Hematology Times

Warfarin tablets

SAN FRANCISCO—Patients with atrial fibrillation (AF) who are taking warfarin have a higher risk of kidney problems if their anticoagulation levels are not properly managed, according to a new study.

Researchers found that patients who had low times in therapeutic range were significantly more likely to develop renal dysfunction and experience renal failure.

Furthermore, all patients were at risk of developing renal dysfunction, whether they began the study with healthy kidney function or moderate to severe kidney disease.

T. Jared Bunch, MD, of Intermountain Medical Center Heart Institute in Salt Lake City, Utah, and his colleagues presented these findings during the Heart Rhythm Society’s 37th Annual Scientific Sessions (abstract PO02-210).

The researchers studied 2753 AF patients who were anticoagulated with warfarin and managed by Intermountain Healthcare Clinical Pharmacist Anticoagulation Services.

The patients’ mean age was 74.7±10.7, and 50.3% were male. The patients had a baseline creatinine level of less than 2.0 mg/dL or a glomerular filtration rate greater than 30 and serial renal function studies.

Dr Bunch and his colleagues stratified patients into 4 categories based on the amount of time their international normalized ratio levels were determined to be in the therapeutic range (TTR): >75%, 51% to 75%, 26% to 50%, and <25%.

The researchers then performed multivariate, adjusted analyses to calculate odds ratios (ORs) for renal dysfunction and hazard ratios (HRs) for renal failure based on TTR group. The >75% group was the reference.

Among patients with baseline creatinine ≤2.0 mg/dL, the OR for a 25% increase in creatinine was:

• 1.35 for the 51%-75% TTR group (P=0.06)
• 1.80 for the 26-50% TTR group (P=0.003)
• 2.34 for the ≤25% TTR group (P=0.003).

Among patients with baseline creatinine ≤2.0 mg/dL, the HR for renal failure was:

• 1.72 for the 51%-75% TTR group (P=0.001)
• 2.36 for the 26-50% TTR group (P<0.0001)
• 2.38 for the ≤25% TTR group (P<0.0001).

Among patients with baseline glomerular filtration rate >30, the OR for a 25% decrease in glomerular filtration rate was:

• 1.45 for the 51%-75% TTR group (P=0.03)
• 1.46 for the 26-50% TTR group (P=0.08)
• 1.52 for the ≤25% TTR group (P=0.20).

Among patients with a baseline glomerular filtration rate >30, the HR for renal failure was:

• 1.88 for the 51%-75% TTR group (P<0.0001)
• 2.40 for the 26-50% TTR group (P<0.0001)
• 2.60 for the ≤25% TTR group (P<0.0001).

The researchers said these results suggest the quality of anticoagulation management is associated with renal dysfunction and failure, so improving anticoagulation control might improve the long-term risk of end-organ injury in AF patients.

“Patients who use warfarin as part of their anticoagulation treatment for atrial fibrillation should have their anticoagulation levels closely monitored to ensure proper levels,” Dr Bunch said.

“Those who have erratic levels of warfarin despite close monitoring and care should consider other approaches such as newer anticoagulants that have more predictable blood effects, even if they have moderate kidney disease, and non drug-based methods to lower clot risk with atrial fibrillation.”

Warfarin tablets

SAN FRANCISCO—Patients with atrial fibrillation (AF) who are taking warfarin have a higher risk of kidney problems if their anticoagulation levels are not properly managed, according to a new study.

Researchers found that patients who had low times in therapeutic range were significantly more likely to develop renal dysfunction and experience renal failure.

Furthermore, all patients were at risk of developing renal dysfunction, whether they began the study with healthy kidney function or moderate to severe kidney disease.

T. Jared Bunch, MD, of Intermountain Medical Center Heart Institute in Salt Lake City, Utah, and his colleagues presented these findings during the Heart Rhythm Society’s 37th Annual Scientific Sessions (abstract PO02-210).

The researchers studied 2753 AF patients who were anticoagulated with warfarin and managed by Intermountain Healthcare Clinical Pharmacist Anticoagulation Services.

The patients’ mean age was 74.7±10.7, and 50.3% were male. The patients had a baseline creatinine level of less than 2.0 mg/dL or a glomerular filtration rate greater than 30 and serial renal function studies.

Dr Bunch and his colleagues stratified patients into 4 categories based on the amount of time their international normalized ratio levels were determined to be in the therapeutic range (TTR): >75%, 51% to 75%, 26% to 50%, and <25%.

The researchers then performed multivariate, adjusted analyses to calculate odds ratios (ORs) for renal dysfunction and hazard ratios (HRs) for renal failure based on TTR group. The >75% group was the reference.

Among patients with baseline creatinine ≤2.0 mg/dL, the OR for a 25% increase in creatinine was:

• 1.35 for the 51%-75% TTR group (P=0.06)
• 1.80 for the 26-50% TTR group (P=0.003)
• 2.34 for the ≤25% TTR group (P=0.003).

Among patients with baseline creatinine ≤2.0 mg/dL, the HR for renal failure was:

• 1.72 for the 51%-75% TTR group (P=0.001)
• 2.36 for the 26-50% TTR group (P<0.0001)
• 2.38 for the ≤25% TTR group (P<0.0001).

Among patients with baseline glomerular filtration rate >30, the OR for a 25% decrease in glomerular filtration rate was:

• 1.45 for the 51%-75% TTR group (P=0.03)
• 1.46 for the 26-50% TTR group (P=0.08)
• 1.52 for the ≤25% TTR group (P=0.20).

Among patients with a baseline glomerular filtration rate >30, the HR for renal failure was:

• 1.88 for the 51%-75% TTR group (P<0.0001)
• 2.40 for the 26-50% TTR group (P<0.0001)
• 2.60 for the ≤25% TTR group (P<0.0001).

The researchers said these results suggest the quality of anticoagulation management is associated with renal dysfunction and failure, so improving anticoagulation control might improve the long-term risk of end-organ injury in AF patients.

“Patients who use warfarin as part of their anticoagulation treatment for atrial fibrillation should have their anticoagulation levels closely monitored to ensure proper levels,” Dr Bunch said.

“Those who have erratic levels of warfarin despite close monitoring and care should consider other approaches such as newer anticoagulants that have more predictable blood effects, even if they have moderate kidney disease, and non drug-based methods to lower clot risk with atrial fibrillation.”

Warfarin tablets

SAN FRANCISCO—Patients with atrial fibrillation (AF) who are taking warfarin have a higher risk of kidney problems if their anticoagulation levels are not properly managed, according to a new study.

Researchers found that patients who had low times in therapeutic range were significantly more likely to develop renal dysfunction and experience renal failure.

Furthermore, all patients were at risk of developing renal dysfunction, whether they began the study with healthy kidney function or moderate to severe kidney disease.

T. Jared Bunch, MD, of Intermountain Medical Center Heart Institute in Salt Lake City, Utah, and his colleagues presented these findings during the Heart Rhythm Society’s 37th Annual Scientific Sessions (abstract PO02-210).

The researchers studied 2753 AF patients who were anticoagulated with warfarin and managed by Intermountain Healthcare Clinical Pharmacist Anticoagulation Services.

The patients’ mean age was 74.7±10.7, and 50.3% were male. The patients had a baseline creatinine level of less than 2.0 mg/dL or a glomerular filtration rate greater than 30 and serial renal function studies.

Dr Bunch and his colleagues stratified patients into 4 categories based on the amount of time their international normalized ratio levels were determined to be in the therapeutic range (TTR): >75%, 51% to 75%, 26% to 50%, and <25%.

The researchers then performed multivariate, adjusted analyses to calculate odds ratios (ORs) for renal dysfunction and hazard ratios (HRs) for renal failure based on TTR group. The >75% group was the reference.

Among patients with baseline creatinine ≤2.0 mg/dL, the OR for a 25% increase in creatinine was:

• 1.35 for the 51%-75% TTR group (P=0.06)
• 1.80 for the 26-50% TTR group (P=0.003)
• 2.34 for the ≤25% TTR group (P=0.003).

Among patients with baseline creatinine ≤2.0 mg/dL, the HR for renal failure was:

• 1.72 for the 51%-75% TTR group (P=0.001)
• 2.36 for the 26-50% TTR group (P<0.0001)
• 2.38 for the ≤25% TTR group (P<0.0001).

Among patients with baseline glomerular filtration rate >30, the OR for a 25% decrease in glomerular filtration rate was:

• 1.45 for the 51%-75% TTR group (P=0.03)
• 1.46 for the 26-50% TTR group (P=0.08)
• 1.52 for the ≤25% TTR group (P=0.20).

Among patients with a baseline glomerular filtration rate >30, the HR for renal failure was:

• 1.88 for the 51%-75% TTR group (P<0.0001)
• 2.40 for the 26-50% TTR group (P<0.0001)
• 2.60 for the ≤25% TTR group (P<0.0001).

The researchers said these results suggest the quality of anticoagulation management is associated with renal dysfunction and failure, so improving anticoagulation control might improve the long-term risk of end-organ injury in AF patients.

“Patients who use warfarin as part of their anticoagulation treatment for atrial fibrillation should have their anticoagulation levels closely monitored to ensure proper levels,” Dr Bunch said.

“Those who have erratic levels of warfarin despite close monitoring and care should consider other approaches such as newer anticoagulants that have more predictable blood effects, even if they have moderate kidney disease, and non drug-based methods to lower clot risk with atrial fibrillation.”

Thrombus

Image by Andre E.X. Brown

Results of a meta-analysis suggest elastic compression stockings do not significantly reduce the risk of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT).

Investigators analyzed more than 600 past reports and studies involving elastic compression stockings, including the SOX trial.

And the results showed no significant difference in PTS incidence between patients who wore these stockings and those who did not.

Riyaz Bashir, MD, of Temple University Hospital in Philadelphia, Pennsylvania, and his colleagues performed the analysis and reported the results in The Lancet Haematology.

The investigators analyzed 674 reports, which included 6 randomized trials and a total of 1462 patients. The patients’ mean age was 59.5, and 56% were men.

All of the studies used stockings with a pressure range of 20 mm Hg to 40 mm Hg. Patient compliance varied from 55.6% to 91.6% and often decreased during follow-up. In most of the studies, the control group did not wear stockings, but, in 2 studies, the control group wore placebo stockings.

The data showed that use of elastic compression stockings was not associated with PTS prevention. The incidence of PTS was 36% (269/739) among patients who wore the stockings and 45% (322/723) among controls. The odds ratio (OR) was 0.56 (P=0.12).

The investigators observed similar results in subgroup analyses, when they tried to account for patient heterogeneity (27% vs 37%, OR=0.63, P=0.23) or diagnosis by Villalta scoring (43% vs 45%, OR=0.81, P=0.62) and when they looked at patients randomized within 1 month of DVT diagnosis (41% vs 49%, OR=0.57, P=0.24).

Furthermore, there was no significant difference between the treatment groups with regard to mortality or DVT recurrence.

The mortality incidence was 10% in both groups (OR 0.98, P=0.92), while the incidence of DVT recurrence was 6.4% in the compression stocking group and 6.8% in controls (OR=0.93, P=0.69).

“Many questions remain, such as whether certain groups of patients—like females or elderly patients—benefit from [compression stockings] or whether the timing of the intervention would make a difference,” Dr Bashir said.

“Based on the results of our study, we believe it’s too early to recommend that physicians stop using compression stockings and therefore should not give up on this modality of treatment yet. This study also highlights that there is a real need for new and more effective therapies for the treatment and prevention of post-thrombotic syndrome.”

Thrombus

Image by Andre E.X. Brown

Results of a meta-analysis suggest elastic compression stockings do not significantly reduce the risk of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT).

Investigators analyzed more than 600 past reports and studies involving elastic compression stockings, including the SOX trial.

And the results showed no significant difference in PTS incidence between patients who wore these stockings and those who did not.

Riyaz Bashir, MD, of Temple University Hospital in Philadelphia, Pennsylvania, and his colleagues performed the analysis and reported the results in The Lancet Haematology.

The investigators analyzed 674 reports, which included 6 randomized trials and a total of 1462 patients. The patients’ mean age was 59.5, and 56% were men.

All of the studies used stockings with a pressure range of 20 mm Hg to 40 mm Hg. Patient compliance varied from 55.6% to 91.6% and often decreased during follow-up. In most of the studies, the control group did not wear stockings, but, in 2 studies, the control group wore placebo stockings.

The data showed that use of elastic compression stockings was not associated with PTS prevention. The incidence of PTS was 36% (269/739) among patients who wore the stockings and 45% (322/723) among controls. The odds ratio (OR) was 0.56 (P=0.12).

The investigators observed similar results in subgroup analyses, when they tried to account for patient heterogeneity (27% vs 37%, OR=0.63, P=0.23) or diagnosis by Villalta scoring (43% vs 45%, OR=0.81, P=0.62) and when they looked at patients randomized within 1 month of DVT diagnosis (41% vs 49%, OR=0.57, P=0.24).

Furthermore, there was no significant difference between the treatment groups with regard to mortality or DVT recurrence.

The mortality incidence was 10% in both groups (OR 0.98, P=0.92), while the incidence of DVT recurrence was 6.4% in the compression stocking group and 6.8% in controls (OR=0.93, P=0.69).

“Many questions remain, such as whether certain groups of patients—like females or elderly patients—benefit from [compression stockings] or whether the timing of the intervention would make a difference,” Dr Bashir said.

“Based on the results of our study, we believe it’s too early to recommend that physicians stop using compression stockings and therefore should not give up on this modality of treatment yet. This study also highlights that there is a real need for new and more effective therapies for the treatment and prevention of post-thrombotic syndrome.”

Thrombus

Image by Andre E.X. Brown

Results of a meta-analysis suggest elastic compression stockings do not significantly reduce the risk of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT).

Investigators analyzed more than 600 past reports and studies involving elastic compression stockings, including the SOX trial.

And the results showed no significant difference in PTS incidence between patients who wore these stockings and those who did not.

Riyaz Bashir, MD, of Temple University Hospital in Philadelphia, Pennsylvania, and his colleagues performed the analysis and reported the results in The Lancet Haematology.

The investigators analyzed 674 reports, which included 6 randomized trials and a total of 1462 patients. The patients’ mean age was 59.5, and 56% were men.

All of the studies used stockings with a pressure range of 20 mm Hg to 40 mm Hg. Patient compliance varied from 55.6% to 91.6% and often decreased during follow-up. In most of the studies, the control group did not wear stockings, but, in 2 studies, the control group wore placebo stockings.

The data showed that use of elastic compression stockings was not associated with PTS prevention. The incidence of PTS was 36% (269/739) among patients who wore the stockings and 45% (322/723) among controls. The odds ratio (OR) was 0.56 (P=0.12).

The investigators observed similar results in subgroup analyses, when they tried to account for patient heterogeneity (27% vs 37%, OR=0.63, P=0.23) or diagnosis by Villalta scoring (43% vs 45%, OR=0.81, P=0.62) and when they looked at patients randomized within 1 month of DVT diagnosis (41% vs 49%, OR=0.57, P=0.24).

Furthermore, there was no significant difference between the treatment groups with regard to mortality or DVT recurrence.

The mortality incidence was 10% in both groups (OR 0.98, P=0.92), while the incidence of DVT recurrence was 6.4% in the compression stocking group and 6.8% in controls (OR=0.93, P=0.69).

“Many questions remain, such as whether certain groups of patients—like females or elderly patients—benefit from [compression stockings] or whether the timing of the intervention would make a difference,” Dr Bashir said.

“Based on the results of our study, we believe it’s too early to recommend that physicians stop using compression stockings and therefore should not give up on this modality of treatment yet. This study also highlights that there is a real need for new and more effective therapies for the treatment and prevention of post-thrombotic syndrome.”

Doctor evaluating patient

Photo courtesy of the CDC

WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.

The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.

It includes 2 types of forms—a transition-readiness assessment and a clinical summary.

The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.

“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.

“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”

ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.

An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:

• generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
• specific forms for hemophilia
• specific forms for sickle cell disease.

For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.

The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.

This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.

The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.

More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.

Doctor evaluating patient

Photo courtesy of the CDC

WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.

The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.

It includes 2 types of forms—a transition-readiness assessment and a clinical summary.

The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.

“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.

“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”

ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.

An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:

• generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
• specific forms for hemophilia
• specific forms for sickle cell disease.

For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.

The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.

This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.

The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.

More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.

Doctor evaluating patient

Photo courtesy of the CDC

WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.

The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.

It includes 2 types of forms—a transition-readiness assessment and a clinical summary.

The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.

“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.

“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”

ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.

An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:

• generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
• specific forms for hemophilia
• specific forms for sickle cell disease.

For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.

The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.

This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.

The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.

More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.

Bone marrow

Image by Daniel E. Sabath

Engineered bone marrow grown in a microfluidic chip device mimics living bone marrow, according to research published in Tissue Engineering.

Experiments showed the engineered bone marrow responded in a way similar to living bone marrow when exposed to damaging radiation followed by treatment with compounds that aid in blood cell recovery.

The researchers said this new bone marrow-on-a-chip device holds promise for testing and developing improved radiation countermeasures.

Yu-suke Torisawa, PhD, of Kyoto University in Japan, and his colleagues conducted this research.

The team used a tissue engineering approach to induce formation of new marrow-containing bone in mice. They then surgically removed the bone, placed it in a microfluidic device, and continuously perfused it with medium in vitro.

Next, the researchers set out to determine if the device would keep the engineered bone marrow alive so they could perform tests on it.

To test the system, the team analyzed the dynamics of blood cell production and evaluated the radiation-protecting effects of granulocyte-colony stimulating factor (G-CSF) and bactericidal/permeability-increasing protein (BPI).

Experiments showed the microfluidic device could maintain hematopoietic stem and progenitor cells in normal proportions for at least 2 weeks in culture.

Over time, the researchers observed increases in the number of leukocytes and red blood cells in the microfluidic circulation. And they found that adding erythropoietin induced a significant increase in erythrocyte production.

When the researchers exposed the engineered bone marrow to gamma radiation, they saw reduced leukocyte production.

And when they treated the engineered bone marrow with G-CSF or BPI, the team saw significant increases in the number of hematopoietic stem cells and myeloid cells in the fluidic outflow.

On the other hand, BPI did not have such an effect on static bone marrow cultures. But the researchers pointed out that previous work has shown BPI can accelerate recovery from radiation-induced toxicity in vivo.

The team therefore concluded that, unlike static bone marrow cultures, engineered bone marrow grown in a microfluidic device effectively mimics the recovery response of bone marrow in the body.

Bone marrow

Image by Daniel E. Sabath

Engineered bone marrow grown in a microfluidic chip device mimics living bone marrow, according to research published in Tissue Engineering.

Experiments showed the engineered bone marrow responded in a way similar to living bone marrow when exposed to damaging radiation followed by treatment with compounds that aid in blood cell recovery.

The researchers said this new bone marrow-on-a-chip device holds promise for testing and developing improved radiation countermeasures.

Yu-suke Torisawa, PhD, of Kyoto University in Japan, and his colleagues conducted this research.

The team used a tissue engineering approach to induce formation of new marrow-containing bone in mice. They then surgically removed the bone, placed it in a microfluidic device, and continuously perfused it with medium in vitro.

Next, the researchers set out to determine if the device would keep the engineered bone marrow alive so they could perform tests on it.

To test the system, the team analyzed the dynamics of blood cell production and evaluated the radiation-protecting effects of granulocyte-colony stimulating factor (G-CSF) and bactericidal/permeability-increasing protein (BPI).

Experiments showed the microfluidic device could maintain hematopoietic stem and progenitor cells in normal proportions for at least 2 weeks in culture.

Over time, the researchers observed increases in the number of leukocytes and red blood cells in the microfluidic circulation. And they found that adding erythropoietin induced a significant increase in erythrocyte production.

When the researchers exposed the engineered bone marrow to gamma radiation, they saw reduced leukocyte production.

And when they treated the engineered bone marrow with G-CSF or BPI, the team saw significant increases in the number of hematopoietic stem cells and myeloid cells in the fluidic outflow.

On the other hand, BPI did not have such an effect on static bone marrow cultures. But the researchers pointed out that previous work has shown BPI can accelerate recovery from radiation-induced toxicity in vivo.

The team therefore concluded that, unlike static bone marrow cultures, engineered bone marrow grown in a microfluidic device effectively mimics the recovery response of bone marrow in the body.

Bone marrow

Image by Daniel E. Sabath

Engineered bone marrow grown in a microfluidic chip device mimics living bone marrow, according to research published in Tissue Engineering.

Experiments showed the engineered bone marrow responded in a way similar to living bone marrow when exposed to damaging radiation followed by treatment with compounds that aid in blood cell recovery.

The researchers said this new bone marrow-on-a-chip device holds promise for testing and developing improved radiation countermeasures.

Yu-suke Torisawa, PhD, of Kyoto University in Japan, and his colleagues conducted this research.

The team used a tissue engineering approach to induce formation of new marrow-containing bone in mice. They then surgically removed the bone, placed it in a microfluidic device, and continuously perfused it with medium in vitro.

Next, the researchers set out to determine if the device would keep the engineered bone marrow alive so they could perform tests on it.

To test the system, the team analyzed the dynamics of blood cell production and evaluated the radiation-protecting effects of granulocyte-colony stimulating factor (G-CSF) and bactericidal/permeability-increasing protein (BPI).

Experiments showed the microfluidic device could maintain hematopoietic stem and progenitor cells in normal proportions for at least 2 weeks in culture.

Over time, the researchers observed increases in the number of leukocytes and red blood cells in the microfluidic circulation. And they found that adding erythropoietin induced a significant increase in erythrocyte production.

When the researchers exposed the engineered bone marrow to gamma radiation, they saw reduced leukocyte production.

And when they treated the engineered bone marrow with G-CSF or BPI, the team saw significant increases in the number of hematopoietic stem cells and myeloid cells in the fluidic outflow.

On the other hand, BPI did not have such an effect on static bone marrow cultures. But the researchers pointed out that previous work has shown BPI can accelerate recovery from radiation-induced toxicity in vivo.

The team therefore concluded that, unlike static bone marrow cultures, engineered bone marrow grown in a microfluidic device effectively mimics the recovery response of bone marrow in the body.

US dollars

Photo by Petr Kratochvil

Providing patients with a tool that enabled them to search for healthcare prices did not decrease their spending, according to a study published in JAMA.

Researchers studied the Truven Health Analytics Treatment Cost Calculator, an online price transparency tool that tells users how much they would pay out of pocket for services such as X-rays, lab tests, outpatient surgeries, or physician office visits at different sites.

The out-of-pocket cost estimates are based on the users’ health plan benefits and on how much they have already spent on healthcare during the year.

Two large national companies offered this tool to their employees in 2011 and 2012.

The researchers compared the healthcare spending patterns of employees (n=148,655) at these companies in the year before and after the tool was introduced with patterns among employees (n=295,983) of other companies that did not offer the tool.

Overall, having access to the tool was not associated with a reduction in outpatient spending, and subjects did not switch from more expensive outpatient hospital-based care to lower-cost settings.

The average outpatient spending among employees offered the tool was $2021 in the year before the tool was introduced and $2233 in the year after. Among control subjects, average outpatient spending increased from $1985 to $2138.

The average outpatient out-of-pocket spending among employees offered the tool was $507 in the year before it was introduced and $555 in the year after. In the control group, the average outpatient out-of-pocket spending increased from $490 to $520.

After the researchers adjusted for demographic and health characteristics, being offered the tool was associated with an average $59 increase in outpatient spending and an average $18 increase in out-of-pocket spending.

When the researchers looked only at patients with higher deductibles—who would be expected to have greater price-shopping incentives—they also found no evidence of reduction in spending.

“Despite large variation in healthcare prices, prevalence of high-deductible health plans, and widespread interest in price transparency, we did not find evidence that offering price transparency to employees generated savings,” said study author Sunita Desai, PhD, of Harvard Medical School in Boston, Massachusetts.

A possible explanation for this finding is that most patients did not actually use the tool. Only 10% of the employees who were offered the tool used it at least once in the first 12 months.

When patients did use the tool, more than half the searches were for relatively expensive services of over $1000.

“For expensive care that exceeds their deductible, patients may not see any reason to switch,” said study author Ateev Mehrotra, MD, also of Harvard Medical School. “They do not save by choosing a lower-cost provider, even if the health plan does.”

Still, the researchers said the tool does provide patients with valuable information, including their expected out-of-pocket costs, their deductible, and their health plan’s provider network.

“People might use the tools more—and focus more on choosing lower-priced care options—if they are combined with additional health plan benefit features that give greater incentive to price shop,” Dr Desai said.

US dollars

Photo by Petr Kratochvil

Providing patients with a tool that enabled them to search for healthcare prices did not decrease their spending, according to a study published in JAMA.

Researchers studied the Truven Health Analytics Treatment Cost Calculator, an online price transparency tool that tells users how much they would pay out of pocket for services such as X-rays, lab tests, outpatient surgeries, or physician office visits at different sites.

The out-of-pocket cost estimates are based on the users’ health plan benefits and on how much they have already spent on healthcare during the year.

Two large national companies offered this tool to their employees in 2011 and 2012.

The researchers compared the healthcare spending patterns of employees (n=148,655) at these companies in the year before and after the tool was introduced with patterns among employees (n=295,983) of other companies that did not offer the tool.

Overall, having access to the tool was not associated with a reduction in outpatient spending, and subjects did not switch from more expensive outpatient hospital-based care to lower-cost settings.

The average outpatient spending among employees offered the tool was $2021 in the year before the tool was introduced and $2233 in the year after. Among control subjects, average outpatient spending increased from $1985 to $2138.

The average outpatient out-of-pocket spending among employees offered the tool was $507 in the year before it was introduced and $555 in the year after. In the control group, the average outpatient out-of-pocket spending increased from $490 to $520.

After the researchers adjusted for demographic and health characteristics, being offered the tool was associated with an average $59 increase in outpatient spending and an average $18 increase in out-of-pocket spending.

When the researchers looked only at patients with higher deductibles—who would be expected to have greater price-shopping incentives—they also found no evidence of reduction in spending.

“Despite large variation in healthcare prices, prevalence of high-deductible health plans, and widespread interest in price transparency, we did not find evidence that offering price transparency to employees generated savings,” said study author Sunita Desai, PhD, of Harvard Medical School in Boston, Massachusetts.

A possible explanation for this finding is that most patients did not actually use the tool. Only 10% of the employees who were offered the tool used it at least once in the first 12 months.

When patients did use the tool, more than half the searches were for relatively expensive services of over $1000.

“For expensive care that exceeds their deductible, patients may not see any reason to switch,” said study author Ateev Mehrotra, MD, also of Harvard Medical School. “They do not save by choosing a lower-cost provider, even if the health plan does.”

Still, the researchers said the tool does provide patients with valuable information, including their expected out-of-pocket costs, their deductible, and their health plan’s provider network.

“People might use the tools more—and focus more on choosing lower-priced care options—if they are combined with additional health plan benefit features that give greater incentive to price shop,” Dr Desai said.

US dollars

Photo by Petr Kratochvil

Providing patients with a tool that enabled them to search for healthcare prices did not decrease their spending, according to a study published in JAMA.

Researchers studied the Truven Health Analytics Treatment Cost Calculator, an online price transparency tool that tells users how much they would pay out of pocket for services such as X-rays, lab tests, outpatient surgeries, or physician office visits at different sites.

The out-of-pocket cost estimates are based on the users’ health plan benefits and on how much they have already spent on healthcare during the year.

Two large national companies offered this tool to their employees in 2011 and 2012.

The researchers compared the healthcare spending patterns of employees (n=148,655) at these companies in the year before and after the tool was introduced with patterns among employees (n=295,983) of other companies that did not offer the tool.

Overall, having access to the tool was not associated with a reduction in outpatient spending, and subjects did not switch from more expensive outpatient hospital-based care to lower-cost settings.

The average outpatient spending among employees offered the tool was $2021 in the year before the tool was introduced and $2233 in the year after. Among control subjects, average outpatient spending increased from $1985 to $2138.

The average outpatient out-of-pocket spending among employees offered the tool was $507 in the year before it was introduced and $555 in the year after. In the control group, the average outpatient out-of-pocket spending increased from $490 to $520.

After the researchers adjusted for demographic and health characteristics, being offered the tool was associated with an average $59 increase in outpatient spending and an average $18 increase in out-of-pocket spending.

When the researchers looked only at patients with higher deductibles—who would be expected to have greater price-shopping incentives—they also found no evidence of reduction in spending.

“Despite large variation in healthcare prices, prevalence of high-deductible health plans, and widespread interest in price transparency, we did not find evidence that offering price transparency to employees generated savings,” said study author Sunita Desai, PhD, of Harvard Medical School in Boston, Massachusetts.

A possible explanation for this finding is that most patients did not actually use the tool. Only 10% of the employees who were offered the tool used it at least once in the first 12 months.

When patients did use the tool, more than half the searches were for relatively expensive services of over $1000.

“For expensive care that exceeds their deductible, patients may not see any reason to switch,” said study author Ateev Mehrotra, MD, also of Harvard Medical School. “They do not save by choosing a lower-cost provider, even if the health plan does.”

Still, the researchers said the tool does provide patients with valuable information, including their expected out-of-pocket costs, their deductible, and their health plan’s provider network.

“People might use the tools more—and focus more on choosing lower-priced care options—if they are combined with additional health plan benefit features that give greater incentive to price shop,” Dr Desai said.

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application for blinatumomab (Blincyto) as a treatment for pediatric and adolescent patients with Philadelphia chromosome negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.

The priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.

The Prescription Drug User Fee Act target action date for the supplemental biologics license application for blinatumomab is September 1, 2016.

About blinatumomab

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

Blinatumomab was previously granted breakthrough therapy and priority review designations by the FDA and is now approved in the US for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Blinatumomab is marketed by Amgen as Blincyto. The full US prescribing information is available at www.BLINCYTO.com.

‘205 trial

The supplemental biologics license application for blinatumomab in pediatric and adolescent patients is based on data from the phase 1/2 '205 trial.

In this study, researchers evaluated blinatumomab in patients younger than 18 years of age. The patients had B-cell precursor ALL that was refractory, had relapsed at least twice, or relapsed after an allogeneic hematopoietic stem cell transplant.

Treatment in this study has been completed, and subjects are being monitored for long-term efficacy. The data is being submitted for publication.

Preliminary data were presented at the 2014 ASH Annual Meeting (abstract 3703).

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application for blinatumomab (Blincyto) as a treatment for pediatric and adolescent patients with Philadelphia chromosome negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.

The priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.

The Prescription Drug User Fee Act target action date for the supplemental biologics license application for blinatumomab is September 1, 2016.

About blinatumomab

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

Blinatumomab was previously granted breakthrough therapy and priority review designations by the FDA and is now approved in the US for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Blinatumomab is marketed by Amgen as Blincyto. The full US prescribing information is available at www.BLINCYTO.com.

‘205 trial

The supplemental biologics license application for blinatumomab in pediatric and adolescent patients is based on data from the phase 1/2 '205 trial.

In this study, researchers evaluated blinatumomab in patients younger than 18 years of age. The patients had B-cell precursor ALL that was refractory, had relapsed at least twice, or relapsed after an allogeneic hematopoietic stem cell transplant.

Treatment in this study has been completed, and subjects are being monitored for long-term efficacy. The data is being submitted for publication.

Preliminary data were presented at the 2014 ASH Annual Meeting (abstract 3703).

Vials of blinatumomab powder

and solution for infusion

Photo courtesy of Amgen

The US Food and Drug Administration (FDA) has accepted for priority review the supplemental biologics license application for blinatumomab (Blincyto) as a treatment for pediatric and adolescent patients with Philadelphia chromosome negative (Ph-) relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL).

To grant an application priority review, the FDA must believe the drug would provide a significant improvement in the treatment, diagnosis, or prevention of a serious condition.

The priority review designation means the FDA’s goal is to take action on an application within 6 months, rather than the 10 months typically taken for a standard review.

The Prescription Drug User Fee Act target action date for the supplemental biologics license application for blinatumomab is September 1, 2016.

About blinatumomab

Blinatumomab is a bispecific, CD19-directed, CD3 T-cell engager (BiTE®) antibody construct that binds specifically to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T cells.

Blinatumomab was previously granted breakthrough therapy and priority review designations by the FDA and is now approved in the US for the treatment of adults with Ph- relapsed or refractory B-cell precursor ALL.

This indication is approved under accelerated approval. Continued approval for this indication may be contingent upon verification of clinical benefit in subsequent trials.

Blinatumomab is marketed by Amgen as Blincyto. The full US prescribing information is available at www.BLINCYTO.com.

‘205 trial

The supplemental biologics license application for blinatumomab in pediatric and adolescent patients is based on data from the phase 1/2 '205 trial.

In this study, researchers evaluated blinatumomab in patients younger than 18 years of age. The patients had B-cell precursor ALL that was refractory, had relapsed at least twice, or relapsed after an allogeneic hematopoietic stem cell transplant.

Treatment in this study has been completed, and subjects are being monitored for long-term efficacy. The data is being submitted for publication.

Preliminary data were presented at the 2014 ASH Annual Meeting (abstract 3703).

Fitness class

Women with poor physical fitness may have an increased risk of thrombotic events due to increased platelet activation, according to research published in Medicine & Science in Sports & Exercise.

In a study of 62 young women, those with poor cardiorespiratory fitness (CRF) had significantly higher platelet activation than women with average to very good CRF.

However, the study also showed that women with poor CRF were able to achieve normal platelet function by increasing their physical fitness.

The women achieved platelet normalization via endurance training—running for a maximum of 40 minutes—3 times a week over a 2-month period.

“Latently activated platelets release a number of mediators that can encourage the development of atherosclerotic vascular changes,” said study author Stefan Heber, of the Medical University of Vienna in Austria.

“If poor physical fitness is accompanied by a higher level of platelet activation, one can conclude that it also has an influence upon the early stages of this pathogenesis. The training effects we’ve found here are consistent with epidemiological data, according to which fit people have an approximately 40% lower risk of cardiovascular events than those who were physically inactive.”

To uncover their findings, Heber and his colleagues analyzed different aspects of platelet function in healthy, non-smoking women with low CRF, medium CRF, and high CRF.

The team assessed CRF using maximal oxygen consumption (VO₂max), which was determined by an incremental treadmill exercise test. VO₂max criteria were:

• less than 45 ml/min/kg bodyweight for the low CRF group
• 45 to 55 ml/min/kg bodyweight for the medium CRF group
• more than 55 ml/min/kg bodyweight for the high CRF group.

The researchers assessed platelet activation state and platelet reactivity in these groups of women by evaluating basal and agonist-induced surface expression of CD62P and CD40L, as well as the intraplatelet amount of reactive oxygen species.

The team observed higher basal platelet activation and agonist-induced platelet reactivity in the low CRF group, when compared to the medium and high CRF groups. However, platelet activation and reactivity were roughly the same in the medium and high CRF groups.

For the low CRF group, the researchers assessed platelet function again after the women completed a supervised endurance training program that lasted 2 menstrual cycles. The team found this program was able to normalize platelet function.

Fitness class

Women with poor physical fitness may have an increased risk of thrombotic events due to increased platelet activation, according to research published in Medicine & Science in Sports & Exercise.

In a study of 62 young women, those with poor cardiorespiratory fitness (CRF) had significantly higher platelet activation than women with average to very good CRF.

However, the study also showed that women with poor CRF were able to achieve normal platelet function by increasing their physical fitness.

The women achieved platelet normalization via endurance training—running for a maximum of 40 minutes—3 times a week over a 2-month period.

“Latently activated platelets release a number of mediators that can encourage the development of atherosclerotic vascular changes,” said study author Stefan Heber, of the Medical University of Vienna in Austria.

“If poor physical fitness is accompanied by a higher level of platelet activation, one can conclude that it also has an influence upon the early stages of this pathogenesis. The training effects we’ve found here are consistent with epidemiological data, according to which fit people have an approximately 40% lower risk of cardiovascular events than those who were physically inactive.”

To uncover their findings, Heber and his colleagues analyzed different aspects of platelet function in healthy, non-smoking women with low CRF, medium CRF, and high CRF.

The team assessed CRF using maximal oxygen consumption (VO₂max), which was determined by an incremental treadmill exercise test. VO₂max criteria were:

• less than 45 ml/min/kg bodyweight for the low CRF group
• 45 to 55 ml/min/kg bodyweight for the medium CRF group
• more than 55 ml/min/kg bodyweight for the high CRF group.

The researchers assessed platelet activation state and platelet reactivity in these groups of women by evaluating basal and agonist-induced surface expression of CD62P and CD40L, as well as the intraplatelet amount of reactive oxygen species.

The team observed higher basal platelet activation and agonist-induced platelet reactivity in the low CRF group, when compared to the medium and high CRF groups. However, platelet activation and reactivity were roughly the same in the medium and high CRF groups.

For the low CRF group, the researchers assessed platelet function again after the women completed a supervised endurance training program that lasted 2 menstrual cycles. The team found this program was able to normalize platelet function.

Fitness class

Women with poor physical fitness may have an increased risk of thrombotic events due to increased platelet activation, according to research published in Medicine & Science in Sports & Exercise.

In a study of 62 young women, those with poor cardiorespiratory fitness (CRF) had significantly higher platelet activation than women with average to very good CRF.

However, the study also showed that women with poor CRF were able to achieve normal platelet function by increasing their physical fitness.

The women achieved platelet normalization via endurance training—running for a maximum of 40 minutes—3 times a week over a 2-month period.

“Latently activated platelets release a number of mediators that can encourage the development of atherosclerotic vascular changes,” said study author Stefan Heber, of the Medical University of Vienna in Austria.

“If poor physical fitness is accompanied by a higher level of platelet activation, one can conclude that it also has an influence upon the early stages of this pathogenesis. The training effects we’ve found here are consistent with epidemiological data, according to which fit people have an approximately 40% lower risk of cardiovascular events than those who were physically inactive.”

To uncover their findings, Heber and his colleagues analyzed different aspects of platelet function in healthy, non-smoking women with low CRF, medium CRF, and high CRF.

The team assessed CRF using maximal oxygen consumption (VO₂max), which was determined by an incremental treadmill exercise test. VO₂max criteria were:

• less than 45 ml/min/kg bodyweight for the low CRF group
• 45 to 55 ml/min/kg bodyweight for the medium CRF group
• more than 55 ml/min/kg bodyweight for the high CRF group.

The researchers assessed platelet activation state and platelet reactivity in these groups of women by evaluating basal and agonist-induced surface expression of CD62P and CD40L, as well as the intraplatelet amount of reactive oxygen species.

The team observed higher basal platelet activation and agonist-induced platelet reactivity in the low CRF group, when compared to the medium and high CRF groups. However, platelet activation and reactivity were roughly the same in the medium and high CRF groups.

For the low CRF group, the researchers assessed platelet function again after the women completed a supervised endurance training program that lasted 2 menstrual cycles. The team found this program was able to normalize platelet function.

Hagop Kantarjian, MD

Photo from MD Anderson

Data from two phase 2 studies suggests single-agent blinatumomab produces similar outcomes in adults with relapsed/refractory acute lymphoblastic leukemia (ALL), regardless of age.

Patients age 65 and older had similar hematologic response rates and relapse-free survival rates as patients younger than 65.

The incidence of grade 3 or higher adverse events (AEs) was similar between the age groups as well.

Older patients did have more serious AEs, however. And they had more neurologic events, but these were reversible.

Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in Cancer. The research was funded by Amgen Inc., makers of blinatumomab.

Patients

The researchers examined 261 adults with relapsed/refractory ALL who were enrolled in 2 different studies. There were 36 patients who were 65 or older and 225 patients who were younger than 65. The median ages were 70 (range, 65-79) and 34 (range, 18-64), respectively.

Among the older patients, 14% had primary refractory disease, 67% had 1 prior relapse, 14% had 2 prior relapses, and 6% had 3 or more. Among the younger patients, 9% had primary refractory disease, 55% had 1 prior relapse, 26% had 2 prior relapses, and 10% had 3 or more.

The younger patients were more likely to have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) than the older patients—37% and 11%, respectively.

But older patients were more likely to have mild renal impairment (42% vs 13%) or moderate renal impairment (22% vs 1%).

Treatment

All patients received blinatumomab, and stepwise dosing was used to reduce the risk of cytokine release syndrome. A treatment cycle consisted of 4 weeks of continuous intravenous infusions, followed by a 2-week treatment-free interval.

The patients received 2 initial cycles. If they achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) at this point, they could receive an additional 3 cycles as consolidation, unless they were scheduled to receive an allo-HSCT.

Patients also received intrathecal prophylaxis with dexamethasone and/or steroids, cytarabine, and methotrexate. And patients with a high blast percentage at baseline received a pre-phase treatment with dexamethasone and/or cyclophosphamide.

Older patients received a median of 2 cycles of blinatumomab (range, 1-6), as did the younger patients (range, 1-7).

Response and survival

Fifty-six percent of the older patients (20/36) achieved a CR/CRh during the first 2 cycles of blinatumomab, as did 46% of the younger patients (46/225). There were 14 CRs among the older patients (39%) and 78 CRs among the younger patients (35%).

There were 12 complete minimal residual disease responses among older patients (60% of responders) and 73 among the younger patients (70% of responders).

Of the responders, 3 older patients (15%) and 61 younger patients (59%) went on to allo-HSCT. Most of the patients received a transplant while in remission. However, 1 of the older patients and 8 of the younger patients went to transplant after an initial response to blinatumomab that was followed by a relapse.

The median relapse-free survival was 7.4 months for both age groups. The median overall survival was 5.5 months for older patients and 7.6 months for younger patients.

Safety

All of the older patients had at least 1 AE, and all but 1 of the younger patients had at least 1 AE. Older patients had higher rates of peripheral edema (42% vs 24%), fatigue (28% vs 18%), and dizziness (25% vs 11%) of any grade.

The incidence of grade 3 or higher AEs was similar between the groups—86% in the older group and 80% in the younger group. The same was true for AEs leading to treatment discontinuation—22% and 19%, respectively.

However, there was a higher incidence of serious AEs in the older patients (72% vs 64%). Device-related infection and encephalopathy were more common among older patients than younger patients (both 11% vs 3%).

The incidence of cytokine release syndrome was higher in the older group than the younger group—19% and 10%, respectively.

Older patients also had more neurologic events of any grade (72% vs 48%) and more grade 3 or higher neurologic events (28% vs 13%). However, all neurologic events were reversed by temporarily or permanently discontinuing blinatumomab.

There were 7 fatal treatment-emergent AEs in the older adults, including pneumonia (n=3), B-cell lymphoma (n=1), and disease progression (n=3). None of the fatal AEs were considered treatment-related. And none of the patients who were in remission died during treatment with blinatumomab.

Hagop Kantarjian, MD

Photo from MD Anderson

Data from two phase 2 studies suggests single-agent blinatumomab produces similar outcomes in adults with relapsed/refractory acute lymphoblastic leukemia (ALL), regardless of age.

Patients age 65 and older had similar hematologic response rates and relapse-free survival rates as patients younger than 65.

The incidence of grade 3 or higher adverse events (AEs) was similar between the age groups as well.

Older patients did have more serious AEs, however. And they had more neurologic events, but these were reversible.

Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in Cancer. The research was funded by Amgen Inc., makers of blinatumomab.

Patients

The researchers examined 261 adults with relapsed/refractory ALL who were enrolled in 2 different studies. There were 36 patients who were 65 or older and 225 patients who were younger than 65. The median ages were 70 (range, 65-79) and 34 (range, 18-64), respectively.

Among the older patients, 14% had primary refractory disease, 67% had 1 prior relapse, 14% had 2 prior relapses, and 6% had 3 or more. Among the younger patients, 9% had primary refractory disease, 55% had 1 prior relapse, 26% had 2 prior relapses, and 10% had 3 or more.

The younger patients were more likely to have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) than the older patients—37% and 11%, respectively.

But older patients were more likely to have mild renal impairment (42% vs 13%) or moderate renal impairment (22% vs 1%).

Treatment

All patients received blinatumomab, and stepwise dosing was used to reduce the risk of cytokine release syndrome. A treatment cycle consisted of 4 weeks of continuous intravenous infusions, followed by a 2-week treatment-free interval.

The patients received 2 initial cycles. If they achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) at this point, they could receive an additional 3 cycles as consolidation, unless they were scheduled to receive an allo-HSCT.

Patients also received intrathecal prophylaxis with dexamethasone and/or steroids, cytarabine, and methotrexate. And patients with a high blast percentage at baseline received a pre-phase treatment with dexamethasone and/or cyclophosphamide.

Older patients received a median of 2 cycles of blinatumomab (range, 1-6), as did the younger patients (range, 1-7).

Response and survival

Fifty-six percent of the older patients (20/36) achieved a CR/CRh during the first 2 cycles of blinatumomab, as did 46% of the younger patients (46/225). There were 14 CRs among the older patients (39%) and 78 CRs among the younger patients (35%).

There were 12 complete minimal residual disease responses among older patients (60% of responders) and 73 among the younger patients (70% of responders).

Of the responders, 3 older patients (15%) and 61 younger patients (59%) went on to allo-HSCT. Most of the patients received a transplant while in remission. However, 1 of the older patients and 8 of the younger patients went to transplant after an initial response to blinatumomab that was followed by a relapse.

The median relapse-free survival was 7.4 months for both age groups. The median overall survival was 5.5 months for older patients and 7.6 months for younger patients.

Safety

All of the older patients had at least 1 AE, and all but 1 of the younger patients had at least 1 AE. Older patients had higher rates of peripheral edema (42% vs 24%), fatigue (28% vs 18%), and dizziness (25% vs 11%) of any grade.

The incidence of grade 3 or higher AEs was similar between the groups—86% in the older group and 80% in the younger group. The same was true for AEs leading to treatment discontinuation—22% and 19%, respectively.

However, there was a higher incidence of serious AEs in the older patients (72% vs 64%). Device-related infection and encephalopathy were more common among older patients than younger patients (both 11% vs 3%).

The incidence of cytokine release syndrome was higher in the older group than the younger group—19% and 10%, respectively.

Older patients also had more neurologic events of any grade (72% vs 48%) and more grade 3 or higher neurologic events (28% vs 13%). However, all neurologic events were reversed by temporarily or permanently discontinuing blinatumomab.

There were 7 fatal treatment-emergent AEs in the older adults, including pneumonia (n=3), B-cell lymphoma (n=1), and disease progression (n=3). None of the fatal AEs were considered treatment-related. And none of the patients who were in remission died during treatment with blinatumomab.

Hagop Kantarjian, MD

Photo from MD Anderson

Data from two phase 2 studies suggests single-agent blinatumomab produces similar outcomes in adults with relapsed/refractory acute lymphoblastic leukemia (ALL), regardless of age.

Patients age 65 and older had similar hematologic response rates and relapse-free survival rates as patients younger than 65.

The incidence of grade 3 or higher adverse events (AEs) was similar between the age groups as well.

Older patients did have more serious AEs, however. And they had more neurologic events, but these were reversible.

Hagop M. Kantarjian, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues reported these results in Cancer. The research was funded by Amgen Inc., makers of blinatumomab.

Patients

The researchers examined 261 adults with relapsed/refractory ALL who were enrolled in 2 different studies. There were 36 patients who were 65 or older and 225 patients who were younger than 65. The median ages were 70 (range, 65-79) and 34 (range, 18-64), respectively.

Among the older patients, 14% had primary refractory disease, 67% had 1 prior relapse, 14% had 2 prior relapses, and 6% had 3 or more. Among the younger patients, 9% had primary refractory disease, 55% had 1 prior relapse, 26% had 2 prior relapses, and 10% had 3 or more.

The younger patients were more likely to have received an allogeneic hematopoietic stem cell transplant (allo-HSCT) than the older patients—37% and 11%, respectively.

But older patients were more likely to have mild renal impairment (42% vs 13%) or moderate renal impairment (22% vs 1%).

Treatment

All patients received blinatumomab, and stepwise dosing was used to reduce the risk of cytokine release syndrome. A treatment cycle consisted of 4 weeks of continuous intravenous infusions, followed by a 2-week treatment-free interval.

The patients received 2 initial cycles. If they achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) at this point, they could receive an additional 3 cycles as consolidation, unless they were scheduled to receive an allo-HSCT.

Patients also received intrathecal prophylaxis with dexamethasone and/or steroids, cytarabine, and methotrexate. And patients with a high blast percentage at baseline received a pre-phase treatment with dexamethasone and/or cyclophosphamide.

Older patients received a median of 2 cycles of blinatumomab (range, 1-6), as did the younger patients (range, 1-7).

Response and survival

Fifty-six percent of the older patients (20/36) achieved a CR/CRh during the first 2 cycles of blinatumomab, as did 46% of the younger patients (46/225). There were 14 CRs among the older patients (39%) and 78 CRs among the younger patients (35%).

There were 12 complete minimal residual disease responses among older patients (60% of responders) and 73 among the younger patients (70% of responders).

Of the responders, 3 older patients (15%) and 61 younger patients (59%) went on to allo-HSCT. Most of the patients received a transplant while in remission. However, 1 of the older patients and 8 of the younger patients went to transplant after an initial response to blinatumomab that was followed by a relapse.

The median relapse-free survival was 7.4 months for both age groups. The median overall survival was 5.5 months for older patients and 7.6 months for younger patients.

Safety

All of the older patients had at least 1 AE, and all but 1 of the younger patients had at least 1 AE. Older patients had higher rates of peripheral edema (42% vs 24%), fatigue (28% vs 18%), and dizziness (25% vs 11%) of any grade.

The incidence of grade 3 or higher AEs was similar between the groups—86% in the older group and 80% in the younger group. The same was true for AEs leading to treatment discontinuation—22% and 19%, respectively.

However, there was a higher incidence of serious AEs in the older patients (72% vs 64%). Device-related infection and encephalopathy were more common among older patients than younger patients (both 11% vs 3%).

The incidence of cytokine release syndrome was higher in the older group than the younger group—19% and 10%, respectively.

Older patients also had more neurologic events of any grade (72% vs 48%) and more grade 3 or higher neurologic events (28% vs 13%). However, all neurologic events were reversed by temporarily or permanently discontinuing blinatumomab.

There were 7 fatal treatment-emergent AEs in the older adults, including pneumonia (n=3), B-cell lymphoma (n=1), and disease progression (n=3). None of the fatal AEs were considered treatment-related. And none of the patients who were in remission died during treatment with blinatumomab.

Cells undergoing autophagy

Image by Sarah Pfau

Research published in Cell has revealed a new function of genes in the Fanconi anemia (FA) pathway, and investigators believe this finding could have

implications for the treatment of FA and related disorders.

The team found that FA genes are required for selective autophagy.

In particular, the FANCC gene plays a key role in 2 types of selective autophagy: virophagy (the removal of viruses inside the cell) and mitophagy (the removal of mitochondria).

Experiments in mice showed that genetic deletion of FANCC blocks virophagy and increases the animals’ susceptibility to lethal viral encephalitis.

The investigators also found that FANCC protein is required for the clearance of damaged mitochondria and decreases the production of mitochondrial reactive oxygen species and inflammasome activation.

And other genes in the FA pathway are required for mitophagy as well—FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2.

“There’s increasing evidence that the failure of cells to appropriately clear damaged mitochondria leads to abnormal activation of the inflammasome—a process that is emerging as an important contributor to many different diseases,” said study author Beth Levine, MD, of UT Southwestern Medical Center in Dallas, Texas.

“The finding that FA genes function in clearing mitochondria and decreasing inflammasome activation provides a potential new inflammasome-targeted avenue of therapy for patients with diseases related to mutations in the FA genes.”

FA pathway genes were already known to play a role in DNA repair. The investigators said this new link to autophagy opens up unexplored horizons for understanding the function of these genes in human health and disease.

“Our findings suggest a novel mechanism by which mutations in FA genes may lead to the clinical manifestations in patients with FA and to cancers in patients with mutations in FA genes,” said study author Rhea Sumpter, MD, PhD, of UT Southwestern Medical Center.

“We’ve shown that this new function of the FA genes in the selective autophagy pathways does not depend on their role in DNA repair.”

In addition, the autophagy function may partly explain why patients with FA are highly susceptible to infection and cancer, Dr Levine said.

While further research is needed to understand how these findings may be used to treat disease, the investigators said they have identified a novel avenue for developing potential therapies for FA and cancer patients.

“I believe the clearest therapeutic possibilities to come from our study results are the development of new FA agents that target the inflammasome and production of interleukin 1 beta (IL-1β), a pro-inflammatory cytokine,” Dr Sumpter said.

“Clinically, IL-1β signaling has been targeted with FDA-approved drugs very successfully in several auto-inflammatory diseases that involve excessive inflammasome activation. Our results suggest that FA patients may also benefit from these therapies.”

Cells undergoing autophagy

Image by Sarah Pfau

Research published in Cell has revealed a new function of genes in the Fanconi anemia (FA) pathway, and investigators believe this finding could have

implications for the treatment of FA and related disorders.

The team found that FA genes are required for selective autophagy.

In particular, the FANCC gene plays a key role in 2 types of selective autophagy: virophagy (the removal of viruses inside the cell) and mitophagy (the removal of mitochondria).

Experiments in mice showed that genetic deletion of FANCC blocks virophagy and increases the animals’ susceptibility to lethal viral encephalitis.

The investigators also found that FANCC protein is required for the clearance of damaged mitochondria and decreases the production of mitochondrial reactive oxygen species and inflammasome activation.

And other genes in the FA pathway are required for mitophagy as well—FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2.

“There’s increasing evidence that the failure of cells to appropriately clear damaged mitochondria leads to abnormal activation of the inflammasome—a process that is emerging as an important contributor to many different diseases,” said study author Beth Levine, MD, of UT Southwestern Medical Center in Dallas, Texas.

“The finding that FA genes function in clearing mitochondria and decreasing inflammasome activation provides a potential new inflammasome-targeted avenue of therapy for patients with diseases related to mutations in the FA genes.”

FA pathway genes were already known to play a role in DNA repair. The investigators said this new link to autophagy opens up unexplored horizons for understanding the function of these genes in human health and disease.

“Our findings suggest a novel mechanism by which mutations in FA genes may lead to the clinical manifestations in patients with FA and to cancers in patients with mutations in FA genes,” said study author Rhea Sumpter, MD, PhD, of UT Southwestern Medical Center.

“We’ve shown that this new function of the FA genes in the selective autophagy pathways does not depend on their role in DNA repair.”

In addition, the autophagy function may partly explain why patients with FA are highly susceptible to infection and cancer, Dr Levine said.

While further research is needed to understand how these findings may be used to treat disease, the investigators said they have identified a novel avenue for developing potential therapies for FA and cancer patients.

“I believe the clearest therapeutic possibilities to come from our study results are the development of new FA agents that target the inflammasome and production of interleukin 1 beta (IL-1β), a pro-inflammatory cytokine,” Dr Sumpter said.

“Clinically, IL-1β signaling has been targeted with FDA-approved drugs very successfully in several auto-inflammatory diseases that involve excessive inflammasome activation. Our results suggest that FA patients may also benefit from these therapies.”

Cells undergoing autophagy

Image by Sarah Pfau

Research published in Cell has revealed a new function of genes in the Fanconi anemia (FA) pathway, and investigators believe this finding could have

implications for the treatment of FA and related disorders.

The team found that FA genes are required for selective autophagy.

In particular, the FANCC gene plays a key role in 2 types of selective autophagy: virophagy (the removal of viruses inside the cell) and mitophagy (the removal of mitochondria).

Experiments in mice showed that genetic deletion of FANCC blocks virophagy and increases the animals’ susceptibility to lethal viral encephalitis.

The investigators also found that FANCC protein is required for the clearance of damaged mitochondria and decreases the production of mitochondrial reactive oxygen species and inflammasome activation.

And other genes in the FA pathway are required for mitophagy as well—FANCA, FANCF, FANCL, FANCD2, BRCA1, and BRCA2.

“There’s increasing evidence that the failure of cells to appropriately clear damaged mitochondria leads to abnormal activation of the inflammasome—a process that is emerging as an important contributor to many different diseases,” said study author Beth Levine, MD, of UT Southwestern Medical Center in Dallas, Texas.

“The finding that FA genes function in clearing mitochondria and decreasing inflammasome activation provides a potential new inflammasome-targeted avenue of therapy for patients with diseases related to mutations in the FA genes.”

FA pathway genes were already known to play a role in DNA repair. The investigators said this new link to autophagy opens up unexplored horizons for understanding the function of these genes in human health and disease.

“Our findings suggest a novel mechanism by which mutations in FA genes may lead to the clinical manifestations in patients with FA and to cancers in patients with mutations in FA genes,” said study author Rhea Sumpter, MD, PhD, of UT Southwestern Medical Center.

“We’ve shown that this new function of the FA genes in the selective autophagy pathways does not depend on their role in DNA repair.”

In addition, the autophagy function may partly explain why patients with FA are highly susceptible to infection and cancer, Dr Levine said.

While further research is needed to understand how these findings may be used to treat disease, the investigators said they have identified a novel avenue for developing potential therapies for FA and cancer patients.

“I believe the clearest therapeutic possibilities to come from our study results are the development of new FA agents that target the inflammasome and production of interleukin 1 beta (IL-1β), a pro-inflammatory cytokine,” Dr Sumpter said.

“Clinically, IL-1β signaling has been targeted with FDA-approved drugs very successfully in several auto-inflammatory diseases that involve excessive inflammasome activation. Our results suggest that FA patients may also benefit from these therapies.”

One doctor examines a patient

while another looks on

Photo courtesy of NCI

In recent years, medical errors may have become one of the top causes of death in the US, according to a study published in The BMJ.

Investigators analyzed medical death rate data over an 8-year period and calculated that more than 250,000 deaths per year may be due to medical error.

That figure surpasses the US Centers for Disease Control and Prevention’s (CDC) third leading cause of death—respiratory disease, which kills close to 150,000 people per year.

The investigators said the CDC’s way of collecting national health statistics fails to classify medical errors separately on the death certificate. So the team is advocating for updated criteria for classifying deaths.

“Incidence rates for deaths directly attributable to medical care gone awry haven’t been recognized in any standardized method for collecting national statistics,” said study author Martin Makary, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“The medical coding system was designed to maximize billing for physician services, not to collect national health statistics, as it is currently being used.”

Dr Makary noted that, in 1949, the US adopted an international form that used International Classification of Diseases (ICD) billing codes to tally causes of death.

“At that time, it was under-recognized that diagnostic errors, medical mistakes, and the absence of safety nets could result in someone’s death, and because of that, medical errors were unintentionally excluded from national health statistics,” Dr Makary said.

He pointed out that, since that time, national mortality statistics have been tabulated using billing codes, which don’t have a built-in way to recognize incidence rates of mortality due to medical care gone wrong.

For the current study, Dr Makary and Michael Daniel, also of Johns Hopkins, examined 4 separate studies that analyzed medical death rate data from 2000 to 2008.

Then, using hospital admission rates from 2013, the investigators extrapolated that, based on a total of 35,416,020 hospitalizations, 251,454 deaths stemmed from medical error. This translates to 9.5% of all deaths each year in the US.

According to the CDC, in 2013, 611,105 people died of heart disease, 584,881 died of cancer, and 149,205 died of chronic respiratory disease.

These were the top 3 causes of death in the US. The newly calculated figure for medical errors puts this cause of death behind cancer but ahead of respiratory disease.

“Top-ranked causes of death as reported by the CDC inform our country’s research funding and public health priorities,” Dr Makary said. “Right now, cancer and heart disease get a ton of attention, but since medical errors don’t appear on the list, the problem doesn’t get the funding and attention it deserves.”

The investigators said most medical errors aren’t due to inherently bad doctors, and reporting these errors shouldn’t be addressed by punishment or legal action.

Rather, the pair believes that most errors represent systemic problems, including poorly coordinated care, fragmented insurance networks, the absence or underuse of safety nets, and other protocols, in addition to unwarranted variation in physician practice patterns that lack accountability.

“Unwarranted variation is endemic in healthcare,” Dr Makary said. “Developing consensus protocols that streamline the delivery of medicine and reduce variability can improve quality and lower costs in healthcare. More research on preventing medical errors from occurring is needed to address the problem.”

One doctor examines a patient

while another looks on

Photo courtesy of NCI

In recent years, medical errors may have become one of the top causes of death in the US, according to a study published in The BMJ.

Investigators analyzed medical death rate data over an 8-year period and calculated that more than 250,000 deaths per year may be due to medical error.

That figure surpasses the US Centers for Disease Control and Prevention’s (CDC) third leading cause of death—respiratory disease, which kills close to 150,000 people per year.

The investigators said the CDC’s way of collecting national health statistics fails to classify medical errors separately on the death certificate. So the team is advocating for updated criteria for classifying deaths.

“Incidence rates for deaths directly attributable to medical care gone awry haven’t been recognized in any standardized method for collecting national statistics,” said study author Martin Makary, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“The medical coding system was designed to maximize billing for physician services, not to collect national health statistics, as it is currently being used.”

Dr Makary noted that, in 1949, the US adopted an international form that used International Classification of Diseases (ICD) billing codes to tally causes of death.

“At that time, it was under-recognized that diagnostic errors, medical mistakes, and the absence of safety nets could result in someone’s death, and because of that, medical errors were unintentionally excluded from national health statistics,” Dr Makary said.

He pointed out that, since that time, national mortality statistics have been tabulated using billing codes, which don’t have a built-in way to recognize incidence rates of mortality due to medical care gone wrong.

For the current study, Dr Makary and Michael Daniel, also of Johns Hopkins, examined 4 separate studies that analyzed medical death rate data from 2000 to 2008.

Then, using hospital admission rates from 2013, the investigators extrapolated that, based on a total of 35,416,020 hospitalizations, 251,454 deaths stemmed from medical error. This translates to 9.5% of all deaths each year in the US.

According to the CDC, in 2013, 611,105 people died of heart disease, 584,881 died of cancer, and 149,205 died of chronic respiratory disease.

These were the top 3 causes of death in the US. The newly calculated figure for medical errors puts this cause of death behind cancer but ahead of respiratory disease.

“Top-ranked causes of death as reported by the CDC inform our country’s research funding and public health priorities,” Dr Makary said. “Right now, cancer and heart disease get a ton of attention, but since medical errors don’t appear on the list, the problem doesn’t get the funding and attention it deserves.”

The investigators said most medical errors aren’t due to inherently bad doctors, and reporting these errors shouldn’t be addressed by punishment or legal action.

Rather, the pair believes that most errors represent systemic problems, including poorly coordinated care, fragmented insurance networks, the absence or underuse of safety nets, and other protocols, in addition to unwarranted variation in physician practice patterns that lack accountability.

“Unwarranted variation is endemic in healthcare,” Dr Makary said. “Developing consensus protocols that streamline the delivery of medicine and reduce variability can improve quality and lower costs in healthcare. More research on preventing medical errors from occurring is needed to address the problem.”

One doctor examines a patient

while another looks on

Photo courtesy of NCI

In recent years, medical errors may have become one of the top causes of death in the US, according to a study published in The BMJ.

Investigators analyzed medical death rate data over an 8-year period and calculated that more than 250,000 deaths per year may be due to medical error.

That figure surpasses the US Centers for Disease Control and Prevention’s (CDC) third leading cause of death—respiratory disease, which kills close to 150,000 people per year.

The investigators said the CDC’s way of collecting national health statistics fails to classify medical errors separately on the death certificate. So the team is advocating for updated criteria for classifying deaths.

“Incidence rates for deaths directly attributable to medical care gone awry haven’t been recognized in any standardized method for collecting national statistics,” said study author Martin Makary, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“The medical coding system was designed to maximize billing for physician services, not to collect national health statistics, as it is currently being used.”

Dr Makary noted that, in 1949, the US adopted an international form that used International Classification of Diseases (ICD) billing codes to tally causes of death.

“At that time, it was under-recognized that diagnostic errors, medical mistakes, and the absence of safety nets could result in someone’s death, and because of that, medical errors were unintentionally excluded from national health statistics,” Dr Makary said.

He pointed out that, since that time, national mortality statistics have been tabulated using billing codes, which don’t have a built-in way to recognize incidence rates of mortality due to medical care gone wrong.

For the current study, Dr Makary and Michael Daniel, also of Johns Hopkins, examined 4 separate studies that analyzed medical death rate data from 2000 to 2008.

Then, using hospital admission rates from 2013, the investigators extrapolated that, based on a total of 35,416,020 hospitalizations, 251,454 deaths stemmed from medical error. This translates to 9.5% of all deaths each year in the US.

According to the CDC, in 2013, 611,105 people died of heart disease, 584,881 died of cancer, and 149,205 died of chronic respiratory disease.

These were the top 3 causes of death in the US. The newly calculated figure for medical errors puts this cause of death behind cancer but ahead of respiratory disease.

“Top-ranked causes of death as reported by the CDC inform our country’s research funding and public health priorities,” Dr Makary said. “Right now, cancer and heart disease get a ton of attention, but since medical errors don’t appear on the list, the problem doesn’t get the funding and attention it deserves.”

The investigators said most medical errors aren’t due to inherently bad doctors, and reporting these errors shouldn’t be addressed by punishment or legal action.

Rather, the pair believes that most errors represent systemic problems, including poorly coordinated care, fragmented insurance networks, the absence or underuse of safety nets, and other protocols, in addition to unwarranted variation in physician practice patterns that lack accountability.

“Unwarranted variation is endemic in healthcare,” Dr Makary said. “Developing consensus protocols that streamline the delivery of medicine and reduce variability can improve quality and lower costs in healthcare. More research on preventing medical errors from occurring is needed to address the problem.”