Background The American Society of Clinical Oncology (ASCO) launched the Quality Oncology Practice Initiative (QOPI) program in 2010 to promote quality cancer care. The association has subsequently influenced the use of neurokinin 1 (NK-1) receptor antagonists through articles published in peer-reviewed publications and its Choosing Wisely campaign.

Objective To explore the rationale behind the use of NK-1 receptor antagonists in clinical practice.

Methods We distributed an anonymous 12-question online survey to 650 medical oncologists in 5 states, inquiring about their use of these agents. A total of 155 responses were analyzed.

Results QOPI-certified physicians were significantly more likely than noncertified physicians to use NK-1 receptor antagonists with moderately emetogenic regimens, including weekly cisplatin for head and neck cancer (82.6% vs 27.0%, respectively; P < .001), cervical and bladder cancer (81.4% vs 32.7%, P < .001), and with CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone) with or without rituximab in lymphoma (81.4 vs 17.3%, P < .001). The majority of QOPI-certified physicians reported using these agents for the sole purpose of maintaining QOPI certification (80.0%-86.0%). Certified physicians were also significantly more likely to appropriately prescribe NK-1 antagonists with highly emetogenic chemotherapy.

Limitations Responder bias; short survey that precludes detailed analysis; small sample size may limit generalizability to the field of medical oncology.

Conclusion Our data demonstrate that providers in QOPI-certified practices are significantly more likely than those in noncertified practices to prescribe NK-1 receptor antagonists. Certified physicians report that satisfying ASCO-QOPI requirements is their primary motivation for offering these agents.

Click on the PDF icon at the top of this introduction to read the full article.

Background The American Society of Clinical Oncology (ASCO) launched the Quality Oncology Practice Initiative (QOPI) program in 2010 to promote quality cancer care. The association has subsequently influenced the use of neurokinin 1 (NK-1) receptor antagonists through articles published in peer-reviewed publications and its Choosing Wisely campaign.

Objective To explore the rationale behind the use of NK-1 receptor antagonists in clinical practice.

Methods We distributed an anonymous 12-question online survey to 650 medical oncologists in 5 states, inquiring about their use of these agents. A total of 155 responses were analyzed.

Results QOPI-certified physicians were significantly more likely than noncertified physicians to use NK-1 receptor antagonists with moderately emetogenic regimens, including weekly cisplatin for head and neck cancer (82.6% vs 27.0%, respectively; P < .001), cervical and bladder cancer (81.4% vs 32.7%, P < .001), and with CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone) with or without rituximab in lymphoma (81.4 vs 17.3%, P < .001). The majority of QOPI-certified physicians reported using these agents for the sole purpose of maintaining QOPI certification (80.0%-86.0%). Certified physicians were also significantly more likely to appropriately prescribe NK-1 antagonists with highly emetogenic chemotherapy.

Limitations Responder bias; short survey that precludes detailed analysis; small sample size may limit generalizability to the field of medical oncology.

Conclusion Our data demonstrate that providers in QOPI-certified practices are significantly more likely than those in noncertified practices to prescribe NK-1 receptor antagonists. Certified physicians report that satisfying ASCO-QOPI requirements is their primary motivation for offering these agents.

Click on the PDF icon at the top of this introduction to read the full article.

Background The American Society of Clinical Oncology (ASCO) launched the Quality Oncology Practice Initiative (QOPI) program in 2010 to promote quality cancer care. The association has subsequently influenced the use of neurokinin 1 (NK-1) receptor antagonists through articles published in peer-reviewed publications and its Choosing Wisely campaign.

Objective To explore the rationale behind the use of NK-1 receptor antagonists in clinical practice.

Methods We distributed an anonymous 12-question online survey to 650 medical oncologists in 5 states, inquiring about their use of these agents. A total of 155 responses were analyzed.

Results QOPI-certified physicians were significantly more likely than noncertified physicians to use NK-1 receptor antagonists with moderately emetogenic regimens, including weekly cisplatin for head and neck cancer (82.6% vs 27.0%, respectively; P < .001), cervical and bladder cancer (81.4% vs 32.7%, P < .001), and with CHOP (cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone) with or without rituximab in lymphoma (81.4 vs 17.3%, P < .001). The majority of QOPI-certified physicians reported using these agents for the sole purpose of maintaining QOPI certification (80.0%-86.0%). Certified physicians were also significantly more likely to appropriately prescribe NK-1 antagonists with highly emetogenic chemotherapy.

Limitations Responder bias; short survey that precludes detailed analysis; small sample size may limit generalizability to the field of medical oncology.

Conclusion Our data demonstrate that providers in QOPI-certified practices are significantly more likely than those in noncertified practices to prescribe NK-1 receptor antagonists. Certified physicians report that satisfying ASCO-QOPI requirements is their primary motivation for offering these agents.

Click on the PDF icon at the top of this introduction to read the full article.

Background Multicenter clinical trials conducted primarily at academic centers have shown that breast-conserving therapy (BCT) and mastectomy lead to equivalent overall survival (OS) for women with early-stage breast cancer.

Objective To determine rates of BCT and OS after conservation therapy in a large urban community practice, compare them with national rates, and identify risk factors for survival.

Methods We identified 1,172 T1-2, N0 breast cancer patients diagnosed during 1997-2007 in our hospital tumor registry and compared the rates of BCT and adjuvant radiotherapy with a similar population in the SEER [Surveillance, Epidemiology, and End Results] database (N = 232,898) for the same treatment period. Cox proportional hazards models were used to assess the influence of age at diagnosis, tumor grade, biomarker status, margin status, and receipt of hormones, radiation, or chemotherapy on OS after BCT.

Results The rate of breast-conserving surgery (BCS) was higher in our practice compared with the national average (90.9% and 66.4%, respectively). The rate of adjuvant radiation after BCS in our practice was 93.7%; survival estimates were higher for patients treated with adjuvant radiation across all age groups, compared with the national estimates (92.5% and 72.9%). Younger age and receipt of radiation were associated with improved survival.

Limitations Retrospective study design; confounding factors such as comorbidities were not considered.

Conclusions We had high rates of BCT and adjuvant radiation in early-stage breast cancer patients in our community practice, which resulted in excellent survival rates that compared favorably with those in large academic centers and emphasizes the role of appropriate use of adjuvant radiation.

Funding Vantage Oncology

Click on the PDF icon at the top of this introduction to read the full article.

Background Multicenter clinical trials conducted primarily at academic centers have shown that breast-conserving therapy (BCT) and mastectomy lead to equivalent overall survival (OS) for women with early-stage breast cancer.

Objective To determine rates of BCT and OS after conservation therapy in a large urban community practice, compare them with national rates, and identify risk factors for survival.

Methods We identified 1,172 T1-2, N0 breast cancer patients diagnosed during 1997-2007 in our hospital tumor registry and compared the rates of BCT and adjuvant radiotherapy with a similar population in the SEER [Surveillance, Epidemiology, and End Results] database (N = 232,898) for the same treatment period. Cox proportional hazards models were used to assess the influence of age at diagnosis, tumor grade, biomarker status, margin status, and receipt of hormones, radiation, or chemotherapy on OS after BCT.

Results The rate of breast-conserving surgery (BCS) was higher in our practice compared with the national average (90.9% and 66.4%, respectively). The rate of adjuvant radiation after BCS in our practice was 93.7%; survival estimates were higher for patients treated with adjuvant radiation across all age groups, compared with the national estimates (92.5% and 72.9%). Younger age and receipt of radiation were associated with improved survival.

Limitations Retrospective study design; confounding factors such as comorbidities were not considered.

Conclusions We had high rates of BCT and adjuvant radiation in early-stage breast cancer patients in our community practice, which resulted in excellent survival rates that compared favorably with those in large academic centers and emphasizes the role of appropriate use of adjuvant radiation.

Funding Vantage Oncology

Click on the PDF icon at the top of this introduction to read the full article.

Background Multicenter clinical trials conducted primarily at academic centers have shown that breast-conserving therapy (BCT) and mastectomy lead to equivalent overall survival (OS) for women with early-stage breast cancer.

Objective To determine rates of BCT and OS after conservation therapy in a large urban community practice, compare them with national rates, and identify risk factors for survival.

Methods We identified 1,172 T1-2, N0 breast cancer patients diagnosed during 1997-2007 in our hospital tumor registry and compared the rates of BCT and adjuvant radiotherapy with a similar population in the SEER [Surveillance, Epidemiology, and End Results] database (N = 232,898) for the same treatment period. Cox proportional hazards models were used to assess the influence of age at diagnosis, tumor grade, biomarker status, margin status, and receipt of hormones, radiation, or chemotherapy on OS after BCT.

Results The rate of breast-conserving surgery (BCS) was higher in our practice compared with the national average (90.9% and 66.4%, respectively). The rate of adjuvant radiation after BCS in our practice was 93.7%; survival estimates were higher for patients treated with adjuvant radiation across all age groups, compared with the national estimates (92.5% and 72.9%). Younger age and receipt of radiation were associated with improved survival.

Limitations Retrospective study design; confounding factors such as comorbidities were not considered.

Conclusions We had high rates of BCT and adjuvant radiation in early-stage breast cancer patients in our community practice, which resulted in excellent survival rates that compared favorably with those in large academic centers and emphasizes the role of appropriate use of adjuvant radiation.

Funding Vantage Oncology

Click on the PDF icon at the top of this introduction to read the full article.

The Communication and Optimal Resolution tool kit, offered by the Agency for Healthcare Research and Quality, helps hospitals, health systems, and clinicians respond to patients who are harmed by the care they receive, Andy Bindman, MD, AHRQ director, said in a blog post.

The tool kit is a new addition to AHRQ’s suite of patient safety tools and training materials.

Poor communication can lead to life-and-death mistakes, which can then become legal issues, said Dr. Bindman. The Communication and Optimal Resolution (CANDOR) tool kit uses time as a key factor by disclosing harm to patients and families as soon as it happens.

“It has been estimated that medical errors are the third-leading cause of death in the United States and that the majority of clinicians have experience with a medical error that resulted in harm to a patient. Often these ‘mistakes’ are not the result of poorly trained individuals but the result of the faulty systems we sometimes work in,” Dr. Bindman noted.

“It is also important for us to engage with colleagues to reflect on the mistake and explore the root causes of how it happened. This helps us to learn from the situation and take steps to minimize the chances of a similar mistake happening again to another patient,” he said.

Funding for CANDOR was provided by the AHRQ’s $23 million Patient Safety and Medical Liability grant initiative, launched in 2009. The initiative is the largest federal investment in research linking improved patient safety to reduced medical liability, according to Dr. Bindman.

[email protected]

The Communication and Optimal Resolution tool kit, offered by the Agency for Healthcare Research and Quality, helps hospitals, health systems, and clinicians respond to patients who are harmed by the care they receive, Andy Bindman, MD, AHRQ director, said in a blog post.

The tool kit is a new addition to AHRQ’s suite of patient safety tools and training materials.

Poor communication can lead to life-and-death mistakes, which can then become legal issues, said Dr. Bindman. The Communication and Optimal Resolution (CANDOR) tool kit uses time as a key factor by disclosing harm to patients and families as soon as it happens.

“It has been estimated that medical errors are the third-leading cause of death in the United States and that the majority of clinicians have experience with a medical error that resulted in harm to a patient. Often these ‘mistakes’ are not the result of poorly trained individuals but the result of the faulty systems we sometimes work in,” Dr. Bindman noted.

“It is also important for us to engage with colleagues to reflect on the mistake and explore the root causes of how it happened. This helps us to learn from the situation and take steps to minimize the chances of a similar mistake happening again to another patient,” he said.

Funding for CANDOR was provided by the AHRQ’s $23 million Patient Safety and Medical Liability grant initiative, launched in 2009. The initiative is the largest federal investment in research linking improved patient safety to reduced medical liability, according to Dr. Bindman.

[email protected]

The Communication and Optimal Resolution tool kit, offered by the Agency for Healthcare Research and Quality, helps hospitals, health systems, and clinicians respond to patients who are harmed by the care they receive, Andy Bindman, MD, AHRQ director, said in a blog post.

The tool kit is a new addition to AHRQ’s suite of patient safety tools and training materials.

Poor communication can lead to life-and-death mistakes, which can then become legal issues, said Dr. Bindman. The Communication and Optimal Resolution (CANDOR) tool kit uses time as a key factor by disclosing harm to patients and families as soon as it happens.

“It has been estimated that medical errors are the third-leading cause of death in the United States and that the majority of clinicians have experience with a medical error that resulted in harm to a patient. Often these ‘mistakes’ are not the result of poorly trained individuals but the result of the faulty systems we sometimes work in,” Dr. Bindman noted.

“It is also important for us to engage with colleagues to reflect on the mistake and explore the root causes of how it happened. This helps us to learn from the situation and take steps to minimize the chances of a similar mistake happening again to another patient,” he said.

Funding for CANDOR was provided by the AHRQ’s $23 million Patient Safety and Medical Liability grant initiative, launched in 2009. The initiative is the largest federal investment in research linking improved patient safety to reduced medical liability, according to Dr. Bindman.

[email protected]

DENVER – Young to early middle-aged men with insomnia symptoms are at increased risk for cardiovascular and cerebrovascular events, according to an analysis from the landmark CARDIA study.

“We found that younger to mid-life men with difficulty initiating sleep or with more than one insomnia symptom were at greater risk for incident cardiovascular disease events. And despite the fact that women in general seemed to be more prone to report those sleep difficulties, those that did were not at increased risk,” Megan E. Petrov, PhD, reported at the annual meeting of the Associated Professional Sleep Societies.

©KatarzynaBialasiewicz/ Thinkstock

It is well established that insomnia in older adults is associated with increased cardiovascular risk. For example, a meta-analysis of 13 prospective studies with more than 123,000 subjects concluded that insomnia was associated with a 45% increased risk of fatal and nonfatal cardiovascular events (Eur J Prev Cardiol. 2014 Jan;21[1]:57-64). But those studies typically involved older individuals, which makes cause and effect more difficult to determine because so many chronic conditions become more prevalent with advancing age, noted Dr. Petrov of Arizona State University in Phoenix.

“We wanted to see if insomnia is truly an early risk factor in the pathogenesis of cardiovascular disease and stroke,” she said.

To do so, she and her coinvestigators turned to the CARDIA database. CARDIA (the Coronary Artery Risk Development in Young Adults study), is a National Heart, Lung, and Blood Institute–sponsored prospective, epidemiologic study.

She reported on 2,950 non-Hispanic black or white participants aged 33-45 and free of any history of cardiovascular disease in 2000-2001, when they answered questions about insomnia symptoms. Difficulty in initiating sleep was reported by 16.3% of men and 20.7% of women. Difficulty maintaining sleep was a problem for 9.3% of men and 14.5% of women. And 20.6% of men and 20.1% of women reported frequent early morning awakening.

During a mean 11.5 years of prospective follow-up, 4.1% of men and 2.3% of women had a fatal or nonfatal MI, stroke, transient ischemic attack, heart failure, peripheral vascular disease, or hospitalization for an acute coronary syndrome.

In a multivariate logistic regression analysis fully adjusted for demographics, socioeconomic status, body mass index, blood pressure, diabetes, depression, health behaviors, medications, thyroid disease, and kidney problems, men who reported difficulty in getting to sleep had a 2.64-fold increased risk of one of these adverse outcomes. That was the only insomnia symptom associated with significantly increased risk. However, men but not women who reported having more than one insomnia symptom had a 39% increased risk of a cardiovascular event for each additional symptom.

Prior studies have shown that insomnia is associated with cardiac sympathetic hyperactivation. That observation suggests a plausible mechanism for increased cardiovascular and cerebrovascular risk, but it doesn’t explain why that risk was confined to young men in CARDIA. One possibility is that because of gender-related differences in perception, men tend to report having insomnia symptoms only when the insomnia is more severe, Dr. Petrov suggested.

The strengths of the CARDIA study are that all cardiovascular endpoints had to be physician certified, and the study includes a large black population. A study limitation is the relatively small number of cardiovascular events, as to be expected in a younger population. Thus, confirmation of the new findings in another large data set will be important, she noted.

As a next step in her research, Dr. Petrov said she plans to drill down in the CARDIA data to see if race modified the impact of insomnia symptoms on cardiovascular outcomes. Black participants reported all insomnia symptoms more frequently than did whites. For example, difficulty initiating sleep was reported by 25.7% of blacks, compared with just 13.5% of whites, and early morning awakening was twice as prevalent among the black participants.

Also, CARDIA participants provided self-reported sleep duration data. It will be illuminating to see if sleep duration had a modifying effect upon the insomnia/cardiovascular risk association observed in men, she said.

Dr. Petrov reported having no relevant financial conflicts.

DENVER – Young to early middle-aged men with insomnia symptoms are at increased risk for cardiovascular and cerebrovascular events, according to an analysis from the landmark CARDIA study.

“We found that younger to mid-life men with difficulty initiating sleep or with more than one insomnia symptom were at greater risk for incident cardiovascular disease events. And despite the fact that women in general seemed to be more prone to report those sleep difficulties, those that did were not at increased risk,” Megan E. Petrov, PhD, reported at the annual meeting of the Associated Professional Sleep Societies.

©KatarzynaBialasiewicz/ Thinkstock

It is well established that insomnia in older adults is associated with increased cardiovascular risk. For example, a meta-analysis of 13 prospective studies with more than 123,000 subjects concluded that insomnia was associated with a 45% increased risk of fatal and nonfatal cardiovascular events (Eur J Prev Cardiol. 2014 Jan;21[1]:57-64). But those studies typically involved older individuals, which makes cause and effect more difficult to determine because so many chronic conditions become more prevalent with advancing age, noted Dr. Petrov of Arizona State University in Phoenix.

“We wanted to see if insomnia is truly an early risk factor in the pathogenesis of cardiovascular disease and stroke,” she said.

To do so, she and her coinvestigators turned to the CARDIA database. CARDIA (the Coronary Artery Risk Development in Young Adults study), is a National Heart, Lung, and Blood Institute–sponsored prospective, epidemiologic study.

She reported on 2,950 non-Hispanic black or white participants aged 33-45 and free of any history of cardiovascular disease in 2000-2001, when they answered questions about insomnia symptoms. Difficulty in initiating sleep was reported by 16.3% of men and 20.7% of women. Difficulty maintaining sleep was a problem for 9.3% of men and 14.5% of women. And 20.6% of men and 20.1% of women reported frequent early morning awakening.

During a mean 11.5 years of prospective follow-up, 4.1% of men and 2.3% of women had a fatal or nonfatal MI, stroke, transient ischemic attack, heart failure, peripheral vascular disease, or hospitalization for an acute coronary syndrome.

In a multivariate logistic regression analysis fully adjusted for demographics, socioeconomic status, body mass index, blood pressure, diabetes, depression, health behaviors, medications, thyroid disease, and kidney problems, men who reported difficulty in getting to sleep had a 2.64-fold increased risk of one of these adverse outcomes. That was the only insomnia symptom associated with significantly increased risk. However, men but not women who reported having more than one insomnia symptom had a 39% increased risk of a cardiovascular event for each additional symptom.

Prior studies have shown that insomnia is associated with cardiac sympathetic hyperactivation. That observation suggests a plausible mechanism for increased cardiovascular and cerebrovascular risk, but it doesn’t explain why that risk was confined to young men in CARDIA. One possibility is that because of gender-related differences in perception, men tend to report having insomnia symptoms only when the insomnia is more severe, Dr. Petrov suggested.

The strengths of the CARDIA study are that all cardiovascular endpoints had to be physician certified, and the study includes a large black population. A study limitation is the relatively small number of cardiovascular events, as to be expected in a younger population. Thus, confirmation of the new findings in another large data set will be important, she noted.

As a next step in her research, Dr. Petrov said she plans to drill down in the CARDIA data to see if race modified the impact of insomnia symptoms on cardiovascular outcomes. Black participants reported all insomnia symptoms more frequently than did whites. For example, difficulty initiating sleep was reported by 25.7% of blacks, compared with just 13.5% of whites, and early morning awakening was twice as prevalent among the black participants.

Also, CARDIA participants provided self-reported sleep duration data. It will be illuminating to see if sleep duration had a modifying effect upon the insomnia/cardiovascular risk association observed in men, she said.

Dr. Petrov reported having no relevant financial conflicts.

DENVER – Young to early middle-aged men with insomnia symptoms are at increased risk for cardiovascular and cerebrovascular events, according to an analysis from the landmark CARDIA study.

“We found that younger to mid-life men with difficulty initiating sleep or with more than one insomnia symptom were at greater risk for incident cardiovascular disease events. And despite the fact that women in general seemed to be more prone to report those sleep difficulties, those that did were not at increased risk,” Megan E. Petrov, PhD, reported at the annual meeting of the Associated Professional Sleep Societies.

©KatarzynaBialasiewicz/ Thinkstock

It is well established that insomnia in older adults is associated with increased cardiovascular risk. For example, a meta-analysis of 13 prospective studies with more than 123,000 subjects concluded that insomnia was associated with a 45% increased risk of fatal and nonfatal cardiovascular events (Eur J Prev Cardiol. 2014 Jan;21[1]:57-64). But those studies typically involved older individuals, which makes cause and effect more difficult to determine because so many chronic conditions become more prevalent with advancing age, noted Dr. Petrov of Arizona State University in Phoenix.

“We wanted to see if insomnia is truly an early risk factor in the pathogenesis of cardiovascular disease and stroke,” she said.

To do so, she and her coinvestigators turned to the CARDIA database. CARDIA (the Coronary Artery Risk Development in Young Adults study), is a National Heart, Lung, and Blood Institute–sponsored prospective, epidemiologic study.

She reported on 2,950 non-Hispanic black or white participants aged 33-45 and free of any history of cardiovascular disease in 2000-2001, when they answered questions about insomnia symptoms. Difficulty in initiating sleep was reported by 16.3% of men and 20.7% of women. Difficulty maintaining sleep was a problem for 9.3% of men and 14.5% of women. And 20.6% of men and 20.1% of women reported frequent early morning awakening.

During a mean 11.5 years of prospective follow-up, 4.1% of men and 2.3% of women had a fatal or nonfatal MI, stroke, transient ischemic attack, heart failure, peripheral vascular disease, or hospitalization for an acute coronary syndrome.

In a multivariate logistic regression analysis fully adjusted for demographics, socioeconomic status, body mass index, blood pressure, diabetes, depression, health behaviors, medications, thyroid disease, and kidney problems, men who reported difficulty in getting to sleep had a 2.64-fold increased risk of one of these adverse outcomes. That was the only insomnia symptom associated with significantly increased risk. However, men but not women who reported having more than one insomnia symptom had a 39% increased risk of a cardiovascular event for each additional symptom.

Prior studies have shown that insomnia is associated with cardiac sympathetic hyperactivation. That observation suggests a plausible mechanism for increased cardiovascular and cerebrovascular risk, but it doesn’t explain why that risk was confined to young men in CARDIA. One possibility is that because of gender-related differences in perception, men tend to report having insomnia symptoms only when the insomnia is more severe, Dr. Petrov suggested.

The strengths of the CARDIA study are that all cardiovascular endpoints had to be physician certified, and the study includes a large black population. A study limitation is the relatively small number of cardiovascular events, as to be expected in a younger population. Thus, confirmation of the new findings in another large data set will be important, she noted.

As a next step in her research, Dr. Petrov said she plans to drill down in the CARDIA data to see if race modified the impact of insomnia symptoms on cardiovascular outcomes. Black participants reported all insomnia symptoms more frequently than did whites. For example, difficulty initiating sleep was reported by 25.7% of blacks, compared with just 13.5% of whites, and early morning awakening was twice as prevalent among the black participants.

Also, CARDIA participants provided self-reported sleep duration data. It will be illuminating to see if sleep duration had a modifying effect upon the insomnia/cardiovascular risk association observed in men, she said.

Dr. Petrov reported having no relevant financial conflicts.

DENVER – Young to early middle-aged men with insomnia symptoms are at increased risk for cardiovascular and cerebrovascular events, according to an analysis from the landmark CARDIA study.

“We found that younger to mid-life men with difficulty initiating sleep or with more than one insomnia symptom were at greater risk for incident cardiovascular disease events. And despite the fact that women in general seemed to be more prone to report those sleep difficulties, those that did were not at increased risk,” Megan E. Petrov, PhD, reported at the annual meeting of the Associated Professional Sleep Societies.

©KatarzynaBialasiewicz/ Thinkstock

It is well established that insomnia in older adults is associated with increased cardiovascular risk. For example, a meta-analysis of 13 prospective studies with more than 123,000 subjects concluded that insomnia was associated with a 45% increased risk of fatal and nonfatal cardiovascular events (Eur J Prev Cardiol. 2014 Jan;21[1]:57-64). But those studies typically involved older individuals, which makes cause and effect more difficult to determine because so many chronic conditions become more prevalent with advancing age, noted Dr. Petrov of Arizona State University in Phoenix.

“We wanted to see if insomnia is truly an early risk factor in the pathogenesis of cardiovascular disease and stroke,” she said.

To do so, she and her coinvestigators turned to the CARDIA database. CARDIA (the Coronary Artery Risk Development in Young Adults study), is a National Heart, Lung, and Blood Institute–sponsored prospective, epidemiologic study.

She reported on 2,950 non-Hispanic black or white participants aged 33-45 and free of any history of cardiovascular disease in 2000-2001, when they answered questions about insomnia symptoms. Difficulty in initiating sleep was reported by 16.3% of men and 20.7% of women. Difficulty maintaining sleep was a problem for 9.3% of men and 14.5% of women. And 20.6% of men and 20.1% of women reported frequent early morning awakening.

During a mean 11.5 years of prospective follow-up, 4.1% of men and 2.3% of women had a fatal or nonfatal MI, stroke, transient ischemic attack, heart failure, peripheral vascular disease, or hospitalization for an acute coronary syndrome.

In a multivariate logistic regression analysis fully adjusted for demographics, socioeconomic status, body mass index, blood pressure, diabetes, depression, health behaviors, medications, thyroid disease, and kidney problems, men who reported difficulty in getting to sleep had a 2.64-fold increased risk of one of these adverse outcomes. That was the only insomnia symptom associated with significantly increased risk. However, men but not women who reported having more than one insomnia symptom had a 39% increased risk of a cardiovascular event for each additional symptom.

Prior studies have shown that insomnia is associated with cardiac sympathetic hyperactivation. That observation suggests a plausible mechanism for increased cardiovascular and cerebrovascular risk, but it doesn’t explain why that risk was confined to young men in CARDIA. One possibility is that because of gender-related differences in perception, men tend to report having insomnia symptoms only when the insomnia is more severe, Dr. Petrov suggested.

The strengths of the CARDIA study are that all cardiovascular endpoints had to be physician certified, and the study includes a large black population. A study limitation is the relatively small number of cardiovascular events, as to be expected in a younger population. Thus, confirmation of the new findings in another large data set will be important, she noted.

As a next step in her research, Dr. Petrov said she plans to drill down in the CARDIA data to see if race modified the impact of insomnia symptoms on cardiovascular outcomes. Black participants reported all insomnia symptoms more frequently than did whites. For example, difficulty initiating sleep was reported by 25.7% of blacks, compared with just 13.5% of whites, and early morning awakening was twice as prevalent among the black participants.

Also, CARDIA participants provided self-reported sleep duration data. It will be illuminating to see if sleep duration had a modifying effect upon the insomnia/cardiovascular risk association observed in men, she said.

Dr. Petrov reported having no relevant financial conflicts.

[email protected]

DENVER – Young to early middle-aged men with insomnia symptoms are at increased risk for cardiovascular and cerebrovascular events, according to an analysis from the landmark CARDIA study.

“We found that younger to mid-life men with difficulty initiating sleep or with more than one insomnia symptom were at greater risk for incident cardiovascular disease events. And despite the fact that women in general seemed to be more prone to report those sleep difficulties, those that did were not at increased risk,” Megan E. Petrov, PhD, reported at the annual meeting of the Associated Professional Sleep Societies.

©KatarzynaBialasiewicz/ Thinkstock

It is well established that insomnia in older adults is associated with increased cardiovascular risk. For example, a meta-analysis of 13 prospective studies with more than 123,000 subjects concluded that insomnia was associated with a 45% increased risk of fatal and nonfatal cardiovascular events (Eur J Prev Cardiol. 2014 Jan;21[1]:57-64). But those studies typically involved older individuals, which makes cause and effect more difficult to determine because so many chronic conditions become more prevalent with advancing age, noted Dr. Petrov of Arizona State University in Phoenix.

“We wanted to see if insomnia is truly an early risk factor in the pathogenesis of cardiovascular disease and stroke,” she said.

To do so, she and her coinvestigators turned to the CARDIA database. CARDIA (the Coronary Artery Risk Development in Young Adults study), is a National Heart, Lung, and Blood Institute–sponsored prospective, epidemiologic study.

She reported on 2,950 non-Hispanic black or white participants aged 33-45 and free of any history of cardiovascular disease in 2000-2001, when they answered questions about insomnia symptoms. Difficulty in initiating sleep was reported by 16.3% of men and 20.7% of women. Difficulty maintaining sleep was a problem for 9.3% of men and 14.5% of women. And 20.6% of men and 20.1% of women reported frequent early morning awakening.

During a mean 11.5 years of prospective follow-up, 4.1% of men and 2.3% of women had a fatal or nonfatal MI, stroke, transient ischemic attack, heart failure, peripheral vascular disease, or hospitalization for an acute coronary syndrome.

In a multivariate logistic regression analysis fully adjusted for demographics, socioeconomic status, body mass index, blood pressure, diabetes, depression, health behaviors, medications, thyroid disease, and kidney problems, men who reported difficulty in getting to sleep had a 2.64-fold increased risk of one of these adverse outcomes. That was the only insomnia symptom associated with significantly increased risk. However, men but not women who reported having more than one insomnia symptom had a 39% increased risk of a cardiovascular event for each additional symptom.

Prior studies have shown that insomnia is associated with cardiac sympathetic hyperactivation. That observation suggests a plausible mechanism for increased cardiovascular and cerebrovascular risk, but it doesn’t explain why that risk was confined to young men in CARDIA. One possibility is that because of gender-related differences in perception, men tend to report having insomnia symptoms only when the insomnia is more severe, Dr. Petrov suggested.

The strengths of the CARDIA study are that all cardiovascular endpoints had to be physician certified, and the study includes a large black population. A study limitation is the relatively small number of cardiovascular events, as to be expected in a younger population. Thus, confirmation of the new findings in another large data set will be important, she noted.

As a next step in her research, Dr. Petrov said she plans to drill down in the CARDIA data to see if race modified the impact of insomnia symptoms on cardiovascular outcomes. Black participants reported all insomnia symptoms more frequently than did whites. For example, difficulty initiating sleep was reported by 25.7% of blacks, compared with just 13.5% of whites, and early morning awakening was twice as prevalent among the black participants.

Also, CARDIA participants provided self-reported sleep duration data. It will be illuminating to see if sleep duration had a modifying effect upon the insomnia/cardiovascular risk association observed in men, she said.

Dr. Petrov reported having no relevant financial conflicts.

[email protected]

DENVER – Young to early middle-aged men with insomnia symptoms are at increased risk for cardiovascular and cerebrovascular events, according to an analysis from the landmark CARDIA study.

“We found that younger to mid-life men with difficulty initiating sleep or with more than one insomnia symptom were at greater risk for incident cardiovascular disease events. And despite the fact that women in general seemed to be more prone to report those sleep difficulties, those that did were not at increased risk,” Megan E. Petrov, PhD, reported at the annual meeting of the Associated Professional Sleep Societies.

©KatarzynaBialasiewicz/ Thinkstock

It is well established that insomnia in older adults is associated with increased cardiovascular risk. For example, a meta-analysis of 13 prospective studies with more than 123,000 subjects concluded that insomnia was associated with a 45% increased risk of fatal and nonfatal cardiovascular events (Eur J Prev Cardiol. 2014 Jan;21[1]:57-64). But those studies typically involved older individuals, which makes cause and effect more difficult to determine because so many chronic conditions become more prevalent with advancing age, noted Dr. Petrov of Arizona State University in Phoenix.

“We wanted to see if insomnia is truly an early risk factor in the pathogenesis of cardiovascular disease and stroke,” she said.

To do so, she and her coinvestigators turned to the CARDIA database. CARDIA (the Coronary Artery Risk Development in Young Adults study), is a National Heart, Lung, and Blood Institute–sponsored prospective, epidemiologic study.

She reported on 2,950 non-Hispanic black or white participants aged 33-45 and free of any history of cardiovascular disease in 2000-2001, when they answered questions about insomnia symptoms. Difficulty in initiating sleep was reported by 16.3% of men and 20.7% of women. Difficulty maintaining sleep was a problem for 9.3% of men and 14.5% of women. And 20.6% of men and 20.1% of women reported frequent early morning awakening.

During a mean 11.5 years of prospective follow-up, 4.1% of men and 2.3% of women had a fatal or nonfatal MI, stroke, transient ischemic attack, heart failure, peripheral vascular disease, or hospitalization for an acute coronary syndrome.

In a multivariate logistic regression analysis fully adjusted for demographics, socioeconomic status, body mass index, blood pressure, diabetes, depression, health behaviors, medications, thyroid disease, and kidney problems, men who reported difficulty in getting to sleep had a 2.64-fold increased risk of one of these adverse outcomes. That was the only insomnia symptom associated with significantly increased risk. However, men but not women who reported having more than one insomnia symptom had a 39% increased risk of a cardiovascular event for each additional symptom.

Prior studies have shown that insomnia is associated with cardiac sympathetic hyperactivation. That observation suggests a plausible mechanism for increased cardiovascular and cerebrovascular risk, but it doesn’t explain why that risk was confined to young men in CARDIA. One possibility is that because of gender-related differences in perception, men tend to report having insomnia symptoms only when the insomnia is more severe, Dr. Petrov suggested.

The strengths of the CARDIA study are that all cardiovascular endpoints had to be physician certified, and the study includes a large black population. A study limitation is the relatively small number of cardiovascular events, as to be expected in a younger population. Thus, confirmation of the new findings in another large data set will be important, she noted.

As a next step in her research, Dr. Petrov said she plans to drill down in the CARDIA data to see if race modified the impact of insomnia symptoms on cardiovascular outcomes. Black participants reported all insomnia symptoms more frequently than did whites. For example, difficulty initiating sleep was reported by 25.7% of blacks, compared with just 13.5% of whites, and early morning awakening was twice as prevalent among the black participants.

Also, CARDIA participants provided self-reported sleep duration data. It will be illuminating to see if sleep duration had a modifying effect upon the insomnia/cardiovascular risk association observed in men, she said.

Dr. Petrov reported having no relevant financial conflicts.

[email protected]

NEW YORK - A new protein-based risk score outperforms the Framingham model for predicting cardiovascular outcomes in patients with stable coronary heart disease.

"Patients who carry the diagnosis of stable coronary heart disease have been viewed traditionally as a homogeneous population within which all individuals tend to be treated similarly," Dr. Peter Ganz, from the University of California, San Francisco, told Reuters Health by email.

"Instead, we found that individuals who all carried the same clinical diagnosis of stable coronary heart disease had a risk of adverse events (heart attacks, strokes, heart failure, and death) that varied by as much as 10-fold, as revealed by analysis of the levels of nine proteins in their blood," he said.

Dr. Ganz and colleagues sought to derive and validate a score to predict the risk of cardiovascular outcomes among patients with coronary heart disease, using modified aptamers to measure 1,130 proteins in plasma samples.

Aptamers are small nucleic acids that can form secondary and tertiary structures capable of specifically binding proteins and thus can be considered the chemical equivalent of antibodies.

The researchers' unbiased statistical approach identified nine proteins, from which they derived a risk score that reflects the probability of a cardiovascular event occurring within four years.

In both the derivation and validation cohorts, participants had four-year cumulative event rates of 60% to 80% in the highest risk score decile and less than 10% in the lowest risk score decile, according to the June 21 JAMA report.

Compared with the Framingham model, the protein-based risk score showed an absolute increase of 12% in average risk for participants with events compared with participants without events.

The protein-based risk score was within two percentage points of the observed event rate in the external validation cohort.

Moreover, the protein-based risk score changed more than the Framingham model among participants approaching new events, and the protein-based risk score at follow-up was a stronger predictor of subsequent outcomes than the preceding baseline risk score.

"We may now be able to tell individual patients with coronary heart disease, 'You are at a very high risk, medium risk, or a very low risk,' and they may opt to be treated differently from other patients with the same diagnosis," Dr. Ganz said.

"In addition to the results described in the JAMA paper that apply to patients with coronary heart disease, we have an ongoing discovery program to identify proteins that can predict the risk of cardiovascular disease in additional patient populations, including lower-risk individuals who appear healthy but may actually be at high risk of coronary heart disease due to high cholesterol, high blood pressure, diabetes, or smoking, or among individuals who may be at high risk due to kidney disease or HIV infection," Dr. Ganz said.

"Although more accurate risk prediction is always welcome, clinicians more readily embrace measuring a prognostic biomarker or calculating a risk score if the results could alter therapeutic decision making," writes Dr. Marc S. Sabatine from Brigham and Women's Hospital, Boston, in an accompanying editorial.

"To that end, it would be interesting to apply these arrays to samples from patients in randomized clinical trials of therapies," he said. "If a gradient of treatment benefit existed, such data would make measurement of the relevant proteins in clinical practice more compelling (which, for the current list, is impractical). Furthermore, part of the long-term value of this sort of proteomics work may come from exploring the basic pathways that underline some of the novel associations described."

Dr. Matthew Sherwood, from Duke University Medical Center, Durham, North Carolina, who recently described multimarker risk stratification in patients with acute myocardial infarction, told Reuters Health by email, "While the results are impressive, their scope is limited. Since the population studied is already at high risk for further cardiovascular events, more refined risk stratification may not have significant clinical import. These patients have indications for treatment of CAD at present, thus changes in medical management are unlikely."

"Our ability to use proteomic signatures to predict cardiovascular risk continues to expand, and may become available to a broad cohort of patients in the future," Dr. Sherwood said. "The clinical utility of these platforms remains uncertain, and further investigation is needed to determine if proteomic based risk scores could help to modify therapeutic management in lower risk populations."

SomaLogic provided funding for protein assays and employed two coauthors. Four coauthors and the editorialist reported disclosures.

SOURCE: http://bit.ly/28L6oEy and http://bit.ly/28NgaJg

JAMA 2016.

NEW YORK - A new protein-based risk score outperforms the Framingham model for predicting cardiovascular outcomes in patients with stable coronary heart disease.

"Patients who carry the diagnosis of stable coronary heart disease have been viewed traditionally as a homogeneous population within which all individuals tend to be treated similarly," Dr. Peter Ganz, from the University of California, San Francisco, told Reuters Health by email.

"Instead, we found that individuals who all carried the same clinical diagnosis of stable coronary heart disease had a risk of adverse events (heart attacks, strokes, heart failure, and death) that varied by as much as 10-fold, as revealed by analysis of the levels of nine proteins in their blood," he said.

Dr. Ganz and colleagues sought to derive and validate a score to predict the risk of cardiovascular outcomes among patients with coronary heart disease, using modified aptamers to measure 1,130 proteins in plasma samples.

Aptamers are small nucleic acids that can form secondary and tertiary structures capable of specifically binding proteins and thus can be considered the chemical equivalent of antibodies.

The researchers' unbiased statistical approach identified nine proteins, from which they derived a risk score that reflects the probability of a cardiovascular event occurring within four years.

In both the derivation and validation cohorts, participants had four-year cumulative event rates of 60% to 80% in the highest risk score decile and less than 10% in the lowest risk score decile, according to the June 21 JAMA report.

Compared with the Framingham model, the protein-based risk score showed an absolute increase of 12% in average risk for participants with events compared with participants without events.

The protein-based risk score was within two percentage points of the observed event rate in the external validation cohort.

Moreover, the protein-based risk score changed more than the Framingham model among participants approaching new events, and the protein-based risk score at follow-up was a stronger predictor of subsequent outcomes than the preceding baseline risk score.

"We may now be able to tell individual patients with coronary heart disease, 'You are at a very high risk, medium risk, or a very low risk,' and they may opt to be treated differently from other patients with the same diagnosis," Dr. Ganz said.

"In addition to the results described in the JAMA paper that apply to patients with coronary heart disease, we have an ongoing discovery program to identify proteins that can predict the risk of cardiovascular disease in additional patient populations, including lower-risk individuals who appear healthy but may actually be at high risk of coronary heart disease due to high cholesterol, high blood pressure, diabetes, or smoking, or among individuals who may be at high risk due to kidney disease or HIV infection," Dr. Ganz said.

"Although more accurate risk prediction is always welcome, clinicians more readily embrace measuring a prognostic biomarker or calculating a risk score if the results could alter therapeutic decision making," writes Dr. Marc S. Sabatine from Brigham and Women's Hospital, Boston, in an accompanying editorial.

"To that end, it would be interesting to apply these arrays to samples from patients in randomized clinical trials of therapies," he said. "If a gradient of treatment benefit existed, such data would make measurement of the relevant proteins in clinical practice more compelling (which, for the current list, is impractical). Furthermore, part of the long-term value of this sort of proteomics work may come from exploring the basic pathways that underline some of the novel associations described."

Dr. Matthew Sherwood, from Duke University Medical Center, Durham, North Carolina, who recently described multimarker risk stratification in patients with acute myocardial infarction, told Reuters Health by email, "While the results are impressive, their scope is limited. Since the population studied is already at high risk for further cardiovascular events, more refined risk stratification may not have significant clinical import. These patients have indications for treatment of CAD at present, thus changes in medical management are unlikely."

"Our ability to use proteomic signatures to predict cardiovascular risk continues to expand, and may become available to a broad cohort of patients in the future," Dr. Sherwood said. "The clinical utility of these platforms remains uncertain, and further investigation is needed to determine if proteomic based risk scores could help to modify therapeutic management in lower risk populations."

SomaLogic provided funding for protein assays and employed two coauthors. Four coauthors and the editorialist reported disclosures.

SOURCE: http://bit.ly/28L6oEy and http://bit.ly/28NgaJg

JAMA 2016.

NEW YORK - A new protein-based risk score outperforms the Framingham model for predicting cardiovascular outcomes in patients with stable coronary heart disease.

"Patients who carry the diagnosis of stable coronary heart disease have been viewed traditionally as a homogeneous population within which all individuals tend to be treated similarly," Dr. Peter Ganz, from the University of California, San Francisco, told Reuters Health by email.

"Instead, we found that individuals who all carried the same clinical diagnosis of stable coronary heart disease had a risk of adverse events (heart attacks, strokes, heart failure, and death) that varied by as much as 10-fold, as revealed by analysis of the levels of nine proteins in their blood," he said.

Dr. Ganz and colleagues sought to derive and validate a score to predict the risk of cardiovascular outcomes among patients with coronary heart disease, using modified aptamers to measure 1,130 proteins in plasma samples.

Aptamers are small nucleic acids that can form secondary and tertiary structures capable of specifically binding proteins and thus can be considered the chemical equivalent of antibodies.

The researchers' unbiased statistical approach identified nine proteins, from which they derived a risk score that reflects the probability of a cardiovascular event occurring within four years.

In both the derivation and validation cohorts, participants had four-year cumulative event rates of 60% to 80% in the highest risk score decile and less than 10% in the lowest risk score decile, according to the June 21 JAMA report.

Compared with the Framingham model, the protein-based risk score showed an absolute increase of 12% in average risk for participants with events compared with participants without events.

The protein-based risk score was within two percentage points of the observed event rate in the external validation cohort.

Moreover, the protein-based risk score changed more than the Framingham model among participants approaching new events, and the protein-based risk score at follow-up was a stronger predictor of subsequent outcomes than the preceding baseline risk score.

"We may now be able to tell individual patients with coronary heart disease, 'You are at a very high risk, medium risk, or a very low risk,' and they may opt to be treated differently from other patients with the same diagnosis," Dr. Ganz said.

"In addition to the results described in the JAMA paper that apply to patients with coronary heart disease, we have an ongoing discovery program to identify proteins that can predict the risk of cardiovascular disease in additional patient populations, including lower-risk individuals who appear healthy but may actually be at high risk of coronary heart disease due to high cholesterol, high blood pressure, diabetes, or smoking, or among individuals who may be at high risk due to kidney disease or HIV infection," Dr. Ganz said.

"Although more accurate risk prediction is always welcome, clinicians more readily embrace measuring a prognostic biomarker or calculating a risk score if the results could alter therapeutic decision making," writes Dr. Marc S. Sabatine from Brigham and Women's Hospital, Boston, in an accompanying editorial.

"To that end, it would be interesting to apply these arrays to samples from patients in randomized clinical trials of therapies," he said. "If a gradient of treatment benefit existed, such data would make measurement of the relevant proteins in clinical practice more compelling (which, for the current list, is impractical). Furthermore, part of the long-term value of this sort of proteomics work may come from exploring the basic pathways that underline some of the novel associations described."

Dr. Matthew Sherwood, from Duke University Medical Center, Durham, North Carolina, who recently described multimarker risk stratification in patients with acute myocardial infarction, told Reuters Health by email, "While the results are impressive, their scope is limited. Since the population studied is already at high risk for further cardiovascular events, more refined risk stratification may not have significant clinical import. These patients have indications for treatment of CAD at present, thus changes in medical management are unlikely."

"Our ability to use proteomic signatures to predict cardiovascular risk continues to expand, and may become available to a broad cohort of patients in the future," Dr. Sherwood said. "The clinical utility of these platforms remains uncertain, and further investigation is needed to determine if proteomic based risk scores could help to modify therapeutic management in lower risk populations."

SomaLogic provided funding for protein assays and employed two coauthors. Four coauthors and the editorialist reported disclosures.

SOURCE: http://bit.ly/28L6oEy and http://bit.ly/28NgaJg

JAMA 2016.

Lenalidomide led to independence from red blood cell transfusions for 27% of patients with lower-risk non-del(5q) myelodysplastic syndromes who were refractory to or ineligible for erythropoiesis-stimulating agents, based on the results of a phase III placebo-controlled study.

Patients were most likely to reach this primary endpoint if their baseline erythropoietin (EPO) level was less than 100 mU/mL, Dr. Valeria Santini of the University of Florence (Italy) and her associates wrote online June 27 in the Journal of Clinical Oncology.

ksena32/ThinkStock

Erythropoiesis-stimulating agents (ESAs) are first-line therapy for anemia in lower-risk myelodysplastic syndrome (MDS) patients without a deletion 5q, but most patients stop responding over time. “Although azacitidine and decitabine are approved in the United States and other countries in this setting, no approved treatments exist in the European Union and other countries for ESA-refractory patients who are dependent on red blood cell transfusions,” the researchers wrote.

Their international double-blind study enrolled 239 adults with International Prognostic Scoring System lower- or intermediate-risk MDS who lacked the del(5q) mutation and needed at least 2 U of packed red blood cells every 28 days. Patients were randomly assigned 2:1 to lenalidomide (160 patients) or placebo (79 patients), given once daily for 28-day cycles. Patients whose creatinine clearance was 40-60 mL/min received 5 mg lenalidomide, while the rest received 10 mg. Randomization was stratified based on MDS treatment history, baseline transfusion requirements, and time from MDS diagnosis (J Clin Oncol. 2016 Jun 27. doi: 10.1200/JCO.2015.66.0118). A total of 43 lenalidomide patients (27%) and 2 placebo patients (2.5%; P less than .001) did not require packed red blood cell transfusions for at least 8 weeks. Transfusion independence persisted through 24 weeks for 17% of lenalidomide patients and no placebo patients. Of 39 patients given 5-mg lenalidomide, 18% reached the primary endpoint (P = .006, compared with placebo). The median duration of response was nearly 31 weeks (95% confidence interval, 21-59 weeks). Prior use of ESAs was the only significant predictor of response in the multivariate analysis (odds ratio, 4.6; 95% confidence interval, 1.3-16.1; P = .01), although low baseline transfusion burden reached significance in the univariate model and borderline significance in the multivariate model (OR, 2.7; 95% CI, 0.96-7.6; P = .06).

The highest response rate (43%) occurred among the 40 patients who had previously received ESAs and had a baseline erythropoietin level under 100 mU/mL. The response rates for other patients previously treated with ESAs fell as baseline EPO level increased, and the response rate was only 9% among patients whose relatively high endogenous EPO level had made them ineligible for ESA treatment. “Patients with higher endogenous EPO levels may be less responsive due to marked intrinsic defects in erythroid signaling pathways, including signal transducer and activator of transcription extracellular regulated kinase 1/2, and lipid raft assembly, which are restored or stimulated by lenalidomide exposure,” the researchers wrote.

As in previous studies, grade 3-4 adverse events with lenalidomide usually were due to myelosuppression. Grade 3-4 neutropenia affected 99 lenalidomide patients (62%) and 10 placebo patients (13%). Grade 3-4 thrombocytopenia affected 57 lenalidomide patients (36%) and 3 placebo patients (4%). Lenalidomide was associated with a 3% rate of venous thrombosis but did not cause detectable pulmonary embolism. Lenalidomide was stopped in 32% of patients because of thrombocytopenia, neutropenia, or other adverse events, compared with 11% of placebo patients. In all, 2.5% of patients in each group died while on treatment.

Celgene makes lenalidomide and funded the study. Dr. Santini disclosed consulting or advisory roles and honoraria from Celgene, Janssen Pharmaceuticals, and Novartis. Seventeen coinvestigators also disclosed ties to Celgene.

Lenalidomide led to independence from red blood cell transfusions for 27% of patients with lower-risk non-del(5q) myelodysplastic syndromes who were refractory to or ineligible for erythropoiesis-stimulating agents, based on the results of a phase III placebo-controlled study.

Patients were most likely to reach this primary endpoint if their baseline erythropoietin (EPO) level was less than 100 mU/mL, Dr. Valeria Santini of the University of Florence (Italy) and her associates wrote online June 27 in the Journal of Clinical Oncology.

ksena32/ThinkStock

Erythropoiesis-stimulating agents (ESAs) are first-line therapy for anemia in lower-risk myelodysplastic syndrome (MDS) patients without a deletion 5q, but most patients stop responding over time. “Although azacitidine and decitabine are approved in the United States and other countries in this setting, no approved treatments exist in the European Union and other countries for ESA-refractory patients who are dependent on red blood cell transfusions,” the researchers wrote.

Their international double-blind study enrolled 239 adults with International Prognostic Scoring System lower- or intermediate-risk MDS who lacked the del(5q) mutation and needed at least 2 U of packed red blood cells every 28 days. Patients were randomly assigned 2:1 to lenalidomide (160 patients) or placebo (79 patients), given once daily for 28-day cycles. Patients whose creatinine clearance was 40-60 mL/min received 5 mg lenalidomide, while the rest received 10 mg. Randomization was stratified based on MDS treatment history, baseline transfusion requirements, and time from MDS diagnosis (J Clin Oncol. 2016 Jun 27. doi: 10.1200/JCO.2015.66.0118). A total of 43 lenalidomide patients (27%) and 2 placebo patients (2.5%; P less than .001) did not require packed red blood cell transfusions for at least 8 weeks. Transfusion independence persisted through 24 weeks for 17% of lenalidomide patients and no placebo patients. Of 39 patients given 5-mg lenalidomide, 18% reached the primary endpoint (P = .006, compared with placebo). The median duration of response was nearly 31 weeks (95% confidence interval, 21-59 weeks). Prior use of ESAs was the only significant predictor of response in the multivariate analysis (odds ratio, 4.6; 95% confidence interval, 1.3-16.1; P = .01), although low baseline transfusion burden reached significance in the univariate model and borderline significance in the multivariate model (OR, 2.7; 95% CI, 0.96-7.6; P = .06).

The highest response rate (43%) occurred among the 40 patients who had previously received ESAs and had a baseline erythropoietin level under 100 mU/mL. The response rates for other patients previously treated with ESAs fell as baseline EPO level increased, and the response rate was only 9% among patients whose relatively high endogenous EPO level had made them ineligible for ESA treatment. “Patients with higher endogenous EPO levels may be less responsive due to marked intrinsic defects in erythroid signaling pathways, including signal transducer and activator of transcription extracellular regulated kinase 1/2, and lipid raft assembly, which are restored or stimulated by lenalidomide exposure,” the researchers wrote.

As in previous studies, grade 3-4 adverse events with lenalidomide usually were due to myelosuppression. Grade 3-4 neutropenia affected 99 lenalidomide patients (62%) and 10 placebo patients (13%). Grade 3-4 thrombocytopenia affected 57 lenalidomide patients (36%) and 3 placebo patients (4%). Lenalidomide was associated with a 3% rate of venous thrombosis but did not cause detectable pulmonary embolism. Lenalidomide was stopped in 32% of patients because of thrombocytopenia, neutropenia, or other adverse events, compared with 11% of placebo patients. In all, 2.5% of patients in each group died while on treatment.

Celgene makes lenalidomide and funded the study. Dr. Santini disclosed consulting or advisory roles and honoraria from Celgene, Janssen Pharmaceuticals, and Novartis. Seventeen coinvestigators also disclosed ties to Celgene.

Lenalidomide led to independence from red blood cell transfusions for 27% of patients with lower-risk non-del(5q) myelodysplastic syndromes who were refractory to or ineligible for erythropoiesis-stimulating agents, based on the results of a phase III placebo-controlled study.

Patients were most likely to reach this primary endpoint if their baseline erythropoietin (EPO) level was less than 100 mU/mL, Dr. Valeria Santini of the University of Florence (Italy) and her associates wrote online June 27 in the Journal of Clinical Oncology.

ksena32/ThinkStock

Erythropoiesis-stimulating agents (ESAs) are first-line therapy for anemia in lower-risk myelodysplastic syndrome (MDS) patients without a deletion 5q, but most patients stop responding over time. “Although azacitidine and decitabine are approved in the United States and other countries in this setting, no approved treatments exist in the European Union and other countries for ESA-refractory patients who are dependent on red blood cell transfusions,” the researchers wrote.

Their international double-blind study enrolled 239 adults with International Prognostic Scoring System lower- or intermediate-risk MDS who lacked the del(5q) mutation and needed at least 2 U of packed red blood cells every 28 days. Patients were randomly assigned 2:1 to lenalidomide (160 patients) or placebo (79 patients), given once daily for 28-day cycles. Patients whose creatinine clearance was 40-60 mL/min received 5 mg lenalidomide, while the rest received 10 mg. Randomization was stratified based on MDS treatment history, baseline transfusion requirements, and time from MDS diagnosis (J Clin Oncol. 2016 Jun 27. doi: 10.1200/JCO.2015.66.0118). A total of 43 lenalidomide patients (27%) and 2 placebo patients (2.5%; P less than .001) did not require packed red blood cell transfusions for at least 8 weeks. Transfusion independence persisted through 24 weeks for 17% of lenalidomide patients and no placebo patients. Of 39 patients given 5-mg lenalidomide, 18% reached the primary endpoint (P = .006, compared with placebo). The median duration of response was nearly 31 weeks (95% confidence interval, 21-59 weeks). Prior use of ESAs was the only significant predictor of response in the multivariate analysis (odds ratio, 4.6; 95% confidence interval, 1.3-16.1; P = .01), although low baseline transfusion burden reached significance in the univariate model and borderline significance in the multivariate model (OR, 2.7; 95% CI, 0.96-7.6; P = .06).

The highest response rate (43%) occurred among the 40 patients who had previously received ESAs and had a baseline erythropoietin level under 100 mU/mL. The response rates for other patients previously treated with ESAs fell as baseline EPO level increased, and the response rate was only 9% among patients whose relatively high endogenous EPO level had made them ineligible for ESA treatment. “Patients with higher endogenous EPO levels may be less responsive due to marked intrinsic defects in erythroid signaling pathways, including signal transducer and activator of transcription extracellular regulated kinase 1/2, and lipid raft assembly, which are restored or stimulated by lenalidomide exposure,” the researchers wrote.

As in previous studies, grade 3-4 adverse events with lenalidomide usually were due to myelosuppression. Grade 3-4 neutropenia affected 99 lenalidomide patients (62%) and 10 placebo patients (13%). Grade 3-4 thrombocytopenia affected 57 lenalidomide patients (36%) and 3 placebo patients (4%). Lenalidomide was associated with a 3% rate of venous thrombosis but did not cause detectable pulmonary embolism. Lenalidomide was stopped in 32% of patients because of thrombocytopenia, neutropenia, or other adverse events, compared with 11% of placebo patients. In all, 2.5% of patients in each group died while on treatment.

Celgene makes lenalidomide and funded the study. Dr. Santini disclosed consulting or advisory roles and honoraria from Celgene, Janssen Pharmaceuticals, and Novartis. Seventeen coinvestigators also disclosed ties to Celgene.

Although acute otitis media (AOM) has decreased in number, and especially the more severe difficult to treat versions, I was reminded that this still is a problem for young children based on personal experience with grandchildren. What can be baffling to some families is the fact that some strains of the same organism species cause AOM and some simply colonize the nasopharynx (NP) of children without causing any disease at all. These organisms include Streptococcus pneumoniae (SPN) and nontypeable Haemophilus influenzae (ntHi).

Recent studies have uncovered several molecular reasons for the pathogen vs. colonizer dichotomy:

• Strains within a species can have variants of a gene that make them more disease producing.

• Some usually colonizing strains produce disease after acquiring new genes.

• Some strains have native genes with on-off switches that convert them from a colonizing to disease producing under selected circumstances.

• Molecular targets in the respiratory tract increase, allowing more dense colonization that increases chances of AOM.

Variant gene

J.R. Gilsdorf, MD, and his group at the University of Michigan,¹ Ann Arbor, recently showed that among the various high-molecular-weight molecules (HMW) produced by 170 ntHi from three different geographically diverse countries, one variant in particular (HMW-A) was more likely to be found in strains producing AOM than strains simply colonizing the nasopharynx. The protein product of this gene allows better adherence to respiratory epithelia. So more bacteria sticking in the NP near the eustachian tube opening make development of AOM more likely. Some call this the “more barbarians at the gate” phenomenon.

Gene acquisition

SPN inherently has a somewhat incomplete arginine synthesis pathway. Because arginine is essential for growth of SPN, S. pneumoniae utilizes some host factors to compensate; but this compensation is inefficient. However, SPN strains can acquire new genes – usually from other gram-positive organisms in their environment – by a process called conjugation.

One recently reported acquired gene set is that which completes functionality of SPN’s arginine synthesis pathway.² Investigators showed that SPN that acquire these arginine synthesis genes replicate more readily in bodily fluids, such as serum or cerebrospinal fluid, making these strains more aggressive, more virulent, and more likely to produce disease. More efficient replication makes it very difficult for host immune responses to handle these SPN. This is not limited to AOM alone, but seems important in invasive disease (such as meningitis) from SPN type 7, which had recently become more frequent after introduction of pneumococcal conjugate vaccines.

On-off gene switches

Another group of investigators reported that a thing called “phasevarion,” which is fancy lingo for an on-off switch is at the root of more virulence in ntHi.³ It seems that some strains of ntHi have a version of the ModA2 gene, which is always turned off, while other strains have a gene that is always on. Then, there is a third version in which the gene is usually off, but turns on when in places like the middle ear. The ModA2 gene appears to affect several other downstream protein groups that include HMW-A, antibiotic susceptibility, and biofilm formation. When inoculated into the middle ear in a chinchilla AOM model, the ntHi strains that can turn on their ModA2 gene were much more likely to produce AOM than either version that could not change. Interestingly, the authors postulate that preventing the switch capability could be a novel way to prevent ntHi disease, such as pediatric AOM, acute bacterial sinusitis, or some bronchitis in adults.

Molecular environment becomes more favorable

Another group⁴ reported that adherence receptor for ntHi is intercellular adhesion molecule 1 (ICAM1), a molecule found in modest quantities on respiratory epithelium. You may know it as the attachment molecule for rhinovirus and enteroviruses. What makes this interesting is that adenovirus, respiratory syncytial virus, and exposure to cigarette smoke⁵ markedly increase expression of ICAM1 on respiratory epithelium, predisposing to more ntHi adhering and more likely to produce an inflammatory process, such as AOM. This is another version of the barbarians at the gate phenomenon.

So when families ask why SPN or ntHi sometimes exist quietly (colonize) the nasopharynx and sometimes they cause AOM or acute bacterial sinusitis, you can hopefully use these four examples as partial explanations of why the same bacterial species has strains that can be either colonizers or pathogens.

References

1. Infect Genet Evol. 2014 Dec;28:223-32

2. J Infect Dis. 2014 Jun 1;209:1781-91.

3. J Infect Dis. 2016 Jun 10. pii: jiw243. [Epub ahead of print]

4. Cell Microbiol. 2016 Feb 9. doi: 10.1111/cmi.12575. [Epub ahead of print]

5. Am J Respir Cell Mol Biol. 2003 Oct;29:472-82.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. Email him at [email protected].

Although acute otitis media (AOM) has decreased in number, and especially the more severe difficult to treat versions, I was reminded that this still is a problem for young children based on personal experience with grandchildren. What can be baffling to some families is the fact that some strains of the same organism species cause AOM and some simply colonize the nasopharynx (NP) of children without causing any disease at all. These organisms include Streptococcus pneumoniae (SPN) and nontypeable Haemophilus influenzae (ntHi).

Recent studies have uncovered several molecular reasons for the pathogen vs. colonizer dichotomy:

• Strains within a species can have variants of a gene that make them more disease producing.

• Some usually colonizing strains produce disease after acquiring new genes.

• Some strains have native genes with on-off switches that convert them from a colonizing to disease producing under selected circumstances.

• Molecular targets in the respiratory tract increase, allowing more dense colonization that increases chances of AOM.

Variant gene

J.R. Gilsdorf, MD, and his group at the University of Michigan,¹ Ann Arbor, recently showed that among the various high-molecular-weight molecules (HMW) produced by 170 ntHi from three different geographically diverse countries, one variant in particular (HMW-A) was more likely to be found in strains producing AOM than strains simply colonizing the nasopharynx. The protein product of this gene allows better adherence to respiratory epithelia. So more bacteria sticking in the NP near the eustachian tube opening make development of AOM more likely. Some call this the “more barbarians at the gate” phenomenon.

Gene acquisition

SPN inherently has a somewhat incomplete arginine synthesis pathway. Because arginine is essential for growth of SPN, S. pneumoniae utilizes some host factors to compensate; but this compensation is inefficient. However, SPN strains can acquire new genes – usually from other gram-positive organisms in their environment – by a process called conjugation.

One recently reported acquired gene set is that which completes functionality of SPN’s arginine synthesis pathway.² Investigators showed that SPN that acquire these arginine synthesis genes replicate more readily in bodily fluids, such as serum or cerebrospinal fluid, making these strains more aggressive, more virulent, and more likely to produce disease. More efficient replication makes it very difficult for host immune responses to handle these SPN. This is not limited to AOM alone, but seems important in invasive disease (such as meningitis) from SPN type 7, which had recently become more frequent after introduction of pneumococcal conjugate vaccines.

On-off gene switches

Another group of investigators reported that a thing called “phasevarion,” which is fancy lingo for an on-off switch is at the root of more virulence in ntHi.³ It seems that some strains of ntHi have a version of the ModA2 gene, which is always turned off, while other strains have a gene that is always on. Then, there is a third version in which the gene is usually off, but turns on when in places like the middle ear. The ModA2 gene appears to affect several other downstream protein groups that include HMW-A, antibiotic susceptibility, and biofilm formation. When inoculated into the middle ear in a chinchilla AOM model, the ntHi strains that can turn on their ModA2 gene were much more likely to produce AOM than either version that could not change. Interestingly, the authors postulate that preventing the switch capability could be a novel way to prevent ntHi disease, such as pediatric AOM, acute bacterial sinusitis, or some bronchitis in adults.

Molecular environment becomes more favorable

Another group⁴ reported that adherence receptor for ntHi is intercellular adhesion molecule 1 (ICAM1), a molecule found in modest quantities on respiratory epithelium. You may know it as the attachment molecule for rhinovirus and enteroviruses. What makes this interesting is that adenovirus, respiratory syncytial virus, and exposure to cigarette smoke⁵ markedly increase expression of ICAM1 on respiratory epithelium, predisposing to more ntHi adhering and more likely to produce an inflammatory process, such as AOM. This is another version of the barbarians at the gate phenomenon.

So when families ask why SPN or ntHi sometimes exist quietly (colonize) the nasopharynx and sometimes they cause AOM or acute bacterial sinusitis, you can hopefully use these four examples as partial explanations of why the same bacterial species has strains that can be either colonizers or pathogens.

References

1. Infect Genet Evol. 2014 Dec;28:223-32

2. J Infect Dis. 2014 Jun 1;209:1781-91.

3. J Infect Dis. 2016 Jun 10. pii: jiw243. [Epub ahead of print]

4. Cell Microbiol. 2016 Feb 9. doi: 10.1111/cmi.12575. [Epub ahead of print]

5. Am J Respir Cell Mol Biol. 2003 Oct;29:472-82.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. Email him at [email protected].

Although acute otitis media (AOM) has decreased in number, and especially the more severe difficult to treat versions, I was reminded that this still is a problem for young children based on personal experience with grandchildren. What can be baffling to some families is the fact that some strains of the same organism species cause AOM and some simply colonize the nasopharynx (NP) of children without causing any disease at all. These organisms include Streptococcus pneumoniae (SPN) and nontypeable Haemophilus influenzae (ntHi).

Recent studies have uncovered several molecular reasons for the pathogen vs. colonizer dichotomy:

• Strains within a species can have variants of a gene that make them more disease producing.

• Some usually colonizing strains produce disease after acquiring new genes.

• Some strains have native genes with on-off switches that convert them from a colonizing to disease producing under selected circumstances.

• Molecular targets in the respiratory tract increase, allowing more dense colonization that increases chances of AOM.

Variant gene

J.R. Gilsdorf, MD, and his group at the University of Michigan,¹ Ann Arbor, recently showed that among the various high-molecular-weight molecules (HMW) produced by 170 ntHi from three different geographically diverse countries, one variant in particular (HMW-A) was more likely to be found in strains producing AOM than strains simply colonizing the nasopharynx. The protein product of this gene allows better adherence to respiratory epithelia. So more bacteria sticking in the NP near the eustachian tube opening make development of AOM more likely. Some call this the “more barbarians at the gate” phenomenon.

Gene acquisition

SPN inherently has a somewhat incomplete arginine synthesis pathway. Because arginine is essential for growth of SPN, S. pneumoniae utilizes some host factors to compensate; but this compensation is inefficient. However, SPN strains can acquire new genes – usually from other gram-positive organisms in their environment – by a process called conjugation.

One recently reported acquired gene set is that which completes functionality of SPN’s arginine synthesis pathway.² Investigators showed that SPN that acquire these arginine synthesis genes replicate more readily in bodily fluids, such as serum or cerebrospinal fluid, making these strains more aggressive, more virulent, and more likely to produce disease. More efficient replication makes it very difficult for host immune responses to handle these SPN. This is not limited to AOM alone, but seems important in invasive disease (such as meningitis) from SPN type 7, which had recently become more frequent after introduction of pneumococcal conjugate vaccines.

On-off gene switches

Another group of investigators reported that a thing called “phasevarion,” which is fancy lingo for an on-off switch is at the root of more virulence in ntHi.³ It seems that some strains of ntHi have a version of the ModA2 gene, which is always turned off, while other strains have a gene that is always on. Then, there is a third version in which the gene is usually off, but turns on when in places like the middle ear. The ModA2 gene appears to affect several other downstream protein groups that include HMW-A, antibiotic susceptibility, and biofilm formation. When inoculated into the middle ear in a chinchilla AOM model, the ntHi strains that can turn on their ModA2 gene were much more likely to produce AOM than either version that could not change. Interestingly, the authors postulate that preventing the switch capability could be a novel way to prevent ntHi disease, such as pediatric AOM, acute bacterial sinusitis, or some bronchitis in adults.

Molecular environment becomes more favorable

Another group⁴ reported that adherence receptor for ntHi is intercellular adhesion molecule 1 (ICAM1), a molecule found in modest quantities on respiratory epithelium. You may know it as the attachment molecule for rhinovirus and enteroviruses. What makes this interesting is that adenovirus, respiratory syncytial virus, and exposure to cigarette smoke⁵ markedly increase expression of ICAM1 on respiratory epithelium, predisposing to more ntHi adhering and more likely to produce an inflammatory process, such as AOM. This is another version of the barbarians at the gate phenomenon.

So when families ask why SPN or ntHi sometimes exist quietly (colonize) the nasopharynx and sometimes they cause AOM or acute bacterial sinusitis, you can hopefully use these four examples as partial explanations of why the same bacterial species has strains that can be either colonizers or pathogens.

References

1. Infect Genet Evol. 2014 Dec;28:223-32

2. J Infect Dis. 2014 Jun 1;209:1781-91.

3. J Infect Dis. 2016 Jun 10. pii: jiw243. [Epub ahead of print]

4. Cell Microbiol. 2016 Feb 9. doi: 10.1111/cmi.12575. [Epub ahead of print]

5. Am J Respir Cell Mol Biol. 2003 Oct;29:472-82.

Dr. Harrison is professor of pediatrics and pediatric infectious diseases at Children’s Mercy Hospitals and Clinics, Kansas City, Mo. He said he had no relevant financial disclosures. Email him at [email protected].

The monoclonal antibody ipilimumab was the first treatment in more than 30 years to improve long-term survival in metastatic melanoma patients. Offering expensive ipilimumab treatment presented significant business challenges and potential financial risks for our private oncology practice and for patients because of the high acquisition cost of this agent. There was initial uncertainty about the willingness of insurance companies to reimburse for this new drug based on previous experiences in our practice with other expensive new drugs. Here we describe how our multiphysician practice methodically introduced ipilimumab treatment into the practice.

Click on the PDF icon at the top of this introduction to read the full article.

The monoclonal antibody ipilimumab was the first treatment in more than 30 years to improve long-term survival in metastatic melanoma patients. Offering expensive ipilimumab treatment presented significant business challenges and potential financial risks for our private oncology practice and for patients because of the high acquisition cost of this agent. There was initial uncertainty about the willingness of insurance companies to reimburse for this new drug based on previous experiences in our practice with other expensive new drugs. Here we describe how our multiphysician practice methodically introduced ipilimumab treatment into the practice.

Click on the PDF icon at the top of this introduction to read the full article.

The monoclonal antibody ipilimumab was the first treatment in more than 30 years to improve long-term survival in metastatic melanoma patients. Offering expensive ipilimumab treatment presented significant business challenges and potential financial risks for our private oncology practice and for patients because of the high acquisition cost of this agent. There was initial uncertainty about the willingness of insurance companies to reimburse for this new drug based on previous experiences in our practice with other expensive new drugs. Here we describe how our multiphysician practice methodically introduced ipilimumab treatment into the practice.

Click on the PDF icon at the top of this introduction to read the full article.

In December 2015, alectinib became the third ALK inhibitor approved by the United States Food and Drug Administration for the treatment of non-small-cell lung cancer (NSCLC) that displays rearrangements of the anaplastic lymphoma kinase (ALK) gene. Alectinib is a second-generation small molecule inhibitor of the ALK protein that joins ceritinib in providing a useful treatment option for patients who have progressed on crizotinib, as a result of its ability to target crizotinib-resistant mutant forms of the ALK protein. Alectinib also displays enhanced penetrance of the blood-brain barrier, which improves efficacy against central nervous system (CNS) metastases.

Click on the PDF icon at the top of this introduction to read the full article.

In December 2015, alectinib became the third ALK inhibitor approved by the United States Food and Drug Administration for the treatment of non-small-cell lung cancer (NSCLC) that displays rearrangements of the anaplastic lymphoma kinase (ALK) gene. Alectinib is a second-generation small molecule inhibitor of the ALK protein that joins ceritinib in providing a useful treatment option for patients who have progressed on crizotinib, as a result of its ability to target crizotinib-resistant mutant forms of the ALK protein. Alectinib also displays enhanced penetrance of the blood-brain barrier, which improves efficacy against central nervous system (CNS) metastases.

Click on the PDF icon at the top of this introduction to read the full article.

In December 2015, alectinib became the third ALK inhibitor approved by the United States Food and Drug Administration for the treatment of non-small-cell lung cancer (NSCLC) that displays rearrangements of the anaplastic lymphoma kinase (ALK) gene. Alectinib is a second-generation small molecule inhibitor of the ALK protein that joins ceritinib in providing a useful treatment option for patients who have progressed on crizotinib, as a result of its ability to target crizotinib-resistant mutant forms of the ALK protein. Alectinib also displays enhanced penetrance of the blood-brain barrier, which improves efficacy against central nervous system (CNS) metastases.

Click on the PDF icon at the top of this introduction to read the full article.