Sepsis may have an Achilles heel that would allow for more effective treatment of the condition, according to research published in The FASEB Journal.

The study showed that CD39, an enzyme capable of clearing high levels of adenosine triphosphate (ATP) from the bloodstream, significantly improved survival of mice with severe sepsis.

Based on this finding, the researchers speculate that CD39 may also be used in other diseases associated with inflammation.

“Although we have come a long way in the treatment of sepsis since it was first described by Hippocrates in the fourth century BC, about 250,000 Americans still die from sepsis each year,” said study author Gyorgy Hasko, PhD, of Rutgers New Jersey Medical School in Newark.

“A drug that could cure patients with sepsis would not only save the lives of many, it would also decrease the enormous costs associated with treating septic patients in the intensive care unit and would help unburden the healthcare system.”

To make their discovery, Dr Hasko and his colleagues compared mice lacking the CD39 gene to wild-type mice. When sepsis was induced in both sets of mice, those without CD39 had worse survival.

With this information in hand, the researchers then performed another experiment with two more groups of normal mice that were septic.

The first group was injected with CD39 and the other with placebo. The mice that received CD39 had improved survival compared to those injected with placebo.

“Finding a more effective treatment for sepsis would be a major step forward since far too many people still die from overwhelming microbial infection,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “If CD39 proves to be as critical a factor in humans as in mice, this is a major discovery.”

Sepsis may have an Achilles heel that would allow for more effective treatment of the condition, according to research published in The FASEB Journal.

The study showed that CD39, an enzyme capable of clearing high levels of adenosine triphosphate (ATP) from the bloodstream, significantly improved survival of mice with severe sepsis.

Based on this finding, the researchers speculate that CD39 may also be used in other diseases associated with inflammation.

“Although we have come a long way in the treatment of sepsis since it was first described by Hippocrates in the fourth century BC, about 250,000 Americans still die from sepsis each year,” said study author Gyorgy Hasko, PhD, of Rutgers New Jersey Medical School in Newark.

“A drug that could cure patients with sepsis would not only save the lives of many, it would also decrease the enormous costs associated with treating septic patients in the intensive care unit and would help unburden the healthcare system.”

To make their discovery, Dr Hasko and his colleagues compared mice lacking the CD39 gene to wild-type mice. When sepsis was induced in both sets of mice, those without CD39 had worse survival.

With this information in hand, the researchers then performed another experiment with two more groups of normal mice that were septic.

The first group was injected with CD39 and the other with placebo. The mice that received CD39 had improved survival compared to those injected with placebo.

“Finding a more effective treatment for sepsis would be a major step forward since far too many people still die from overwhelming microbial infection,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “If CD39 proves to be as critical a factor in humans as in mice, this is a major discovery.”

Sepsis may have an Achilles heel that would allow for more effective treatment of the condition, according to research published in The FASEB Journal.

The study showed that CD39, an enzyme capable of clearing high levels of adenosine triphosphate (ATP) from the bloodstream, significantly improved survival of mice with severe sepsis.

Based on this finding, the researchers speculate that CD39 may also be used in other diseases associated with inflammation.

“Although we have come a long way in the treatment of sepsis since it was first described by Hippocrates in the fourth century BC, about 250,000 Americans still die from sepsis each year,” said study author Gyorgy Hasko, PhD, of Rutgers New Jersey Medical School in Newark.

“A drug that could cure patients with sepsis would not only save the lives of many, it would also decrease the enormous costs associated with treating septic patients in the intensive care unit and would help unburden the healthcare system.”

To make their discovery, Dr Hasko and his colleagues compared mice lacking the CD39 gene to wild-type mice. When sepsis was induced in both sets of mice, those without CD39 had worse survival.

With this information in hand, the researchers then performed another experiment with two more groups of normal mice that were septic.

The first group was injected with CD39 and the other with placebo. The mice that received CD39 had improved survival compared to those injected with placebo.

“Finding a more effective treatment for sepsis would be a major step forward since far too many people still die from overwhelming microbial infection,” said Gerald Weissmann, MD, Editor-in-Chief of The FASEB Journal. “If CD39 proves to be as critical a factor in humans as in mice, this is a major discovery.”

The process of pathogen inactivation does not compromise the quality of red blood cells (RBCs), results of a phase 3 study suggest.

Researchers compared untreated RBCs and RBCs treated with the INTERCEPT Blood System, a pathogen inactivation system.

The two sets of RBCs, which were given to cardiovascular surgery patients with acute anemia, had comparable hemoglobin content and in vitro quality, according to Cerus Corporation, makers of the INTERCEPT system.

Cerus recently announced these results, and the researchers plan to submit data from this study for presentation at upcoming scientific congresses.

“In our prior US phase 3 study in a similar patient population, INTERCEPT red cells were shown to be noninferior to control red cells in 148 patients based on a composite endpoint of myocardial infarction, renal failure, and death,” said Laurence Corash, MD, Cerus’s chief medical officer.

“The data from the recent phase 3 study met the European criteria for red blood cell components for transfusion and demonstrated sufficient hemoglobin content and in vitro quality compared to untreated red cells. We believe that the successful results from this study, combined with data from the prior phase 3 study, support the safety and efficacy of the INTERCEPT RBC system for CE Mark registration.”

In the current trial, researchers evaluated the efficacy of the INTERCEPT system to process RBCs with quality and mean hemoglobin content (> 40 g) suitable to support transfusion according to the European Directorate for the Quality of Medicines.

The blood components were transfused in 51 cardiovascular surgery patients at 2 German trial sites. Patients undergoing procedures for coronary artery bypass grafting, valve repair, or combined procedures received transfusions during a 7-day treatment period that included the day of surgery and 6 days post-operatively.

The patients received either INTERCEPT-treated RBCs or control RBCs not treated for pathogen inactivation. RBC components for both clinical sites were manufactured at the German Red Cross blood center in Frankfurt, and the RBCs were stored for up to 35 days prior to transfusion.

The primary endpoint was the equivalence of mean hemoglobin content between INTERCEPT-treated RBCs and conventional RBCs. The mean hemoglobin content of INTERCEPT-treated RBCs on day 35 of storage (53.1 g) fell within the protocol-specified 5g equivalence margin, when compared to control RBCs (55.8 g).

The secondary efficacy endpoints also suggested INTERCEPT-treated RBCs were suitable for transfusion based on mean hematocrit of 60.4% (acceptance range: 55%-70%) and mean end-of-storage hemolysis rate of 0.28% (acceptance range < 0.8%).

There were no statistical differences in the adverse event rates between recipients of INTERCEPT-treated RBCs and control RBCs. There were no clinically relevant trends in severe or serious treatment-related adverse events by system organ class.

The observed adverse events were within the expected spectrum of comorbidity and mortality for patients of similar age and with advanced cardiovascular diseases undergoing cardiovascular surgery requiring RBC transfusion. And none of the patients exhibited an immune response to INTERCEPT-treated RBCs.

The process of pathogen inactivation does not compromise the quality of red blood cells (RBCs), results of a phase 3 study suggest.

Researchers compared untreated RBCs and RBCs treated with the INTERCEPT Blood System, a pathogen inactivation system.

The two sets of RBCs, which were given to cardiovascular surgery patients with acute anemia, had comparable hemoglobin content and in vitro quality, according to Cerus Corporation, makers of the INTERCEPT system.

Cerus recently announced these results, and the researchers plan to submit data from this study for presentation at upcoming scientific congresses.

“In our prior US phase 3 study in a similar patient population, INTERCEPT red cells were shown to be noninferior to control red cells in 148 patients based on a composite endpoint of myocardial infarction, renal failure, and death,” said Laurence Corash, MD, Cerus’s chief medical officer.

“The data from the recent phase 3 study met the European criteria for red blood cell components for transfusion and demonstrated sufficient hemoglobin content and in vitro quality compared to untreated red cells. We believe that the successful results from this study, combined with data from the prior phase 3 study, support the safety and efficacy of the INTERCEPT RBC system for CE Mark registration.”

In the current trial, researchers evaluated the efficacy of the INTERCEPT system to process RBCs with quality and mean hemoglobin content (> 40 g) suitable to support transfusion according to the European Directorate for the Quality of Medicines.

The blood components were transfused in 51 cardiovascular surgery patients at 2 German trial sites. Patients undergoing procedures for coronary artery bypass grafting, valve repair, or combined procedures received transfusions during a 7-day treatment period that included the day of surgery and 6 days post-operatively.

The patients received either INTERCEPT-treated RBCs or control RBCs not treated for pathogen inactivation. RBC components for both clinical sites were manufactured at the German Red Cross blood center in Frankfurt, and the RBCs were stored for up to 35 days prior to transfusion.

The primary endpoint was the equivalence of mean hemoglobin content between INTERCEPT-treated RBCs and conventional RBCs. The mean hemoglobin content of INTERCEPT-treated RBCs on day 35 of storage (53.1 g) fell within the protocol-specified 5g equivalence margin, when compared to control RBCs (55.8 g).

The secondary efficacy endpoints also suggested INTERCEPT-treated RBCs were suitable for transfusion based on mean hematocrit of 60.4% (acceptance range: 55%-70%) and mean end-of-storage hemolysis rate of 0.28% (acceptance range < 0.8%).

There were no statistical differences in the adverse event rates between recipients of INTERCEPT-treated RBCs and control RBCs. There were no clinically relevant trends in severe or serious treatment-related adverse events by system organ class.

The observed adverse events were within the expected spectrum of comorbidity and mortality for patients of similar age and with advanced cardiovascular diseases undergoing cardiovascular surgery requiring RBC transfusion. And none of the patients exhibited an immune response to INTERCEPT-treated RBCs.

The process of pathogen inactivation does not compromise the quality of red blood cells (RBCs), results of a phase 3 study suggest.

Researchers compared untreated RBCs and RBCs treated with the INTERCEPT Blood System, a pathogen inactivation system.

The two sets of RBCs, which were given to cardiovascular surgery patients with acute anemia, had comparable hemoglobin content and in vitro quality, according to Cerus Corporation, makers of the INTERCEPT system.

Cerus recently announced these results, and the researchers plan to submit data from this study for presentation at upcoming scientific congresses.

“In our prior US phase 3 study in a similar patient population, INTERCEPT red cells were shown to be noninferior to control red cells in 148 patients based on a composite endpoint of myocardial infarction, renal failure, and death,” said Laurence Corash, MD, Cerus’s chief medical officer.

“The data from the recent phase 3 study met the European criteria for red blood cell components for transfusion and demonstrated sufficient hemoglobin content and in vitro quality compared to untreated red cells. We believe that the successful results from this study, combined with data from the prior phase 3 study, support the safety and efficacy of the INTERCEPT RBC system for CE Mark registration.”

In the current trial, researchers evaluated the efficacy of the INTERCEPT system to process RBCs with quality and mean hemoglobin content (> 40 g) suitable to support transfusion according to the European Directorate for the Quality of Medicines.

The blood components were transfused in 51 cardiovascular surgery patients at 2 German trial sites. Patients undergoing procedures for coronary artery bypass grafting, valve repair, or combined procedures received transfusions during a 7-day treatment period that included the day of surgery and 6 days post-operatively.

The patients received either INTERCEPT-treated RBCs or control RBCs not treated for pathogen inactivation. RBC components for both clinical sites were manufactured at the German Red Cross blood center in Frankfurt, and the RBCs were stored for up to 35 days prior to transfusion.

The primary endpoint was the equivalence of mean hemoglobin content between INTERCEPT-treated RBCs and conventional RBCs. The mean hemoglobin content of INTERCEPT-treated RBCs on day 35 of storage (53.1 g) fell within the protocol-specified 5g equivalence margin, when compared to control RBCs (55.8 g).

The secondary efficacy endpoints also suggested INTERCEPT-treated RBCs were suitable for transfusion based on mean hematocrit of 60.4% (acceptance range: 55%-70%) and mean end-of-storage hemolysis rate of 0.28% (acceptance range < 0.8%).

There were no statistical differences in the adverse event rates between recipients of INTERCEPT-treated RBCs and control RBCs. There were no clinically relevant trends in severe or serious treatment-related adverse events by system organ class.

The observed adverse events were within the expected spectrum of comorbidity and mortality for patients of similar age and with advanced cardiovascular diseases undergoing cardiovascular surgery requiring RBC transfusion. And none of the patients exhibited an immune response to INTERCEPT-treated RBCs.

CHICAGO – Patients with atrial fibrillation who frequently have a supratherapeutic international normalized ratio are at sharply increased risk for developing dementia, according to a large observational study.

“We postulate that the mechanism is an accumulation of microbleeds in the brain,” Dr. T. Jared Bunch said at the American Heart Association Scientific Sessions.

“In patients with hypertension, a condition that’s extremely common with atrial fibrillation, these repetitive small bleeds are preferentially in the hippocampus, where memory is stored,” added Dr. Bunch, who is medical director for heart rhythm services at the Intermountain Medical Center Heart Institute in Salt Lake City.

He presented a study of 1,031 patients with atrial fibrillation (AF) in Intermountain’s centralized anticoagulation service. All were on dual therapy with warfarin plus aspirin or, much less commonly, another antiplatelet agent. At baseline, their average age was in the early- to mid-70s, and none of the subjects had a history of stroke or any notes in their medical record suggestive of early cognitive decline. At this dedicated anticoagulation center, their INR was measured on a weekly or biweekly basis, as a result of which their average time spent in the therapeutic range of 2.0-3.0 was relatively high at nearly 70%.

The increased risk of dementia in patients with AF has previously been recognized. The association is stronger in patients under age 75 than in those who are older. But the mechanism has been unknown. Dr. Bunch and coinvestigators decided to test their hypothesis that the mechanism involves microbleeds secondary to long-term overanticoagulation by dividing the patients into three groups based upon their percentage of INR measurements above 3.0 during a mean follow-up of more than 4 and up to a maximum of 10 years: 240 patients had a supratherapeutic INR 25% of the time or more; 374 did so less than 10% of the time; and 417 had an elevated INR 10%-24% of the time.

 

The incidence of dementia diagnosed by a consultant neurologist during follow-up was 5.8% in the group with an INR above 3.0 at least 25% of the time, more than twice the 2.7% rate in patients with a high INR less than 10% of the time. In the middle group, the incidence of dementia was 4.1%. In a multivariate Cox regression analysis, having an INR above 3.0 on at least 25% of occasions was independently associated with a 2.59-fold increased risk of developing dementia, making it by far the most potent risk factor in their analysis.

The next step in their research will be to perform serial brain imaging and volumetric scans, Dr. Bunch said. Also, he and his coworkers are 3 years into an ongoing study looking at the incidence of dementia in AF patients on the various novel oral anticoagulants, where INR is a nonissue. Their hypothesis is the dementia risk will be lower than in patients on warfarin. Dr. Bunch has particularly high hopes for AF patients on apixaban (Eliquis) because it’s known to have a reduced risk of large bleeds, stroke, and GI bleeding; the hope is it will cause fewer cerebral microbleeds as well.

In an interview, the cardiologist said he believes his study showing an increased risk of dementia in AF patients with supratherapeutic INRs on warfarin plus antiplatelet therapy holds several important lessons for AF patients and physicians alike.

For patients, the message is don’t just start taking aspirin on your own because you’ve read it’s good for your heart or may reduce cancer risk; consult your physician.

And for physicians, it’s important to ask all patients on warfarin if they’re using aspirin; many don’t ask. Also, periodically reconsider the need for dual therapy with warfarin and aspirin.

“We find the risks of stroke and bleeding change dynamically over time, so the initial therapy for stroke prevention may not be the ideal therapy after 5-10 years,” Dr. Bunch said.

Lastly, for patients who are overanticoagulated on a substantial percentage of their INR measurements, it’s essential to consider a change in strategy. Either follow their INRs more closely and adjust warfarin dosing accordingly, or switch to one of the novel, more predictable oral anticoagulants, he concluded.

This study was funded internally by Intermountain Healthcare. Dr. Bunch reported having no financial conflicts.

[email protected]

CHICAGO – Patients with atrial fibrillation who frequently have a supratherapeutic international normalized ratio are at sharply increased risk for developing dementia, according to a large observational study.

“We postulate that the mechanism is an accumulation of microbleeds in the brain,” Dr. T. Jared Bunch said at the American Heart Association Scientific Sessions.

“In patients with hypertension, a condition that’s extremely common with atrial fibrillation, these repetitive small bleeds are preferentially in the hippocampus, where memory is stored,” added Dr. Bunch, who is medical director for heart rhythm services at the Intermountain Medical Center Heart Institute in Salt Lake City.

He presented a study of 1,031 patients with atrial fibrillation (AF) in Intermountain’s centralized anticoagulation service. All were on dual therapy with warfarin plus aspirin or, much less commonly, another antiplatelet agent. At baseline, their average age was in the early- to mid-70s, and none of the subjects had a history of stroke or any notes in their medical record suggestive of early cognitive decline. At this dedicated anticoagulation center, their INR was measured on a weekly or biweekly basis, as a result of which their average time spent in the therapeutic range of 2.0-3.0 was relatively high at nearly 70%.

The increased risk of dementia in patients with AF has previously been recognized. The association is stronger in patients under age 75 than in those who are older. But the mechanism has been unknown. Dr. Bunch and coinvestigators decided to test their hypothesis that the mechanism involves microbleeds secondary to long-term overanticoagulation by dividing the patients into three groups based upon their percentage of INR measurements above 3.0 during a mean follow-up of more than 4 and up to a maximum of 10 years: 240 patients had a supratherapeutic INR 25% of the time or more; 374 did so less than 10% of the time; and 417 had an elevated INR 10%-24% of the time.

 

The incidence of dementia diagnosed by a consultant neurologist during follow-up was 5.8% in the group with an INR above 3.0 at least 25% of the time, more than twice the 2.7% rate in patients with a high INR less than 10% of the time. In the middle group, the incidence of dementia was 4.1%. In a multivariate Cox regression analysis, having an INR above 3.0 on at least 25% of occasions was independently associated with a 2.59-fold increased risk of developing dementia, making it by far the most potent risk factor in their analysis.

The next step in their research will be to perform serial brain imaging and volumetric scans, Dr. Bunch said. Also, he and his coworkers are 3 years into an ongoing study looking at the incidence of dementia in AF patients on the various novel oral anticoagulants, where INR is a nonissue. Their hypothesis is the dementia risk will be lower than in patients on warfarin. Dr. Bunch has particularly high hopes for AF patients on apixaban (Eliquis) because it’s known to have a reduced risk of large bleeds, stroke, and GI bleeding; the hope is it will cause fewer cerebral microbleeds as well.

In an interview, the cardiologist said he believes his study showing an increased risk of dementia in AF patients with supratherapeutic INRs on warfarin plus antiplatelet therapy holds several important lessons for AF patients and physicians alike.

For patients, the message is don’t just start taking aspirin on your own because you’ve read it’s good for your heart or may reduce cancer risk; consult your physician.

And for physicians, it’s important to ask all patients on warfarin if they’re using aspirin; many don’t ask. Also, periodically reconsider the need for dual therapy with warfarin and aspirin.

“We find the risks of stroke and bleeding change dynamically over time, so the initial therapy for stroke prevention may not be the ideal therapy after 5-10 years,” Dr. Bunch said.

Lastly, for patients who are overanticoagulated on a substantial percentage of their INR measurements, it’s essential to consider a change in strategy. Either follow their INRs more closely and adjust warfarin dosing accordingly, or switch to one of the novel, more predictable oral anticoagulants, he concluded.

This study was funded internally by Intermountain Healthcare. Dr. Bunch reported having no financial conflicts.

[email protected]

CHICAGO – Patients with atrial fibrillation who frequently have a supratherapeutic international normalized ratio are at sharply increased risk for developing dementia, according to a large observational study.

“We postulate that the mechanism is an accumulation of microbleeds in the brain,” Dr. T. Jared Bunch said at the American Heart Association Scientific Sessions.

“In patients with hypertension, a condition that’s extremely common with atrial fibrillation, these repetitive small bleeds are preferentially in the hippocampus, where memory is stored,” added Dr. Bunch, who is medical director for heart rhythm services at the Intermountain Medical Center Heart Institute in Salt Lake City.

He presented a study of 1,031 patients with atrial fibrillation (AF) in Intermountain’s centralized anticoagulation service. All were on dual therapy with warfarin plus aspirin or, much less commonly, another antiplatelet agent. At baseline, their average age was in the early- to mid-70s, and none of the subjects had a history of stroke or any notes in their medical record suggestive of early cognitive decline. At this dedicated anticoagulation center, their INR was measured on a weekly or biweekly basis, as a result of which their average time spent in the therapeutic range of 2.0-3.0 was relatively high at nearly 70%.

The increased risk of dementia in patients with AF has previously been recognized. The association is stronger in patients under age 75 than in those who are older. But the mechanism has been unknown. Dr. Bunch and coinvestigators decided to test their hypothesis that the mechanism involves microbleeds secondary to long-term overanticoagulation by dividing the patients into three groups based upon their percentage of INR measurements above 3.0 during a mean follow-up of more than 4 and up to a maximum of 10 years: 240 patients had a supratherapeutic INR 25% of the time or more; 374 did so less than 10% of the time; and 417 had an elevated INR 10%-24% of the time.

 

The incidence of dementia diagnosed by a consultant neurologist during follow-up was 5.8% in the group with an INR above 3.0 at least 25% of the time, more than twice the 2.7% rate in patients with a high INR less than 10% of the time. In the middle group, the incidence of dementia was 4.1%. In a multivariate Cox regression analysis, having an INR above 3.0 on at least 25% of occasions was independently associated with a 2.59-fold increased risk of developing dementia, making it by far the most potent risk factor in their analysis.

The next step in their research will be to perform serial brain imaging and volumetric scans, Dr. Bunch said. Also, he and his coworkers are 3 years into an ongoing study looking at the incidence of dementia in AF patients on the various novel oral anticoagulants, where INR is a nonissue. Their hypothesis is the dementia risk will be lower than in patients on warfarin. Dr. Bunch has particularly high hopes for AF patients on apixaban (Eliquis) because it’s known to have a reduced risk of large bleeds, stroke, and GI bleeding; the hope is it will cause fewer cerebral microbleeds as well.

In an interview, the cardiologist said he believes his study showing an increased risk of dementia in AF patients with supratherapeutic INRs on warfarin plus antiplatelet therapy holds several important lessons for AF patients and physicians alike.

For patients, the message is don’t just start taking aspirin on your own because you’ve read it’s good for your heart or may reduce cancer risk; consult your physician.

And for physicians, it’s important to ask all patients on warfarin if they’re using aspirin; many don’t ask. Also, periodically reconsider the need for dual therapy with warfarin and aspirin.

“We find the risks of stroke and bleeding change dynamically over time, so the initial therapy for stroke prevention may not be the ideal therapy after 5-10 years,” Dr. Bunch said.

Lastly, for patients who are overanticoagulated on a substantial percentage of their INR measurements, it’s essential to consider a change in strategy. Either follow their INRs more closely and adjust warfarin dosing accordingly, or switch to one of the novel, more predictable oral anticoagulants, he concluded.

This study was funded internally by Intermountain Healthcare. Dr. Bunch reported having no financial conflicts.

[email protected]

In this podcast, two hospitalists who’ve seen the flip side of their practice as hospital patients talk about their experience as doctor-patients. Dr. Brett Hendel-Paterson of Health Partners Regional in St. Paul  shares how his diagnosis with chronic lymphocytic leukemia has impacted his practice. Dr. Matthew Dudley, a hospitalist with the Alaska Hospitalist Group in Anchorage and a patient with acute myelogenous leukemia, tells how the experience has deepened his conviction in the value of hospitalists.

[audio mp3="http://www.the-hospitalist.org/wp-content/uploads/2015/01/Doctor-As-Patient.mp3"][/audio]

In this podcast, two hospitalists who’ve seen the flip side of their practice as hospital patients talk about their experience as doctor-patients. Dr. Brett Hendel-Paterson of Health Partners Regional in St. Paul  shares how his diagnosis with chronic lymphocytic leukemia has impacted his practice. Dr. Matthew Dudley, a hospitalist with the Alaska Hospitalist Group in Anchorage and a patient with acute myelogenous leukemia, tells how the experience has deepened his conviction in the value of hospitalists.

[audio mp3="http://www.the-hospitalist.org/wp-content/uploads/2015/01/Doctor-As-Patient.mp3"][/audio]

In this podcast, two hospitalists who’ve seen the flip side of their practice as hospital patients talk about their experience as doctor-patients. Dr. Brett Hendel-Paterson of Health Partners Regional in St. Paul  shares how his diagnosis with chronic lymphocytic leukemia has impacted his practice. Dr. Matthew Dudley, a hospitalist with the Alaska Hospitalist Group in Anchorage and a patient with acute myelogenous leukemia, tells how the experience has deepened his conviction in the value of hospitalists.

[audio mp3="http://www.the-hospitalist.org/wp-content/uploads/2015/01/Doctor-As-Patient.mp3"][/audio]

This month in our issue, one of our cover stories looks to answer the question, “Do You Really Need an MBA?” if your career goals include a leadership role. In a news brief, we cover the long-awaited confirmation of Dr. Vivek Murthy to the post of U.S. Surgeon General. We also launch "After Seven," a column profiling hospitalists' hobbies, starting with a feature on part-time robot-builder, Dr. Jim Yeh. Our book review addresses caring for older patients, and we profile the newest member of Team Hospitalist, Dr. Joshua Allen-Dicker. We also feature the latest in clinical literature, and our Key Clinical Question asks who should be tested for HIV in the hospital.

[audio mp3="http://www.the-hospitalist.org/wp-content/uploads/2015/01/2015-January-Highlights.mp3"][/audio]

This month in our issue, one of our cover stories looks to answer the question, “Do You Really Need an MBA?” if your career goals include a leadership role. In a news brief, we cover the long-awaited confirmation of Dr. Vivek Murthy to the post of U.S. Surgeon General. We also launch "After Seven," a column profiling hospitalists' hobbies, starting with a feature on part-time robot-builder, Dr. Jim Yeh. Our book review addresses caring for older patients, and we profile the newest member of Team Hospitalist, Dr. Joshua Allen-Dicker. We also feature the latest in clinical literature, and our Key Clinical Question asks who should be tested for HIV in the hospital.

[audio mp3="http://www.the-hospitalist.org/wp-content/uploads/2015/01/2015-January-Highlights.mp3"][/audio]

This month in our issue, one of our cover stories looks to answer the question, “Do You Really Need an MBA?” if your career goals include a leadership role. In a news brief, we cover the long-awaited confirmation of Dr. Vivek Murthy to the post of U.S. Surgeon General. We also launch "After Seven," a column profiling hospitalists' hobbies, starting with a feature on part-time robot-builder, Dr. Jim Yeh. Our book review addresses caring for older patients, and we profile the newest member of Team Hospitalist, Dr. Joshua Allen-Dicker. We also feature the latest in clinical literature, and our Key Clinical Question asks who should be tested for HIV in the hospital.

[audio mp3="http://www.the-hospitalist.org/wp-content/uploads/2015/01/2015-January-Highlights.mp3"][/audio]

In this podcast, hospitalists discuss why co-management in hospital medicine is still a work in progress. Dr. Bradley Flansbaum, a founding member of SHM and current member of SHM’s Public Policy Committee, says every member of a medical team needs to pull their weight and communicate. Dr. Steven Cohn, Medical Director of the Preoperative Assessment Center at the University of Miami and Director of the Medical Consultation Service at U Miami Hospital, tallies the pluses and minuses of co-management programs, and Dr. Eric Siegel, Director of the Critical Care Service at Aurora Health Care, Aurora St. Luke’s Medical Center in Milwaukee, makes his case for assessing a co-management approach.

[audio mp3="http://www.the-hospitalist.org/wp-content/uploads/2015/01/Hospital-Medicine-co-management-Jan2015.mp3"][/audio]

In this podcast, hospitalists discuss why co-management in hospital medicine is still a work in progress. Dr. Bradley Flansbaum, a founding member of SHM and current member of SHM’s Public Policy Committee, says every member of a medical team needs to pull their weight and communicate. Dr. Steven Cohn, Medical Director of the Preoperative Assessment Center at the University of Miami and Director of the Medical Consultation Service at U Miami Hospital, tallies the pluses and minuses of co-management programs, and Dr. Eric Siegel, Director of the Critical Care Service at Aurora Health Care, Aurora St. Luke’s Medical Center in Milwaukee, makes his case for assessing a co-management approach.

[audio mp3="http://www.the-hospitalist.org/wp-content/uploads/2015/01/Hospital-Medicine-co-management-Jan2015.mp3"][/audio]

In this podcast, hospitalists discuss why co-management in hospital medicine is still a work in progress. Dr. Bradley Flansbaum, a founding member of SHM and current member of SHM’s Public Policy Committee, says every member of a medical team needs to pull their weight and communicate. Dr. Steven Cohn, Medical Director of the Preoperative Assessment Center at the University of Miami and Director of the Medical Consultation Service at U Miami Hospital, tallies the pluses and minuses of co-management programs, and Dr. Eric Siegel, Director of the Critical Care Service at Aurora Health Care, Aurora St. Luke’s Medical Center in Milwaukee, makes his case for assessing a co-management approach.

[audio mp3="http://www.the-hospitalist.org/wp-content/uploads/2015/01/Hospital-Medicine-co-management-Jan2015.mp3"][/audio]

SAN FRANCISCO—Younger patients with Hodgkin lymphoma fare well on brentuximab vedotin, experiencing an overall objective response rate (ORR) of 75% and a complete response (CR) rate of 34% in the pivotal phase 2 study of patients with relapsed/refractory disease.

And a retrospective study of patients older than 60 years showed that single-agent therapy was well tolerated, prompting an ORR of 53% and a CR rate of 40% in a relapsed or refractory population.

So investigators decided to explore in a prospective study whether patients 60 years or older could benefit from up-front treatment with brentuximab as a single agent or in combination.

Andres Forero-Torres, MD, of the University of Alabama in Birmingham, presented the results of this trial at the 2014 ASH Annual Meeting (abstract 294).*

Enrolled patients had classic Hodgkin lymphoma, were treatment-naïve, and were ineligible for or declined conventional front-line treatment. The primary endpoint was ORR.

The study is being conducted in 3 parts—brentuximab as a single agent, brentuximab plus dacarbazine, and brentuximab plus bendamustine. At the time of the ASH presentation, data for the brentuximab-bendamustine combination were not available.

Single-agent brentuximab

Twenty-seven patients on the single-agent arm were evaluable for efficacy and safety. They were a median age of 78 (range, 64 to 92). About half (52%) were male, and 78% had an ECOG performance status of grade 0 or 1.

Forty-four percent had moderate renal function impairment with a creatinine clearance between 30 and 60 mL/min. Thirty percent had B symptoms, 22% had bulky disease, and 52% had extra-nodal involvement.

Patients received 1.8 mg/kg of brentuximab intravenously on day 1 of a 21-day cycle. Response was assessed by CT scan during cycles 2, 4, 8, and 16, and by CT plus PET scan during cycles 2 and 8.

The median follow-up was 8.7 months. Dr Forero-Torres pointed out that, initially, “there were no progressions,” and all patients achieved tumor reduction.

The ORR was 93%, the CR rate was 70%, the partial response rate was 22%, and the rate of stable disease was 7%.

The median duration of response was 9.1 months (range, 0.03 to 13.14), and the median progression-free survival was 10.5 months (range, 2.6 to 14.3). For patients who had a CR, the median progression-free survival was about 12 months, Dr Forero-Torres said.

The median number of treatment cycles administered per patient was 8 (range, 3 to 23). Patients discontinued treatment primarily because of progressive disease (41%) or adverse events (AEs, 37%).

AEs occurring in 20% or more of patients were constipation, decreased appetite, diarrhea, peripheral edema, nausea, fatigue, and peripheral sensory neuropathy. All were grade 1 or 2, except for peripheral sensory neuropathy, which also had about 20% grade 3 events.

Grade 3 or higher treatment-related AEs included peripheral sensory neuropathy (n=7), peripheral motor neuropathy (n=2), rash (n=2), and 1 patient each with anemia, increased aspartate aminotransferase, asthenia, neutropenia, orthostatic hypotension, generalized rash, and maculopapular rash.

Serious AEs (SAEs) were minimal, Dr Forero-Torres said, and included 1 patient each with pyrexia, orthostatic hypotension, asthenia and rash, and deep vein thrombosis.

Seven patients discontinued treatment due to peripheral sensory neuropathy, 2 due to peripheral motor neuropathy, and 1 due to orthostatic hypotension.

Dr Forero-Torres emphasized that there were no grade 4 AEs, no AE-related deaths, and no deaths within 30 days of the last dose of medication.

Brentuximab plus dacarbazine

Fourteen of 18 patients in the combination arm were evaluable for efficacy and safety. Their median age was 72.5 (range, 62 to 87), 72% were male, 67% had an ECOG status of grade 0 or 1, and 56% had normal renal function with a creatinine clearance greater than 80 mL/min.

 

Forty-four percent exhibited B symptoms, 11% had bulky disease, and 50% had extra-nodal involvement.

They received brentuximab at 1.8 mg/kg plus dacarbazine at 375 mg/m² for cycles 1-12, followed by monotherapy for cycles 13-16.

At the time of the interim analysis, 83% of patients were still on treatment, “so this is very early preliminary data,” Dr Forero-Torres noted.

All of the patients achieved tumor reduction, and 4 patients achieved a CR.

They had a median treatment duration of 16.7 weeks (range, 3 to 36), received a median of 5.5 cycles (range, 1 to 12), and had a median follow-up time of 19.1 weeks (range, 6.1 to 36.1).

The most common grade 1 or 2 AEs were peripheral sensory neuropathy (33%), nausea (33%), diarrhea (28%), constipation (28%), fatigue (22%), alopecia (22%), arthralgia (22%), and headache (22%).

Grade 3 AEs or SAEs, with 1 patient each, were C difficile colitis (SAE), hypotension (SAE), and hyperglycemia.

Dr Forero-Torres noted that investigators observed “robust antitumor activity” among these older patients receiving front-line brentuximab.

The cohort combining brentuximab with bendamustine is currently enrolling patients.

The study is sponsored by Seattle Genetics, Inc., developer of brentuximab vedotin (Adcetris).

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

SAN FRANCISCO—Younger patients with Hodgkin lymphoma fare well on brentuximab vedotin, experiencing an overall objective response rate (ORR) of 75% and a complete response (CR) rate of 34% in the pivotal phase 2 study of patients with relapsed/refractory disease.

And a retrospective study of patients older than 60 years showed that single-agent therapy was well tolerated, prompting an ORR of 53% and a CR rate of 40% in a relapsed or refractory population.

So investigators decided to explore in a prospective study whether patients 60 years or older could benefit from up-front treatment with brentuximab as a single agent or in combination.

Andres Forero-Torres, MD, of the University of Alabama in Birmingham, presented the results of this trial at the 2014 ASH Annual Meeting (abstract 294).*

Enrolled patients had classic Hodgkin lymphoma, were treatment-naïve, and were ineligible for or declined conventional front-line treatment. The primary endpoint was ORR.

The study is being conducted in 3 parts—brentuximab as a single agent, brentuximab plus dacarbazine, and brentuximab plus bendamustine. At the time of the ASH presentation, data for the brentuximab-bendamustine combination were not available.

Single-agent brentuximab

Twenty-seven patients on the single-agent arm were evaluable for efficacy and safety. They were a median age of 78 (range, 64 to 92). About half (52%) were male, and 78% had an ECOG performance status of grade 0 or 1.

Forty-four percent had moderate renal function impairment with a creatinine clearance between 30 and 60 mL/min. Thirty percent had B symptoms, 22% had bulky disease, and 52% had extra-nodal involvement.

Patients received 1.8 mg/kg of brentuximab intravenously on day 1 of a 21-day cycle. Response was assessed by CT scan during cycles 2, 4, 8, and 16, and by CT plus PET scan during cycles 2 and 8.

The median follow-up was 8.7 months. Dr Forero-Torres pointed out that, initially, “there were no progressions,” and all patients achieved tumor reduction.

The ORR was 93%, the CR rate was 70%, the partial response rate was 22%, and the rate of stable disease was 7%.

The median duration of response was 9.1 months (range, 0.03 to 13.14), and the median progression-free survival was 10.5 months (range, 2.6 to 14.3). For patients who had a CR, the median progression-free survival was about 12 months, Dr Forero-Torres said.

The median number of treatment cycles administered per patient was 8 (range, 3 to 23). Patients discontinued treatment primarily because of progressive disease (41%) or adverse events (AEs, 37%).

AEs occurring in 20% or more of patients were constipation, decreased appetite, diarrhea, peripheral edema, nausea, fatigue, and peripheral sensory neuropathy. All were grade 1 or 2, except for peripheral sensory neuropathy, which also had about 20% grade 3 events.

Grade 3 or higher treatment-related AEs included peripheral sensory neuropathy (n=7), peripheral motor neuropathy (n=2), rash (n=2), and 1 patient each with anemia, increased aspartate aminotransferase, asthenia, neutropenia, orthostatic hypotension, generalized rash, and maculopapular rash.

Serious AEs (SAEs) were minimal, Dr Forero-Torres said, and included 1 patient each with pyrexia, orthostatic hypotension, asthenia and rash, and deep vein thrombosis.

Seven patients discontinued treatment due to peripheral sensory neuropathy, 2 due to peripheral motor neuropathy, and 1 due to orthostatic hypotension.

Dr Forero-Torres emphasized that there were no grade 4 AEs, no AE-related deaths, and no deaths within 30 days of the last dose of medication.

Brentuximab plus dacarbazine

Fourteen of 18 patients in the combination arm were evaluable for efficacy and safety. Their median age was 72.5 (range, 62 to 87), 72% were male, 67% had an ECOG status of grade 0 or 1, and 56% had normal renal function with a creatinine clearance greater than 80 mL/min.

 

Forty-four percent exhibited B symptoms, 11% had bulky disease, and 50% had extra-nodal involvement.

They received brentuximab at 1.8 mg/kg plus dacarbazine at 375 mg/m² for cycles 1-12, followed by monotherapy for cycles 13-16.

At the time of the interim analysis, 83% of patients were still on treatment, “so this is very early preliminary data,” Dr Forero-Torres noted.

All of the patients achieved tumor reduction, and 4 patients achieved a CR.

They had a median treatment duration of 16.7 weeks (range, 3 to 36), received a median of 5.5 cycles (range, 1 to 12), and had a median follow-up time of 19.1 weeks (range, 6.1 to 36.1).

The most common grade 1 or 2 AEs were peripheral sensory neuropathy (33%), nausea (33%), diarrhea (28%), constipation (28%), fatigue (22%), alopecia (22%), arthralgia (22%), and headache (22%).

Grade 3 AEs or SAEs, with 1 patient each, were C difficile colitis (SAE), hypotension (SAE), and hyperglycemia.

Dr Forero-Torres noted that investigators observed “robust antitumor activity” among these older patients receiving front-line brentuximab.

The cohort combining brentuximab with bendamustine is currently enrolling patients.

The study is sponsored by Seattle Genetics, Inc., developer of brentuximab vedotin (Adcetris).

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

SAN FRANCISCO—Younger patients with Hodgkin lymphoma fare well on brentuximab vedotin, experiencing an overall objective response rate (ORR) of 75% and a complete response (CR) rate of 34% in the pivotal phase 2 study of patients with relapsed/refractory disease.

And a retrospective study of patients older than 60 years showed that single-agent therapy was well tolerated, prompting an ORR of 53% and a CR rate of 40% in a relapsed or refractory population.

So investigators decided to explore in a prospective study whether patients 60 years or older could benefit from up-front treatment with brentuximab as a single agent or in combination.

Andres Forero-Torres, MD, of the University of Alabama in Birmingham, presented the results of this trial at the 2014 ASH Annual Meeting (abstract 294).*

Enrolled patients had classic Hodgkin lymphoma, were treatment-naïve, and were ineligible for or declined conventional front-line treatment. The primary endpoint was ORR.

The study is being conducted in 3 parts—brentuximab as a single agent, brentuximab plus dacarbazine, and brentuximab plus bendamustine. At the time of the ASH presentation, data for the brentuximab-bendamustine combination were not available.

Single-agent brentuximab

Twenty-seven patients on the single-agent arm were evaluable for efficacy and safety. They were a median age of 78 (range, 64 to 92). About half (52%) were male, and 78% had an ECOG performance status of grade 0 or 1.

Forty-four percent had moderate renal function impairment with a creatinine clearance between 30 and 60 mL/min. Thirty percent had B symptoms, 22% had bulky disease, and 52% had extra-nodal involvement.

Patients received 1.8 mg/kg of brentuximab intravenously on day 1 of a 21-day cycle. Response was assessed by CT scan during cycles 2, 4, 8, and 16, and by CT plus PET scan during cycles 2 and 8.

The median follow-up was 8.7 months. Dr Forero-Torres pointed out that, initially, “there were no progressions,” and all patients achieved tumor reduction.

The ORR was 93%, the CR rate was 70%, the partial response rate was 22%, and the rate of stable disease was 7%.

The median duration of response was 9.1 months (range, 0.03 to 13.14), and the median progression-free survival was 10.5 months (range, 2.6 to 14.3). For patients who had a CR, the median progression-free survival was about 12 months, Dr Forero-Torres said.

The median number of treatment cycles administered per patient was 8 (range, 3 to 23). Patients discontinued treatment primarily because of progressive disease (41%) or adverse events (AEs, 37%).

AEs occurring in 20% or more of patients were constipation, decreased appetite, diarrhea, peripheral edema, nausea, fatigue, and peripheral sensory neuropathy. All were grade 1 or 2, except for peripheral sensory neuropathy, which also had about 20% grade 3 events.

Grade 3 or higher treatment-related AEs included peripheral sensory neuropathy (n=7), peripheral motor neuropathy (n=2), rash (n=2), and 1 patient each with anemia, increased aspartate aminotransferase, asthenia, neutropenia, orthostatic hypotension, generalized rash, and maculopapular rash.

Serious AEs (SAEs) were minimal, Dr Forero-Torres said, and included 1 patient each with pyrexia, orthostatic hypotension, asthenia and rash, and deep vein thrombosis.

Seven patients discontinued treatment due to peripheral sensory neuropathy, 2 due to peripheral motor neuropathy, and 1 due to orthostatic hypotension.

Dr Forero-Torres emphasized that there were no grade 4 AEs, no AE-related deaths, and no deaths within 30 days of the last dose of medication.

Brentuximab plus dacarbazine

Fourteen of 18 patients in the combination arm were evaluable for efficacy and safety. Their median age was 72.5 (range, 62 to 87), 72% were male, 67% had an ECOG status of grade 0 or 1, and 56% had normal renal function with a creatinine clearance greater than 80 mL/min.

 

Forty-four percent exhibited B symptoms, 11% had bulky disease, and 50% had extra-nodal involvement.

They received brentuximab at 1.8 mg/kg plus dacarbazine at 375 mg/m² for cycles 1-12, followed by monotherapy for cycles 13-16.

At the time of the interim analysis, 83% of patients were still on treatment, “so this is very early preliminary data,” Dr Forero-Torres noted.

All of the patients achieved tumor reduction, and 4 patients achieved a CR.

They had a median treatment duration of 16.7 weeks (range, 3 to 36), received a median of 5.5 cycles (range, 1 to 12), and had a median follow-up time of 19.1 weeks (range, 6.1 to 36.1).

The most common grade 1 or 2 AEs were peripheral sensory neuropathy (33%), nausea (33%), diarrhea (28%), constipation (28%), fatigue (22%), alopecia (22%), arthralgia (22%), and headache (22%).

Grade 3 AEs or SAEs, with 1 patient each, were C difficile colitis (SAE), hypotension (SAE), and hyperglycemia.

Dr Forero-Torres noted that investigators observed “robust antitumor activity” among these older patients receiving front-line brentuximab.

The cohort combining brentuximab with bendamustine is currently enrolling patients.

The study is sponsored by Seattle Genetics, Inc., developer of brentuximab vedotin (Adcetris).

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

The gene-editing technology CRISPR can precisely and efficiently alter human stem cells, according to research published in Molecular Therapy.

Using JAK2 and other genes as models, researchers showed that CRISPR offers advantages over TALEN, another gene-editing technique, for manipulating induced pluripotent stem cells (iPSCs).

And, unlike in a previous study, CRISPR did not produce any off-target effects.

The team believes their findings could streamline and speed up efforts to modify human iPSCs for use as treatments or in the development of model systems to study diseases and test drugs.

“Stem cell technology is quickly advancing, and we think that the days when we can use iPSCs for human therapy aren’t that far away,” said study author Zhaohui Ye, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“This is one of the first studies to detail the use of CRISPR in human iPSCs, showcasing its potential in these cells.”

CRISPR originated from a microbial immune system that contains DNA segments known as “clustered regularly interspaced short palindromic repeats.” The system makes use of an enzyme that nicks together DNA with a piece of small RNA that guides the tool to where researchers want to introduce cuts or other changes in the genome.

Previous research has shown that CRISPR can generate genomic changes or mutations through these interventions more efficiently than other gene-editing techniques, such as TALEN, which is short for “transcription activator-like effector nuclease.”

Despite CRISPR’s advantages, a recent study suggested it might also produce a large number of off-target effects in human cancer cell lines; specifically, modification of genes that researchers didn’t mean to change.

To see if this unwanted effect occurred in other human cell types, Dr Ye and his colleagues pitted CRISPR against TALEN in human iPSCs. The researchers compared the ability of both techniques to either cut out pieces of known genes in iPSCs or cut out a piece of these genes and replace it with another.

As model genes, the researchers used JAK2, a gene that, when mutated, causes myeloproliferative neoplasms; SERPINA1, a gene that, when mutated, causes alpha1-antitrypsin deficiency, an inherited disorder that may cause lung and liver disease; and AAVS1, a gene that’s been recently discovered to be a “safe harbor” in the human genome for inserting foreign genes.

The comparison showed that, when simply cutting out portions of genes, the CRISPR system was significantly more efficient than TALEN in all 3 gene systems, inducing up to 100 times more cuts.

However, when using these genome-editing tools for replacing portions of the genes, such as the disease-causing mutations in JAK2 and SERPINA1 genes, CRISPR and TALEN showed about the same efficiency in patient-derived iPSCs.

Contrary to results of the human cancer cell line study, both CRISPR and TALEN had the same targeting specificity in human iPSCs, hitting only the genes they were designed to affect.

The researchers also found that the CRISPR system has a second advantage over TALEN. It can be designed to target only the mutation-containing gene without affecting the healthy gene in patients where only one copy of a gene is affected.

These findings, according to the researchers, offer reassurance that CRISPR will be a useful tool for editing the genes of human iPSCs with little risk of off-target effects.

The gene-editing technology CRISPR can precisely and efficiently alter human stem cells, according to research published in Molecular Therapy.

Using JAK2 and other genes as models, researchers showed that CRISPR offers advantages over TALEN, another gene-editing technique, for manipulating induced pluripotent stem cells (iPSCs).

And, unlike in a previous study, CRISPR did not produce any off-target effects.

The team believes their findings could streamline and speed up efforts to modify human iPSCs for use as treatments or in the development of model systems to study diseases and test drugs.

“Stem cell technology is quickly advancing, and we think that the days when we can use iPSCs for human therapy aren’t that far away,” said study author Zhaohui Ye, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“This is one of the first studies to detail the use of CRISPR in human iPSCs, showcasing its potential in these cells.”

CRISPR originated from a microbial immune system that contains DNA segments known as “clustered regularly interspaced short palindromic repeats.” The system makes use of an enzyme that nicks together DNA with a piece of small RNA that guides the tool to where researchers want to introduce cuts or other changes in the genome.

Previous research has shown that CRISPR can generate genomic changes or mutations through these interventions more efficiently than other gene-editing techniques, such as TALEN, which is short for “transcription activator-like effector nuclease.”

Despite CRISPR’s advantages, a recent study suggested it might also produce a large number of off-target effects in human cancer cell lines; specifically, modification of genes that researchers didn’t mean to change.

To see if this unwanted effect occurred in other human cell types, Dr Ye and his colleagues pitted CRISPR against TALEN in human iPSCs. The researchers compared the ability of both techniques to either cut out pieces of known genes in iPSCs or cut out a piece of these genes and replace it with another.

As model genes, the researchers used JAK2, a gene that, when mutated, causes myeloproliferative neoplasms; SERPINA1, a gene that, when mutated, causes alpha1-antitrypsin deficiency, an inherited disorder that may cause lung and liver disease; and AAVS1, a gene that’s been recently discovered to be a “safe harbor” in the human genome for inserting foreign genes.

The comparison showed that, when simply cutting out portions of genes, the CRISPR system was significantly more efficient than TALEN in all 3 gene systems, inducing up to 100 times more cuts.

However, when using these genome-editing tools for replacing portions of the genes, such as the disease-causing mutations in JAK2 and SERPINA1 genes, CRISPR and TALEN showed about the same efficiency in patient-derived iPSCs.

Contrary to results of the human cancer cell line study, both CRISPR and TALEN had the same targeting specificity in human iPSCs, hitting only the genes they were designed to affect.

The researchers also found that the CRISPR system has a second advantage over TALEN. It can be designed to target only the mutation-containing gene without affecting the healthy gene in patients where only one copy of a gene is affected.

These findings, according to the researchers, offer reassurance that CRISPR will be a useful tool for editing the genes of human iPSCs with little risk of off-target effects.

The gene-editing technology CRISPR can precisely and efficiently alter human stem cells, according to research published in Molecular Therapy.

Using JAK2 and other genes as models, researchers showed that CRISPR offers advantages over TALEN, another gene-editing technique, for manipulating induced pluripotent stem cells (iPSCs).

And, unlike in a previous study, CRISPR did not produce any off-target effects.

The team believes their findings could streamline and speed up efforts to modify human iPSCs for use as treatments or in the development of model systems to study diseases and test drugs.

“Stem cell technology is quickly advancing, and we think that the days when we can use iPSCs for human therapy aren’t that far away,” said study author Zhaohui Ye, PhD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland.

“This is one of the first studies to detail the use of CRISPR in human iPSCs, showcasing its potential in these cells.”

CRISPR originated from a microbial immune system that contains DNA segments known as “clustered regularly interspaced short palindromic repeats.” The system makes use of an enzyme that nicks together DNA with a piece of small RNA that guides the tool to where researchers want to introduce cuts or other changes in the genome.

Previous research has shown that CRISPR can generate genomic changes or mutations through these interventions more efficiently than other gene-editing techniques, such as TALEN, which is short for “transcription activator-like effector nuclease.”

Despite CRISPR’s advantages, a recent study suggested it might also produce a large number of off-target effects in human cancer cell lines; specifically, modification of genes that researchers didn’t mean to change.

To see if this unwanted effect occurred in other human cell types, Dr Ye and his colleagues pitted CRISPR against TALEN in human iPSCs. The researchers compared the ability of both techniques to either cut out pieces of known genes in iPSCs or cut out a piece of these genes and replace it with another.

As model genes, the researchers used JAK2, a gene that, when mutated, causes myeloproliferative neoplasms; SERPINA1, a gene that, when mutated, causes alpha1-antitrypsin deficiency, an inherited disorder that may cause lung and liver disease; and AAVS1, a gene that’s been recently discovered to be a “safe harbor” in the human genome for inserting foreign genes.

The comparison showed that, when simply cutting out portions of genes, the CRISPR system was significantly more efficient than TALEN in all 3 gene systems, inducing up to 100 times more cuts.

However, when using these genome-editing tools for replacing portions of the genes, such as the disease-causing mutations in JAK2 and SERPINA1 genes, CRISPR and TALEN showed about the same efficiency in patient-derived iPSCs.

Contrary to results of the human cancer cell line study, both CRISPR and TALEN had the same targeting specificity in human iPSCs, hitting only the genes they were designed to affect.

The researchers also found that the CRISPR system has a second advantage over TALEN. It can be designed to target only the mutation-containing gene without affecting the healthy gene in patients where only one copy of a gene is affected.

These findings, according to the researchers, offer reassurance that CRISPR will be a useful tool for editing the genes of human iPSCs with little risk of off-target effects.

Single-agent ibrutinib can elicit a high response rate in patients with high-risk chronic lymphocytic leukemia (CLL), results of a phase 2 trial suggest.

The Bruton’s tyrosine kinase inhibitor prompted a 92% objective response rate in patients who had previously untreated or relapsed/refractory CLL with either 17p deletion (del 17p) or tumor protein 53 (TP53) aberrations.

Researchers reported this and other results of the trial in The Lancet Oncology.

“Ibrutinib treatment results observed in CLL patients with del 17p or TP53 aberrations are very encouraging given that these patients have a high relapse rate after chemotherapy and are in need of tolerable, effective, and durable treatment options,” said study author Mohammed Farooqui, DO, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland.

He and his colleagues studied 51 patients in this trial, 35 with previously untreated CLL and 16 with relapsed or refractory CLL. Forty-seven of the patients (92%) had del 17p, and 4 patients carried the TP53 aberration but did not have del 17p.

The study’s primary endpoint was overall response rate after 24 weeks. Secondary endpoints included safety, overall survival, progression-free survival, best response, and nodal response.

The median follow-up for all patients was 24 months (15 months for the previously untreated cohort). At 24 weeks, 48 patients were evaluable for response, assessed according to the modified IWCLL 2008 criteria.

Response rates

At 24 weeks, 92% (n=44) of the 48 evaluable patients achieved an objective response. Fifty percent of all evaluable patients achieved a partial response (n=24)—55% of previously untreated patients (n=18) and 40% of relapsed/refractory patients (n=6).

As for best response, 10% of all patients achieved a complete response (n=5)—12% of previously untreated patients (n=4) and 7% of relapsed/refractory patients (n=1). And 67% of patients had a partial response (n=32)—70% of previously untreated patients (n=23) and 60% of relapsed/refractory patients (n=9).

After 8 weeks on therapy, ibrutinib was associated with a more than 50% mean reduction in tumor burden in the bone marrow (44%), lymph nodes (70%), and spleen (79%). After 24 weeks of therapy, the rates of tumor burden reduction (> 50%) increased to 83%, 93%, and 95%, respectively.

Survival and safety

The estimated progression-free survival at 24 months for all patients on an intention-to-treat basis was 82%. Forty-two of the 51 patients (82%) continued on ibrutinib treatment without disease progression.

The estimated overall survival at 24 months was 80% for all patients—84% for previously untreated patients and 74% for patients with relapsed or refractory disease.

At the final follow-up, 8 (16%) patients had died—5 (10%) from progressive disease, 2 (4%) from infection, and 1 (2%) patient with a sudden, unexplained death that may have been treatment-related.

The most common adverse events (occurring in more than 30% of all patients) potentially related to ibrutinib were arthralgia (59%), diarrhea (51%), rash (47%), nail ridging (43%), bruising (33%), and muscle spasms (31%).

The most frequent grade 3 or 4 hematologic adverse events were neutropenia (24%), anemia (14%), and thrombocytopenia (10%). The most common nonhematologic grade 3 adverse event was pneumonia, which occurred in 3 patients (6%).

Nine patients (18%) discontinued treatment. The reasons for discontinuation included disease progression in 5 patients (10%) and death for 3 patients (6%).

This research was sponsored by the Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute; Danish Cancer Society; Novo Nordisk Foundation; National Institutes of Health Medical Research Scholars Program; and Pharmacyclics Inc.

Ibrutinib is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

Single-agent ibrutinib can elicit a high response rate in patients with high-risk chronic lymphocytic leukemia (CLL), results of a phase 2 trial suggest.

The Bruton’s tyrosine kinase inhibitor prompted a 92% objective response rate in patients who had previously untreated or relapsed/refractory CLL with either 17p deletion (del 17p) or tumor protein 53 (TP53) aberrations.

Researchers reported this and other results of the trial in The Lancet Oncology.

“Ibrutinib treatment results observed in CLL patients with del 17p or TP53 aberrations are very encouraging given that these patients have a high relapse rate after chemotherapy and are in need of tolerable, effective, and durable treatment options,” said study author Mohammed Farooqui, DO, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland.

He and his colleagues studied 51 patients in this trial, 35 with previously untreated CLL and 16 with relapsed or refractory CLL. Forty-seven of the patients (92%) had del 17p, and 4 patients carried the TP53 aberration but did not have del 17p.

The study’s primary endpoint was overall response rate after 24 weeks. Secondary endpoints included safety, overall survival, progression-free survival, best response, and nodal response.

The median follow-up for all patients was 24 months (15 months for the previously untreated cohort). At 24 weeks, 48 patients were evaluable for response, assessed according to the modified IWCLL 2008 criteria.

Response rates

At 24 weeks, 92% (n=44) of the 48 evaluable patients achieved an objective response. Fifty percent of all evaluable patients achieved a partial response (n=24)—55% of previously untreated patients (n=18) and 40% of relapsed/refractory patients (n=6).

As for best response, 10% of all patients achieved a complete response (n=5)—12% of previously untreated patients (n=4) and 7% of relapsed/refractory patients (n=1). And 67% of patients had a partial response (n=32)—70% of previously untreated patients (n=23) and 60% of relapsed/refractory patients (n=9).

After 8 weeks on therapy, ibrutinib was associated with a more than 50% mean reduction in tumor burden in the bone marrow (44%), lymph nodes (70%), and spleen (79%). After 24 weeks of therapy, the rates of tumor burden reduction (> 50%) increased to 83%, 93%, and 95%, respectively.

Survival and safety

The estimated progression-free survival at 24 months for all patients on an intention-to-treat basis was 82%. Forty-two of the 51 patients (82%) continued on ibrutinib treatment without disease progression.

The estimated overall survival at 24 months was 80% for all patients—84% for previously untreated patients and 74% for patients with relapsed or refractory disease.

At the final follow-up, 8 (16%) patients had died—5 (10%) from progressive disease, 2 (4%) from infection, and 1 (2%) patient with a sudden, unexplained death that may have been treatment-related.

The most common adverse events (occurring in more than 30% of all patients) potentially related to ibrutinib were arthralgia (59%), diarrhea (51%), rash (47%), nail ridging (43%), bruising (33%), and muscle spasms (31%).

The most frequent grade 3 or 4 hematologic adverse events were neutropenia (24%), anemia (14%), and thrombocytopenia (10%). The most common nonhematologic grade 3 adverse event was pneumonia, which occurred in 3 patients (6%).

Nine patients (18%) discontinued treatment. The reasons for discontinuation included disease progression in 5 patients (10%) and death for 3 patients (6%).

This research was sponsored by the Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute; Danish Cancer Society; Novo Nordisk Foundation; National Institutes of Health Medical Research Scholars Program; and Pharmacyclics Inc.

Ibrutinib is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

Single-agent ibrutinib can elicit a high response rate in patients with high-risk chronic lymphocytic leukemia (CLL), results of a phase 2 trial suggest.

The Bruton’s tyrosine kinase inhibitor prompted a 92% objective response rate in patients who had previously untreated or relapsed/refractory CLL with either 17p deletion (del 17p) or tumor protein 53 (TP53) aberrations.

Researchers reported this and other results of the trial in The Lancet Oncology.

“Ibrutinib treatment results observed in CLL patients with del 17p or TP53 aberrations are very encouraging given that these patients have a high relapse rate after chemotherapy and are in need of tolerable, effective, and durable treatment options,” said study author Mohammed Farooqui, DO, of the National Heart, Lung, and Blood Institute in Bethesda, Maryland.

He and his colleagues studied 51 patients in this trial, 35 with previously untreated CLL and 16 with relapsed or refractory CLL. Forty-seven of the patients (92%) had del 17p, and 4 patients carried the TP53 aberration but did not have del 17p.

The study’s primary endpoint was overall response rate after 24 weeks. Secondary endpoints included safety, overall survival, progression-free survival, best response, and nodal response.

The median follow-up for all patients was 24 months (15 months for the previously untreated cohort). At 24 weeks, 48 patients were evaluable for response, assessed according to the modified IWCLL 2008 criteria.

Response rates

At 24 weeks, 92% (n=44) of the 48 evaluable patients achieved an objective response. Fifty percent of all evaluable patients achieved a partial response (n=24)—55% of previously untreated patients (n=18) and 40% of relapsed/refractory patients (n=6).

As for best response, 10% of all patients achieved a complete response (n=5)—12% of previously untreated patients (n=4) and 7% of relapsed/refractory patients (n=1). And 67% of patients had a partial response (n=32)—70% of previously untreated patients (n=23) and 60% of relapsed/refractory patients (n=9).

After 8 weeks on therapy, ibrutinib was associated with a more than 50% mean reduction in tumor burden in the bone marrow (44%), lymph nodes (70%), and spleen (79%). After 24 weeks of therapy, the rates of tumor burden reduction (> 50%) increased to 83%, 93%, and 95%, respectively.

Survival and safety

The estimated progression-free survival at 24 months for all patients on an intention-to-treat basis was 82%. Forty-two of the 51 patients (82%) continued on ibrutinib treatment without disease progression.

The estimated overall survival at 24 months was 80% for all patients—84% for previously untreated patients and 74% for patients with relapsed or refractory disease.

At the final follow-up, 8 (16%) patients had died—5 (10%) from progressive disease, 2 (4%) from infection, and 1 (2%) patient with a sudden, unexplained death that may have been treatment-related.

The most common adverse events (occurring in more than 30% of all patients) potentially related to ibrutinib were arthralgia (59%), diarrhea (51%), rash (47%), nail ridging (43%), bruising (33%), and muscle spasms (31%).

The most frequent grade 3 or 4 hematologic adverse events were neutropenia (24%), anemia (14%), and thrombocytopenia (10%). The most common nonhematologic grade 3 adverse event was pneumonia, which occurred in 3 patients (6%).

Nine patients (18%) discontinued treatment. The reasons for discontinuation included disease progression in 5 patients (10%) and death for 3 patients (6%).

This research was sponsored by the Intramural Research Program of the National Heart, Lung, and Blood Institute and the National Cancer Institute; Danish Cancer Society; Novo Nordisk Foundation; National Institutes of Health Medical Research Scholars Program; and Pharmacyclics Inc.

Ibrutinib is jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.

Preclinical research suggests that using the whole plant Artemesia annua, from which the drug artemisinin is extracted, may treat malaria more effectively than artemisinin itself.

Whole-plant treatment withstood the evolution of resistance and remained effective for up to 3 times longer than pure artemisinin.

Whole-plant therapy was also more effective in killing rodent parasites that have previously evolved resistance to pure artemisinin.

Stephen Rich, PhD, of the University of Massachusetts Amherst, and his colleagues reported these findings in PNAS.

The team previously showed that the whole-plant approach is more effective at killing rodent malaria than purified artemisinin.

In the present study, the investigators conducted a series of experiments to determine the rates at which parasites become resistant to whole-plant treatment compared to the rate with pure artemisinin, and if the whole-plant treatment can overcome resistance to pharmaceutical artemisinin.

The team chose 2 rodent malaria species for particular characteristics. They chose Plasmodium yoelii because an artemisinin-resistant strain exists and could be used to test whether the whole plant can overcome that resistance.

And they chose Plasmodium chabaudi because, among several species of rodent malaria, it most closely biologically resembles the deadliest of the 5 human malaria parasites, Plasmodium falciparum.

“Conducting these experiments in different rodent malaria species also provides a robust test of the therapy,” Dr Rich noted.

To determine the respective evolutionary rates of resistance to whole-plant therapy and artemisinin, Dr Rich and his colleagues conducted artificial evolution experiments. The goal was to compare the rates at which resistance to these two treatments arises in serial passage among wild-type parasite lines.

In this technique, parasite proliferation rates determine resistance. Resistant parasites are expected to reach a certain target level at the same time, whether treatment is present or absent. Sensitive parasite strains will grow more slowly in the presence of treatment and reach the target later than untreated strains.

The investigators found that artemisinin-treated parasites achieved stable resistance to low-dose (100 mg/kg) therapy on passage 16. Those parasites were then treated with a doubled artemisinin dose, and they became resistant to this after an additional 24 passages.

By comparison, parasites did not become resistant to even the low dose of whole-plant therapy (100 mg/kg) after 49 passages.

From this, the investigators concluded that the whole-plant therapy lasts at least 3 times longer than its artemisinin counterpart, and at least twice as long as the doubled dose of pure artemisinin.

“This is especially important given the recent reports of resistance to artemisinin in malaria-endemic regions of the world,” Dr Rich said.

He and his colleagues also tested whether dried, whole-plant therapy can overcome existing resistance to pharmaceutical artemisinin.

They fed groups of mice infected with artemisinin-resistant malaria either the whole-plant therapy or artemisinin mixed with water. Single treatments were given in low (40 mg) and high (200 mg) doses. Control groups received a mouse chow placebo.

The investigators then measured the parasite levels in the rodents’ bloodstream at 9 points after treatment began.

Mice given either the low or high dose of whole-plant therapy showed a significantly greater reduction in parasitemia than those in their respective artemisinin groups. As expected for these resistant parasites, parasitemia in mice in the low-dose artemisinin group did not differ from controls.

The investigators said consuming the whole plant may be more effective than the single purified drug because the whole plant “may constitute a naturally occurring combination therapy that augments artemisinin delivery and synergizes the drug’s activity.”

 

Dr Rich did note that the exact mechanisms of whole-plant therapy’s effectiveness still need to be identified. But he also said the antimalarial activity of whole-plant therapy against artemisinin-resistant parasites provides “compelling reasons to further explore the role of non-pharmaceutical forms of artemisinin to treat human malaria.”

Preclinical research suggests that using the whole plant Artemesia annua, from which the drug artemisinin is extracted, may treat malaria more effectively than artemisinin itself.

Whole-plant treatment withstood the evolution of resistance and remained effective for up to 3 times longer than pure artemisinin.

Whole-plant therapy was also more effective in killing rodent parasites that have previously evolved resistance to pure artemisinin.

Stephen Rich, PhD, of the University of Massachusetts Amherst, and his colleagues reported these findings in PNAS.

The team previously showed that the whole-plant approach is more effective at killing rodent malaria than purified artemisinin.

In the present study, the investigators conducted a series of experiments to determine the rates at which parasites become resistant to whole-plant treatment compared to the rate with pure artemisinin, and if the whole-plant treatment can overcome resistance to pharmaceutical artemisinin.

The team chose 2 rodent malaria species for particular characteristics. They chose Plasmodium yoelii because an artemisinin-resistant strain exists and could be used to test whether the whole plant can overcome that resistance.

And they chose Plasmodium chabaudi because, among several species of rodent malaria, it most closely biologically resembles the deadliest of the 5 human malaria parasites, Plasmodium falciparum.

“Conducting these experiments in different rodent malaria species also provides a robust test of the therapy,” Dr Rich noted.

To determine the respective evolutionary rates of resistance to whole-plant therapy and artemisinin, Dr Rich and his colleagues conducted artificial evolution experiments. The goal was to compare the rates at which resistance to these two treatments arises in serial passage among wild-type parasite lines.

In this technique, parasite proliferation rates determine resistance. Resistant parasites are expected to reach a certain target level at the same time, whether treatment is present or absent. Sensitive parasite strains will grow more slowly in the presence of treatment and reach the target later than untreated strains.

The investigators found that artemisinin-treated parasites achieved stable resistance to low-dose (100 mg/kg) therapy on passage 16. Those parasites were then treated with a doubled artemisinin dose, and they became resistant to this after an additional 24 passages.

By comparison, parasites did not become resistant to even the low dose of whole-plant therapy (100 mg/kg) after 49 passages.

From this, the investigators concluded that the whole-plant therapy lasts at least 3 times longer than its artemisinin counterpart, and at least twice as long as the doubled dose of pure artemisinin.

“This is especially important given the recent reports of resistance to artemisinin in malaria-endemic regions of the world,” Dr Rich said.

He and his colleagues also tested whether dried, whole-plant therapy can overcome existing resistance to pharmaceutical artemisinin.

They fed groups of mice infected with artemisinin-resistant malaria either the whole-plant therapy or artemisinin mixed with water. Single treatments were given in low (40 mg) and high (200 mg) doses. Control groups received a mouse chow placebo.

The investigators then measured the parasite levels in the rodents’ bloodstream at 9 points after treatment began.

Mice given either the low or high dose of whole-plant therapy showed a significantly greater reduction in parasitemia than those in their respective artemisinin groups. As expected for these resistant parasites, parasitemia in mice in the low-dose artemisinin group did not differ from controls.

The investigators said consuming the whole plant may be more effective than the single purified drug because the whole plant “may constitute a naturally occurring combination therapy that augments artemisinin delivery and synergizes the drug’s activity.”

 

Dr Rich did note that the exact mechanisms of whole-plant therapy’s effectiveness still need to be identified. But he also said the antimalarial activity of whole-plant therapy against artemisinin-resistant parasites provides “compelling reasons to further explore the role of non-pharmaceutical forms of artemisinin to treat human malaria.”

Preclinical research suggests that using the whole plant Artemesia annua, from which the drug artemisinin is extracted, may treat malaria more effectively than artemisinin itself.

Whole-plant treatment withstood the evolution of resistance and remained effective for up to 3 times longer than pure artemisinin.

Whole-plant therapy was also more effective in killing rodent parasites that have previously evolved resistance to pure artemisinin.

Stephen Rich, PhD, of the University of Massachusetts Amherst, and his colleagues reported these findings in PNAS.

The team previously showed that the whole-plant approach is more effective at killing rodent malaria than purified artemisinin.

In the present study, the investigators conducted a series of experiments to determine the rates at which parasites become resistant to whole-plant treatment compared to the rate with pure artemisinin, and if the whole-plant treatment can overcome resistance to pharmaceutical artemisinin.

The team chose 2 rodent malaria species for particular characteristics. They chose Plasmodium yoelii because an artemisinin-resistant strain exists and could be used to test whether the whole plant can overcome that resistance.

And they chose Plasmodium chabaudi because, among several species of rodent malaria, it most closely biologically resembles the deadliest of the 5 human malaria parasites, Plasmodium falciparum.

“Conducting these experiments in different rodent malaria species also provides a robust test of the therapy,” Dr Rich noted.

To determine the respective evolutionary rates of resistance to whole-plant therapy and artemisinin, Dr Rich and his colleagues conducted artificial evolution experiments. The goal was to compare the rates at which resistance to these two treatments arises in serial passage among wild-type parasite lines.

In this technique, parasite proliferation rates determine resistance. Resistant parasites are expected to reach a certain target level at the same time, whether treatment is present or absent. Sensitive parasite strains will grow more slowly in the presence of treatment and reach the target later than untreated strains.

The investigators found that artemisinin-treated parasites achieved stable resistance to low-dose (100 mg/kg) therapy on passage 16. Those parasites were then treated with a doubled artemisinin dose, and they became resistant to this after an additional 24 passages.

By comparison, parasites did not become resistant to even the low dose of whole-plant therapy (100 mg/kg) after 49 passages.

From this, the investigators concluded that the whole-plant therapy lasts at least 3 times longer than its artemisinin counterpart, and at least twice as long as the doubled dose of pure artemisinin.

“This is especially important given the recent reports of resistance to artemisinin in malaria-endemic regions of the world,” Dr Rich said.

He and his colleagues also tested whether dried, whole-plant therapy can overcome existing resistance to pharmaceutical artemisinin.

They fed groups of mice infected with artemisinin-resistant malaria either the whole-plant therapy or artemisinin mixed with water. Single treatments were given in low (40 mg) and high (200 mg) doses. Control groups received a mouse chow placebo.

The investigators then measured the parasite levels in the rodents’ bloodstream at 9 points after treatment began.

Mice given either the low or high dose of whole-plant therapy showed a significantly greater reduction in parasitemia than those in their respective artemisinin groups. As expected for these resistant parasites, parasitemia in mice in the low-dose artemisinin group did not differ from controls.

The investigators said consuming the whole plant may be more effective than the single purified drug because the whole plant “may constitute a naturally occurring combination therapy that augments artemisinin delivery and synergizes the drug’s activity.”

 

Dr Rich did note that the exact mechanisms of whole-plant therapy’s effectiveness still need to be identified. But he also said the antimalarial activity of whole-plant therapy against artemisinin-resistant parasites provides “compelling reasons to further explore the role of non-pharmaceutical forms of artemisinin to treat human malaria.”