said Dr. Hertzel C. Gerstein.

Source Courtesy McMaster University

ST. PETERSBURG, FLA. – Both the bidirectional cavopulmonary shunt and the hemi-Fontan procedure have been used in children with hypoplastic left heart syndrome. Is one better than the other?

Dr. Tom Karl, deputy director of pediatric cardiac surgery at Mater Children's Hospital in South Brisbane, Queensland, sought to answer this question at the symposium.

One potential benefit of the bidirectional cavopulmonary shunt, he said, is decreased tricuspid insufficiency as the right ventricle's geometry normalizes from volume unloading.

Other potential benefits include avoidance of later hypertrophy and subendocardial ischemic damage. General hemodynamic stability is promoted by improvement in effective systemic output – with reduced interstage mortality, better somatic growth, and the opportunity to correct associated abnormalities out of the neonatal period, he added.

But is the bidirectional cavopulmonary shunt better than the hemi-Fontan procedure when it is used as the second stage in the typical three-stage treatment sequence (between neonatal palliation, e.g., Norwood procedure, and a Fontan operation) for the univentricular heart?

It does have some advantages: It is technically simpler; it can be performed on a beating heart at normothermia, and off pump in many cases; and it requires no prosthetic material. It also is a good setup for an extracardiac variant of the Fontan operation.

“On the other hand, there is some potential for stenosis, and there is probably some asymmetry of flow in many cases,” said Dr. Karl.

The hemi-Fontan doesn't have asymmetry of flow; there is actually very good flow to the left lung, he said. Also, there is a long, favorable history of this type of anastomosis specifically in hypoplastic left heart syndrome, and the hemi-Fontan provides a good setup for a lateral tunnel Fontan completion. Stenosis risk is minimal.

However, the hemi-Fontan is technically more complex. It requires cardiopulmonary bypass, which some surgeons choose to do using deep hypothermic circulatory arrest, and it may pose greater risk to the sinoatrial node. The hemi-Fontan also requires a considerable load of prosthetic material, but this is not seen as a disadvantage if the procedure follows a Norwood procedure, noted Dr. Karl, who said he had no conflicts of interest.

ST. PETERSBURG, FLA. – Both the bidirectional cavopulmonary shunt and the hemi-Fontan procedure have been used in children with hypoplastic left heart syndrome. Is one better than the other?

Dr. Tom Karl, deputy director of pediatric cardiac surgery at Mater Children's Hospital in South Brisbane, Queensland, sought to answer this question at the symposium.

One potential benefit of the bidirectional cavopulmonary shunt, he said, is decreased tricuspid insufficiency as the right ventricle's geometry normalizes from volume unloading.

Other potential benefits include avoidance of later hypertrophy and subendocardial ischemic damage. General hemodynamic stability is promoted by improvement in effective systemic output – with reduced interstage mortality, better somatic growth, and the opportunity to correct associated abnormalities out of the neonatal period, he added.

But is the bidirectional cavopulmonary shunt better than the hemi-Fontan procedure when it is used as the second stage in the typical three-stage treatment sequence (between neonatal palliation, e.g., Norwood procedure, and a Fontan operation) for the univentricular heart?

It does have some advantages: It is technically simpler; it can be performed on a beating heart at normothermia, and off pump in many cases; and it requires no prosthetic material. It also is a good setup for an extracardiac variant of the Fontan operation.

“On the other hand, there is some potential for stenosis, and there is probably some asymmetry of flow in many cases,” said Dr. Karl.

The hemi-Fontan doesn't have asymmetry of flow; there is actually very good flow to the left lung, he said. Also, there is a long, favorable history of this type of anastomosis specifically in hypoplastic left heart syndrome, and the hemi-Fontan provides a good setup for a lateral tunnel Fontan completion. Stenosis risk is minimal.

However, the hemi-Fontan is technically more complex. It requires cardiopulmonary bypass, which some surgeons choose to do using deep hypothermic circulatory arrest, and it may pose greater risk to the sinoatrial node. The hemi-Fontan also requires a considerable load of prosthetic material, but this is not seen as a disadvantage if the procedure follows a Norwood procedure, noted Dr. Karl, who said he had no conflicts of interest.

ST. PETERSBURG, FLA. – Both the bidirectional cavopulmonary shunt and the hemi-Fontan procedure have been used in children with hypoplastic left heart syndrome. Is one better than the other?

Dr. Tom Karl, deputy director of pediatric cardiac surgery at Mater Children's Hospital in South Brisbane, Queensland, sought to answer this question at the symposium.

One potential benefit of the bidirectional cavopulmonary shunt, he said, is decreased tricuspid insufficiency as the right ventricle's geometry normalizes from volume unloading.

Other potential benefits include avoidance of later hypertrophy and subendocardial ischemic damage. General hemodynamic stability is promoted by improvement in effective systemic output – with reduced interstage mortality, better somatic growth, and the opportunity to correct associated abnormalities out of the neonatal period, he added.

But is the bidirectional cavopulmonary shunt better than the hemi-Fontan procedure when it is used as the second stage in the typical three-stage treatment sequence (between neonatal palliation, e.g., Norwood procedure, and a Fontan operation) for the univentricular heart?

It does have some advantages: It is technically simpler; it can be performed on a beating heart at normothermia, and off pump in many cases; and it requires no prosthetic material. It also is a good setup for an extracardiac variant of the Fontan operation.

“On the other hand, there is some potential for stenosis, and there is probably some asymmetry of flow in many cases,” said Dr. Karl.

The hemi-Fontan doesn't have asymmetry of flow; there is actually very good flow to the left lung, he said. Also, there is a long, favorable history of this type of anastomosis specifically in hypoplastic left heart syndrome, and the hemi-Fontan provides a good setup for a lateral tunnel Fontan completion. Stenosis risk is minimal.

However, the hemi-Fontan is technically more complex. It requires cardiopulmonary bypass, which some surgeons choose to do using deep hypothermic circulatory arrest, and it may pose greater risk to the sinoatrial node. The hemi-Fontan also requires a considerable load of prosthetic material, but this is not seen as a disadvantage if the procedure follows a Norwood procedure, noted Dr. Karl, who said he had no conflicts of interest.

The American Academy of Pediatrics has officially endorsed a 2010 recommendation by the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices that reduces by one the number of vaccine doses required for postexposure rabies prophylaxis.

The recommendation calls for reduction in the number of postexposure doses of human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) from five to four doses, with the first dose of 1 mL to be given intramuscularly as soon as possible after exposure (day 0) and subsequent doses to be given on days 3, 7, and 14 after the first dose except in people with immune suppression, who should continue to receive the five-dose regimen with the fifth dose given on day 28.

The recommendation is the result of a review beginning in 2007 during a time when human rabies vaccine was in limited supply. The Advisory Committee on Immunization Practices (ACIP) formed a work group to review rabies vaccine options, and found that four doses were adequate for inducing rabies-neutralizing antibody, according to an AAP Policy Statement published in Pediatrics, which announced the AAP's endorsement of the recommendation (Pediatrics 2011 March 28 [doi: 10.1542/peds.2011-0095]).

A detailed review by the ACIP rabies work group of the evidence in support of the reduced dosing schedule showed that in all of approximately 1,000 patients, an adequate immune response to vaccination was achieved by day 14 (when the fourth dose of cell-derived rabies vaccine was given).

In addition, observational studies of people with likely rabies exposure showed that no cases of rabies have been attributed to the lack of a fifth dose.

Furthermore, animal models demonstrated that the number of vaccine doses did not contribute to significant differences in survival rate, and, theoretically, a reduced dosing schedule would result in similar or reduced rates of adverse reactions, which already are uncommon in children even when five doses are given.

Finally, the ACIP recommendation, which was published in 2010 (MMWR 2010;59[RR-2]:1–9), showed that reducing the dosing schedule to four doses would result in an estimated $16.6 million cost savings to the U.S. health care system.

Approximately 20,000–30,000 people receive rabies postexposure prophylaxis (PEP) in the United States each year, and one to three cases of human rabies occur each year, according to the AAP Policy Statement. Since the 1970s, with the introduction of modern cell-derived vaccines, no PEP failures have occurred.

Effective PEP has been attributed to prompt washing of the wound with copious amounts of soap and water, infiltration of human rabies immunoglobulin (HRIG) into and around the wound, and an appropriate dose schedule of intramuscular vaccine, which is now considered to be four doses in most patients, according to the Policy Statement. All other rabies PEP recommendations remain the same.

It is important that pediatricians be up to date on the new recommendations for rabies PEP, Dr. Mary Ann Jackson said in an interview.

“Despite the rarity of human rabies infection in the United States, questions for the pediatrician arising from potential animal exposures are surprisingly frequent, as animal bites and even bat exposures occur not uncommonly in the pediatric population,” said Dr. Jackson, chief of the pediatric infectious diseases section at Children's Mercy Hospitals & Clinics, Kansas City, Mo.

Pediatricians also need to know that the decision to embark on rabies PEP should be urgently but not emergently handled, she added, explaining that most exposures relate to domestic animal encounters (often strays) or incidents in which bats are found in the family home. “Careful attention to information gathering related to the exposure is key (see our form at www.childrensmercy.org/rabiesform

Dr. Jackson, who also is a professor of pediatrics at the University of Missouri–Kansas City, advised that in any instance where PEP is being considered, it is important to keep in mind that wound cleansing is essential and the child's tetanus vaccine history should be confirmed, with vaccine provided in appropriate cases. Rabies immune globulin must be concurrently given in the wound site in addition to rabies vaccine in an alternative site in every case where PEP is being provided for the first time in an otherwise healthy child.

In the instance where a bat is discovered in the room of a sleeping child, the PEP decision is certainly straightforward if the animal is available for rabies testing, and results can be ascertained promptly. In an otherwise healthy domestic pet exposure, a 10-day observation period should be ensured, utilizing the assistance of the local animal control and public health officials and in low-risk situations, which may obviate the need for PEP, said Dr. Jackson, who is a member of the AAP Committee on Infectious Diseases that wrote the new AAP Policy Statement.

All authors have filed conflict of interest statements with the AAP. Any conflicts have been resolved through a process approved by the AAP Board of Directors, according to Pediatrics.

The American Academy of Pediatrics has officially endorsed a 2010 recommendation by the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices that reduces by one the number of vaccine doses required for postexposure rabies prophylaxis.

The recommendation calls for reduction in the number of postexposure doses of human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) from five to four doses, with the first dose of 1 mL to be given intramuscularly as soon as possible after exposure (day 0) and subsequent doses to be given on days 3, 7, and 14 after the first dose except in people with immune suppression, who should continue to receive the five-dose regimen with the fifth dose given on day 28.

The recommendation is the result of a review beginning in 2007 during a time when human rabies vaccine was in limited supply. The Advisory Committee on Immunization Practices (ACIP) formed a work group to review rabies vaccine options, and found that four doses were adequate for inducing rabies-neutralizing antibody, according to an AAP Policy Statement published in Pediatrics, which announced the AAP's endorsement of the recommendation (Pediatrics 2011 March 28 [doi: 10.1542/peds.2011-0095]).

A detailed review by the ACIP rabies work group of the evidence in support of the reduced dosing schedule showed that in all of approximately 1,000 patients, an adequate immune response to vaccination was achieved by day 14 (when the fourth dose of cell-derived rabies vaccine was given).

In addition, observational studies of people with likely rabies exposure showed that no cases of rabies have been attributed to the lack of a fifth dose.

Furthermore, animal models demonstrated that the number of vaccine doses did not contribute to significant differences in survival rate, and, theoretically, a reduced dosing schedule would result in similar or reduced rates of adverse reactions, which already are uncommon in children even when five doses are given.

Finally, the ACIP recommendation, which was published in 2010 (MMWR 2010;59[RR-2]:1–9), showed that reducing the dosing schedule to four doses would result in an estimated $16.6 million cost savings to the U.S. health care system.

Approximately 20,000–30,000 people receive rabies postexposure prophylaxis (PEP) in the United States each year, and one to three cases of human rabies occur each year, according to the AAP Policy Statement. Since the 1970s, with the introduction of modern cell-derived vaccines, no PEP failures have occurred.

Effective PEP has been attributed to prompt washing of the wound with copious amounts of soap and water, infiltration of human rabies immunoglobulin (HRIG) into and around the wound, and an appropriate dose schedule of intramuscular vaccine, which is now considered to be four doses in most patients, according to the Policy Statement. All other rabies PEP recommendations remain the same.

It is important that pediatricians be up to date on the new recommendations for rabies PEP, Dr. Mary Ann Jackson said in an interview.

“Despite the rarity of human rabies infection in the United States, questions for the pediatrician arising from potential animal exposures are surprisingly frequent, as animal bites and even bat exposures occur not uncommonly in the pediatric population,” said Dr. Jackson, chief of the pediatric infectious diseases section at Children's Mercy Hospitals & Clinics, Kansas City, Mo.

Pediatricians also need to know that the decision to embark on rabies PEP should be urgently but not emergently handled, she added, explaining that most exposures relate to domestic animal encounters (often strays) or incidents in which bats are found in the family home. “Careful attention to information gathering related to the exposure is key (see our form at www.childrensmercy.org/rabiesform

Dr. Jackson, who also is a professor of pediatrics at the University of Missouri–Kansas City, advised that in any instance where PEP is being considered, it is important to keep in mind that wound cleansing is essential and the child's tetanus vaccine history should be confirmed, with vaccine provided in appropriate cases. Rabies immune globulin must be concurrently given in the wound site in addition to rabies vaccine in an alternative site in every case where PEP is being provided for the first time in an otherwise healthy child.

In the instance where a bat is discovered in the room of a sleeping child, the PEP decision is certainly straightforward if the animal is available for rabies testing, and results can be ascertained promptly. In an otherwise healthy domestic pet exposure, a 10-day observation period should be ensured, utilizing the assistance of the local animal control and public health officials and in low-risk situations, which may obviate the need for PEP, said Dr. Jackson, who is a member of the AAP Committee on Infectious Diseases that wrote the new AAP Policy Statement.

All authors have filed conflict of interest statements with the AAP. Any conflicts have been resolved through a process approved by the AAP Board of Directors, according to Pediatrics.

The American Academy of Pediatrics has officially endorsed a 2010 recommendation by the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices that reduces by one the number of vaccine doses required for postexposure rabies prophylaxis.

The recommendation calls for reduction in the number of postexposure doses of human diploid cell vaccine (HDCV) or purified chick embryo cell vaccine (PCECV) from five to four doses, with the first dose of 1 mL to be given intramuscularly as soon as possible after exposure (day 0) and subsequent doses to be given on days 3, 7, and 14 after the first dose except in people with immune suppression, who should continue to receive the five-dose regimen with the fifth dose given on day 28.

The recommendation is the result of a review beginning in 2007 during a time when human rabies vaccine was in limited supply. The Advisory Committee on Immunization Practices (ACIP) formed a work group to review rabies vaccine options, and found that four doses were adequate for inducing rabies-neutralizing antibody, according to an AAP Policy Statement published in Pediatrics, which announced the AAP's endorsement of the recommendation (Pediatrics 2011 March 28 [doi: 10.1542/peds.2011-0095]).

A detailed review by the ACIP rabies work group of the evidence in support of the reduced dosing schedule showed that in all of approximately 1,000 patients, an adequate immune response to vaccination was achieved by day 14 (when the fourth dose of cell-derived rabies vaccine was given).

In addition, observational studies of people with likely rabies exposure showed that no cases of rabies have been attributed to the lack of a fifth dose.

Furthermore, animal models demonstrated that the number of vaccine doses did not contribute to significant differences in survival rate, and, theoretically, a reduced dosing schedule would result in similar or reduced rates of adverse reactions, which already are uncommon in children even when five doses are given.

Finally, the ACIP recommendation, which was published in 2010 (MMWR 2010;59[RR-2]:1–9), showed that reducing the dosing schedule to four doses would result in an estimated $16.6 million cost savings to the U.S. health care system.

Approximately 20,000–30,000 people receive rabies postexposure prophylaxis (PEP) in the United States each year, and one to three cases of human rabies occur each year, according to the AAP Policy Statement. Since the 1970s, with the introduction of modern cell-derived vaccines, no PEP failures have occurred.

Effective PEP has been attributed to prompt washing of the wound with copious amounts of soap and water, infiltration of human rabies immunoglobulin (HRIG) into and around the wound, and an appropriate dose schedule of intramuscular vaccine, which is now considered to be four doses in most patients, according to the Policy Statement. All other rabies PEP recommendations remain the same.

It is important that pediatricians be up to date on the new recommendations for rabies PEP, Dr. Mary Ann Jackson said in an interview.

“Despite the rarity of human rabies infection in the United States, questions for the pediatrician arising from potential animal exposures are surprisingly frequent, as animal bites and even bat exposures occur not uncommonly in the pediatric population,” said Dr. Jackson, chief of the pediatric infectious diseases section at Children's Mercy Hospitals & Clinics, Kansas City, Mo.

Pediatricians also need to know that the decision to embark on rabies PEP should be urgently but not emergently handled, she added, explaining that most exposures relate to domestic animal encounters (often strays) or incidents in which bats are found in the family home. “Careful attention to information gathering related to the exposure is key (see our form at www.childrensmercy.org/rabiesform

Dr. Jackson, who also is a professor of pediatrics at the University of Missouri–Kansas City, advised that in any instance where PEP is being considered, it is important to keep in mind that wound cleansing is essential and the child's tetanus vaccine history should be confirmed, with vaccine provided in appropriate cases. Rabies immune globulin must be concurrently given in the wound site in addition to rabies vaccine in an alternative site in every case where PEP is being provided for the first time in an otherwise healthy child.

In the instance where a bat is discovered in the room of a sleeping child, the PEP decision is certainly straightforward if the animal is available for rabies testing, and results can be ascertained promptly. In an otherwise healthy domestic pet exposure, a 10-day observation period should be ensured, utilizing the assistance of the local animal control and public health officials and in low-risk situations, which may obviate the need for PEP, said Dr. Jackson, who is a member of the AAP Committee on Infectious Diseases that wrote the new AAP Policy Statement.

All authors have filed conflict of interest statements with the AAP. Any conflicts have been resolved through a process approved by the AAP Board of Directors, according to Pediatrics.

Children receiving the fifth dose of the DTaP vaccine are significantly less likely to experience a local injection site reaction if they receive the injection in the thigh rather than the arm.

Of 233,616 children aged 4–6 years who received a diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccination in 2002–2006, only 1,017 (0.4%) experienced a local reaction that required medical attention, but the rate of reactions was 47.4 vs. 32.1 per 10,000 vaccinations for arm vs. thigh injections, respectively, Dr. Lisa A. Jackson of the Group Health Research Institute, Seattle, and her colleagues from the Vaccine Safety Datalink (VSD) team reported.

After adjustment for age, sex, and study site, the risk of a local reaction requiring medical attention was 78% higher with arm vs. thigh injections (Pediatrics 2011;127:e581–7). In children with a valid body mass index measurement, injection in the arm was associated with a 2.3-fold higher risk of a local reaction, and in that model, BMI also was shown to be an independent risk factor for a reaction. After adjustment for age, sex, and managed care organization site, similar associations of higher BMI and greater risk for a local injection-site reaction persisted among those who received an arm injection and in those vaccinated in the thigh, Dr. Jackson and her associates said, noting that the factors contributing to this association are unclear, but might be a result of an increased likelihood of inadequate intramuscular injection in larger children.

Children included in the study were from the VSD population; VSD is a collaborative project between the Centers for Disease Control and Prevention and a group of eight managed care organizations in the United States that was established in 1991 to monitor and evaluate vaccine safety. Injection-site reactions were identified by using administrative data, and were confirmed by a medical records review.

The findings confirm those from a previous prospective study of 1,315 children, who also had less redness and swelling at the injections site with thigh vs. arm injections, the investigators noted.

According to current recommendations from the CDC's Advisory Committee on Immunization Practices and the American Academy of Pediatrics, the deltoid muscle in the arm is the preferred site for intramuscular injections in children older than age 1 year, but those recommendations were based on data from 18-month-old children, and reflected an increased likelihood of discomfort and difficulty with movement of the extremity when thigh injections were used. Indeed, in the current study, nearly 14% of children with a medically attended local reaction following thigh vaccination were noted to have had difficulty walking as a result, which raises the question of whether the lower risk of a reaction with a thigh injection is counterbalanced by the risk of problems with ambulation.

However, the current data do not bear this out.

“If it is assumed that reactions resulting in a medical visit are reactions of greater concern to the parent, for whatever reason, it can be argued that, on balance, the risk of a concerning reaction is lower with thigh injections than with deltoid injections,” they said.

Dr. Jackson received research funding (unrelated to DTaP vaccine) from Sanofi Pasteur and served as a consultant for GlaxoSmithKline. Coauthor Jennifer C. Nelson, Ph.D., reported serving as a statistical consultant to GlaxoSmithKline, and coauthor Dr. Roger Baxter reported receiving research grants from Sanofi Pasteur. The study received funding from the CDC through America's Health Insurance Plans.

Children receiving the fifth dose of the DTaP vaccine are significantly less likely to experience a local injection site reaction if they receive the injection in the thigh rather than the arm.

Of 233,616 children aged 4–6 years who received a diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccination in 2002–2006, only 1,017 (0.4%) experienced a local reaction that required medical attention, but the rate of reactions was 47.4 vs. 32.1 per 10,000 vaccinations for arm vs. thigh injections, respectively, Dr. Lisa A. Jackson of the Group Health Research Institute, Seattle, and her colleagues from the Vaccine Safety Datalink (VSD) team reported.

After adjustment for age, sex, and study site, the risk of a local reaction requiring medical attention was 78% higher with arm vs. thigh injections (Pediatrics 2011;127:e581–7). In children with a valid body mass index measurement, injection in the arm was associated with a 2.3-fold higher risk of a local reaction, and in that model, BMI also was shown to be an independent risk factor for a reaction. After adjustment for age, sex, and managed care organization site, similar associations of higher BMI and greater risk for a local injection-site reaction persisted among those who received an arm injection and in those vaccinated in the thigh, Dr. Jackson and her associates said, noting that the factors contributing to this association are unclear, but might be a result of an increased likelihood of inadequate intramuscular injection in larger children.

Children included in the study were from the VSD population; VSD is a collaborative project between the Centers for Disease Control and Prevention and a group of eight managed care organizations in the United States that was established in 1991 to monitor and evaluate vaccine safety. Injection-site reactions were identified by using administrative data, and were confirmed by a medical records review.

The findings confirm those from a previous prospective study of 1,315 children, who also had less redness and swelling at the injections site with thigh vs. arm injections, the investigators noted.

According to current recommendations from the CDC's Advisory Committee on Immunization Practices and the American Academy of Pediatrics, the deltoid muscle in the arm is the preferred site for intramuscular injections in children older than age 1 year, but those recommendations were based on data from 18-month-old children, and reflected an increased likelihood of discomfort and difficulty with movement of the extremity when thigh injections were used. Indeed, in the current study, nearly 14% of children with a medically attended local reaction following thigh vaccination were noted to have had difficulty walking as a result, which raises the question of whether the lower risk of a reaction with a thigh injection is counterbalanced by the risk of problems with ambulation.

However, the current data do not bear this out.

“If it is assumed that reactions resulting in a medical visit are reactions of greater concern to the parent, for whatever reason, it can be argued that, on balance, the risk of a concerning reaction is lower with thigh injections than with deltoid injections,” they said.

Dr. Jackson received research funding (unrelated to DTaP vaccine) from Sanofi Pasteur and served as a consultant for GlaxoSmithKline. Coauthor Jennifer C. Nelson, Ph.D., reported serving as a statistical consultant to GlaxoSmithKline, and coauthor Dr. Roger Baxter reported receiving research grants from Sanofi Pasteur. The study received funding from the CDC through America's Health Insurance Plans.

Children receiving the fifth dose of the DTaP vaccine are significantly less likely to experience a local injection site reaction if they receive the injection in the thigh rather than the arm.

Of 233,616 children aged 4–6 years who received a diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccination in 2002–2006, only 1,017 (0.4%) experienced a local reaction that required medical attention, but the rate of reactions was 47.4 vs. 32.1 per 10,000 vaccinations for arm vs. thigh injections, respectively, Dr. Lisa A. Jackson of the Group Health Research Institute, Seattle, and her colleagues from the Vaccine Safety Datalink (VSD) team reported.

After adjustment for age, sex, and study site, the risk of a local reaction requiring medical attention was 78% higher with arm vs. thigh injections (Pediatrics 2011;127:e581–7). In children with a valid body mass index measurement, injection in the arm was associated with a 2.3-fold higher risk of a local reaction, and in that model, BMI also was shown to be an independent risk factor for a reaction. After adjustment for age, sex, and managed care organization site, similar associations of higher BMI and greater risk for a local injection-site reaction persisted among those who received an arm injection and in those vaccinated in the thigh, Dr. Jackson and her associates said, noting that the factors contributing to this association are unclear, but might be a result of an increased likelihood of inadequate intramuscular injection in larger children.

Children included in the study were from the VSD population; VSD is a collaborative project between the Centers for Disease Control and Prevention and a group of eight managed care organizations in the United States that was established in 1991 to monitor and evaluate vaccine safety. Injection-site reactions were identified by using administrative data, and were confirmed by a medical records review.

The findings confirm those from a previous prospective study of 1,315 children, who also had less redness and swelling at the injections site with thigh vs. arm injections, the investigators noted.

According to current recommendations from the CDC's Advisory Committee on Immunization Practices and the American Academy of Pediatrics, the deltoid muscle in the arm is the preferred site for intramuscular injections in children older than age 1 year, but those recommendations were based on data from 18-month-old children, and reflected an increased likelihood of discomfort and difficulty with movement of the extremity when thigh injections were used. Indeed, in the current study, nearly 14% of children with a medically attended local reaction following thigh vaccination were noted to have had difficulty walking as a result, which raises the question of whether the lower risk of a reaction with a thigh injection is counterbalanced by the risk of problems with ambulation.

However, the current data do not bear this out.

“If it is assumed that reactions resulting in a medical visit are reactions of greater concern to the parent, for whatever reason, it can be argued that, on balance, the risk of a concerning reaction is lower with thigh injections than with deltoid injections,” they said.

Dr. Jackson received research funding (unrelated to DTaP vaccine) from Sanofi Pasteur and served as a consultant for GlaxoSmithKline. Coauthor Jennifer C. Nelson, Ph.D., reported serving as a statistical consultant to GlaxoSmithKline, and coauthor Dr. Roger Baxter reported receiving research grants from Sanofi Pasteur. The study received funding from the CDC through America's Health Insurance Plans.