Hematopoietic stem cells

in the bone marrow

Whole-genome sequencing has revealed hundreds of somatic mutations in healthy white blood cells (WBCs) from a 115-year-old woman, but the mutations appear to be harmless.

The research also suggests that most of the woman’s peripheral WBCs originated from 2 related hematopoietic stem cell (HSC) clones.

And the WBCs had telomeres that were significantly shorter than telomeres from other tissues.

Study investigators said these findings indicate that the finite lifespan of HSCs, rather than the effects of somatic mutations, may lead to hematopoietic clonal evolution at “extreme ages.”

Henne Holstege, PhD, of VU University Medical Center in Amsterdam, The Netherlands, and her colleagues detailed these findings in Genome Research.

The team conducted this study to determine if, over a long lifetime, mutations can accumulate in healthy WBCs. The WBCs were donated by a supercentenarian woman, who, at the time of her death in 2005, was the oldest person in the world.

The investigators performed deep whole-genome sequencing of the woman’s WBCs. And, based on the results, they estimated that about 450 somatic mutations accumulated in the non-repetitive genome within the healthy blood compartment, which suggests that about 600 somatic mutations accumulated in the whole genome of the HSC clone.

The mutations were not tumor-derived, and only a few were detected at minimal frequencies in other tissues. The team did not detect these mutations in the brain, which rarely undergoes cell division after birth.

In addition, the mutations appeared to be tolerated by the body. And they resided primarily in non-coding regions of the genome not previously associated with disease. This included sites that are especially mutation-prone, such as methylated cytosine DNA bases and solvent-accessible stretches of DNA.

Another key finding of this research was that about 65% of the healthy blood compartment was populated by the offspring of 2 HSC clones, and 1 of these was likely derived from the other.

The investigators said a possible explanation for this oligoclonality might be found in the extremely short telomere lengths of the woman’s WBCs. The WBC telomeres were 17 times shorter than telomeres in the brain.

“Because these blood cells had extremely short telomeres, we speculate that most hematopoietic stem cells may have died from stem cell exhaustion, reaching the upper limit of stem cell divisions,” Dr Holstege said.

So the team believes the oligoclonality they observed may be a consequence of HSCs’ finite lifespan.

Hematopoietic stem cells

in the bone marrow

Whole-genome sequencing has revealed hundreds of somatic mutations in healthy white blood cells (WBCs) from a 115-year-old woman, but the mutations appear to be harmless.

The research also suggests that most of the woman’s peripheral WBCs originated from 2 related hematopoietic stem cell (HSC) clones.

And the WBCs had telomeres that were significantly shorter than telomeres from other tissues.

Study investigators said these findings indicate that the finite lifespan of HSCs, rather than the effects of somatic mutations, may lead to hematopoietic clonal evolution at “extreme ages.”

Henne Holstege, PhD, of VU University Medical Center in Amsterdam, The Netherlands, and her colleagues detailed these findings in Genome Research.

The team conducted this study to determine if, over a long lifetime, mutations can accumulate in healthy WBCs. The WBCs were donated by a supercentenarian woman, who, at the time of her death in 2005, was the oldest person in the world.

The investigators performed deep whole-genome sequencing of the woman’s WBCs. And, based on the results, they estimated that about 450 somatic mutations accumulated in the non-repetitive genome within the healthy blood compartment, which suggests that about 600 somatic mutations accumulated in the whole genome of the HSC clone.

The mutations were not tumor-derived, and only a few were detected at minimal frequencies in other tissues. The team did not detect these mutations in the brain, which rarely undergoes cell division after birth.

In addition, the mutations appeared to be tolerated by the body. And they resided primarily in non-coding regions of the genome not previously associated with disease. This included sites that are especially mutation-prone, such as methylated cytosine DNA bases and solvent-accessible stretches of DNA.

Another key finding of this research was that about 65% of the healthy blood compartment was populated by the offspring of 2 HSC clones, and 1 of these was likely derived from the other.

The investigators said a possible explanation for this oligoclonality might be found in the extremely short telomere lengths of the woman’s WBCs. The WBC telomeres were 17 times shorter than telomeres in the brain.

“Because these blood cells had extremely short telomeres, we speculate that most hematopoietic stem cells may have died from stem cell exhaustion, reaching the upper limit of stem cell divisions,” Dr Holstege said.

So the team believes the oligoclonality they observed may be a consequence of HSCs’ finite lifespan.

Hematopoietic stem cells

in the bone marrow

Whole-genome sequencing has revealed hundreds of somatic mutations in healthy white blood cells (WBCs) from a 115-year-old woman, but the mutations appear to be harmless.

The research also suggests that most of the woman’s peripheral WBCs originated from 2 related hematopoietic stem cell (HSC) clones.

And the WBCs had telomeres that were significantly shorter than telomeres from other tissues.

Study investigators said these findings indicate that the finite lifespan of HSCs, rather than the effects of somatic mutations, may lead to hematopoietic clonal evolution at “extreme ages.”

Henne Holstege, PhD, of VU University Medical Center in Amsterdam, The Netherlands, and her colleagues detailed these findings in Genome Research.

The team conducted this study to determine if, over a long lifetime, mutations can accumulate in healthy WBCs. The WBCs were donated by a supercentenarian woman, who, at the time of her death in 2005, was the oldest person in the world.

The investigators performed deep whole-genome sequencing of the woman’s WBCs. And, based on the results, they estimated that about 450 somatic mutations accumulated in the non-repetitive genome within the healthy blood compartment, which suggests that about 600 somatic mutations accumulated in the whole genome of the HSC clone.

The mutations were not tumor-derived, and only a few were detected at minimal frequencies in other tissues. The team did not detect these mutations in the brain, which rarely undergoes cell division after birth.

In addition, the mutations appeared to be tolerated by the body. And they resided primarily in non-coding regions of the genome not previously associated with disease. This included sites that are especially mutation-prone, such as methylated cytosine DNA bases and solvent-accessible stretches of DNA.

Another key finding of this research was that about 65% of the healthy blood compartment was populated by the offspring of 2 HSC clones, and 1 of these was likely derived from the other.

The investigators said a possible explanation for this oligoclonality might be found in the extremely short telomere lengths of the woman’s WBCs. The WBC telomeres were 17 times shorter than telomeres in the brain.

“Because these blood cells had extremely short telomeres, we speculate that most hematopoietic stem cells may have died from stem cell exhaustion, reaching the upper limit of stem cell divisions,” Dr Holstege said.

So the team believes the oligoclonality they observed may be a consequence of HSCs’ finite lifespan.

Vials of siltuximab

Credit: Janssen Biotech, Inc.

The US Food and Drug Administration (FDA) has authorized marketing of siltuximab (Sylvant), the first drug approved to treat patients with multicentric Castleman’s disease (MCD) who are negative for human immunodeficiency virus (HIV) and human herpes virus 8 (HHV-8).

Siltuximab is a chimeric monoclonal antibody that binds to interleukin-6 (IL-6). Dysregulated overproduction of IL-6 has been implicated in the pathogenesis of MCD.

Siltuximab has not been studied in MCD patients who are HIV- or HHV-8 positive because the drug did not bind to virally produced IL-6 in a nonclinical study.

MCD is a rare blood disorder in which lymphocytes are overproduced, leading to enlarged lymph nodes. MCD can also affect lymphoid tissue of internal organs, causing enlargement of the liver, spleen, or other organs.

Patients with MCD have a high risk of death. Infections, multisystem organ failure, and malignancies such as lymphoma are common causes of death in patients with MCD.

“There has been a serious need for treatment options for patients with MCD,” said Frits van Rhee, MD, PhD, a professor at the University of Arkansas for Medical Sciences and lead investigator of the MCD2001 study.

“MCD is a complex disease, and, up until this point, physicians have tried to reduce lymph node masses and put the disease in remission through a combination of treatments, but MCD often returns. [The approval of siltuximab] gives physicians a long-awaited treatment option for [patients] suffering with this chronic, serious, and debilitating disease.”

The FDA reviewed siltuximab under its priority review program, which provides an expedited review for drugs that demonstrate the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. The drug was also granted orphan designation, as it is intended to treat a rare disease.

MCD2001: A phase 2 study of siltuximab

The FDA approval of siltuximab is based on results of the phase 2 MCD2001 trial. This randomized, double-blind, placebo-controlled study enrolled 79 patients with symptomatic MCD that was HIV- and HHV-8 negative.

Fifty-three patients were randomized to receive siltuximab at a dose of 11 mg/kg, plus best supportive care. The remaining 26 patients were randomized to receive placebo plus best supportive care.

The researchers defined a durable response as a tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. Thirty-four percent of patients in the siltuximab arm achieved this endpoint, but none of the patients in the placebo arm did (P=0.0012).

On the other hand, 4% of patients in the placebo arm experienced a tumor response, as did 38% of patients in the siltuximab arm (P<0.05).

The median time to treatment failure was not reached for patients in the siltuximab arm. But patients in the placebo arm experienced treatment failure at a median of 134 days (P<0.05).

The most frequent adverse events in siltuximab-treated patients (greater than 10% compared to placebo) were rash (28%), pruritus (28%), upper respiratory tract infection (26%), weight gain (19%), and hyperuricemia (11%).

Results of this study were presented at the 2013 ASH Annual Meeting and published in Blood. The study was sponsored by Janssen Research & Development, the company developing siltuximab.

Access to siltuximab

Siltuximab is marketed as Sylvant by Janssen Biotech Inc., which is based in Horsham, Pennsylvania. To promote access to the drug, Janssen has created the SylvantOne™ Support program.

The program offers services for providers and patients that can help assess insurance coverage and identify cost support options, such as the SylvantOne™ Patient Rebate Program for eligible commercial patients, as well as a potential option for those who are uninsured.

Patients and providers can contact SylvantOne™ Support by calling 1-855-299-8844.

Siltuximab is available in a 100-mg, single-use vial of lyophilized powder and a 400-mg, single-use vial of lyophilized powder. The recommended dose of siltuximab is 11 mg/kg given over 1 hour, via intravenous infusion, every 3 weeks.

For more information on siltuximab, see the full prescribing information.

Vials of siltuximab

Credit: Janssen Biotech, Inc.

The US Food and Drug Administration (FDA) has authorized marketing of siltuximab (Sylvant), the first drug approved to treat patients with multicentric Castleman’s disease (MCD) who are negative for human immunodeficiency virus (HIV) and human herpes virus 8 (HHV-8).

Siltuximab is a chimeric monoclonal antibody that binds to interleukin-6 (IL-6). Dysregulated overproduction of IL-6 has been implicated in the pathogenesis of MCD.

Siltuximab has not been studied in MCD patients who are HIV- or HHV-8 positive because the drug did not bind to virally produced IL-6 in a nonclinical study.

MCD is a rare blood disorder in which lymphocytes are overproduced, leading to enlarged lymph nodes. MCD can also affect lymphoid tissue of internal organs, causing enlargement of the liver, spleen, or other organs.

Patients with MCD have a high risk of death. Infections, multisystem organ failure, and malignancies such as lymphoma are common causes of death in patients with MCD.

“There has been a serious need for treatment options for patients with MCD,” said Frits van Rhee, MD, PhD, a professor at the University of Arkansas for Medical Sciences and lead investigator of the MCD2001 study.

“MCD is a complex disease, and, up until this point, physicians have tried to reduce lymph node masses and put the disease in remission through a combination of treatments, but MCD often returns. [The approval of siltuximab] gives physicians a long-awaited treatment option for [patients] suffering with this chronic, serious, and debilitating disease.”

The FDA reviewed siltuximab under its priority review program, which provides an expedited review for drugs that demonstrate the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. The drug was also granted orphan designation, as it is intended to treat a rare disease.

MCD2001: A phase 2 study of siltuximab

The FDA approval of siltuximab is based on results of the phase 2 MCD2001 trial. This randomized, double-blind, placebo-controlled study enrolled 79 patients with symptomatic MCD that was HIV- and HHV-8 negative.

Fifty-three patients were randomized to receive siltuximab at a dose of 11 mg/kg, plus best supportive care. The remaining 26 patients were randomized to receive placebo plus best supportive care.

The researchers defined a durable response as a tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. Thirty-four percent of patients in the siltuximab arm achieved this endpoint, but none of the patients in the placebo arm did (P=0.0012).

On the other hand, 4% of patients in the placebo arm experienced a tumor response, as did 38% of patients in the siltuximab arm (P<0.05).

The median time to treatment failure was not reached for patients in the siltuximab arm. But patients in the placebo arm experienced treatment failure at a median of 134 days (P<0.05).

The most frequent adverse events in siltuximab-treated patients (greater than 10% compared to placebo) were rash (28%), pruritus (28%), upper respiratory tract infection (26%), weight gain (19%), and hyperuricemia (11%).

Results of this study were presented at the 2013 ASH Annual Meeting and published in Blood. The study was sponsored by Janssen Research & Development, the company developing siltuximab.

Access to siltuximab

Siltuximab is marketed as Sylvant by Janssen Biotech Inc., which is based in Horsham, Pennsylvania. To promote access to the drug, Janssen has created the SylvantOne™ Support program.

The program offers services for providers and patients that can help assess insurance coverage and identify cost support options, such as the SylvantOne™ Patient Rebate Program for eligible commercial patients, as well as a potential option for those who are uninsured.

Patients and providers can contact SylvantOne™ Support by calling 1-855-299-8844.

Siltuximab is available in a 100-mg, single-use vial of lyophilized powder and a 400-mg, single-use vial of lyophilized powder. The recommended dose of siltuximab is 11 mg/kg given over 1 hour, via intravenous infusion, every 3 weeks.

For more information on siltuximab, see the full prescribing information.

Vials of siltuximab

Credit: Janssen Biotech, Inc.

The US Food and Drug Administration (FDA) has authorized marketing of siltuximab (Sylvant), the first drug approved to treat patients with multicentric Castleman’s disease (MCD) who are negative for human immunodeficiency virus (HIV) and human herpes virus 8 (HHV-8).

Siltuximab is a chimeric monoclonal antibody that binds to interleukin-6 (IL-6). Dysregulated overproduction of IL-6 has been implicated in the pathogenesis of MCD.

Siltuximab has not been studied in MCD patients who are HIV- or HHV-8 positive because the drug did not bind to virally produced IL-6 in a nonclinical study.

MCD is a rare blood disorder in which lymphocytes are overproduced, leading to enlarged lymph nodes. MCD can also affect lymphoid tissue of internal organs, causing enlargement of the liver, spleen, or other organs.

Patients with MCD have a high risk of death. Infections, multisystem organ failure, and malignancies such as lymphoma are common causes of death in patients with MCD.

“There has been a serious need for treatment options for patients with MCD,” said Frits van Rhee, MD, PhD, a professor at the University of Arkansas for Medical Sciences and lead investigator of the MCD2001 study.

“MCD is a complex disease, and, up until this point, physicians have tried to reduce lymph node masses and put the disease in remission through a combination of treatments, but MCD often returns. [The approval of siltuximab] gives physicians a long-awaited treatment option for [patients] suffering with this chronic, serious, and debilitating disease.”

The FDA reviewed siltuximab under its priority review program, which provides an expedited review for drugs that demonstrate the potential to be a significant improvement in safety or effectiveness in the treatment of a serious condition. The drug was also granted orphan designation, as it is intended to treat a rare disease.

MCD2001: A phase 2 study of siltuximab

The FDA approval of siltuximab is based on results of the phase 2 MCD2001 trial. This randomized, double-blind, placebo-controlled study enrolled 79 patients with symptomatic MCD that was HIV- and HHV-8 negative.

Fifty-three patients were randomized to receive siltuximab at a dose of 11 mg/kg, plus best supportive care. The remaining 26 patients were randomized to receive placebo plus best supportive care.

The researchers defined a durable response as a tumor and symptomatic response that persisted for a minimum of 18 weeks without treatment failure. Thirty-four percent of patients in the siltuximab arm achieved this endpoint, but none of the patients in the placebo arm did (P=0.0012).

On the other hand, 4% of patients in the placebo arm experienced a tumor response, as did 38% of patients in the siltuximab arm (P<0.05).

The median time to treatment failure was not reached for patients in the siltuximab arm. But patients in the placebo arm experienced treatment failure at a median of 134 days (P<0.05).

The most frequent adverse events in siltuximab-treated patients (greater than 10% compared to placebo) were rash (28%), pruritus (28%), upper respiratory tract infection (26%), weight gain (19%), and hyperuricemia (11%).

Results of this study were presented at the 2013 ASH Annual Meeting and published in Blood. The study was sponsored by Janssen Research & Development, the company developing siltuximab.

Access to siltuximab

Siltuximab is marketed as Sylvant by Janssen Biotech Inc., which is based in Horsham, Pennsylvania. To promote access to the drug, Janssen has created the SylvantOne™ Support program.

The program offers services for providers and patients that can help assess insurance coverage and identify cost support options, such as the SylvantOne™ Patient Rebate Program for eligible commercial patients, as well as a potential option for those who are uninsured.

Patients and providers can contact SylvantOne™ Support by calling 1-855-299-8844.

Siltuximab is available in a 100-mg, single-use vial of lyophilized powder and a 400-mg, single-use vial of lyophilized powder. The recommended dose of siltuximab is 11 mg/kg given over 1 hour, via intravenous infusion, every 3 weeks.

For more information on siltuximab, see the full prescribing information.

In patients with leukemic cutaneous T-cell lymphoma, diffuse cutaneous erythema without plaques or tumors predicted complete remission with low-dose alemtuzumab therapy, investigators reported online April 23 in a JAMA Dermatology research letter.

"Initial clinical presentation was more predictive of response than was complex cellular phenotyping of T cells from blood and skin," wrote Dr. Rei Watanabe at Brigham and Women’s Hospital in Boston and associates. "In other words, the eyes of a well-trained dermatologist were more powerful than a comprehensive translational research program in identifying complete responders to LDA [low-dose alemtuzumab] therapy."

The researchers treated 23 patients with leukemic cutaneous T-cell lymphoma with 10 mg subcutaneous LDA three times weekly. Seventeen patients presented with diffuse erythema without superimposed plaques or tumors, of whom 13 experienced complete remission after LDA treatment and 4 had residual or emergent disease that could be controlled with skin-directed therapy (JAMA Dermatol. 2014 [doi:10.1001/jamadermatol.2013.10099]).

However, none of the six patients who presented with discrete patches, plaques, or tumors experienced full remission with LDA, the researchers reported. One patient later remitted with electron beam therapy, while five had their disease recur or progress, including two who developed large cell transformation.

Patients also were more likely to respond to LDA if more than 80% of their malignant T cells had TCM markers (CCR7⁺/L-selectin⁺), but clinical presentation better predicted response, the investigators reported.

"On a scientific level, diffuse erythema is likely caused by migrating T cells, and only T cells that migrate into blood are cleared by LDA," noted Dr. Watanabe and her associates. "Fixed skin lesions are more likely to be caused by TRM [nonmigratory skin resident memory T cells], cells that escape LDA clearance by remaining long-term in skin."

Based on the findings, the investigators recommended using LDA with or without adjuvant skin-directed treatments in patients who present with diffuse cutaneous erythema. But "we caution against its use in patients with preexisting plaques and/or tumors," the researchers said.

The Leukemia & Lymphoma Society, the National Institutes of Health, the Damon Runyon Cancer Research Foundation, and a private contribution from Edward P. Lawrence, Esq., funded the study. Coauthor Dr. Clark reported receiving honoraria from Novartis and Stiefel Laboratories. The authors disclosed no other conflicts of interest.

In patients with leukemic cutaneous T-cell lymphoma, diffuse cutaneous erythema without plaques or tumors predicted complete remission with low-dose alemtuzumab therapy, investigators reported online April 23 in a JAMA Dermatology research letter.

"Initial clinical presentation was more predictive of response than was complex cellular phenotyping of T cells from blood and skin," wrote Dr. Rei Watanabe at Brigham and Women’s Hospital in Boston and associates. "In other words, the eyes of a well-trained dermatologist were more powerful than a comprehensive translational research program in identifying complete responders to LDA [low-dose alemtuzumab] therapy."

The researchers treated 23 patients with leukemic cutaneous T-cell lymphoma with 10 mg subcutaneous LDA three times weekly. Seventeen patients presented with diffuse erythema without superimposed plaques or tumors, of whom 13 experienced complete remission after LDA treatment and 4 had residual or emergent disease that could be controlled with skin-directed therapy (JAMA Dermatol. 2014 [doi:10.1001/jamadermatol.2013.10099]).

However, none of the six patients who presented with discrete patches, plaques, or tumors experienced full remission with LDA, the researchers reported. One patient later remitted with electron beam therapy, while five had their disease recur or progress, including two who developed large cell transformation.

Patients also were more likely to respond to LDA if more than 80% of their malignant T cells had TCM markers (CCR7⁺/L-selectin⁺), but clinical presentation better predicted response, the investigators reported.

"On a scientific level, diffuse erythema is likely caused by migrating T cells, and only T cells that migrate into blood are cleared by LDA," noted Dr. Watanabe and her associates. "Fixed skin lesions are more likely to be caused by TRM [nonmigratory skin resident memory T cells], cells that escape LDA clearance by remaining long-term in skin."

Based on the findings, the investigators recommended using LDA with or without adjuvant skin-directed treatments in patients who present with diffuse cutaneous erythema. But "we caution against its use in patients with preexisting plaques and/or tumors," the researchers said.

The Leukemia & Lymphoma Society, the National Institutes of Health, the Damon Runyon Cancer Research Foundation, and a private contribution from Edward P. Lawrence, Esq., funded the study. Coauthor Dr. Clark reported receiving honoraria from Novartis and Stiefel Laboratories. The authors disclosed no other conflicts of interest.

In patients with leukemic cutaneous T-cell lymphoma, diffuse cutaneous erythema without plaques or tumors predicted complete remission with low-dose alemtuzumab therapy, investigators reported online April 23 in a JAMA Dermatology research letter.

"Initial clinical presentation was more predictive of response than was complex cellular phenotyping of T cells from blood and skin," wrote Dr. Rei Watanabe at Brigham and Women’s Hospital in Boston and associates. "In other words, the eyes of a well-trained dermatologist were more powerful than a comprehensive translational research program in identifying complete responders to LDA [low-dose alemtuzumab] therapy."

The researchers treated 23 patients with leukemic cutaneous T-cell lymphoma with 10 mg subcutaneous LDA three times weekly. Seventeen patients presented with diffuse erythema without superimposed plaques or tumors, of whom 13 experienced complete remission after LDA treatment and 4 had residual or emergent disease that could be controlled with skin-directed therapy (JAMA Dermatol. 2014 [doi:10.1001/jamadermatol.2013.10099]).

However, none of the six patients who presented with discrete patches, plaques, or tumors experienced full remission with LDA, the researchers reported. One patient later remitted with electron beam therapy, while five had their disease recur or progress, including two who developed large cell transformation.

Patients also were more likely to respond to LDA if more than 80% of their malignant T cells had TCM markers (CCR7⁺/L-selectin⁺), but clinical presentation better predicted response, the investigators reported.

"On a scientific level, diffuse erythema is likely caused by migrating T cells, and only T cells that migrate into blood are cleared by LDA," noted Dr. Watanabe and her associates. "Fixed skin lesions are more likely to be caused by TRM [nonmigratory skin resident memory T cells], cells that escape LDA clearance by remaining long-term in skin."

Based on the findings, the investigators recommended using LDA with or without adjuvant skin-directed treatments in patients who present with diffuse cutaneous erythema. But "we caution against its use in patients with preexisting plaques and/or tumors," the researchers said.

The Leukemia & Lymphoma Society, the National Institutes of Health, the Damon Runyon Cancer Research Foundation, and a private contribution from Edward P. Lawrence, Esq., funded the study. Coauthor Dr. Clark reported receiving honoraria from Novartis and Stiefel Laboratories. The authors disclosed no other conflicts of interest.

WASHINGTON - Being married is independently associated with a significantly reduced rate of vascular disease across all arterial beds, according to a population-based study of more than 3.5 million subjects,  Dr. Carlos L. Alviar reported at the annual meeting of the American College of Cardiology.

This apparent protective effect was strongest in younger individuals. In a multivariate regression analysis adjusted for demographics and cardiovascular risk factors, married subjects under age 50 years were 12% less likely to have prevalent vascular disease than were those who were single. The risk advantage shrank with advancing age such that married participants above age 70 years had a 4% lower risk of vascular disease than did those who were single, a difference that was statistically significant because of the huge size of the study population. And those who were single were at lower risk than were widowed or divorced subjects.

He presented an analysis of slightly more than 3.5 million participants in the Life Line Screening Diabetes Mellitus and Vascular Disease survey conducted during 2003-2008. Unlike most other studies of the relationship between marital status and health, which have focused on the risk of coronary disease, this study also included screening for peripheral artery disease, abdominal aortic aneurysm, and cerebrovascular disease.

Among participants of all ages, the risk of prevalent vascular disease was 5% less in those who were married than in those who were single. The risk was 3.2% greater in subjects who were divorced than in those who were single, and 5.1% greater in subjects who were widowed, according to Dr. Alviar of New York University.

The mean age of the study population was 63.7 years. Among women, 63.4% were married, 8.1% were single, 10.5% divorced, and 18% widowed. The male demographics were somewhat different: 80.4% of the men were married, 8.8% single, 6.1% divorced, and 4.7% were widowed.

Being widowed was associated with a higher prevalence of diabetes, hypertension, physical inactivity, and dyslipidemia, although investigators adjusted for that in their multivariate analysis. Divorced subjects were more likely to be smokers and have a family history of premature cardiovascular disease.

Dr. Alviar proposed as potential explanations for the reduced prevalence of vascular disease among married individuals their possibly lower levels of psychologic and physical stress, better access to medical care, and improved adherence to medication.

He reported having no financial disclosures regarding this study.

[email protected]

WASHINGTON - Being married is independently associated with a significantly reduced rate of vascular disease across all arterial beds, according to a population-based study of more than 3.5 million subjects,  Dr. Carlos L. Alviar reported at the annual meeting of the American College of Cardiology.

This apparent protective effect was strongest in younger individuals. In a multivariate regression analysis adjusted for demographics and cardiovascular risk factors, married subjects under age 50 years were 12% less likely to have prevalent vascular disease than were those who were single. The risk advantage shrank with advancing age such that married participants above age 70 years had a 4% lower risk of vascular disease than did those who were single, a difference that was statistically significant because of the huge size of the study population. And those who were single were at lower risk than were widowed or divorced subjects.

He presented an analysis of slightly more than 3.5 million participants in the Life Line Screening Diabetes Mellitus and Vascular Disease survey conducted during 2003-2008. Unlike most other studies of the relationship between marital status and health, which have focused on the risk of coronary disease, this study also included screening for peripheral artery disease, abdominal aortic aneurysm, and cerebrovascular disease.

Among participants of all ages, the risk of prevalent vascular disease was 5% less in those who were married than in those who were single. The risk was 3.2% greater in subjects who were divorced than in those who were single, and 5.1% greater in subjects who were widowed, according to Dr. Alviar of New York University.

The mean age of the study population was 63.7 years. Among women, 63.4% were married, 8.1% were single, 10.5% divorced, and 18% widowed. The male demographics were somewhat different: 80.4% of the men were married, 8.8% single, 6.1% divorced, and 4.7% were widowed.

Being widowed was associated with a higher prevalence of diabetes, hypertension, physical inactivity, and dyslipidemia, although investigators adjusted for that in their multivariate analysis. Divorced subjects were more likely to be smokers and have a family history of premature cardiovascular disease.

Dr. Alviar proposed as potential explanations for the reduced prevalence of vascular disease among married individuals their possibly lower levels of psychologic and physical stress, better access to medical care, and improved adherence to medication.

He reported having no financial disclosures regarding this study.

[email protected]

WASHINGTON - Being married is independently associated with a significantly reduced rate of vascular disease across all arterial beds, according to a population-based study of more than 3.5 million subjects,  Dr. Carlos L. Alviar reported at the annual meeting of the American College of Cardiology.

This apparent protective effect was strongest in younger individuals. In a multivariate regression analysis adjusted for demographics and cardiovascular risk factors, married subjects under age 50 years were 12% less likely to have prevalent vascular disease than were those who were single. The risk advantage shrank with advancing age such that married participants above age 70 years had a 4% lower risk of vascular disease than did those who were single, a difference that was statistically significant because of the huge size of the study population. And those who were single were at lower risk than were widowed or divorced subjects.

He presented an analysis of slightly more than 3.5 million participants in the Life Line Screening Diabetes Mellitus and Vascular Disease survey conducted during 2003-2008. Unlike most other studies of the relationship between marital status and health, which have focused on the risk of coronary disease, this study also included screening for peripheral artery disease, abdominal aortic aneurysm, and cerebrovascular disease.

Among participants of all ages, the risk of prevalent vascular disease was 5% less in those who were married than in those who were single. The risk was 3.2% greater in subjects who were divorced than in those who were single, and 5.1% greater in subjects who were widowed, according to Dr. Alviar of New York University.

The mean age of the study population was 63.7 years. Among women, 63.4% were married, 8.1% were single, 10.5% divorced, and 18% widowed. The male demographics were somewhat different: 80.4% of the men were married, 8.8% single, 6.1% divorced, and 4.7% were widowed.

Being widowed was associated with a higher prevalence of diabetes, hypertension, physical inactivity, and dyslipidemia, although investigators adjusted for that in their multivariate analysis. Divorced subjects were more likely to be smokers and have a family history of premature cardiovascular disease.

Dr. Alviar proposed as potential explanations for the reduced prevalence of vascular disease among married individuals their possibly lower levels of psychologic and physical stress, better access to medical care, and improved adherence to medication.

He reported having no financial disclosures regarding this study.

[email protected]

Two variations of the Mediterranean diet were associated with a lower risk of peripheral artery disease, compared with a control diet, in a secondary analysis of the PREDIMED randomized clinical trial, as reported in a Research Letter to the editor in JAMA.

Among older adults at high cardiovascular risk, following a Mediterranean diet supplemented by extra virgin olive oil (EVOO) for a median of five years was associated with a reduced risk of PAD (hazard ratio, 0.34), compared with the control diet. Similarly, following a Mediterranean diet supplemented with extra nuts was associated with a reduced risk of PAD (HR, 0.50), said Miguel Ruiz-Canela, Ph.D., of the department of preventive medicine and public health, University of Navarra, Pamplona (Spain), and his associates in the PREDIMED (Prevencion con Dieta Mediterranea) trial.

©Alex Bramwell/thinkstockphotos

The number needed to treat to prevent one case of PAD was 336 for the Mediterranean diet plus EVOO and 448 for the Mediterranean diet plus extra nuts, they said (JAMA 2014;311:415-7).

The PREDIMED investigators enrolled men aged 55-80 years and women aged 60-80 years without clinical PAD or baseline cardiovascular disease but with type 2 diabetes mellitus or at least three cardiovascular risk factors. Those patients were randomly assigned to follow a Mediterranean diet supplemented with EVOO (1,154 patients), a Mediterranean diet supplemented with mixed walnuts, almonds, and hazelnuts (1,240 patients), or a diet advising reduced intake of all types of fat (1,147 control patients).

PREDIMED’s primary endpoint was a composite of myocardial infarction, stroke, and death from cardiovascular causes. The hazard ratios were 0.70 and 0.72 for the Mediterranean diet with EVOO and the Mediterranean diet with nuts, respectively, compared with controls (N. Engl. J. Med. 2013;368:1279-90).

The investigators cautioned that this must be considered an exploratory analysis, because PAD wasn’t a prespecified endpoint of PREDIMED. “Replication by another randomized controlled trial with PAD as a prespecified end point is needed before causal conclusions can be drawn,” they noted.

“We cannot ascertain whether the observed association is due to a reduced incidence of asymptomatic PAD (true primary prevention) or to a reduced conversion from this early stage of PAD to symptomatic and clinically meaningful PAD,” they added.

This study was supported by numerous government and university sources in Spain. Supplemental foods used in the study were donated by Patrimonio Comunal Olivarero and Hojiblanca, the California Walnut Commission, Borges S. A., and LaMorella Nuts. Dr. Ruiz-Canela reported no financial conflicts of interest; one of his associates reported receiving funding from and serving as a consultant to the International Nut Council.

Two variations of the Mediterranean diet were associated with a lower risk of peripheral artery disease, compared with a control diet, in a secondary analysis of the PREDIMED randomized clinical trial, as reported in a Research Letter to the editor in JAMA.

Among older adults at high cardiovascular risk, following a Mediterranean diet supplemented by extra virgin olive oil (EVOO) for a median of five years was associated with a reduced risk of PAD (hazard ratio, 0.34), compared with the control diet. Similarly, following a Mediterranean diet supplemented with extra nuts was associated with a reduced risk of PAD (HR, 0.50), said Miguel Ruiz-Canela, Ph.D., of the department of preventive medicine and public health, University of Navarra, Pamplona (Spain), and his associates in the PREDIMED (Prevencion con Dieta Mediterranea) trial.

©Alex Bramwell/thinkstockphotos

The number needed to treat to prevent one case of PAD was 336 for the Mediterranean diet plus EVOO and 448 for the Mediterranean diet plus extra nuts, they said (JAMA 2014;311:415-7).

The PREDIMED investigators enrolled men aged 55-80 years and women aged 60-80 years without clinical PAD or baseline cardiovascular disease but with type 2 diabetes mellitus or at least three cardiovascular risk factors. Those patients were randomly assigned to follow a Mediterranean diet supplemented with EVOO (1,154 patients), a Mediterranean diet supplemented with mixed walnuts, almonds, and hazelnuts (1,240 patients), or a diet advising reduced intake of all types of fat (1,147 control patients).

PREDIMED’s primary endpoint was a composite of myocardial infarction, stroke, and death from cardiovascular causes. The hazard ratios were 0.70 and 0.72 for the Mediterranean diet with EVOO and the Mediterranean diet with nuts, respectively, compared with controls (N. Engl. J. Med. 2013;368:1279-90).

The investigators cautioned that this must be considered an exploratory analysis, because PAD wasn’t a prespecified endpoint of PREDIMED. “Replication by another randomized controlled trial with PAD as a prespecified end point is needed before causal conclusions can be drawn,” they noted.

“We cannot ascertain whether the observed association is due to a reduced incidence of asymptomatic PAD (true primary prevention) or to a reduced conversion from this early stage of PAD to symptomatic and clinically meaningful PAD,” they added.

This study was supported by numerous government and university sources in Spain. Supplemental foods used in the study were donated by Patrimonio Comunal Olivarero and Hojiblanca, the California Walnut Commission, Borges S. A., and LaMorella Nuts. Dr. Ruiz-Canela reported no financial conflicts of interest; one of his associates reported receiving funding from and serving as a consultant to the International Nut Council.

Two variations of the Mediterranean diet were associated with a lower risk of peripheral artery disease, compared with a control diet, in a secondary analysis of the PREDIMED randomized clinical trial, as reported in a Research Letter to the editor in JAMA.

Among older adults at high cardiovascular risk, following a Mediterranean diet supplemented by extra virgin olive oil (EVOO) for a median of five years was associated with a reduced risk of PAD (hazard ratio, 0.34), compared with the control diet. Similarly, following a Mediterranean diet supplemented with extra nuts was associated with a reduced risk of PAD (HR, 0.50), said Miguel Ruiz-Canela, Ph.D., of the department of preventive medicine and public health, University of Navarra, Pamplona (Spain), and his associates in the PREDIMED (Prevencion con Dieta Mediterranea) trial.

©Alex Bramwell/thinkstockphotos

The number needed to treat to prevent one case of PAD was 336 for the Mediterranean diet plus EVOO and 448 for the Mediterranean diet plus extra nuts, they said (JAMA 2014;311:415-7).

The PREDIMED investigators enrolled men aged 55-80 years and women aged 60-80 years without clinical PAD or baseline cardiovascular disease but with type 2 diabetes mellitus or at least three cardiovascular risk factors. Those patients were randomly assigned to follow a Mediterranean diet supplemented with EVOO (1,154 patients), a Mediterranean diet supplemented with mixed walnuts, almonds, and hazelnuts (1,240 patients), or a diet advising reduced intake of all types of fat (1,147 control patients).

PREDIMED’s primary endpoint was a composite of myocardial infarction, stroke, and death from cardiovascular causes. The hazard ratios were 0.70 and 0.72 for the Mediterranean diet with EVOO and the Mediterranean diet with nuts, respectively, compared with controls (N. Engl. J. Med. 2013;368:1279-90).

The investigators cautioned that this must be considered an exploratory analysis, because PAD wasn’t a prespecified endpoint of PREDIMED. “Replication by another randomized controlled trial with PAD as a prespecified end point is needed before causal conclusions can be drawn,” they noted.

“We cannot ascertain whether the observed association is due to a reduced incidence of asymptomatic PAD (true primary prevention) or to a reduced conversion from this early stage of PAD to symptomatic and clinically meaningful PAD,” they added.

This study was supported by numerous government and university sources in Spain. Supplemental foods used in the study were donated by Patrimonio Comunal Olivarero and Hojiblanca, the California Walnut Commission, Borges S. A., and LaMorella Nuts. Dr. Ruiz-Canela reported no financial conflicts of interest; one of his associates reported receiving funding from and serving as a consultant to the International Nut Council.

PALM BEACH, FLA. – Costs of three different endovascular repair systems for abdominal aortic aneurysms were slightly lower than that of open repair, but the implants still took up a substantial portion of the initial hospitalization costs, according to a study from a Veterans Affairs database. 

“Device performance doesn’t appear to result in statistically different downstream fiscal performance. That should not be a factor in your procurement committees, I believe,” said Dr. Jon Matsumura, chairman of Division of Vascular Surgery at the University of Wisconsin School of Medicine, Madison.

Naseem S. Miller/Frontline Medical News

He presented the new set of findings from the 881-patient Open Versus Endovascular Repair Veterans Affairs Cooperative Study, or OVER, at the Southern Association for Vascular Surgery annual meeting.

The cost-effectiveness of endovascular repair of abdominal aortic aneurysm (AAA) has been the subject of several studies, and the findings have changed since the method arrived in the market more than a decade ago.

In 2010, long-term follow-up of the United Kingdom EVAR Trial 1 cohort showed that “Endovascular repair was associated with increased rates of graft-related complications and reinterventions,” and that it was more costly. But the study also showed that there were no differences in total mortality or aneurysm-related mortality in the long term when comparing the two methods.

Meanwhile, in 2012, results of the randomized multicenter trial OVER showed that the method was a cost-effective alternative to open surgery, at least for the first two years after the procedure.

In the latest analysis of the OVER trial, Dr. Matsumura reported that 437 patients were randomized to open repair and 444 to endovascular repair (EVR). Open repair controls were matched to each device cohort, which included Zenith, Excluder, and AneuRx systems. 

At the VA, the device takes up to 38% of the cost of EVR, said Dr. Matsumura, so it was important to find out what were the benefits of having one system versus another, or if all the systems were needed. 

Although the statistical analysis showed that there were no significant differences between the cost of each device and open repair – in fact, the mean cost of EVR was less than open repair with each system – there were noticeable dollar differences between the systems:

• The Zenith system’s mean total 2-year cost was $78,200, compared with $82,000 in the open repair cohort, leading to a difference of $3,800.
• The Excluder system’s mean cost was $73,400, compared with $82,000 for open repair, leading to a difference of $8,300.
• The AneuRx system’s mean cost was $72,400, compared with $75,600 for open repair, with a cost difference $3,100. 

However, device costs didn’t vary much.

The analysis also showed that the total health care costs – the final bill – were not statistically significant different between the two methods.

Dr. Matsumura said understanding the cost-effectiveness of different systems and procedures is imperative in light of the Affordable Care Act, which is shifting the focus of health care delivery from volume toward value.

Dr. Matsumura has received several research grants through his university, and not personally.

[email protected]<[lb]>

On Twitter @NaseemMiller

PALM BEACH, FLA. – Costs of three different endovascular repair systems for abdominal aortic aneurysms were slightly lower than that of open repair, but the implants still took up a substantial portion of the initial hospitalization costs, according to a study from a Veterans Affairs database. 

“Device performance doesn’t appear to result in statistically different downstream fiscal performance. That should not be a factor in your procurement committees, I believe,” said Dr. Jon Matsumura, chairman of Division of Vascular Surgery at the University of Wisconsin School of Medicine, Madison.

Naseem S. Miller/Frontline Medical News

He presented the new set of findings from the 881-patient Open Versus Endovascular Repair Veterans Affairs Cooperative Study, or OVER, at the Southern Association for Vascular Surgery annual meeting.

The cost-effectiveness of endovascular repair of abdominal aortic aneurysm (AAA) has been the subject of several studies, and the findings have changed since the method arrived in the market more than a decade ago.

In 2010, long-term follow-up of the United Kingdom EVAR Trial 1 cohort showed that “Endovascular repair was associated with increased rates of graft-related complications and reinterventions,” and that it was more costly. But the study also showed that there were no differences in total mortality or aneurysm-related mortality in the long term when comparing the two methods.

Meanwhile, in 2012, results of the randomized multicenter trial OVER showed that the method was a cost-effective alternative to open surgery, at least for the first two years after the procedure.

In the latest analysis of the OVER trial, Dr. Matsumura reported that 437 patients were randomized to open repair and 444 to endovascular repair (EVR). Open repair controls were matched to each device cohort, which included Zenith, Excluder, and AneuRx systems. 

At the VA, the device takes up to 38% of the cost of EVR, said Dr. Matsumura, so it was important to find out what were the benefits of having one system versus another, or if all the systems were needed. 

Although the statistical analysis showed that there were no significant differences between the cost of each device and open repair – in fact, the mean cost of EVR was less than open repair with each system – there were noticeable dollar differences between the systems:

• The Zenith system’s mean total 2-year cost was $78,200, compared with $82,000 in the open repair cohort, leading to a difference of $3,800.
• The Excluder system’s mean cost was $73,400, compared with $82,000 for open repair, leading to a difference of $8,300.
• The AneuRx system’s mean cost was $72,400, compared with $75,600 for open repair, with a cost difference $3,100. 

However, device costs didn’t vary much.

The analysis also showed that the total health care costs – the final bill – were not statistically significant different between the two methods.

Dr. Matsumura said understanding the cost-effectiveness of different systems and procedures is imperative in light of the Affordable Care Act, which is shifting the focus of health care delivery from volume toward value.

Dr. Matsumura has received several research grants through his university, and not personally.

[email protected]<[lb]>

On Twitter @NaseemMiller

PALM BEACH, FLA. – Costs of three different endovascular repair systems for abdominal aortic aneurysms were slightly lower than that of open repair, but the implants still took up a substantial portion of the initial hospitalization costs, according to a study from a Veterans Affairs database. 

“Device performance doesn’t appear to result in statistically different downstream fiscal performance. That should not be a factor in your procurement committees, I believe,” said Dr. Jon Matsumura, chairman of Division of Vascular Surgery at the University of Wisconsin School of Medicine, Madison.

Naseem S. Miller/Frontline Medical News

He presented the new set of findings from the 881-patient Open Versus Endovascular Repair Veterans Affairs Cooperative Study, or OVER, at the Southern Association for Vascular Surgery annual meeting.

The cost-effectiveness of endovascular repair of abdominal aortic aneurysm (AAA) has been the subject of several studies, and the findings have changed since the method arrived in the market more than a decade ago.

In 2010, long-term follow-up of the United Kingdom EVAR Trial 1 cohort showed that “Endovascular repair was associated with increased rates of graft-related complications and reinterventions,” and that it was more costly. But the study also showed that there were no differences in total mortality or aneurysm-related mortality in the long term when comparing the two methods.

Meanwhile, in 2012, results of the randomized multicenter trial OVER showed that the method was a cost-effective alternative to open surgery, at least for the first two years after the procedure.

In the latest analysis of the OVER trial, Dr. Matsumura reported that 437 patients were randomized to open repair and 444 to endovascular repair (EVR). Open repair controls were matched to each device cohort, which included Zenith, Excluder, and AneuRx systems. 

At the VA, the device takes up to 38% of the cost of EVR, said Dr. Matsumura, so it was important to find out what were the benefits of having one system versus another, or if all the systems were needed. 

Although the statistical analysis showed that there were no significant differences between the cost of each device and open repair – in fact, the mean cost of EVR was less than open repair with each system – there were noticeable dollar differences between the systems:

• The Zenith system’s mean total 2-year cost was $78,200, compared with $82,000 in the open repair cohort, leading to a difference of $3,800.
• The Excluder system’s mean cost was $73,400, compared with $82,000 for open repair, leading to a difference of $8,300.
• The AneuRx system’s mean cost was $72,400, compared with $75,600 for open repair, with a cost difference $3,100. 

However, device costs didn’t vary much.

The analysis also showed that the total health care costs – the final bill – were not statistically significant different between the two methods.

Dr. Matsumura said understanding the cost-effectiveness of different systems and procedures is imperative in light of the Affordable Care Act, which is shifting the focus of health care delivery from volume toward value.

Dr. Matsumura has received several research grants through his university, and not personally.

[email protected]<[lb]>

On Twitter @NaseemMiller

WASHINGTON – Long-term dual-antiplatelet therapy may provide a mortality benefit over aspirin alone in patients with symptomatic peripheral artery disease.

In an observational study of 629 patients with claudication or critical limb ischemia, the 348 who were on dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel had a 3-year all-cause mortality rate of 11%, compared with 21% for those on aspirin monotherapy, Dr. Ehrin J. Armstrong said at the annual meeting of the American College of Cardiology.

The group on DAPT also had a significantly lower 3-year rate of major adverse cardiovascular events: 20%, compared with 28% in the monotherapy group. However, this was driven by the reduced risk of mortality. Rates of nonfatal MI and stroke were similar in the two groups. So were rates of lower extremity bypass surgery and major amputations, according to Dr. Armstrong, a cardiologist at the University of California, Davis.

The group on DAPT had a significantly higher baseline prevalence of diabetes at the time of angiography: 54%, compared with 45% for patients on aspirin alone. The DAPT group also had a higher baseline prevalence of known coronary artery disease – 56% vs. 45% – and greater use of beta-blockers, by a margin of 55%, compared with 48%. In a multivariate regression analysis adjusted for these and other potential confounders, DAPT was associated with a 45% reduction in the risk of mortality and a 35% decrease in major adverse cardiovascular events.

The rate of the combined endpoint of death or major amputation was 18% in the DAPT group and 27% with aspirin monotherapy, for a highly significant 47% relative risk reduction.

Although a study such as this can’t be considered definitive, these data suggest DAPT is worth considering in patients with symptomatic peripheral artery disease, the cardiologist said.

He reported having no financial conflicts of interest.

[email protected]

WASHINGTON – Long-term dual-antiplatelet therapy may provide a mortality benefit over aspirin alone in patients with symptomatic peripheral artery disease.

In an observational study of 629 patients with claudication or critical limb ischemia, the 348 who were on dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel had a 3-year all-cause mortality rate of 11%, compared with 21% for those on aspirin monotherapy, Dr. Ehrin J. Armstrong said at the annual meeting of the American College of Cardiology.

The group on DAPT also had a significantly lower 3-year rate of major adverse cardiovascular events: 20%, compared with 28% in the monotherapy group. However, this was driven by the reduced risk of mortality. Rates of nonfatal MI and stroke were similar in the two groups. So were rates of lower extremity bypass surgery and major amputations, according to Dr. Armstrong, a cardiologist at the University of California, Davis.

The group on DAPT had a significantly higher baseline prevalence of diabetes at the time of angiography: 54%, compared with 45% for patients on aspirin alone. The DAPT group also had a higher baseline prevalence of known coronary artery disease – 56% vs. 45% – and greater use of beta-blockers, by a margin of 55%, compared with 48%. In a multivariate regression analysis adjusted for these and other potential confounders, DAPT was associated with a 45% reduction in the risk of mortality and a 35% decrease in major adverse cardiovascular events.

The rate of the combined endpoint of death or major amputation was 18% in the DAPT group and 27% with aspirin monotherapy, for a highly significant 47% relative risk reduction.

Although a study such as this can’t be considered definitive, these data suggest DAPT is worth considering in patients with symptomatic peripheral artery disease, the cardiologist said.

He reported having no financial conflicts of interest.

[email protected]

WASHINGTON – Long-term dual-antiplatelet therapy may provide a mortality benefit over aspirin alone in patients with symptomatic peripheral artery disease.

In an observational study of 629 patients with claudication or critical limb ischemia, the 348 who were on dual antiplatelet therapy (DAPT) with aspirin plus clopidogrel had a 3-year all-cause mortality rate of 11%, compared with 21% for those on aspirin monotherapy, Dr. Ehrin J. Armstrong said at the annual meeting of the American College of Cardiology.

The group on DAPT also had a significantly lower 3-year rate of major adverse cardiovascular events: 20%, compared with 28% in the monotherapy group. However, this was driven by the reduced risk of mortality. Rates of nonfatal MI and stroke were similar in the two groups. So were rates of lower extremity bypass surgery and major amputations, according to Dr. Armstrong, a cardiologist at the University of California, Davis.

The group on DAPT had a significantly higher baseline prevalence of diabetes at the time of angiography: 54%, compared with 45% for patients on aspirin alone. The DAPT group also had a higher baseline prevalence of known coronary artery disease – 56% vs. 45% – and greater use of beta-blockers, by a margin of 55%, compared with 48%. In a multivariate regression analysis adjusted for these and other potential confounders, DAPT was associated with a 45% reduction in the risk of mortality and a 35% decrease in major adverse cardiovascular events.

The rate of the combined endpoint of death or major amputation was 18% in the DAPT group and 27% with aspirin monotherapy, for a highly significant 47% relative risk reduction.

Although a study such as this can’t be considered definitive, these data suggest DAPT is worth considering in patients with symptomatic peripheral artery disease, the cardiologist said.

He reported having no financial conflicts of interest.

[email protected]

Dyschromias are one of the most common skin concerns among women and persons of color. In the April issue of Journal of Drugs in Dermatology, Dr. S.J. Kang and associates conducted an excellent study to determine whether racial or ethnic groups are treated differently for dyschromia.

The investigators searched the National Ambulatory Medical Care Survey (NAMCS) database for visits including the diagnosis of dyschromia (ICD-9 codes 709.00 or 709.09) during an 18-year period (1993-2010). They found 24.7 million visits for dyschromia and 5,531,000 patients with a sole diagnosis of dyschromia. Of those with a sole diagnosis of dyschromia, 76% were seen by a dermatologist, and more than half were female. Seventy-five percent were white, 11% African American, 7% Asian/Pacific Islander, and 9% Hispanic, although Asians demonstrated the highest number of visits per 100,000 persons.

In this review, hydroquinone monotherapy was the most commonly prescribed medication by dermatologists. Combination therapy with hydroquinone plus a retinoid and corticosteroid was utilized for women 10 times more than for men. African American patients were less likely to be prescribed combination therapy or receive procedures (such as cryotherapy, chemical peels or lasers). Additionally, sunscreens were recommended less often to black and Asian patients, compared with white patients.

While the underlying reason for dyschromia plays a role in the type of treatment given, overall combination therapies are often more effective than therapy with hydroquinone alone. This study demonstrates that combination therapy may be under-utilized in patients of color.

In my practice, I find that unless the patient’s skin is completely hydroquinone-naive, combination therapy with hydroquinone, retinoid, and corticosteroid is often a first-line treatment that may achieve faster results. Sun protection is a vital component in the treatment of dyschromia, and it is recommended for every patient, regardless of race or ethnicity. Nonhydroquinone topical agents containing ingredients such as kojic acid, arbutin, licorice, niacinamide, resveratrol, and superficial chemical peels are also used in all ethnic groups. In my Asian, Hispanic, and African American or darker-skinned patients, I do use caution with deeper peels and lasers and often perform a test spot first if this type of therapy is considered.

Dr. Wesley practices dermatology in Beverly Hills, Calif.

Dyschromias are one of the most common skin concerns among women and persons of color. In the April issue of Journal of Drugs in Dermatology, Dr. S.J. Kang and associates conducted an excellent study to determine whether racial or ethnic groups are treated differently for dyschromia.

The investigators searched the National Ambulatory Medical Care Survey (NAMCS) database for visits including the diagnosis of dyschromia (ICD-9 codes 709.00 or 709.09) during an 18-year period (1993-2010). They found 24.7 million visits for dyschromia and 5,531,000 patients with a sole diagnosis of dyschromia. Of those with a sole diagnosis of dyschromia, 76% were seen by a dermatologist, and more than half were female. Seventy-five percent were white, 11% African American, 7% Asian/Pacific Islander, and 9% Hispanic, although Asians demonstrated the highest number of visits per 100,000 persons.

In this review, hydroquinone monotherapy was the most commonly prescribed medication by dermatologists. Combination therapy with hydroquinone plus a retinoid and corticosteroid was utilized for women 10 times more than for men. African American patients were less likely to be prescribed combination therapy or receive procedures (such as cryotherapy, chemical peels or lasers). Additionally, sunscreens were recommended less often to black and Asian patients, compared with white patients.

While the underlying reason for dyschromia plays a role in the type of treatment given, overall combination therapies are often more effective than therapy with hydroquinone alone. This study demonstrates that combination therapy may be under-utilized in patients of color.

In my practice, I find that unless the patient’s skin is completely hydroquinone-naive, combination therapy with hydroquinone, retinoid, and corticosteroid is often a first-line treatment that may achieve faster results. Sun protection is a vital component in the treatment of dyschromia, and it is recommended for every patient, regardless of race or ethnicity. Nonhydroquinone topical agents containing ingredients such as kojic acid, arbutin, licorice, niacinamide, resveratrol, and superficial chemical peels are also used in all ethnic groups. In my Asian, Hispanic, and African American or darker-skinned patients, I do use caution with deeper peels and lasers and often perform a test spot first if this type of therapy is considered.

Dr. Wesley practices dermatology in Beverly Hills, Calif.

Dyschromias are one of the most common skin concerns among women and persons of color. In the April issue of Journal of Drugs in Dermatology, Dr. S.J. Kang and associates conducted an excellent study to determine whether racial or ethnic groups are treated differently for dyschromia.

The investigators searched the National Ambulatory Medical Care Survey (NAMCS) database for visits including the diagnosis of dyschromia (ICD-9 codes 709.00 or 709.09) during an 18-year period (1993-2010). They found 24.7 million visits for dyschromia and 5,531,000 patients with a sole diagnosis of dyschromia. Of those with a sole diagnosis of dyschromia, 76% were seen by a dermatologist, and more than half were female. Seventy-five percent were white, 11% African American, 7% Asian/Pacific Islander, and 9% Hispanic, although Asians demonstrated the highest number of visits per 100,000 persons.

In this review, hydroquinone monotherapy was the most commonly prescribed medication by dermatologists. Combination therapy with hydroquinone plus a retinoid and corticosteroid was utilized for women 10 times more than for men. African American patients were less likely to be prescribed combination therapy or receive procedures (such as cryotherapy, chemical peels or lasers). Additionally, sunscreens were recommended less often to black and Asian patients, compared with white patients.

While the underlying reason for dyschromia plays a role in the type of treatment given, overall combination therapies are often more effective than therapy with hydroquinone alone. This study demonstrates that combination therapy may be under-utilized in patients of color.

In my practice, I find that unless the patient’s skin is completely hydroquinone-naive, combination therapy with hydroquinone, retinoid, and corticosteroid is often a first-line treatment that may achieve faster results. Sun protection is a vital component in the treatment of dyschromia, and it is recommended for every patient, regardless of race or ethnicity. Nonhydroquinone topical agents containing ingredients such as kojic acid, arbutin, licorice, niacinamide, resveratrol, and superficial chemical peels are also used in all ethnic groups. In my Asian, Hispanic, and African American or darker-skinned patients, I do use caution with deeper peels and lasers and often perform a test spot first if this type of therapy is considered.

Dr. Wesley practices dermatology in Beverly Hills, Calif.

SAN DIEGO—One woman’s curiosity and self-described “aggressive” approach to research have led to some unexpected discoveries about acute leukemias.

Isabel Cunningham, MD, of Columbia University in New York, has found evidence to suggest that treatment resistance in leukemia patients may sometimes result from an interaction between leukemic cells and the breast.

She discovered that leukemic cells in extramedullary niches can adopt a tumor phenotype similar to breast cancer.

And many genes are similarly upregulated in leukemic and epithelial breast tumors.

Her research indicates that a new approach to resistant leukemias that incorporates the principles of solid-tumor treatment—scans to identify any tumors and surgery to remove them—could decrease marrow relapse and death.

Dr Cunningham and her colleagues presented these findings in a poster at the AACR Annual Meeting 2014 (abstract 3996*).

“Chemotherapy resistance is our main problem in treating leukemia,” Dr Cunningham said. “It’s been known for a long time that, occasionally, leukemia forms tumors in an organ, but there’s never been a unified approach to treatment, except for leukemia that occurs in the testis and the meninges.”

Dr Cunningham had encountered many patients with resistant leukemia throughout her career, but her research actually began with a patient she had never met. A case study of a leukemia patient with a breast tumor sparked Dr Cunningham’s interest, and she emailed the study’s author to find out what ultimately became of the patient.

The response she received peaked her curiosity further. So she began seeking more of these cases, contacting authors, and collecting information on this phenomenon.

“I took this on as sort of a hobby,” Dr Cunningham said. “I never had any idea where this was going to lead.”

Eventually, she had amassed information on 235 cases—163 patients with acute myeloid leukemia (AML) and 72 with acute lymphoblastic leukemia (ALL)—who ranged from 1 year to 75 years of age. And an analysis of these cases led to some surprising discoveries.

Clinical findings

Dr Cunningham found these leukemic breast tumors can occur before, during, or after marrow leukemia. And, clinically, they resemble breast cancer. Most tumors were palpable, and some were detected only on routine mammograms.

There were single or multiple nodules that may have involved the entire breast. Sixty percent of cases were unilateral on presentation, but, often, the other breast became involved. Seventy percent of cases exhibited axillary lymphadenopathy that was ipsilateral.

Most tumors grew rapidly, to as large as 12 cm. The tumor behavior was similar in AML and ALL. And the tumors had a metastatic pattern similar to lobular breast cancer—spreading to the contralateral breast, the abdomen or pelvis, the meninges, and culminating in death.

However, some patients did survive. Four percent of patients who were treated only with chemotherapy were alive at 4 years. Twenty-five percent of patients had their tumors excised prior to chemotherapy and were alive anywhere from 3 years to more than 26 years after treatment.

Histology and gene expression

To build upon these findings, Dr Cunningham set her sights on patient samples. She was able to obtain paraffin blocks of leukemic breast tumors from 25 patients and perform immunohistochemical staining.

“It became clear that the leukemic tumors—which are marked by leukemic markers and not breast cancer markers—look, histologically, like breast cancer, specifically, lobular breast cancer,” Dr Cunningham said. “An additional pathologic finding was a specific type of desmoplastic fibrosis seen in all 25 contributed biopsies.”

Dr Cunningham also performed gene expression studies on 3 of the tumors (2 ALL and 1 AML), which were collected 8 months to 22 months after diagnosis, while marrows were in remission. The analyses revealed that a number of genes are significantly upregulated in both leukemic breast tumors and breast cancer.

These include genes involved in adhesion and interactions with the extracellular matrix (ADAM8, COMP, and CDH22), genes involved in the ubiquitin-proteasome pathway (UBE2S, USP32, MDM2, and UBE2C), genes encoding for kinases (MAP4K1, PIM1, and NEK2), and genes involved in RAS signaling (RANBP1 and RAB10).

Conclusions and next steps

“It seems that there’s some kind of crosstalk between the organ microenvironment and leukemic cells that make the leukemic cells have the phenotype of breast cancer,” Dr Cunningham said. “And it may well be that relapse sometimes results from the presence of an undiagnosed collection of these cells.”

Therefore, Dr Cunningham suggests performing scans in treatment-resistant leukemia patients. If a patient relapses, and particularly if lactic dehydrogenase levels are increased, a scan might be in order.

“If we can recognize these tumors and cut them out, the patient could be cured, because we’re successful at treating the bone marrow,” Dr Cunningham said. “We’ve had very good bone marrow drugs for 50 years.”

For her part, Dr Cunningham is delving further into this phenomenon. She is now conducting gene expression studies on the rest of the 25 leukemic breast tumor samples and comparing these tumors to breast cancer to identify the most significant dysregulated genes in both entities. The long-term goal is to find a way to predict which patients will develop leukemic breast tumors.

*Information in the abstract differs from that presented at the meeting.

SAN DIEGO—One woman’s curiosity and self-described “aggressive” approach to research have led to some unexpected discoveries about acute leukemias.

Isabel Cunningham, MD, of Columbia University in New York, has found evidence to suggest that treatment resistance in leukemia patients may sometimes result from an interaction between leukemic cells and the breast.

She discovered that leukemic cells in extramedullary niches can adopt a tumor phenotype similar to breast cancer.

And many genes are similarly upregulated in leukemic and epithelial breast tumors.

Her research indicates that a new approach to resistant leukemias that incorporates the principles of solid-tumor treatment—scans to identify any tumors and surgery to remove them—could decrease marrow relapse and death.

Dr Cunningham and her colleagues presented these findings in a poster at the AACR Annual Meeting 2014 (abstract 3996*).

“Chemotherapy resistance is our main problem in treating leukemia,” Dr Cunningham said. “It’s been known for a long time that, occasionally, leukemia forms tumors in an organ, but there’s never been a unified approach to treatment, except for leukemia that occurs in the testis and the meninges.”

Dr Cunningham had encountered many patients with resistant leukemia throughout her career, but her research actually began with a patient she had never met. A case study of a leukemia patient with a breast tumor sparked Dr Cunningham’s interest, and she emailed the study’s author to find out what ultimately became of the patient.

The response she received peaked her curiosity further. So she began seeking more of these cases, contacting authors, and collecting information on this phenomenon.

“I took this on as sort of a hobby,” Dr Cunningham said. “I never had any idea where this was going to lead.”

Eventually, she had amassed information on 235 cases—163 patients with acute myeloid leukemia (AML) and 72 with acute lymphoblastic leukemia (ALL)—who ranged from 1 year to 75 years of age. And an analysis of these cases led to some surprising discoveries.

Clinical findings

Dr Cunningham found these leukemic breast tumors can occur before, during, or after marrow leukemia. And, clinically, they resemble breast cancer. Most tumors were palpable, and some were detected only on routine mammograms.

There were single or multiple nodules that may have involved the entire breast. Sixty percent of cases were unilateral on presentation, but, often, the other breast became involved. Seventy percent of cases exhibited axillary lymphadenopathy that was ipsilateral.

Most tumors grew rapidly, to as large as 12 cm. The tumor behavior was similar in AML and ALL. And the tumors had a metastatic pattern similar to lobular breast cancer—spreading to the contralateral breast, the abdomen or pelvis, the meninges, and culminating in death.

However, some patients did survive. Four percent of patients who were treated only with chemotherapy were alive at 4 years. Twenty-five percent of patients had their tumors excised prior to chemotherapy and were alive anywhere from 3 years to more than 26 years after treatment.

Histology and gene expression

To build upon these findings, Dr Cunningham set her sights on patient samples. She was able to obtain paraffin blocks of leukemic breast tumors from 25 patients and perform immunohistochemical staining.

“It became clear that the leukemic tumors—which are marked by leukemic markers and not breast cancer markers—look, histologically, like breast cancer, specifically, lobular breast cancer,” Dr Cunningham said. “An additional pathologic finding was a specific type of desmoplastic fibrosis seen in all 25 contributed biopsies.”

Dr Cunningham also performed gene expression studies on 3 of the tumors (2 ALL and 1 AML), which were collected 8 months to 22 months after diagnosis, while marrows were in remission. The analyses revealed that a number of genes are significantly upregulated in both leukemic breast tumors and breast cancer.

These include genes involved in adhesion and interactions with the extracellular matrix (ADAM8, COMP, and CDH22), genes involved in the ubiquitin-proteasome pathway (UBE2S, USP32, MDM2, and UBE2C), genes encoding for kinases (MAP4K1, PIM1, and NEK2), and genes involved in RAS signaling (RANBP1 and RAB10).

Conclusions and next steps

“It seems that there’s some kind of crosstalk between the organ microenvironment and leukemic cells that make the leukemic cells have the phenotype of breast cancer,” Dr Cunningham said. “And it may well be that relapse sometimes results from the presence of an undiagnosed collection of these cells.”

Therefore, Dr Cunningham suggests performing scans in treatment-resistant leukemia patients. If a patient relapses, and particularly if lactic dehydrogenase levels are increased, a scan might be in order.

“If we can recognize these tumors and cut them out, the patient could be cured, because we’re successful at treating the bone marrow,” Dr Cunningham said. “We’ve had very good bone marrow drugs for 50 years.”

For her part, Dr Cunningham is delving further into this phenomenon. She is now conducting gene expression studies on the rest of the 25 leukemic breast tumor samples and comparing these tumors to breast cancer to identify the most significant dysregulated genes in both entities. The long-term goal is to find a way to predict which patients will develop leukemic breast tumors.

*Information in the abstract differs from that presented at the meeting.

SAN DIEGO—One woman’s curiosity and self-described “aggressive” approach to research have led to some unexpected discoveries about acute leukemias.

Isabel Cunningham, MD, of Columbia University in New York, has found evidence to suggest that treatment resistance in leukemia patients may sometimes result from an interaction between leukemic cells and the breast.

She discovered that leukemic cells in extramedullary niches can adopt a tumor phenotype similar to breast cancer.

And many genes are similarly upregulated in leukemic and epithelial breast tumors.

Her research indicates that a new approach to resistant leukemias that incorporates the principles of solid-tumor treatment—scans to identify any tumors and surgery to remove them—could decrease marrow relapse and death.

Dr Cunningham and her colleagues presented these findings in a poster at the AACR Annual Meeting 2014 (abstract 3996*).

“Chemotherapy resistance is our main problem in treating leukemia,” Dr Cunningham said. “It’s been known for a long time that, occasionally, leukemia forms tumors in an organ, but there’s never been a unified approach to treatment, except for leukemia that occurs in the testis and the meninges.”

Dr Cunningham had encountered many patients with resistant leukemia throughout her career, but her research actually began with a patient she had never met. A case study of a leukemia patient with a breast tumor sparked Dr Cunningham’s interest, and she emailed the study’s author to find out what ultimately became of the patient.

The response she received peaked her curiosity further. So she began seeking more of these cases, contacting authors, and collecting information on this phenomenon.

“I took this on as sort of a hobby,” Dr Cunningham said. “I never had any idea where this was going to lead.”

Eventually, she had amassed information on 235 cases—163 patients with acute myeloid leukemia (AML) and 72 with acute lymphoblastic leukemia (ALL)—who ranged from 1 year to 75 years of age. And an analysis of these cases led to some surprising discoveries.

Clinical findings

Dr Cunningham found these leukemic breast tumors can occur before, during, or after marrow leukemia. And, clinically, they resemble breast cancer. Most tumors were palpable, and some were detected only on routine mammograms.

There were single or multiple nodules that may have involved the entire breast. Sixty percent of cases were unilateral on presentation, but, often, the other breast became involved. Seventy percent of cases exhibited axillary lymphadenopathy that was ipsilateral.

Most tumors grew rapidly, to as large as 12 cm. The tumor behavior was similar in AML and ALL. And the tumors had a metastatic pattern similar to lobular breast cancer—spreading to the contralateral breast, the abdomen or pelvis, the meninges, and culminating in death.

However, some patients did survive. Four percent of patients who were treated only with chemotherapy were alive at 4 years. Twenty-five percent of patients had their tumors excised prior to chemotherapy and were alive anywhere from 3 years to more than 26 years after treatment.

Histology and gene expression

To build upon these findings, Dr Cunningham set her sights on patient samples. She was able to obtain paraffin blocks of leukemic breast tumors from 25 patients and perform immunohistochemical staining.

“It became clear that the leukemic tumors—which are marked by leukemic markers and not breast cancer markers—look, histologically, like breast cancer, specifically, lobular breast cancer,” Dr Cunningham said. “An additional pathologic finding was a specific type of desmoplastic fibrosis seen in all 25 contributed biopsies.”

Dr Cunningham also performed gene expression studies on 3 of the tumors (2 ALL and 1 AML), which were collected 8 months to 22 months after diagnosis, while marrows were in remission. The analyses revealed that a number of genes are significantly upregulated in both leukemic breast tumors and breast cancer.

These include genes involved in adhesion and interactions with the extracellular matrix (ADAM8, COMP, and CDH22), genes involved in the ubiquitin-proteasome pathway (UBE2S, USP32, MDM2, and UBE2C), genes encoding for kinases (MAP4K1, PIM1, and NEK2), and genes involved in RAS signaling (RANBP1 and RAB10).

Conclusions and next steps

“It seems that there’s some kind of crosstalk between the organ microenvironment and leukemic cells that make the leukemic cells have the phenotype of breast cancer,” Dr Cunningham said. “And it may well be that relapse sometimes results from the presence of an undiagnosed collection of these cells.”

Therefore, Dr Cunningham suggests performing scans in treatment-resistant leukemia patients. If a patient relapses, and particularly if lactic dehydrogenase levels are increased, a scan might be in order.

“If we can recognize these tumors and cut them out, the patient could be cured, because we’re successful at treating the bone marrow,” Dr Cunningham said. “We’ve had very good bone marrow drugs for 50 years.”

For her part, Dr Cunningham is delving further into this phenomenon. She is now conducting gene expression studies on the rest of the 25 leukemic breast tumor samples and comparing these tumors to breast cancer to identify the most significant dysregulated genes in both entities. The long-term goal is to find a way to predict which patients will develop leukemic breast tumors.

*Information in the abstract differs from that presented at the meeting.

AML cells

Credit: Lance Liotta

A small gene embedded in a larger gene appears to be the driving force behind acute myeloid leukemia (AML) development, according to research published in Science Signaling.

The smaller gene, microRNA-3151 (miR-3151), is embedded in intron 1 of the larger gene, BAALC.

As both genes have been associated with poor prognosis in AML, researchers wanted to determine the degree to which each of the genes contributes to AML.

“We discovered that the smaller microRNA gene, and not the larger host gene, is the major oncogenic driver of the 2 molecules in AML,” said principal investigator Albert de la Chapelle, MD, PhD, of The Ohio State University Comprehensive Cancer Center (OSUCCC) in Columbus.

“When both genes are highly expressed, it means a bad prognosis for patients, but our experiments indicate that it is high expression of miR-3151 that really matters. Overexpression of BAALC alone had only limited cancer-causing activity.”

Dr de la Chapelle and his colleagues used AML cells derived from patients, AML cell lines, and an animal model of the disease to investigate the role of miR-3151 and BAALC in older patients with cytogenetically normal AML.

The team found that miR-3151 promotes leukemia development by targeting the tumor suppressor TP53 and 7 other genes in the TP53 pathway.

“When miR-3151 blocks TP53 in the tumor cells, it enables the cells to survive, divide, and grow faster,” said study author Clara D. Bloomfield, MD, of OSUCCC.

Experiments also showed that overexpressing miR-3151 promotes AML cell growth. BAALC overexpression enhances that effect, but blocking miR-3151 or overexpressing TP53 reverses it.

In mice, miR-3151 alone and in combination with BAALC promoted leukemia development.

Finally, the researchers discovered that miR-3151 overexpression can be inhibited by the proteasome inhibitor bortezomib, which suggests a possible therapy for miR-3151 overexpression.

“About one-third of the several hundred known human microRNAs are encoded in host genes,” said study author Ann-Kathrin Eisfeld, MD, of OSUCCC.

“We know very little about how microRNAs located within introns are regulated and how they interact with their host genes. These findings provide an important example of that interaction.”

AML cells

Credit: Lance Liotta

A small gene embedded in a larger gene appears to be the driving force behind acute myeloid leukemia (AML) development, according to research published in Science Signaling.

The smaller gene, microRNA-3151 (miR-3151), is embedded in intron 1 of the larger gene, BAALC.

As both genes have been associated with poor prognosis in AML, researchers wanted to determine the degree to which each of the genes contributes to AML.

“We discovered that the smaller microRNA gene, and not the larger host gene, is the major oncogenic driver of the 2 molecules in AML,” said principal investigator Albert de la Chapelle, MD, PhD, of The Ohio State University Comprehensive Cancer Center (OSUCCC) in Columbus.

“When both genes are highly expressed, it means a bad prognosis for patients, but our experiments indicate that it is high expression of miR-3151 that really matters. Overexpression of BAALC alone had only limited cancer-causing activity.”

Dr de la Chapelle and his colleagues used AML cells derived from patients, AML cell lines, and an animal model of the disease to investigate the role of miR-3151 and BAALC in older patients with cytogenetically normal AML.

The team found that miR-3151 promotes leukemia development by targeting the tumor suppressor TP53 and 7 other genes in the TP53 pathway.

“When miR-3151 blocks TP53 in the tumor cells, it enables the cells to survive, divide, and grow faster,” said study author Clara D. Bloomfield, MD, of OSUCCC.

Experiments also showed that overexpressing miR-3151 promotes AML cell growth. BAALC overexpression enhances that effect, but blocking miR-3151 or overexpressing TP53 reverses it.

In mice, miR-3151 alone and in combination with BAALC promoted leukemia development.

Finally, the researchers discovered that miR-3151 overexpression can be inhibited by the proteasome inhibitor bortezomib, which suggests a possible therapy for miR-3151 overexpression.

“About one-third of the several hundred known human microRNAs are encoded in host genes,” said study author Ann-Kathrin Eisfeld, MD, of OSUCCC.

“We know very little about how microRNAs located within introns are regulated and how they interact with their host genes. These findings provide an important example of that interaction.”

AML cells

Credit: Lance Liotta

A small gene embedded in a larger gene appears to be the driving force behind acute myeloid leukemia (AML) development, according to research published in Science Signaling.

The smaller gene, microRNA-3151 (miR-3151), is embedded in intron 1 of the larger gene, BAALC.

As both genes have been associated with poor prognosis in AML, researchers wanted to determine the degree to which each of the genes contributes to AML.

“We discovered that the smaller microRNA gene, and not the larger host gene, is the major oncogenic driver of the 2 molecules in AML,” said principal investigator Albert de la Chapelle, MD, PhD, of The Ohio State University Comprehensive Cancer Center (OSUCCC) in Columbus.

“When both genes are highly expressed, it means a bad prognosis for patients, but our experiments indicate that it is high expression of miR-3151 that really matters. Overexpression of BAALC alone had only limited cancer-causing activity.”

Dr de la Chapelle and his colleagues used AML cells derived from patients, AML cell lines, and an animal model of the disease to investigate the role of miR-3151 and BAALC in older patients with cytogenetically normal AML.

The team found that miR-3151 promotes leukemia development by targeting the tumor suppressor TP53 and 7 other genes in the TP53 pathway.

“When miR-3151 blocks TP53 in the tumor cells, it enables the cells to survive, divide, and grow faster,” said study author Clara D. Bloomfield, MD, of OSUCCC.

Experiments also showed that overexpressing miR-3151 promotes AML cell growth. BAALC overexpression enhances that effect, but blocking miR-3151 or overexpressing TP53 reverses it.

In mice, miR-3151 alone and in combination with BAALC promoted leukemia development.

Finally, the researchers discovered that miR-3151 overexpression can be inhibited by the proteasome inhibitor bortezomib, which suggests a possible therapy for miR-3151 overexpression.

“About one-third of the several hundred known human microRNAs are encoded in host genes,” said study author Ann-Kathrin Eisfeld, MD, of OSUCCC.

“We know very little about how microRNAs located within introns are regulated and how they interact with their host genes. These findings provide an important example of that interaction.”