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Distribution of PTCL subtypes varies by race/ethnicity
SAN FRANCISCO—The distribution of peripheral T-cell lymphoma (PTCL) subtypes in the US varies greatly according to race and ethnicity, new research suggests.
The retrospective study showed that the overall incidence of PTCL and its subtypes is lower in American Indians and Alaskan Natives than in other ethnic groups.
And the black population has a significantly higher incidence of PTCL—and the most common subtype, PTCL-not otherwise specified (NOS)—than other populations.
Andrei Shustov, MD, of the University of Washington Medical Center in Seattle, presented these and other findings at the 7th Annual T-cell Lymphoma Forum.
The findings were derived from data collected by the Surveillance, Epidemiology, and End Results (SEER) Cancer Registries, which cover 28% of the US population. The data included patients older than 15 years of age who were treated at 18 centers from 2000 through 2011.
Of all cancer patients registered over the 12-year period, 60% were non-Hispanic whites (n=470,864,199), 17% were Hispanic whites (n=134,464,006), 12% were black (n=92,294,395), 10% were Asian/Pacific Islanders (n=74,973,831), and 1% were American Indian/Alaskan Natives (n=10,802,898).
The overall incidence of PTCL was highest in blacks—2.11 per 100,000 persons per year, compared to 1.63 in non-Hispanic whites, 1.53 in Hispanic whites, 1.46 in Asian/Pacific Islanders, and 0.97 in American Indian/Alaskan Natives.
Although American Indian/Alaskan Natives appear to have the lowest overall rate of PTCLs, some cases may have been misclassified, Dr Shustov noted.
“The data collected for ethnicity in the SEER registry are self-reported, and a lot of American Indian/Alaskan Natives misreport their ethnic background,” he said.
Subtype analyses
PTCL-NOS was the most common subtype among all the racial/ethnic groups. The highest rate of PTCL-NOS (per 100,000 persons per year) was in blacks—at 0.77, compared to 0.47 in non-Hispanic whites, 0.46 in Hispanic whites, 0.45 in Asian/Pacific Islanders, and 0.28 in American Indian/Alaskan Natives.
The proportion of PTCL-NOS cases was 29.5% in non-Hispanic whites, 35.7% in blacks, 29.8% in Asian/Pacific Islanders, 27% in Hispanic whites, and 23.1% in American Indian/Alaskan Natives.
The proportion of angioimmunoblastic T-cell lymphoma cases was 9.9% in non-Hispanic whites, 5.2% in blacks, 15.3% in Asian/Pacific Islanders, 9.9% in Hispanic whites, and 2.6% in American Indian/Alaskan Natives.
The proportion of anaplastic large-cell lymphoma cases was 17.6% in non-Hispanic whites, 17.3% in blacks, 12.4% in Asian/Pacific Islanders, 21.2% in Hispanic whites, and 28.2% in American Indian/Alaskan Natives.
And the proportion of NK/T-cell lymphoma cases was 3.4% in non-Hispanic whites, 2.0% in blacks, 13.9% in Asian/Pacific Islanders, 14.6% in Hispanic whites, and 14.1% in American Indian/Alaskan Natives.
“That data indicates that, given the overall incidence of T-cell lymphoma in Natives is lower than in whites, if you’re a Native American/Alaskan Native [with] T-cell lymphoma, you’re 4 times more likely to have nasal NK-cell lymphoma than non-Hispanic whites,” Dr Shustov said.
He then showed a pairwise comparison of the percentage of PTCL subtypes. All of the racial/ethnic groups were significantly different from one another (P<0.001), except when Hispanic whites were compared to American Indian/Alaskan Natives (P=0.14).
Dr Shustov said this might be explained by the fact that these two groups have similar genetic backgrounds. 
SAN FRANCISCO—The distribution of peripheral T-cell lymphoma (PTCL) subtypes in the US varies greatly according to race and ethnicity, new research suggests.
The retrospective study showed that the overall incidence of PTCL and its subtypes is lower in American Indians and Alaskan Natives than in other ethnic groups.
And the black population has a significantly higher incidence of PTCL—and the most common subtype, PTCL-not otherwise specified (NOS)—than other populations.
Andrei Shustov, MD, of the University of Washington Medical Center in Seattle, presented these and other findings at the 7th Annual T-cell Lymphoma Forum.
The findings were derived from data collected by the Surveillance, Epidemiology, and End Results (SEER) Cancer Registries, which cover 28% of the US population. The data included patients older than 15 years of age who were treated at 18 centers from 2000 through 2011.
Of all cancer patients registered over the 12-year period, 60% were non-Hispanic whites (n=470,864,199), 17% were Hispanic whites (n=134,464,006), 12% were black (n=92,294,395), 10% were Asian/Pacific Islanders (n=74,973,831), and 1% were American Indian/Alaskan Natives (n=10,802,898).
The overall incidence of PTCL was highest in blacks—2.11 per 100,000 persons per year, compared to 1.63 in non-Hispanic whites, 1.53 in Hispanic whites, 1.46 in Asian/Pacific Islanders, and 0.97 in American Indian/Alaskan Natives.
Although American Indian/Alaskan Natives appear to have the lowest overall rate of PTCLs, some cases may have been misclassified, Dr Shustov noted.
“The data collected for ethnicity in the SEER registry are self-reported, and a lot of American Indian/Alaskan Natives misreport their ethnic background,” he said.
Subtype analyses
PTCL-NOS was the most common subtype among all the racial/ethnic groups. The highest rate of PTCL-NOS (per 100,000 persons per year) was in blacks—at 0.77, compared to 0.47 in non-Hispanic whites, 0.46 in Hispanic whites, 0.45 in Asian/Pacific Islanders, and 0.28 in American Indian/Alaskan Natives.
The proportion of PTCL-NOS cases was 29.5% in non-Hispanic whites, 35.7% in blacks, 29.8% in Asian/Pacific Islanders, 27% in Hispanic whites, and 23.1% in American Indian/Alaskan Natives.
The proportion of angioimmunoblastic T-cell lymphoma cases was 9.9% in non-Hispanic whites, 5.2% in blacks, 15.3% in Asian/Pacific Islanders, 9.9% in Hispanic whites, and 2.6% in American Indian/Alaskan Natives.
The proportion of anaplastic large-cell lymphoma cases was 17.6% in non-Hispanic whites, 17.3% in blacks, 12.4% in Asian/Pacific Islanders, 21.2% in Hispanic whites, and 28.2% in American Indian/Alaskan Natives.
And the proportion of NK/T-cell lymphoma cases was 3.4% in non-Hispanic whites, 2.0% in blacks, 13.9% in Asian/Pacific Islanders, 14.6% in Hispanic whites, and 14.1% in American Indian/Alaskan Natives.
“That data indicates that, given the overall incidence of T-cell lymphoma in Natives is lower than in whites, if you’re a Native American/Alaskan Native [with] T-cell lymphoma, you’re 4 times more likely to have nasal NK-cell lymphoma than non-Hispanic whites,” Dr Shustov said.
He then showed a pairwise comparison of the percentage of PTCL subtypes. All of the racial/ethnic groups were significantly different from one another (P<0.001), except when Hispanic whites were compared to American Indian/Alaskan Natives (P=0.14).
Dr Shustov said this might be explained by the fact that these two groups have similar genetic backgrounds.
SAN FRANCISCO—The distribution of peripheral T-cell lymphoma (PTCL) subtypes in the US varies greatly according to race and ethnicity, new research suggests.
The retrospective study showed that the overall incidence of PTCL and its subtypes is lower in American Indians and Alaskan Natives than in other ethnic groups.
And the black population has a significantly higher incidence of PTCL—and the most common subtype, PTCL-not otherwise specified (NOS)—than other populations.
Andrei Shustov, MD, of the University of Washington Medical Center in Seattle, presented these and other findings at the 7th Annual T-cell Lymphoma Forum.
The findings were derived from data collected by the Surveillance, Epidemiology, and End Results (SEER) Cancer Registries, which cover 28% of the US population. The data included patients older than 15 years of age who were treated at 18 centers from 2000 through 2011.
Of all cancer patients registered over the 12-year period, 60% were non-Hispanic whites (n=470,864,199), 17% were Hispanic whites (n=134,464,006), 12% were black (n=92,294,395), 10% were Asian/Pacific Islanders (n=74,973,831), and 1% were American Indian/Alaskan Natives (n=10,802,898).
The overall incidence of PTCL was highest in blacks—2.11 per 100,000 persons per year, compared to 1.63 in non-Hispanic whites, 1.53 in Hispanic whites, 1.46 in Asian/Pacific Islanders, and 0.97 in American Indian/Alaskan Natives.
Although American Indian/Alaskan Natives appear to have the lowest overall rate of PTCLs, some cases may have been misclassified, Dr Shustov noted.
“The data collected for ethnicity in the SEER registry are self-reported, and a lot of American Indian/Alaskan Natives misreport their ethnic background,” he said.
Subtype analyses
PTCL-NOS was the most common subtype among all the racial/ethnic groups. The highest rate of PTCL-NOS (per 100,000 persons per year) was in blacks—at 0.77, compared to 0.47 in non-Hispanic whites, 0.46 in Hispanic whites, 0.45 in Asian/Pacific Islanders, and 0.28 in American Indian/Alaskan Natives.
The proportion of PTCL-NOS cases was 29.5% in non-Hispanic whites, 35.7% in blacks, 29.8% in Asian/Pacific Islanders, 27% in Hispanic whites, and 23.1% in American Indian/Alaskan Natives.
The proportion of angioimmunoblastic T-cell lymphoma cases was 9.9% in non-Hispanic whites, 5.2% in blacks, 15.3% in Asian/Pacific Islanders, 9.9% in Hispanic whites, and 2.6% in American Indian/Alaskan Natives.
The proportion of anaplastic large-cell lymphoma cases was 17.6% in non-Hispanic whites, 17.3% in blacks, 12.4% in Asian/Pacific Islanders, 21.2% in Hispanic whites, and 28.2% in American Indian/Alaskan Natives.
And the proportion of NK/T-cell lymphoma cases was 3.4% in non-Hispanic whites, 2.0% in blacks, 13.9% in Asian/Pacific Islanders, 14.6% in Hispanic whites, and 14.1% in American Indian/Alaskan Natives.
“That data indicates that, given the overall incidence of T-cell lymphoma in Natives is lower than in whites, if you’re a Native American/Alaskan Native [with] T-cell lymphoma, you’re 4 times more likely to have nasal NK-cell lymphoma than non-Hispanic whites,” Dr Shustov said.
He then showed a pairwise comparison of the percentage of PTCL subtypes. All of the racial/ethnic groups were significantly different from one another (P<0.001), except when Hispanic whites were compared to American Indian/Alaskan Natives (P=0.14).
Dr Shustov said this might be explained by the fact that these two groups have similar genetic backgrounds.
Team touts a new, improved hydrogel
Louis Heiser & Robert Ackland
A new hydrogel improves on previous models by enabling the generation of more mature blood vessels, according to research published in ACS Nano.
The hydrogel also overcomes several other issues that have kept previous hydrogels from reaching their potential to treat injuries and forming new vasculature to treat heart attack, stroke, and ischemic tissue diseases.
Like earlier versions, the new hydrogel can be injected in liquid form and turns into a nanofiber-infused gel at the site of the injury. The difference with this hydrogel, according to researchers, is the quality of the blood vessels that are formed.
This hydrogel is made of self-assembling synthetic peptides that form nanofiber scaffolds. And the peptides incorporate a mimic of vascular endothelial growth factor, a signal protein that promotes angiogenesis.
Furthermore, the hydrogel can be easily delivered by syringe, is quickly infiltrated by hematopoietic and mesenchymal cells, and quickly forms a mature vascular network.
“In a lot of the published literature, you see rings that only have the endothelial cell lining, and that indicates a very immature blood vessel,” said study author Jeffrey Hartgerink, PhD, of Rice University in Houston, Texas.
“These types of vessels usually don’t persist and disappear shortly after they show up. In ours, you see that same endothelial cell layer, but surrounding it is a smooth muscle cell layer that indicates a much more mature vessel that’s likely to persist.”
Furthermore, the scaffolds the hydrogel forms show no signs of fibrous encapsulation. After 3 weeks, they are resorbed into the native tissue.
In previous studies, implanted synthetic materials tended to become encapsulated by fibrous barriers that kept cells and blood vessels from infiltrating the scaffold, Dr Hartgerink said.
“That is an extremely common problem in synthetic materials put into the body,” he explained. “Some avoid this problem, but if the body doesn’t like a material and isn’t able to destroy it, the solution is to wall it off.”
“As soon as that happens, the flow of nutrients across that barrier decreases to almost nothing. So the fact that we’ve developed syringe-directed delivery of a material that doesn’t develop fibrous encapsulation is really important.”
Other negative characteristics of earlier hydrogels—unwanted immune responses, surface degradation preceding their integration into biological systems, and the release of artificial degradation byproducts—have been eliminated as well, Dr Hartgerink said.
“There are a lot of features about this hydrogel that come together to make it a unique system,” he added. “If you look through the literature at what other people have done, each concept that is involved in our system probably exists somewhere already. The difference is that we have all these features in one place working together.”
Louis Heiser & Robert Ackland
A new hydrogel improves on previous models by enabling the generation of more mature blood vessels, according to research published in ACS Nano.
The hydrogel also overcomes several other issues that have kept previous hydrogels from reaching their potential to treat injuries and forming new vasculature to treat heart attack, stroke, and ischemic tissue diseases.
Like earlier versions, the new hydrogel can be injected in liquid form and turns into a nanofiber-infused gel at the site of the injury. The difference with this hydrogel, according to researchers, is the quality of the blood vessels that are formed.
This hydrogel is made of self-assembling synthetic peptides that form nanofiber scaffolds. And the peptides incorporate a mimic of vascular endothelial growth factor, a signal protein that promotes angiogenesis.
Furthermore, the hydrogel can be easily delivered by syringe, is quickly infiltrated by hematopoietic and mesenchymal cells, and quickly forms a mature vascular network.
“In a lot of the published literature, you see rings that only have the endothelial cell lining, and that indicates a very immature blood vessel,” said study author Jeffrey Hartgerink, PhD, of Rice University in Houston, Texas.
“These types of vessels usually don’t persist and disappear shortly after they show up. In ours, you see that same endothelial cell layer, but surrounding it is a smooth muscle cell layer that indicates a much more mature vessel that’s likely to persist.”
Furthermore, the scaffolds the hydrogel forms show no signs of fibrous encapsulation. After 3 weeks, they are resorbed into the native tissue.
In previous studies, implanted synthetic materials tended to become encapsulated by fibrous barriers that kept cells and blood vessels from infiltrating the scaffold, Dr Hartgerink said.
“That is an extremely common problem in synthetic materials put into the body,” he explained. “Some avoid this problem, but if the body doesn’t like a material and isn’t able to destroy it, the solution is to wall it off.”
“As soon as that happens, the flow of nutrients across that barrier decreases to almost nothing. So the fact that we’ve developed syringe-directed delivery of a material that doesn’t develop fibrous encapsulation is really important.”
Other negative characteristics of earlier hydrogels—unwanted immune responses, surface degradation preceding their integration into biological systems, and the release of artificial degradation byproducts—have been eliminated as well, Dr Hartgerink said.
“There are a lot of features about this hydrogel that come together to make it a unique system,” he added. “If you look through the literature at what other people have done, each concept that is involved in our system probably exists somewhere already. The difference is that we have all these features in one place working together.”
Louis Heiser & Robert Ackland
A new hydrogel improves on previous models by enabling the generation of more mature blood vessels, according to research published in ACS Nano.
The hydrogel also overcomes several other issues that have kept previous hydrogels from reaching their potential to treat injuries and forming new vasculature to treat heart attack, stroke, and ischemic tissue diseases.
Like earlier versions, the new hydrogel can be injected in liquid form and turns into a nanofiber-infused gel at the site of the injury. The difference with this hydrogel, according to researchers, is the quality of the blood vessels that are formed.
This hydrogel is made of self-assembling synthetic peptides that form nanofiber scaffolds. And the peptides incorporate a mimic of vascular endothelial growth factor, a signal protein that promotes angiogenesis.
Furthermore, the hydrogel can be easily delivered by syringe, is quickly infiltrated by hematopoietic and mesenchymal cells, and quickly forms a mature vascular network.
“In a lot of the published literature, you see rings that only have the endothelial cell lining, and that indicates a very immature blood vessel,” said study author Jeffrey Hartgerink, PhD, of Rice University in Houston, Texas.
“These types of vessels usually don’t persist and disappear shortly after they show up. In ours, you see that same endothelial cell layer, but surrounding it is a smooth muscle cell layer that indicates a much more mature vessel that’s likely to persist.”
Furthermore, the scaffolds the hydrogel forms show no signs of fibrous encapsulation. After 3 weeks, they are resorbed into the native tissue.
In previous studies, implanted synthetic materials tended to become encapsulated by fibrous barriers that kept cells and blood vessels from infiltrating the scaffold, Dr Hartgerink said.
“That is an extremely common problem in synthetic materials put into the body,” he explained. “Some avoid this problem, but if the body doesn’t like a material and isn’t able to destroy it, the solution is to wall it off.”
“As soon as that happens, the flow of nutrients across that barrier decreases to almost nothing. So the fact that we’ve developed syringe-directed delivery of a material that doesn’t develop fibrous encapsulation is really important.”
Other negative characteristics of earlier hydrogels—unwanted immune responses, surface degradation preceding their integration into biological systems, and the release of artificial degradation byproducts—have been eliminated as well, Dr Hartgerink said.
“There are a lot of features about this hydrogel that come together to make it a unique system,” he added. “If you look through the literature at what other people have done, each concept that is involved in our system probably exists somewhere already. The difference is that we have all these features in one place working together.”
RBC transfusions during CABG increase risk of pneumonia
Credit: Elise Amendola
SAN DIEGO—Patients who receive red blood cell (RBC) transfusions during coronary artery bypass grafting (CABG) surgery are at an increased risk of
developing pneumonia, according to research presented at the 51st Annual Meeting of The Society of Thoracic Surgeons.
And the risk appears to increase with the volume of RBCs transfused. Patients who received 6 or more units had a 14 times higher risk of developing pneumonia than their untransfused peers.
“Pneumonia is a known risk following CABG surgery, and developing it has been shown to significantly increase a patient’s risk of morbidity and mortality,” said study investigator Donald S. Likosky, PhD, of the University of Michigan Health System in Ann Arbor.
“Previous research has shown that 1 in every 20 CABG patients develop a major infection, with pneumonia being the most common type of infection.”
For this study, Dr Liksoky and his colleagues examined data on 16,182 patients who underwent CABG between 2011 and 2013 at any of the 33 hospitals participating in the Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative.
They used propensity scoring to match the 4585 patients (32.3%) who received RBCs to the 9612 who did not (total=14,197). The team matched patients based on age, sex, body mass index, history of smoking, congestive heart failure, chronic obstructive pulmonary disease, diabetes, prior cardiac surgery, vascular disease, ejection fraction, preoperative hematocrit, and preoperative pneumonia.
The researchers then calculated adjusted odds ratios (ORs) reflecting the association between the number of RBC units transfused (0 to 6+) and postoperative pneumonia.
In all, 450 patients (3.2%) developed pneumonia. And the analysis revealed a significant association between any RBC transfusion and pneumonia (OR=4.0, P<0.001), as well as associations between the number of units transfused and the odds of developing pneumonia.
The OR was 1.6 (P=0.02) for patients who received 1 RBC unit, 2.1 for those who received 2 units (P<0.001), 4.9 for those who received 3 units (P<0.001), 5.5 for those who received 4 units (P<0.001), 8.9 for those who received 5 units (P<0.001), and 14.4 for patients who received 6 or more units (P<0.001).
“The ability to store and transfuse blood is one of medicine’s greatest accomplishments, but we are continuing to see that receiving a blood transfusion may alter a patient’s ability to fight infection,” said James R. Edgerton, MD, from The Heart Hospital Baylor Plano in Texas, who was not affiliated with this study.
“In their study, Dr Likosky and colleagues have identified an increased risk of pneumonia after transfusion, which is an important breakthrough because it allows physicians to remain vigilant for the onset of pneumonia and initiate therapy early in hopes of shortening its course and severity. It also enables physicians to initiate preventive therapies in patients who have been transfused, which will contribute to better care of our patients.”
“Patients should receive red blood cell transfusions based on clinical need,” Dr Likosky added. “Surgical teams may have opportunities to reduce the need for transfusions among patients, thereby reducing the risk of secondary complications.”
Credit: Elise Amendola
SAN DIEGO—Patients who receive red blood cell (RBC) transfusions during coronary artery bypass grafting (CABG) surgery are at an increased risk of
developing pneumonia, according to research presented at the 51st Annual Meeting of The Society of Thoracic Surgeons.
And the risk appears to increase with the volume of RBCs transfused. Patients who received 6 or more units had a 14 times higher risk of developing pneumonia than their untransfused peers.
“Pneumonia is a known risk following CABG surgery, and developing it has been shown to significantly increase a patient’s risk of morbidity and mortality,” said study investigator Donald S. Likosky, PhD, of the University of Michigan Health System in Ann Arbor.
“Previous research has shown that 1 in every 20 CABG patients develop a major infection, with pneumonia being the most common type of infection.”
For this study, Dr Liksoky and his colleagues examined data on 16,182 patients who underwent CABG between 2011 and 2013 at any of the 33 hospitals participating in the Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative.
They used propensity scoring to match the 4585 patients (32.3%) who received RBCs to the 9612 who did not (total=14,197). The team matched patients based on age, sex, body mass index, history of smoking, congestive heart failure, chronic obstructive pulmonary disease, diabetes, prior cardiac surgery, vascular disease, ejection fraction, preoperative hematocrit, and preoperative pneumonia.
The researchers then calculated adjusted odds ratios (ORs) reflecting the association between the number of RBC units transfused (0 to 6+) and postoperative pneumonia.
In all, 450 patients (3.2%) developed pneumonia. And the analysis revealed a significant association between any RBC transfusion and pneumonia (OR=4.0, P<0.001), as well as associations between the number of units transfused and the odds of developing pneumonia.
The OR was 1.6 (P=0.02) for patients who received 1 RBC unit, 2.1 for those who received 2 units (P<0.001), 4.9 for those who received 3 units (P<0.001), 5.5 for those who received 4 units (P<0.001), 8.9 for those who received 5 units (P<0.001), and 14.4 for patients who received 6 or more units (P<0.001).
“The ability to store and transfuse blood is one of medicine’s greatest accomplishments, but we are continuing to see that receiving a blood transfusion may alter a patient’s ability to fight infection,” said James R. Edgerton, MD, from The Heart Hospital Baylor Plano in Texas, who was not affiliated with this study.
“In their study, Dr Likosky and colleagues have identified an increased risk of pneumonia after transfusion, which is an important breakthrough because it allows physicians to remain vigilant for the onset of pneumonia and initiate therapy early in hopes of shortening its course and severity. It also enables physicians to initiate preventive therapies in patients who have been transfused, which will contribute to better care of our patients.”
“Patients should receive red blood cell transfusions based on clinical need,” Dr Likosky added. “Surgical teams may have opportunities to reduce the need for transfusions among patients, thereby reducing the risk of secondary complications.”
Credit: Elise Amendola
SAN DIEGO—Patients who receive red blood cell (RBC) transfusions during coronary artery bypass grafting (CABG) surgery are at an increased risk of
developing pneumonia, according to research presented at the 51st Annual Meeting of The Society of Thoracic Surgeons.
And the risk appears to increase with the volume of RBCs transfused. Patients who received 6 or more units had a 14 times higher risk of developing pneumonia than their untransfused peers.
“Pneumonia is a known risk following CABG surgery, and developing it has been shown to significantly increase a patient’s risk of morbidity and mortality,” said study investigator Donald S. Likosky, PhD, of the University of Michigan Health System in Ann Arbor.
“Previous research has shown that 1 in every 20 CABG patients develop a major infection, with pneumonia being the most common type of infection.”
For this study, Dr Liksoky and his colleagues examined data on 16,182 patients who underwent CABG between 2011 and 2013 at any of the 33 hospitals participating in the Michigan Society of Thoracic and Cardiovascular Surgeons Quality Collaborative.
They used propensity scoring to match the 4585 patients (32.3%) who received RBCs to the 9612 who did not (total=14,197). The team matched patients based on age, sex, body mass index, history of smoking, congestive heart failure, chronic obstructive pulmonary disease, diabetes, prior cardiac surgery, vascular disease, ejection fraction, preoperative hematocrit, and preoperative pneumonia.
The researchers then calculated adjusted odds ratios (ORs) reflecting the association between the number of RBC units transfused (0 to 6+) and postoperative pneumonia.
In all, 450 patients (3.2%) developed pneumonia. And the analysis revealed a significant association between any RBC transfusion and pneumonia (OR=4.0, P<0.001), as well as associations between the number of units transfused and the odds of developing pneumonia.
The OR was 1.6 (P=0.02) for patients who received 1 RBC unit, 2.1 for those who received 2 units (P<0.001), 4.9 for those who received 3 units (P<0.001), 5.5 for those who received 4 units (P<0.001), 8.9 for those who received 5 units (P<0.001), and 14.4 for patients who received 6 or more units (P<0.001).
“The ability to store and transfuse blood is one of medicine’s greatest accomplishments, but we are continuing to see that receiving a blood transfusion may alter a patient’s ability to fight infection,” said James R. Edgerton, MD, from The Heart Hospital Baylor Plano in Texas, who was not affiliated with this study.
“In their study, Dr Likosky and colleagues have identified an increased risk of pneumonia after transfusion, which is an important breakthrough because it allows physicians to remain vigilant for the onset of pneumonia and initiate therapy early in hopes of shortening its course and severity. It also enables physicians to initiate preventive therapies in patients who have been transfused, which will contribute to better care of our patients.”
“Patients should receive red blood cell transfusions based on clinical need,” Dr Likosky added. “Surgical teams may have opportunities to reduce the need for transfusions among patients, thereby reducing the risk of secondary complications.”
FDA approves ibrutinib for WM
Credit: CDC
The US Food and Drug Administration (FDA) has granted approval for ibrutinib (Imbruvica) as the first and only treatment for patients with Waldenstrom’s macroglobulinemia (WM).
The drug is now approved as a single agent for use in all lines of therapy.
This is the fourth indication for ibrutinib, which is also FDA-approved to treat patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, CLL patients with del 17p, and patients with mantle cell lymphoma.
Ibrutinib is being jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.
The latest FDA approval is based on results from a multicenter, phase 2 study in which researchers evaluated the efficacy and tolerability of ibrutinib in 63 patients with previously treated WM.
The response rate, according to an independent review committee, was 62%. Eleven percent of patients had a very good partial response rate, and 51% had a partial response rate.
The median duration of response has not been reached, with a range of 2.8 to 18.8 months.
The most commonly occurring adverse events (>20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue.
Six percent of patients discontinued treatment due to adverse events. Events leading to dose reduction occurred in 11% of patients.
For more details, see the full prescribing information.
Credit: CDC
The US Food and Drug Administration (FDA) has granted approval for ibrutinib (Imbruvica) as the first and only treatment for patients with Waldenstrom’s macroglobulinemia (WM).
The drug is now approved as a single agent for use in all lines of therapy.
This is the fourth indication for ibrutinib, which is also FDA-approved to treat patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, CLL patients with del 17p, and patients with mantle cell lymphoma.
Ibrutinib is being jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.
The latest FDA approval is based on results from a multicenter, phase 2 study in which researchers evaluated the efficacy and tolerability of ibrutinib in 63 patients with previously treated WM.
The response rate, according to an independent review committee, was 62%. Eleven percent of patients had a very good partial response rate, and 51% had a partial response rate.
The median duration of response has not been reached, with a range of 2.8 to 18.8 months.
The most commonly occurring adverse events (>20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue.
Six percent of patients discontinued treatment due to adverse events. Events leading to dose reduction occurred in 11% of patients.
For more details, see the full prescribing information.
Credit: CDC
The US Food and Drug Administration (FDA) has granted approval for ibrutinib (Imbruvica) as the first and only treatment for patients with Waldenstrom’s macroglobulinemia (WM).
The drug is now approved as a single agent for use in all lines of therapy.
This is the fourth indication for ibrutinib, which is also FDA-approved to treat patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, CLL patients with del 17p, and patients with mantle cell lymphoma.
Ibrutinib is being jointly developed and commercialized by Pharmacyclics and Janssen Biotech, Inc.
The latest FDA approval is based on results from a multicenter, phase 2 study in which researchers evaluated the efficacy and tolerability of ibrutinib in 63 patients with previously treated WM.
The response rate, according to an independent review committee, was 62%. Eleven percent of patients had a very good partial response rate, and 51% had a partial response rate.
The median duration of response has not been reached, with a range of 2.8 to 18.8 months.
The most commonly occurring adverse events (>20%) were neutropenia, thrombocytopenia, diarrhea, rash, nausea, muscle spasms, and fatigue.
Six percent of patients discontinued treatment due to adverse events. Events leading to dose reduction occurred in 11% of patients.
For more details, see the full prescribing information.
Kinase plays key role in leukemia
Credit: Robert Paulson
Inhibiting the cell-cycle kinase CDK6 may prevent leukemic relapse, according to research published in Blood.
Investigators found that CDK6 regulates the activation of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs), which it does by inhibiting the transcription factor Egr1.
When CDK6 is lost, Egr1 becomes active and prevents stem cells from dividing.
However, the mechanism operates only when HSCs are stressed—such as in leukemia—and not in the normal physiological situation.
“CDK6 is absolutely necessary for leukemic stem cells to induce disease but plays no part in normal hematopoiesis,” said study author Ruth Scheicher, of the University of Veterinary Medicine, Vienna.
“We thus have a novel opportunity to target leukemia at its origin. Inhibiting CDK6 should attack leukemic stem cells while leaving healthy HSCs unaffected.”
Specifically, Scheicher and her colleagues found that Cdk6−/− HSCs did not efficiently repopulate when transplanted into mice. And Cdk6−/− mice could tolerate fewer cycles of treatment with 5-fluorouracil than wild-type mice.
Mice that received BCR-ABLp210+–infected bone marrow harvested from Cdk6−/− mice did not develop leukemia. However, the recipient mice did harbor LSCs.
And knocking down Egr1 in Cdk6−/− BCR-ABLp210+ LSCs enhanced the cells’ ability to form colonies.
The researchers said these results suggest CDK6 is “an important regulator of stem cell activation and an essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.”
Credit: Robert Paulson
Inhibiting the cell-cycle kinase CDK6 may prevent leukemic relapse, according to research published in Blood.
Investigators found that CDK6 regulates the activation of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs), which it does by inhibiting the transcription factor Egr1.
When CDK6 is lost, Egr1 becomes active and prevents stem cells from dividing.
However, the mechanism operates only when HSCs are stressed—such as in leukemia—and not in the normal physiological situation.
“CDK6 is absolutely necessary for leukemic stem cells to induce disease but plays no part in normal hematopoiesis,” said study author Ruth Scheicher, of the University of Veterinary Medicine, Vienna.
“We thus have a novel opportunity to target leukemia at its origin. Inhibiting CDK6 should attack leukemic stem cells while leaving healthy HSCs unaffected.”
Specifically, Scheicher and her colleagues found that Cdk6−/− HSCs did not efficiently repopulate when transplanted into mice. And Cdk6−/− mice could tolerate fewer cycles of treatment with 5-fluorouracil than wild-type mice.
Mice that received BCR-ABLp210+–infected bone marrow harvested from Cdk6−/− mice did not develop leukemia. However, the recipient mice did harbor LSCs.
And knocking down Egr1 in Cdk6−/− BCR-ABLp210+ LSCs enhanced the cells’ ability to form colonies.
The researchers said these results suggest CDK6 is “an important regulator of stem cell activation and an essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.”
Credit: Robert Paulson
Inhibiting the cell-cycle kinase CDK6 may prevent leukemic relapse, according to research published in Blood.
Investigators found that CDK6 regulates the activation of hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs), which it does by inhibiting the transcription factor Egr1.
When CDK6 is lost, Egr1 becomes active and prevents stem cells from dividing.
However, the mechanism operates only when HSCs are stressed—such as in leukemia—and not in the normal physiological situation.
“CDK6 is absolutely necessary for leukemic stem cells to induce disease but plays no part in normal hematopoiesis,” said study author Ruth Scheicher, of the University of Veterinary Medicine, Vienna.
“We thus have a novel opportunity to target leukemia at its origin. Inhibiting CDK6 should attack leukemic stem cells while leaving healthy HSCs unaffected.”
Specifically, Scheicher and her colleagues found that Cdk6−/− HSCs did not efficiently repopulate when transplanted into mice. And Cdk6−/− mice could tolerate fewer cycles of treatment with 5-fluorouracil than wild-type mice.
Mice that received BCR-ABLp210+–infected bone marrow harvested from Cdk6−/− mice did not develop leukemia. However, the recipient mice did harbor LSCs.
And knocking down Egr1 in Cdk6−/− BCR-ABLp210+ LSCs enhanced the cells’ ability to form colonies.
The researchers said these results suggest CDK6 is “an important regulator of stem cell activation and an essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.”
Group uncovers structure of receptor-chemokine complex
in complex with a chemokine
(purple surface)
Credit: Katya Kadyshevskaya
Researchers have reported the first crystal structure of the cellular receptor CXCR4 bound to the viral chemokine antagonist vMIP-II.
The structure, published in Science, answers longstanding questions about a molecular interaction that plays an important role in human development, immune responses, cancer spread, and HIV infections.
“This new information could ultimately aid the development of better small molecular inhibitors of CXCR4-chemokine interactions—inhibitors that have the potential to block cancer metastasis or viral infections,” said study author Tracy M. Handel, PhD, of the University of California, San Diego.
Dr Handel and her colleagues knew that CXCR4 binds chemokines to transmit messages to the inside of the cell. This signal relay helps cells migrate normally during development and inflammation.
But CXCR4 signaling can also play a role in abnormal cell migration, such as when cancer cells metastasize. And CXCR4 is infamous for another reason: HIV uses it to bind and infect human immune cells.
Despite its far-reaching consequences, researchers have long lacked data to show how exactly the CXCR4-chemokine interaction occurs, or even how many CXCR4 receptors a single chemokine molecule might simultaneously engage.
This is because membrane receptors like CXCR4 are exceptionally challenging structural targets. And the difficulty dramatically increases when studying such receptors in complexes with the proteins they bind.
To overcome these experimental challenges, Dr Handel’s team used a novel approach. They combined computational modeling and a technique known as disulfide trapping to stabilize the complex.
Once it was stabilized, the researchers were able to use X-ray crystallography to determine the CXCR4-chemokine complex’s 3D atomic structure.
This is the first time a receptor like CXCR4 has been crystallized with a protein binding partner, and the results revealed several new insights. First, the new crystal structure shows that one chemokine binds to just one receptor.
Additionally, the structure reveals that the contacts between the receptor and its binding partner are more extensive than previously thought. It is one very large, contiguous surface of interaction rather than two separate binding sites.
“The plasticity of the CXCR4 receptor—its ability to bind many unrelated small molecules, peptides, and proteins—is remarkable,” said Irina Kufareva, PhD, also of UC San Diego.
“Our understanding of this plasticity may impact the design of therapeutics with better inhibition and safety profiles.”
“With more than 800 members, 7-transmembrane receptors like CXCR4 are the largest protein family in the human genome,” added Raymond Stevens, PhD, of the Bridge Institute at the University of Southern California in Los Angeles. “Each new structure opens up so many doors to understanding different aspects of human biology, and this time it is about chemokine signaling.”
in complex with a chemokine
(purple surface)
Credit: Katya Kadyshevskaya
Researchers have reported the first crystal structure of the cellular receptor CXCR4 bound to the viral chemokine antagonist vMIP-II.
The structure, published in Science, answers longstanding questions about a molecular interaction that plays an important role in human development, immune responses, cancer spread, and HIV infections.
“This new information could ultimately aid the development of better small molecular inhibitors of CXCR4-chemokine interactions—inhibitors that have the potential to block cancer metastasis or viral infections,” said study author Tracy M. Handel, PhD, of the University of California, San Diego.
Dr Handel and her colleagues knew that CXCR4 binds chemokines to transmit messages to the inside of the cell. This signal relay helps cells migrate normally during development and inflammation.
But CXCR4 signaling can also play a role in abnormal cell migration, such as when cancer cells metastasize. And CXCR4 is infamous for another reason: HIV uses it to bind and infect human immune cells.
Despite its far-reaching consequences, researchers have long lacked data to show how exactly the CXCR4-chemokine interaction occurs, or even how many CXCR4 receptors a single chemokine molecule might simultaneously engage.
This is because membrane receptors like CXCR4 are exceptionally challenging structural targets. And the difficulty dramatically increases when studying such receptors in complexes with the proteins they bind.
To overcome these experimental challenges, Dr Handel’s team used a novel approach. They combined computational modeling and a technique known as disulfide trapping to stabilize the complex.
Once it was stabilized, the researchers were able to use X-ray crystallography to determine the CXCR4-chemokine complex’s 3D atomic structure.
This is the first time a receptor like CXCR4 has been crystallized with a protein binding partner, and the results revealed several new insights. First, the new crystal structure shows that one chemokine binds to just one receptor.
Additionally, the structure reveals that the contacts between the receptor and its binding partner are more extensive than previously thought. It is one very large, contiguous surface of interaction rather than two separate binding sites.
“The plasticity of the CXCR4 receptor—its ability to bind many unrelated small molecules, peptides, and proteins—is remarkable,” said Irina Kufareva, PhD, also of UC San Diego.
“Our understanding of this plasticity may impact the design of therapeutics with better inhibition and safety profiles.”
“With more than 800 members, 7-transmembrane receptors like CXCR4 are the largest protein family in the human genome,” added Raymond Stevens, PhD, of the Bridge Institute at the University of Southern California in Los Angeles. “Each new structure opens up so many doors to understanding different aspects of human biology, and this time it is about chemokine signaling.”
in complex with a chemokine
(purple surface)
Credit: Katya Kadyshevskaya
Researchers have reported the first crystal structure of the cellular receptor CXCR4 bound to the viral chemokine antagonist vMIP-II.
The structure, published in Science, answers longstanding questions about a molecular interaction that plays an important role in human development, immune responses, cancer spread, and HIV infections.
“This new information could ultimately aid the development of better small molecular inhibitors of CXCR4-chemokine interactions—inhibitors that have the potential to block cancer metastasis or viral infections,” said study author Tracy M. Handel, PhD, of the University of California, San Diego.
Dr Handel and her colleagues knew that CXCR4 binds chemokines to transmit messages to the inside of the cell. This signal relay helps cells migrate normally during development and inflammation.
But CXCR4 signaling can also play a role in abnormal cell migration, such as when cancer cells metastasize. And CXCR4 is infamous for another reason: HIV uses it to bind and infect human immune cells.
Despite its far-reaching consequences, researchers have long lacked data to show how exactly the CXCR4-chemokine interaction occurs, or even how many CXCR4 receptors a single chemokine molecule might simultaneously engage.
This is because membrane receptors like CXCR4 are exceptionally challenging structural targets. And the difficulty dramatically increases when studying such receptors in complexes with the proteins they bind.
To overcome these experimental challenges, Dr Handel’s team used a novel approach. They combined computational modeling and a technique known as disulfide trapping to stabilize the complex.
Once it was stabilized, the researchers were able to use X-ray crystallography to determine the CXCR4-chemokine complex’s 3D atomic structure.
This is the first time a receptor like CXCR4 has been crystallized with a protein binding partner, and the results revealed several new insights. First, the new crystal structure shows that one chemokine binds to just one receptor.
Additionally, the structure reveals that the contacts between the receptor and its binding partner are more extensive than previously thought. It is one very large, contiguous surface of interaction rather than two separate binding sites.
“The plasticity of the CXCR4 receptor—its ability to bind many unrelated small molecules, peptides, and proteins—is remarkable,” said Irina Kufareva, PhD, also of UC San Diego.
“Our understanding of this plasticity may impact the design of therapeutics with better inhibition and safety profiles.”
“With more than 800 members, 7-transmembrane receptors like CXCR4 are the largest protein family in the human genome,” added Raymond Stevens, PhD, of the Bridge Institute at the University of Southern California in Los Angeles. “Each new structure opens up so many doors to understanding different aspects of human biology, and this time it is about chemokine signaling.”
Ruxolitinib bests standard treatment for PV
The JAK1/2 inhibitor ruxolitinib can outperform standard therapy in patients with polycythemia vera (PV), results of the RESPONSE trial suggest.
In patients who could not tolerate or were resistant to hydroxyurea, ruxolitinib proved superior to standard therapy for controlling hematocrit levels and reducing spleen volume
“This study indicates that ruxolitinib may represent an important advance for this population of patients with PV,” said Alessandro M. Vannucchi, MD, of the University of Florence in Italy.
Dr Vannucchi and his colleagues reported these findings in NEJM. The trial was funded by Incyte Corporation, the company developing ruxolitinib.
The phase 3 study included 222 patients. They were phlebotomy-dependent, had splenomegaly, and could not tolerate or were resistant to hydroxyurea.
The patients were randomized 1:1 to receive either ruxolitinib (starting dose of 10 mg twice daily) or standard therapy, which was defined as investigator-selected monotherapy or observation only. The ruxolitinib dose was adjusted as needed throughout the study.
The primary endpoint was a composite of hematocrit control and spleen reduction. To meet the endpoint, patients had to experience a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.
And a patient’s hematocrit was considered under control if he was not eligible for phlebotomy from week 8 through 32 (and had no more than one instance of phlebotomy eligibility between randomization and week 8). Patients who were deemed eligible for phlebotomy had hematocrit that was greater than 45% or had increased 3 or more percentage points from the time they entered the study.
So 21% of patients in the ruxolitinib group met the primary endpoint, achieving both hematocrit control and spleen reduction. But only 1% of patients in the standard-therapy group did the same (P<0.001).
In all, 60% of patients in the ruxolitinib arm achieved hematocrit control, compared to 20% of those receiving standard therapy. And 38% of patients in the ruxolitinib arm had at least a 35% spleen reduction, compared to 1% of patients in the standard-therapy arm.
The rate of complete hematologic remission was significantly higher in the ruxolitinib group than in the standard-therapy group, at 24% and 9%, respectively (P=0.003).
And ruxolitinib-treated patients had a greater reduction in overall symptoms. Forty-nine percent of ruxolitinib-treated patients had at least a 50% reduction in their total symptom score at week 32 (as measured by the MPN-SAF 14-item total symptom score), compared to 5% of patients on standard therapy.
Based on these results, most patients in the standard-therapy arm crossed over to receive ruxolitinib immediately after week 32. So the researchers could only compare rates of adverse events through week 32.
They found that grade 3/4 anemia was more common with ruxolitinib than with standard therapy (2% and 0%, respectively). The same was true of grade 3/4 thrombocytopenia (5% and 4%, respectively) and herpes zoster infections of all grades (6% and 0%, respectively).
However, thromboembolic events were more common with standard therapy. They occurred in 6 patients who received standard therapy and 1 ruxolitinib-treated patient.
The most common non-hematologic adverse events in the ruxolitinib arm were headache (16%), diarrhea (15%), and fatigue (15%), which were mainly grade 1 or 2. The rates of these events in the standard therapy arm were 19%, 7%, and 15%, respectively.
The researchers also noted that nearly 85% of patients randomized to ruxolitinib were still receiving treatment at a median follow-up of 81 weeks.
The JAK1/2 inhibitor ruxolitinib can outperform standard therapy in patients with polycythemia vera (PV), results of the RESPONSE trial suggest.
In patients who could not tolerate or were resistant to hydroxyurea, ruxolitinib proved superior to standard therapy for controlling hematocrit levels and reducing spleen volume
“This study indicates that ruxolitinib may represent an important advance for this population of patients with PV,” said Alessandro M. Vannucchi, MD, of the University of Florence in Italy.
Dr Vannucchi and his colleagues reported these findings in NEJM. The trial was funded by Incyte Corporation, the company developing ruxolitinib.
The phase 3 study included 222 patients. They were phlebotomy-dependent, had splenomegaly, and could not tolerate or were resistant to hydroxyurea.
The patients were randomized 1:1 to receive either ruxolitinib (starting dose of 10 mg twice daily) or standard therapy, which was defined as investigator-selected monotherapy or observation only. The ruxolitinib dose was adjusted as needed throughout the study.
The primary endpoint was a composite of hematocrit control and spleen reduction. To meet the endpoint, patients had to experience a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.
And a patient’s hematocrit was considered under control if he was not eligible for phlebotomy from week 8 through 32 (and had no more than one instance of phlebotomy eligibility between randomization and week 8). Patients who were deemed eligible for phlebotomy had hematocrit that was greater than 45% or had increased 3 or more percentage points from the time they entered the study.
So 21% of patients in the ruxolitinib group met the primary endpoint, achieving both hematocrit control and spleen reduction. But only 1% of patients in the standard-therapy group did the same (P<0.001).
In all, 60% of patients in the ruxolitinib arm achieved hematocrit control, compared to 20% of those receiving standard therapy. And 38% of patients in the ruxolitinib arm had at least a 35% spleen reduction, compared to 1% of patients in the standard-therapy arm.
The rate of complete hematologic remission was significantly higher in the ruxolitinib group than in the standard-therapy group, at 24% and 9%, respectively (P=0.003).
And ruxolitinib-treated patients had a greater reduction in overall symptoms. Forty-nine percent of ruxolitinib-treated patients had at least a 50% reduction in their total symptom score at week 32 (as measured by the MPN-SAF 14-item total symptom score), compared to 5% of patients on standard therapy.
Based on these results, most patients in the standard-therapy arm crossed over to receive ruxolitinib immediately after week 32. So the researchers could only compare rates of adverse events through week 32.
They found that grade 3/4 anemia was more common with ruxolitinib than with standard therapy (2% and 0%, respectively). The same was true of grade 3/4 thrombocytopenia (5% and 4%, respectively) and herpes zoster infections of all grades (6% and 0%, respectively).
However, thromboembolic events were more common with standard therapy. They occurred in 6 patients who received standard therapy and 1 ruxolitinib-treated patient.
The most common non-hematologic adverse events in the ruxolitinib arm were headache (16%), diarrhea (15%), and fatigue (15%), which were mainly grade 1 or 2. The rates of these events in the standard therapy arm were 19%, 7%, and 15%, respectively.
The researchers also noted that nearly 85% of patients randomized to ruxolitinib were still receiving treatment at a median follow-up of 81 weeks.
The JAK1/2 inhibitor ruxolitinib can outperform standard therapy in patients with polycythemia vera (PV), results of the RESPONSE trial suggest.
In patients who could not tolerate or were resistant to hydroxyurea, ruxolitinib proved superior to standard therapy for controlling hematocrit levels and reducing spleen volume
“This study indicates that ruxolitinib may represent an important advance for this population of patients with PV,” said Alessandro M. Vannucchi, MD, of the University of Florence in Italy.
Dr Vannucchi and his colleagues reported these findings in NEJM. The trial was funded by Incyte Corporation, the company developing ruxolitinib.
The phase 3 study included 222 patients. They were phlebotomy-dependent, had splenomegaly, and could not tolerate or were resistant to hydroxyurea.
The patients were randomized 1:1 to receive either ruxolitinib (starting dose of 10 mg twice daily) or standard therapy, which was defined as investigator-selected monotherapy or observation only. The ruxolitinib dose was adjusted as needed throughout the study.
The primary endpoint was a composite of hematocrit control and spleen reduction. To meet the endpoint, patients had to experience a 35% or greater reduction in spleen volume from baseline, as assessed by imaging at week 32.
And a patient’s hematocrit was considered under control if he was not eligible for phlebotomy from week 8 through 32 (and had no more than one instance of phlebotomy eligibility between randomization and week 8). Patients who were deemed eligible for phlebotomy had hematocrit that was greater than 45% or had increased 3 or more percentage points from the time they entered the study.
So 21% of patients in the ruxolitinib group met the primary endpoint, achieving both hematocrit control and spleen reduction. But only 1% of patients in the standard-therapy group did the same (P<0.001).
In all, 60% of patients in the ruxolitinib arm achieved hematocrit control, compared to 20% of those receiving standard therapy. And 38% of patients in the ruxolitinib arm had at least a 35% spleen reduction, compared to 1% of patients in the standard-therapy arm.
The rate of complete hematologic remission was significantly higher in the ruxolitinib group than in the standard-therapy group, at 24% and 9%, respectively (P=0.003).
And ruxolitinib-treated patients had a greater reduction in overall symptoms. Forty-nine percent of ruxolitinib-treated patients had at least a 50% reduction in their total symptom score at week 32 (as measured by the MPN-SAF 14-item total symptom score), compared to 5% of patients on standard therapy.
Based on these results, most patients in the standard-therapy arm crossed over to receive ruxolitinib immediately after week 32. So the researchers could only compare rates of adverse events through week 32.
They found that grade 3/4 anemia was more common with ruxolitinib than with standard therapy (2% and 0%, respectively). The same was true of grade 3/4 thrombocytopenia (5% and 4%, respectively) and herpes zoster infections of all grades (6% and 0%, respectively).
However, thromboembolic events were more common with standard therapy. They occurred in 6 patients who received standard therapy and 1 ruxolitinib-treated patient.
The most common non-hematologic adverse events in the ruxolitinib arm were headache (16%), diarrhea (15%), and fatigue (15%), which were mainly grade 1 or 2. The rates of these events in the standard therapy arm were 19%, 7%, and 15%, respectively.
The researchers also noted that nearly 85% of patients randomized to ruxolitinib were still receiving treatment at a median follow-up of 81 weeks.
Discovery could help make Ras druggable
Credit: Jes Andersen/
University of Copenhagen
Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.
The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.
What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.
“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.
“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”
Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.
Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.
Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.
“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.
Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.
The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.
He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.
“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”
All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.
“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”
Credit: Jes Andersen/
University of Copenhagen
Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.
The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.
What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.
“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.
“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”
Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.
Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.
Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.
“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.
Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.
The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.
He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.
“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”
All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.
“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”
Credit: Jes Andersen/
University of Copenhagen
Researchers say they have discovered how Ras proteins find their proper place in cells, a finding that may aid the development of novel approaches to treat cancers.
The team noted that cancers develop if Ras proteins start to trigger misregulation, and Ras misregulates if it misses its correct location on the cell wall—the membrane.
What the researchers discovered is that Ras cannot reach its designated location if the membrane has the wrong shape.
“If the curvature of the cell is right, Ras goes to the right place,” said Dimitrios Stamou, PhD, of the University of Copenhagen in Denmark.
“If the membrane is too straight or too bent, it does not. And Ras is very much like any other worker. If it never finds the way to its workplace, it is not likely to get any work done.”
Dr Stamou and his colleagues described this discovery in Nature Chemical Biology.
Ras proteins are thought to be misregulated in upwards of 30% of all cancers. For 3 decades, researchers have been searching for ways to quell the killer protein.
Their lack of success has given Ras a reputation as the “undruggable cancer target,” but Dr Stamou believes we can change by moving in a new direction.
“If Ras goes off the rails because of changes in the curvature of the cell, perhaps we should target whatever changes the shape of the cell membrane,” he said.
Looking for a correlation between cell shape and Ras misregulation was unusual, even bordering on controversial, said study author Jannik Bruun Larsen, PhD, of the University of Copenhagen.
The researchers were investigating how Ras proteins attach themselves to the cell wall, and Dr Larsen tried to attach Ras to a variety of simulated cell membranes formed into small spheres or vesicles of varying sizes.
He found that Ras would attach more readily to smaller spheres, which were more curved than the large ones, and Dr Larsen started to see a pattern.
“For more than a decade, people thought that the constituents of the cell wall was the thing that controlled where Ras was localized,” Dr Larson said. “We have shown that at least one other aspect—namely, membrane curvature—governs where Ras ends up in the cell and is therefore likely to be a factor in cancer development.”
All of the research so far has been conducted in vitro. Dr Stamou said the next big challenge is to uncover how these effects play out in living systems.
“It will be 10 times more difficult to uncover these effects in living systems, but it needs to happen,” he said. “We have started, and we really hope others will follow. It may prove complicated to develop a drug that changes the shape of cells, but I am certain that the discovery of the shape/misregulation-correlation will at least lead to new ways to diagnose cancers.”
Cell imaging gets colorful
Credit: Rhoda Baer
The detection and imaging of protein-protein interactions in live cells just got a lot more colorful, researchers have reported in Nature Methods.
The team created a technique that converts biochemical processes into color changes that are easily visualized.
The group said this provides a new tool scientists can use to answer questions about fundamental mechanisms in cell biology, aid the discovery of novel therapeutics, and more.
Robert E. Campbell, PhD, of the University of Alberta in Edmonton, Alberta, Canada, and his colleagues conducted this research.
They developed the technique, dubbed FPX, that employs genetically encoded fluorescent proteins to image dynamic biochemical events in live cells and tissues. The FPX method converts a change in protein-protein interactions into a dramatic green to red (or vice versa) color change that is immediately visible.
“Strategies for converting fluorescent proteins into active biosensors of intracellular biochemistry are few in number and technically challenging,” Dr Campbell said. “With this development, we can immediately image activity happening at the cellular level, offering an alternative to existing methods for detecting and imaging of protein-protein interactions in live cells.”
The FPX method is based on green and red dimerization-dependent fluorescent proteins (ddFPs) that Dr Campbell and his colleagues first reported in 2012.
Yidan Ding, PhD, a research assistant at the University of Alberta and the primary contributor to this work, found she could combine the use of both green and red ddFPs in single cells, such that the proteins could be green or red, but not both, at the same time.
By introducing modified versions of the proteins into live cells, and taking advantage of the fact that green and red fluorescence are mutually exclusive, Dr Ding was able to construct a wide variety of biosensors that underwent dramatic changes in fluorescence in response to biochemical processes of interest.
By adding this new dimension to fluorescent proteins and engineering them to be biosensors that change their color in response to specific biological events, Drs Ding and Campbell and their colleagues have provided a tool for researchers to immediately pinpoint a major change at the cellular level.
This minimizes the need for extensive biosensor optimization and provides a versatile new approach to building the next generation of biosensors.
“This allows for a wide scope of applications,” Dr Campbell said. “It will be immediately relevant to many areas of fundamental cell biology research and practical applications such as drug discovery. Ultimately, it will help researchers achieve breakthroughs in a wide variety of areas in the life sciences, such as neuroscience, diabetes, and cancer.”
Dr Campbell has a patent pending on the technology.
Credit: Rhoda Baer
The detection and imaging of protein-protein interactions in live cells just got a lot more colorful, researchers have reported in Nature Methods.
The team created a technique that converts biochemical processes into color changes that are easily visualized.
The group said this provides a new tool scientists can use to answer questions about fundamental mechanisms in cell biology, aid the discovery of novel therapeutics, and more.
Robert E. Campbell, PhD, of the University of Alberta in Edmonton, Alberta, Canada, and his colleagues conducted this research.
They developed the technique, dubbed FPX, that employs genetically encoded fluorescent proteins to image dynamic biochemical events in live cells and tissues. The FPX method converts a change in protein-protein interactions into a dramatic green to red (or vice versa) color change that is immediately visible.
“Strategies for converting fluorescent proteins into active biosensors of intracellular biochemistry are few in number and technically challenging,” Dr Campbell said. “With this development, we can immediately image activity happening at the cellular level, offering an alternative to existing methods for detecting and imaging of protein-protein interactions in live cells.”
The FPX method is based on green and red dimerization-dependent fluorescent proteins (ddFPs) that Dr Campbell and his colleagues first reported in 2012.
Yidan Ding, PhD, a research assistant at the University of Alberta and the primary contributor to this work, found she could combine the use of both green and red ddFPs in single cells, such that the proteins could be green or red, but not both, at the same time.
By introducing modified versions of the proteins into live cells, and taking advantage of the fact that green and red fluorescence are mutually exclusive, Dr Ding was able to construct a wide variety of biosensors that underwent dramatic changes in fluorescence in response to biochemical processes of interest.
By adding this new dimension to fluorescent proteins and engineering them to be biosensors that change their color in response to specific biological events, Drs Ding and Campbell and their colleagues have provided a tool for researchers to immediately pinpoint a major change at the cellular level.
This minimizes the need for extensive biosensor optimization and provides a versatile new approach to building the next generation of biosensors.
“This allows for a wide scope of applications,” Dr Campbell said. “It will be immediately relevant to many areas of fundamental cell biology research and practical applications such as drug discovery. Ultimately, it will help researchers achieve breakthroughs in a wide variety of areas in the life sciences, such as neuroscience, diabetes, and cancer.”
Dr Campbell has a patent pending on the technology.
Credit: Rhoda Baer
The detection and imaging of protein-protein interactions in live cells just got a lot more colorful, researchers have reported in Nature Methods.
The team created a technique that converts biochemical processes into color changes that are easily visualized.
The group said this provides a new tool scientists can use to answer questions about fundamental mechanisms in cell biology, aid the discovery of novel therapeutics, and more.
Robert E. Campbell, PhD, of the University of Alberta in Edmonton, Alberta, Canada, and his colleagues conducted this research.
They developed the technique, dubbed FPX, that employs genetically encoded fluorescent proteins to image dynamic biochemical events in live cells and tissues. The FPX method converts a change in protein-protein interactions into a dramatic green to red (or vice versa) color change that is immediately visible.
“Strategies for converting fluorescent proteins into active biosensors of intracellular biochemistry are few in number and technically challenging,” Dr Campbell said. “With this development, we can immediately image activity happening at the cellular level, offering an alternative to existing methods for detecting and imaging of protein-protein interactions in live cells.”
The FPX method is based on green and red dimerization-dependent fluorescent proteins (ddFPs) that Dr Campbell and his colleagues first reported in 2012.
Yidan Ding, PhD, a research assistant at the University of Alberta and the primary contributor to this work, found she could combine the use of both green and red ddFPs in single cells, such that the proteins could be green or red, but not both, at the same time.
By introducing modified versions of the proteins into live cells, and taking advantage of the fact that green and red fluorescence are mutually exclusive, Dr Ding was able to construct a wide variety of biosensors that underwent dramatic changes in fluorescence in response to biochemical processes of interest.
By adding this new dimension to fluorescent proteins and engineering them to be biosensors that change their color in response to specific biological events, Drs Ding and Campbell and their colleagues have provided a tool for researchers to immediately pinpoint a major change at the cellular level.
This minimizes the need for extensive biosensor optimization and provides a versatile new approach to building the next generation of biosensors.
“This allows for a wide scope of applications,” Dr Campbell said. “It will be immediately relevant to many areas of fundamental cell biology research and practical applications such as drug discovery. Ultimately, it will help researchers achieve breakthroughs in a wide variety of areas in the life sciences, such as neuroscience, diabetes, and cancer.”
Dr Campbell has a patent pending on the technology.
Gene variation explains drug toxicity in ALL
Credit: Peter Barta
Inherited variations in the NUDT15 gene can reduce tolerance of the drug mercaptopurine in children with acute lymphoblastic leukemia (ALL), according to research published in the Journal of Clinical Oncology.
The study showed that patients who inherited one or two copies of the newly identified variation in the NUDT15 gene were extremely sensitive to mercaptopurine.
The patients required dose reductions of as much as 92%.
And when mercaptopurine was given at standard doses, the patients developed side effects that caused treatment delays.
These findings should aid efforts to improve the identification and treatment of patients who need reduced doses of mercaptopurine, according to researchers.
“Mercaptopurine intolerance has been suspected to be a problem for young ALL patients of East Asian ancestry,” said study author Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.
“Even at very low doses, the patients often develop toxicity that delays treatment. But, until now, the genetic basis of the problem was unknown.”
With that in mind, Dr Yang and his colleagues performed a genome-wide association study in children with ALL who received mercaptopurine treatment regimens. The discovery and replication cohorts included 657 and 371 children, respectively, from two prospective trials.
The research revealed that patients of East Asian and Hispanic background were more likely to inherit the NUDT15 variant than patients from other racial and ethnic groups.
Among patients of East Asian ancestry, 9.8% carried at least one copy of the NUDT15 variant, compared to 3.9% of Hispanic patients. (East Asia includes China, Japan, and Korea.)
The NUDT15 variant was rarer among patients of European or African ancestry.
This study also confirmed previous research that showed variations in another gene, TPMT, are associated with an increased risk of mercaptopurine toxicity.
TPMT carries instructions for assembling an enzyme of the same name that inactivates mercaptopurine and related drugs. The TPMT variants are less able to inactivate the drug, which can lead to a dangerous build-up of mercaptopurine and suppression of the immune system.
The researchers suspect the NUDT15 variant acts in a similar fashion.
Regardless, the team found that 100% of children who were homozygous for either TPMT or NUDT15 variants or heterozygous for both required at least a 50% reduction in mercaptopurine dose. Only 7.7% of the other patients required similar reductions.
“The results of this study confirm that TPMT genetic variation is one of the most critical determinants of mercaptopurine tolerance, particularly in non-East Asian populations,” said senior study author Mary Relling, PharmD, of St Jude.
“But we also found that TPMT variants do not completely explain mercaptopurine intolerance, particularly in patients of East Asian ancestry. Other factors, both genetic and non-genetic, are still to be discovered to improve the safety and effectiveness of mercaptopurine treatment for children with ALL.”
Credit: Peter Barta
Inherited variations in the NUDT15 gene can reduce tolerance of the drug mercaptopurine in children with acute lymphoblastic leukemia (ALL), according to research published in the Journal of Clinical Oncology.
The study showed that patients who inherited one or two copies of the newly identified variation in the NUDT15 gene were extremely sensitive to mercaptopurine.
The patients required dose reductions of as much as 92%.
And when mercaptopurine was given at standard doses, the patients developed side effects that caused treatment delays.
These findings should aid efforts to improve the identification and treatment of patients who need reduced doses of mercaptopurine, according to researchers.
“Mercaptopurine intolerance has been suspected to be a problem for young ALL patients of East Asian ancestry,” said study author Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.
“Even at very low doses, the patients often develop toxicity that delays treatment. But, until now, the genetic basis of the problem was unknown.”
With that in mind, Dr Yang and his colleagues performed a genome-wide association study in children with ALL who received mercaptopurine treatment regimens. The discovery and replication cohorts included 657 and 371 children, respectively, from two prospective trials.
The research revealed that patients of East Asian and Hispanic background were more likely to inherit the NUDT15 variant than patients from other racial and ethnic groups.
Among patients of East Asian ancestry, 9.8% carried at least one copy of the NUDT15 variant, compared to 3.9% of Hispanic patients. (East Asia includes China, Japan, and Korea.)
The NUDT15 variant was rarer among patients of European or African ancestry.
This study also confirmed previous research that showed variations in another gene, TPMT, are associated with an increased risk of mercaptopurine toxicity.
TPMT carries instructions for assembling an enzyme of the same name that inactivates mercaptopurine and related drugs. The TPMT variants are less able to inactivate the drug, which can lead to a dangerous build-up of mercaptopurine and suppression of the immune system.
The researchers suspect the NUDT15 variant acts in a similar fashion.
Regardless, the team found that 100% of children who were homozygous for either TPMT or NUDT15 variants or heterozygous for both required at least a 50% reduction in mercaptopurine dose. Only 7.7% of the other patients required similar reductions.
“The results of this study confirm that TPMT genetic variation is one of the most critical determinants of mercaptopurine tolerance, particularly in non-East Asian populations,” said senior study author Mary Relling, PharmD, of St Jude.
“But we also found that TPMT variants do not completely explain mercaptopurine intolerance, particularly in patients of East Asian ancestry. Other factors, both genetic and non-genetic, are still to be discovered to improve the safety and effectiveness of mercaptopurine treatment for children with ALL.”
Credit: Peter Barta
Inherited variations in the NUDT15 gene can reduce tolerance of the drug mercaptopurine in children with acute lymphoblastic leukemia (ALL), according to research published in the Journal of Clinical Oncology.
The study showed that patients who inherited one or two copies of the newly identified variation in the NUDT15 gene were extremely sensitive to mercaptopurine.
The patients required dose reductions of as much as 92%.
And when mercaptopurine was given at standard doses, the patients developed side effects that caused treatment delays.
These findings should aid efforts to improve the identification and treatment of patients who need reduced doses of mercaptopurine, according to researchers.
“Mercaptopurine intolerance has been suspected to be a problem for young ALL patients of East Asian ancestry,” said study author Jun J. Yang, PhD, of St Jude Children’s Research Hospital in Memphis, Tennessee.
“Even at very low doses, the patients often develop toxicity that delays treatment. But, until now, the genetic basis of the problem was unknown.”
With that in mind, Dr Yang and his colleagues performed a genome-wide association study in children with ALL who received mercaptopurine treatment regimens. The discovery and replication cohorts included 657 and 371 children, respectively, from two prospective trials.
The research revealed that patients of East Asian and Hispanic background were more likely to inherit the NUDT15 variant than patients from other racial and ethnic groups.
Among patients of East Asian ancestry, 9.8% carried at least one copy of the NUDT15 variant, compared to 3.9% of Hispanic patients. (East Asia includes China, Japan, and Korea.)
The NUDT15 variant was rarer among patients of European or African ancestry.
This study also confirmed previous research that showed variations in another gene, TPMT, are associated with an increased risk of mercaptopurine toxicity.
TPMT carries instructions for assembling an enzyme of the same name that inactivates mercaptopurine and related drugs. The TPMT variants are less able to inactivate the drug, which can lead to a dangerous build-up of mercaptopurine and suppression of the immune system.
The researchers suspect the NUDT15 variant acts in a similar fashion.
Regardless, the team found that 100% of children who were homozygous for either TPMT or NUDT15 variants or heterozygous for both required at least a 50% reduction in mercaptopurine dose. Only 7.7% of the other patients required similar reductions.
“The results of this study confirm that TPMT genetic variation is one of the most critical determinants of mercaptopurine tolerance, particularly in non-East Asian populations,” said senior study author Mary Relling, PharmD, of St Jude.
“But we also found that TPMT variants do not completely explain mercaptopurine intolerance, particularly in patients of East Asian ancestry. Other factors, both genetic and non-genetic, are still to be discovered to improve the safety and effectiveness of mercaptopurine treatment for children with ALL.”