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How malaria increases the risk of Burkitt lymphoma
Image by Ed Uthman
A link between malaria and Burkitt lymphoma was first described more than 50 years ago, but how the parasitic infection promotes lymphomagenesis has remained a mystery.
Now, research in mice has revealed that B-cell DNA becomes vulnerable to cancer-causing mutations during prolonged combat against the malaria parasite.
Davide Robbiani, MD, PhD, of The Rockefeller University in New York, New York, and his colleagues described this research in Cell.
The team infected mice with the malaria parasite Plasmodium chabaudi and, immediately, the mice experienced an increase in germinal center (GC) B lymphocytes, which can give rise to Burkitt lymphoma.
“In malaria-infected mice, these cells divide very rapidly over the course of months,” Dr Robbiani said.
As the GC B lymphocytes proliferate, they also express high levels of activation-induced cytidine deaminase (AID), which induces mutations in their DNA. As a result, these cells can diversify to generate a wide range of antibodies.
But in addition to beneficial mutations in antibody genes, AID can cause off-target damage and shuffling of cancer-causing genes.
“In mice infected with the malaria parasite, these so-called chromosomal rearrangements occur very frequently in GC lymphocytes,” Dr Robbiani said. “And at least some of the changes are due to AID.”
To further investigate this phenomenon, the researchers bred mice lacking the p53 gene, which is known to protect cells from Burkitt lymphoma. All of the mice that expressed AID but not p53 ultimately developed lymphoma.
And when these mice were infected with the malaria parasite, they developed lymphomas specifically in mature B cells, similar to what happens in Burkitt lymphoma.
“This finding sheds new light on a long-standing mystery of why two seemingly different diseases are associated with each other,” Dr Robbiani said.
Researchers are now attempting to determine how AID causes its off-target damage to DNA, which could lead to new treatments.
“If we could somehow limit this collateral damage to cancer-causing genes without reducing the infection-fighting powers of B cells, that could be very useful,” Dr Robbiani said. “But first, we have to find out how the collateral DNA damage occurs in the first place.”
Dr Robbiani noted that hepatitis C virus and Helicobacter pylori infections, as well as some autoimmune diseases, are also linked with
chronic B lymphocyte activation and an increased risk of lymphoma.
Therefore,
strategies aimed at reducing unintended DNA damage caused by AID might
also help reduce the risk of lymphoma in patients with these conditions.
“It’s possible that AID also plays a role in the association between these other infections and cancer,” Dr Robbiani said. “This is purely a speculation at this point, though highly suggestive.” 
Image by Ed Uthman
A link between malaria and Burkitt lymphoma was first described more than 50 years ago, but how the parasitic infection promotes lymphomagenesis has remained a mystery.
Now, research in mice has revealed that B-cell DNA becomes vulnerable to cancer-causing mutations during prolonged combat against the malaria parasite.
Davide Robbiani, MD, PhD, of The Rockefeller University in New York, New York, and his colleagues described this research in Cell.
The team infected mice with the malaria parasite Plasmodium chabaudi and, immediately, the mice experienced an increase in germinal center (GC) B lymphocytes, which can give rise to Burkitt lymphoma.
“In malaria-infected mice, these cells divide very rapidly over the course of months,” Dr Robbiani said.
As the GC B lymphocytes proliferate, they also express high levels of activation-induced cytidine deaminase (AID), which induces mutations in their DNA. As a result, these cells can diversify to generate a wide range of antibodies.
But in addition to beneficial mutations in antibody genes, AID can cause off-target damage and shuffling of cancer-causing genes.
“In mice infected with the malaria parasite, these so-called chromosomal rearrangements occur very frequently in GC lymphocytes,” Dr Robbiani said. “And at least some of the changes are due to AID.”
To further investigate this phenomenon, the researchers bred mice lacking the p53 gene, which is known to protect cells from Burkitt lymphoma. All of the mice that expressed AID but not p53 ultimately developed lymphoma.
And when these mice were infected with the malaria parasite, they developed lymphomas specifically in mature B cells, similar to what happens in Burkitt lymphoma.
“This finding sheds new light on a long-standing mystery of why two seemingly different diseases are associated with each other,” Dr Robbiani said.
Researchers are now attempting to determine how AID causes its off-target damage to DNA, which could lead to new treatments.
“If we could somehow limit this collateral damage to cancer-causing genes without reducing the infection-fighting powers of B cells, that could be very useful,” Dr Robbiani said. “But first, we have to find out how the collateral DNA damage occurs in the first place.”
Dr Robbiani noted that hepatitis C virus and Helicobacter pylori infections, as well as some autoimmune diseases, are also linked with
chronic B lymphocyte activation and an increased risk of lymphoma.
Therefore,
strategies aimed at reducing unintended DNA damage caused by AID might
also help reduce the risk of lymphoma in patients with these conditions.
“It’s possible that AID also plays a role in the association between these other infections and cancer,” Dr Robbiani said. “This is purely a speculation at this point, though highly suggestive.”
Image by Ed Uthman
A link between malaria and Burkitt lymphoma was first described more than 50 years ago, but how the parasitic infection promotes lymphomagenesis has remained a mystery.
Now, research in mice has revealed that B-cell DNA becomes vulnerable to cancer-causing mutations during prolonged combat against the malaria parasite.
Davide Robbiani, MD, PhD, of The Rockefeller University in New York, New York, and his colleagues described this research in Cell.
The team infected mice with the malaria parasite Plasmodium chabaudi and, immediately, the mice experienced an increase in germinal center (GC) B lymphocytes, which can give rise to Burkitt lymphoma.
“In malaria-infected mice, these cells divide very rapidly over the course of months,” Dr Robbiani said.
As the GC B lymphocytes proliferate, they also express high levels of activation-induced cytidine deaminase (AID), which induces mutations in their DNA. As a result, these cells can diversify to generate a wide range of antibodies.
But in addition to beneficial mutations in antibody genes, AID can cause off-target damage and shuffling of cancer-causing genes.
“In mice infected with the malaria parasite, these so-called chromosomal rearrangements occur very frequently in GC lymphocytes,” Dr Robbiani said. “And at least some of the changes are due to AID.”
To further investigate this phenomenon, the researchers bred mice lacking the p53 gene, which is known to protect cells from Burkitt lymphoma. All of the mice that expressed AID but not p53 ultimately developed lymphoma.
And when these mice were infected with the malaria parasite, they developed lymphomas specifically in mature B cells, similar to what happens in Burkitt lymphoma.
“This finding sheds new light on a long-standing mystery of why two seemingly different diseases are associated with each other,” Dr Robbiani said.
Researchers are now attempting to determine how AID causes its off-target damage to DNA, which could lead to new treatments.
“If we could somehow limit this collateral damage to cancer-causing genes without reducing the infection-fighting powers of B cells, that could be very useful,” Dr Robbiani said. “But first, we have to find out how the collateral DNA damage occurs in the first place.”
Dr Robbiani noted that hepatitis C virus and Helicobacter pylori infections, as well as some autoimmune diseases, are also linked with
chronic B lymphocyte activation and an increased risk of lymphoma.
Therefore,
strategies aimed at reducing unintended DNA damage caused by AID might
also help reduce the risk of lymphoma in patients with these conditions.
“It’s possible that AID also plays a role in the association between these other infections and cancer,” Dr Robbiani said. “This is purely a speculation at this point, though highly suggestive.”
Algorithm can enhance clustering, aid trial design
Chenyue Wendy Hu
Photo courtesy of Jeff Fitlow
and Rice University
A newly developed algorithm for “big data” could have a significant impact on clinical trials, according to researchers.
The algorithm, called progeny clustering, was the only method to successfully reveal “clinically meaningful” groupings of proteomic data from patients with acute myeloid leukemia.
And the algorithm is currently being used in a hospital study to identify optimal treatment for children with leukemia.
Details on progeny clustering have been published in Scientific Reports.
The authors noted that clustering is important for its ability to reveal information in complex sets of data like medical records.
“Doctors who design clinical trials need to know how to group patients so they receive the most appropriate treatment,” said author Amina Qutub, PhD, of Rice University in Houston, Texas. “First, they need to estimate the optimal number of clusters in their data.”
The more accurate the clusters, the more personalized the treatment can be, Dr Qutub said. She added that separating groups by a single data point would be easy, but when separating patients by the types of proteins in their bloodstreams, for example, it becomes more difficult.
“That’s the kind of data that’s become prevalent everywhere in biology, and it’s good to have,” Dr Qutub said. “We want to know hundreds of features about a single person. The problem is identifying how to use all that data.”
Progeny clustering provides a way to ensure the number of clusters is as accurate as possible, Dr Qutub said. The algorithm extracts characteristics about patients from a data set, mixing and matching them randomly to create artificial populations—the “progeny” of the parent data. The characteristics appear in roughly the same ratios in the progeny as they do among the parents.
These characteristics, called dimensions, can be anything: as simple as hair color or place of birth, or as detailed as blood cell count or the proteins expressed by tumor cells. For even a small population, each individual may have hundreds or thousands of dimensions.
By creating progeny with the same dimensions of features, the algorithm increases the size of the data set. With this additional data, the distinct patterns become more apparent, allowing the algorithm to optimize the number of clusters that warrant attention from doctors and researchers.
Dr Qutub said this technique is just as reliable as state-of-the-art clustering evaluation algorithms, but at a fraction of the computational cost. In lab tests, progeny clustering compared favorably to other popular methods.
And it was the only method to provide clinically meaningful groupings in an acute myeloid leukemia reverse-phase protein array data set.
Progeny clustering also allows researchers to determine the ideal number of clusters in small populations, Dr Qutub noted.
The algorithm was used to design an ongoing trial involving leukemia patients at Texas Children’s Hospital.
“Progeny clustering allowed them to design a robust clinical trial, even though that trial did not involve a large number of children,” Dr Qutub said. “It meant they didn’t have to wait to enroll more.”
Dr Qutub added that the algorithm could apply to any data set.
“We could just as easily use it for a population of voters to see who should get campaign materials from a candidate,” she said. “Progeny clustering has a lot of possible applications.”
Dr Qutub and her colleagues plan to make the algorithm available for free on her lab’s website.
Chenyue Wendy Hu
Photo courtesy of Jeff Fitlow
and Rice University
A newly developed algorithm for “big data” could have a significant impact on clinical trials, according to researchers.
The algorithm, called progeny clustering, was the only method to successfully reveal “clinically meaningful” groupings of proteomic data from patients with acute myeloid leukemia.
And the algorithm is currently being used in a hospital study to identify optimal treatment for children with leukemia.
Details on progeny clustering have been published in Scientific Reports.
The authors noted that clustering is important for its ability to reveal information in complex sets of data like medical records.
“Doctors who design clinical trials need to know how to group patients so they receive the most appropriate treatment,” said author Amina Qutub, PhD, of Rice University in Houston, Texas. “First, they need to estimate the optimal number of clusters in their data.”
The more accurate the clusters, the more personalized the treatment can be, Dr Qutub said. She added that separating groups by a single data point would be easy, but when separating patients by the types of proteins in their bloodstreams, for example, it becomes more difficult.
“That’s the kind of data that’s become prevalent everywhere in biology, and it’s good to have,” Dr Qutub said. “We want to know hundreds of features about a single person. The problem is identifying how to use all that data.”
Progeny clustering provides a way to ensure the number of clusters is as accurate as possible, Dr Qutub said. The algorithm extracts characteristics about patients from a data set, mixing and matching them randomly to create artificial populations—the “progeny” of the parent data. The characteristics appear in roughly the same ratios in the progeny as they do among the parents.
These characteristics, called dimensions, can be anything: as simple as hair color or place of birth, or as detailed as blood cell count or the proteins expressed by tumor cells. For even a small population, each individual may have hundreds or thousands of dimensions.
By creating progeny with the same dimensions of features, the algorithm increases the size of the data set. With this additional data, the distinct patterns become more apparent, allowing the algorithm to optimize the number of clusters that warrant attention from doctors and researchers.
Dr Qutub said this technique is just as reliable as state-of-the-art clustering evaluation algorithms, but at a fraction of the computational cost. In lab tests, progeny clustering compared favorably to other popular methods.
And it was the only method to provide clinically meaningful groupings in an acute myeloid leukemia reverse-phase protein array data set.
Progeny clustering also allows researchers to determine the ideal number of clusters in small populations, Dr Qutub noted.
The algorithm was used to design an ongoing trial involving leukemia patients at Texas Children’s Hospital.
“Progeny clustering allowed them to design a robust clinical trial, even though that trial did not involve a large number of children,” Dr Qutub said. “It meant they didn’t have to wait to enroll more.”
Dr Qutub added that the algorithm could apply to any data set.
“We could just as easily use it for a population of voters to see who should get campaign materials from a candidate,” she said. “Progeny clustering has a lot of possible applications.”
Dr Qutub and her colleagues plan to make the algorithm available for free on her lab’s website.
Chenyue Wendy Hu
Photo courtesy of Jeff Fitlow
and Rice University
A newly developed algorithm for “big data” could have a significant impact on clinical trials, according to researchers.
The algorithm, called progeny clustering, was the only method to successfully reveal “clinically meaningful” groupings of proteomic data from patients with acute myeloid leukemia.
And the algorithm is currently being used in a hospital study to identify optimal treatment for children with leukemia.
Details on progeny clustering have been published in Scientific Reports.
The authors noted that clustering is important for its ability to reveal information in complex sets of data like medical records.
“Doctors who design clinical trials need to know how to group patients so they receive the most appropriate treatment,” said author Amina Qutub, PhD, of Rice University in Houston, Texas. “First, they need to estimate the optimal number of clusters in their data.”
The more accurate the clusters, the more personalized the treatment can be, Dr Qutub said. She added that separating groups by a single data point would be easy, but when separating patients by the types of proteins in their bloodstreams, for example, it becomes more difficult.
“That’s the kind of data that’s become prevalent everywhere in biology, and it’s good to have,” Dr Qutub said. “We want to know hundreds of features about a single person. The problem is identifying how to use all that data.”
Progeny clustering provides a way to ensure the number of clusters is as accurate as possible, Dr Qutub said. The algorithm extracts characteristics about patients from a data set, mixing and matching them randomly to create artificial populations—the “progeny” of the parent data. The characteristics appear in roughly the same ratios in the progeny as they do among the parents.
These characteristics, called dimensions, can be anything: as simple as hair color or place of birth, or as detailed as blood cell count or the proteins expressed by tumor cells. For even a small population, each individual may have hundreds or thousands of dimensions.
By creating progeny with the same dimensions of features, the algorithm increases the size of the data set. With this additional data, the distinct patterns become more apparent, allowing the algorithm to optimize the number of clusters that warrant attention from doctors and researchers.
Dr Qutub said this technique is just as reliable as state-of-the-art clustering evaluation algorithms, but at a fraction of the computational cost. In lab tests, progeny clustering compared favorably to other popular methods.
And it was the only method to provide clinically meaningful groupings in an acute myeloid leukemia reverse-phase protein array data set.
Progeny clustering also allows researchers to determine the ideal number of clusters in small populations, Dr Qutub noted.
The algorithm was used to design an ongoing trial involving leukemia patients at Texas Children’s Hospital.
“Progeny clustering allowed them to design a robust clinical trial, even though that trial did not involve a large number of children,” Dr Qutub said. “It meant they didn’t have to wait to enroll more.”
Dr Qutub added that the algorithm could apply to any data set.
“We could just as easily use it for a population of voters to see who should get campaign materials from a candidate,” she said. “Progeny clustering has a lot of possible applications.”
Dr Qutub and her colleagues plan to make the algorithm available for free on her lab’s website.
Nanoparticle-based vaccine could prevent EBV
Photo by Sakura Midori
Researchers say they have developed a nanoparticle-based vaccine against Epstein-Barr virus (EBV) that can induce potent neutralizing antibodies in mice and monkeys.
These results suggest that using a structure-based vaccine design and self-assembling nanoparticles to deliver a viral protein that prompts an immune response could be a promising approach for developing an EBV vaccine for humans.
Most efforts to develop a preventive EBV vaccine have focused on glycoprotein 350 (gp350), a molecule on the surface of EBV that helps the virus attach to B cells. EBV gp350 is thought to be a key target for antibodies capable of preventing viral infection.
Previously, researchers showed that vaccinating monkeys with gp350 protected the animals from developing lymphomas after exposure to a high dose of EBV.
However, in the only large human trial of an experimental EBV vaccine conducted to date, the EBV gp350 vaccine did not prevent EBV infection, although it did reduce the rate of infectious mononucleosis by 78%.
With this in mind, Masaru Kanekiyo, DVM, PhD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues set out to create a better vaccine.
They described their work in a paper published in Cell.
The team designed a nanoparticle-based vaccine that expressed the cell-binding portion of gp350. In tests, the experimental vaccine induced potent neutralizing antibodies in both mice and cynomolgus macaques (Macaca fascicularis).
In fact, compared with soluble gp350, the nanoparticle-based vaccine induced 10- to 100-fold higher levels of neutralizing antibodies in mice.
The researchers believe the nanoparticle vaccine design could be used to create or redesign vaccines against other pathogens as well.
Photo by Sakura Midori
Researchers say they have developed a nanoparticle-based vaccine against Epstein-Barr virus (EBV) that can induce potent neutralizing antibodies in mice and monkeys.
These results suggest that using a structure-based vaccine design and self-assembling nanoparticles to deliver a viral protein that prompts an immune response could be a promising approach for developing an EBV vaccine for humans.
Most efforts to develop a preventive EBV vaccine have focused on glycoprotein 350 (gp350), a molecule on the surface of EBV that helps the virus attach to B cells. EBV gp350 is thought to be a key target for antibodies capable of preventing viral infection.
Previously, researchers showed that vaccinating monkeys with gp350 protected the animals from developing lymphomas after exposure to a high dose of EBV.
However, in the only large human trial of an experimental EBV vaccine conducted to date, the EBV gp350 vaccine did not prevent EBV infection, although it did reduce the rate of infectious mononucleosis by 78%.
With this in mind, Masaru Kanekiyo, DVM, PhD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues set out to create a better vaccine.
They described their work in a paper published in Cell.
The team designed a nanoparticle-based vaccine that expressed the cell-binding portion of gp350. In tests, the experimental vaccine induced potent neutralizing antibodies in both mice and cynomolgus macaques (Macaca fascicularis).
In fact, compared with soluble gp350, the nanoparticle-based vaccine induced 10- to 100-fold higher levels of neutralizing antibodies in mice.
The researchers believe the nanoparticle vaccine design could be used to create or redesign vaccines against other pathogens as well.
Photo by Sakura Midori
Researchers say they have developed a nanoparticle-based vaccine against Epstein-Barr virus (EBV) that can induce potent neutralizing antibodies in mice and monkeys.
These results suggest that using a structure-based vaccine design and self-assembling nanoparticles to deliver a viral protein that prompts an immune response could be a promising approach for developing an EBV vaccine for humans.
Most efforts to develop a preventive EBV vaccine have focused on glycoprotein 350 (gp350), a molecule on the surface of EBV that helps the virus attach to B cells. EBV gp350 is thought to be a key target for antibodies capable of preventing viral infection.
Previously, researchers showed that vaccinating monkeys with gp350 protected the animals from developing lymphomas after exposure to a high dose of EBV.
However, in the only large human trial of an experimental EBV vaccine conducted to date, the EBV gp350 vaccine did not prevent EBV infection, although it did reduce the rate of infectious mononucleosis by 78%.
With this in mind, Masaru Kanekiyo, DVM, PhD, of the National Institutes of Health in Bethesda, Maryland, and his colleagues set out to create a better vaccine.
They described their work in a paper published in Cell.
The team designed a nanoparticle-based vaccine that expressed the cell-binding portion of gp350. In tests, the experimental vaccine induced potent neutralizing antibodies in both mice and cynomolgus macaques (Macaca fascicularis).
In fact, compared with soluble gp350, the nanoparticle-based vaccine induced 10- to 100-fold higher levels of neutralizing antibodies in mice.
The researchers believe the nanoparticle vaccine design could be used to create or redesign vaccines against other pathogens as well.
Tool that lets patients report AEs proves reliable
receiving chemotherapy
Photo by Rhoda Baer
Results of a multicenter study indicate that a tool cancer patients can use to report adverse events (AEs) is as accurate as other, established patient-reported and clinical measures.
The tool is the National Cancer Institute’s Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).
Study investigators were able to validate 119 of 124 PRO-CTCAE questions against 2 established measurement tools.
The 5 questions that were not validated could not be evaluated due to underrepresentation in the study population.
This research was published in JAMA Oncology.
“In most cancer clinical trials, information on side effects is collected by providers who have limited time with their patients, and current patient questionnaires are limited in scope and depth,” said study author Amylou Dueck, PhD, of the Mayo Clinic in Scottsdale, Arizona.
“PRO-CTCAE is a library of items for patients to directly report on the level of each of their symptoms, to enhance the reporting of side effects in cancer clinical trials, which is normally based on information from providers. The study itself is unprecedented, as more than 100 distinct questions about symptomatic adverse events were validated simultaneously.”
To assess the PRO-CTCAE, Dr Dueck and her colleagues recruited 975 cancer patients from 9 clinical practices across the US, including 7 cancer centers.
The patients had a range of cancers and were undergoing outpatient chemotherapy and/or radiation therapy. The investigators said these participants reflected the geographic, ethnic, racial, and economic diversity in cancer clinical trials.
The patients were asked to fill out the PRO-CTCAE questionnaire before appointments. The investigators then compared patient reports to clinician-reported Eastern Cooperative Oncology Group (ECOG) performance status and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30).
A majority of patients completed items on the PRO-CTCAE questionnaire at their first visit (96.4%, 940/975) and second visit (90.6%, 852/940).
Most patients (99.8%, 938/940) reported having at least 1 symptomatic AE, with 81.7% (768/940) reporting at least 1 AE as frequent, severe, and/or interfering “quite a bit” with daily activities.
To gauge the accuracy of the PRO-CTCAE, the investigators assessed construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items.
Construct validity
The investigators explained that construct validity reflects the association between a new measurement tool and an established measure.
Construct validity is often investigated through convergent validity, which determines whether the new tool moves in the same direction as an established instrument, and known-groups validity, which determines whether the tool can distinguish between groups of patients who are thought to be distinct.
When the investigators considered all QLQ-C30 functioning/global scales, they found that all 124 items on the PRO-CTCAE questionnaire were associated in the expected direction with 1 or more scales. One hundred and fourteen of the PRO-CTCAE items demonstrated a meaningful correlation (Pearson r≥0.1), and 111 of them were statistically significant (P<0.05 for all).
Scores for 94 of 124 PRO-CTCAE items were higher among patients with an ECOG performance status of 2 to 4 (17.1% of patients) than among patients with a score of 0 to 1. The difference was significant for 58 of the items (P<0.05 for all).
Test-retest reliability and responsiveness
The investigators said they estimated test-retest reliability using the intraclass correlation coefficient (ICC), based on a 1-way analysis of variance model with an ICC of 0.7 or greater interpreted as high.
Test-retest reliability was 0.7 or greater for 36 of 49 prespecified PRO-CTCAE items. The median ICC was 0.76 [range, 0.53-0.96).
The investigators assessed the responsiveness of PRO-CTCAE items by comparing any change from the first visit to the second visit in 27 items that were selected a priori.
Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were significant for all 27 items (P≤0.006 for all).
“This is a landmark study demonstrating that meaningful information about adverse events can be elicited from patients themselves, which is a major step for advancing the patient-centeredness of clinical trials,” said study author Ethan Basch, MD, of the Lineberger Cancer Center of the University of North Carolina in Chapel Hill.
receiving chemotherapy
Photo by Rhoda Baer
Results of a multicenter study indicate that a tool cancer patients can use to report adverse events (AEs) is as accurate as other, established patient-reported and clinical measures.
The tool is the National Cancer Institute’s Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).
Study investigators were able to validate 119 of 124 PRO-CTCAE questions against 2 established measurement tools.
The 5 questions that were not validated could not be evaluated due to underrepresentation in the study population.
This research was published in JAMA Oncology.
“In most cancer clinical trials, information on side effects is collected by providers who have limited time with their patients, and current patient questionnaires are limited in scope and depth,” said study author Amylou Dueck, PhD, of the Mayo Clinic in Scottsdale, Arizona.
“PRO-CTCAE is a library of items for patients to directly report on the level of each of their symptoms, to enhance the reporting of side effects in cancer clinical trials, which is normally based on information from providers. The study itself is unprecedented, as more than 100 distinct questions about symptomatic adverse events were validated simultaneously.”
To assess the PRO-CTCAE, Dr Dueck and her colleagues recruited 975 cancer patients from 9 clinical practices across the US, including 7 cancer centers.
The patients had a range of cancers and were undergoing outpatient chemotherapy and/or radiation therapy. The investigators said these participants reflected the geographic, ethnic, racial, and economic diversity in cancer clinical trials.
The patients were asked to fill out the PRO-CTCAE questionnaire before appointments. The investigators then compared patient reports to clinician-reported Eastern Cooperative Oncology Group (ECOG) performance status and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30).
A majority of patients completed items on the PRO-CTCAE questionnaire at their first visit (96.4%, 940/975) and second visit (90.6%, 852/940).
Most patients (99.8%, 938/940) reported having at least 1 symptomatic AE, with 81.7% (768/940) reporting at least 1 AE as frequent, severe, and/or interfering “quite a bit” with daily activities.
To gauge the accuracy of the PRO-CTCAE, the investigators assessed construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items.
Construct validity
The investigators explained that construct validity reflects the association between a new measurement tool and an established measure.
Construct validity is often investigated through convergent validity, which determines whether the new tool moves in the same direction as an established instrument, and known-groups validity, which determines whether the tool can distinguish between groups of patients who are thought to be distinct.
When the investigators considered all QLQ-C30 functioning/global scales, they found that all 124 items on the PRO-CTCAE questionnaire were associated in the expected direction with 1 or more scales. One hundred and fourteen of the PRO-CTCAE items demonstrated a meaningful correlation (Pearson r≥0.1), and 111 of them were statistically significant (P<0.05 for all).
Scores for 94 of 124 PRO-CTCAE items were higher among patients with an ECOG performance status of 2 to 4 (17.1% of patients) than among patients with a score of 0 to 1. The difference was significant for 58 of the items (P<0.05 for all).
Test-retest reliability and responsiveness
The investigators said they estimated test-retest reliability using the intraclass correlation coefficient (ICC), based on a 1-way analysis of variance model with an ICC of 0.7 or greater interpreted as high.
Test-retest reliability was 0.7 or greater for 36 of 49 prespecified PRO-CTCAE items. The median ICC was 0.76 [range, 0.53-0.96).
The investigators assessed the responsiveness of PRO-CTCAE items by comparing any change from the first visit to the second visit in 27 items that were selected a priori.
Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were significant for all 27 items (P≤0.006 for all).
“This is a landmark study demonstrating that meaningful information about adverse events can be elicited from patients themselves, which is a major step for advancing the patient-centeredness of clinical trials,” said study author Ethan Basch, MD, of the Lineberger Cancer Center of the University of North Carolina in Chapel Hill.
receiving chemotherapy
Photo by Rhoda Baer
Results of a multicenter study indicate that a tool cancer patients can use to report adverse events (AEs) is as accurate as other, established patient-reported and clinical measures.
The tool is the National Cancer Institute’s Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).
Study investigators were able to validate 119 of 124 PRO-CTCAE questions against 2 established measurement tools.
The 5 questions that were not validated could not be evaluated due to underrepresentation in the study population.
This research was published in JAMA Oncology.
“In most cancer clinical trials, information on side effects is collected by providers who have limited time with their patients, and current patient questionnaires are limited in scope and depth,” said study author Amylou Dueck, PhD, of the Mayo Clinic in Scottsdale, Arizona.
“PRO-CTCAE is a library of items for patients to directly report on the level of each of their symptoms, to enhance the reporting of side effects in cancer clinical trials, which is normally based on information from providers. The study itself is unprecedented, as more than 100 distinct questions about symptomatic adverse events were validated simultaneously.”
To assess the PRO-CTCAE, Dr Dueck and her colleagues recruited 975 cancer patients from 9 clinical practices across the US, including 7 cancer centers.
The patients had a range of cancers and were undergoing outpatient chemotherapy and/or radiation therapy. The investigators said these participants reflected the geographic, ethnic, racial, and economic diversity in cancer clinical trials.
The patients were asked to fill out the PRO-CTCAE questionnaire before appointments. The investigators then compared patient reports to clinician-reported Eastern Cooperative Oncology Group (ECOG) performance status and the European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30).
A majority of patients completed items on the PRO-CTCAE questionnaire at their first visit (96.4%, 940/975) and second visit (90.6%, 852/940).
Most patients (99.8%, 938/940) reported having at least 1 symptomatic AE, with 81.7% (768/940) reporting at least 1 AE as frequent, severe, and/or interfering “quite a bit” with daily activities.
To gauge the accuracy of the PRO-CTCAE, the investigators assessed construct validity, test-retest reliability, and responsiveness of PRO-CTCAE items.
Construct validity
The investigators explained that construct validity reflects the association between a new measurement tool and an established measure.
Construct validity is often investigated through convergent validity, which determines whether the new tool moves in the same direction as an established instrument, and known-groups validity, which determines whether the tool can distinguish between groups of patients who are thought to be distinct.
When the investigators considered all QLQ-C30 functioning/global scales, they found that all 124 items on the PRO-CTCAE questionnaire were associated in the expected direction with 1 or more scales. One hundred and fourteen of the PRO-CTCAE items demonstrated a meaningful correlation (Pearson r≥0.1), and 111 of them were statistically significant (P<0.05 for all).
Scores for 94 of 124 PRO-CTCAE items were higher among patients with an ECOG performance status of 2 to 4 (17.1% of patients) than among patients with a score of 0 to 1. The difference was significant for 58 of the items (P<0.05 for all).
Test-retest reliability and responsiveness
The investigators said they estimated test-retest reliability using the intraclass correlation coefficient (ICC), based on a 1-way analysis of variance model with an ICC of 0.7 or greater interpreted as high.
Test-retest reliability was 0.7 or greater for 36 of 49 prespecified PRO-CTCAE items. The median ICC was 0.76 [range, 0.53-0.96).
The investigators assessed the responsiveness of PRO-CTCAE items by comparing any change from the first visit to the second visit in 27 items that were selected a priori.
Correlations between PRO-CTCAE item changes and corresponding QLQ-C30 scale changes were significant for all 27 items (P≤0.006 for all).
“This is a landmark study demonstrating that meaningful information about adverse events can be elicited from patients themselves, which is a major step for advancing the patient-centeredness of clinical trials,” said study author Ethan Basch, MD, of the Lineberger Cancer Center of the University of North Carolina in Chapel Hill.
New prognostic model for follicular lymphoma
Photo courtesy of NIH
A newly developed prognostic model can identify follicular lymphoma (FL) patients at the highest risk for treatment failure, according to researchers.
To create this model, called m7-FLIPI, the team combined the Follicular Lymphoma International Prognostic Index (FLIPI), Eastern Cooperative Oncology Group (ECOG) performance status, and the mutation status of 7 genes—EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11.
The researchers said this is the first prognostic model for FL that accounts for both clinical factors and genetic mutations.
They described the creation and testing of the model in The Lancet Oncology.
“We set out to determine, at the time of diagnosis, which patients’ disease will have sustained responses after treatment and whether new genetic data could help inform which patients are at risk for developing progressive lymphoma so clinicians would be able to offer these high-risk patients more effective therapies,” said Randy Gascoyne, MD, of the British Columbia Cancer Agency in Vancouver, Canada.
He and his colleagues created the m7-FLIPI by conducting a retrospective analysis of genetic mutations and clinical risk factors in 2 cohorts of patients with symptomatic, advanced stage, or bulky FL grade 1, 2, or 3A.
The patients had a biopsy specimen collected 12 months or less before they began first-line treatment with an immunochemotherapy regimen containing rituximab.
Training cohort
The training cohort consisted of 151 FL patients who received R-CHOP. The median follow-up for these patients was 7.7 years.
When the researchers applied the m7-FLIPI to this cohort, they found 28% of patients (43/151) were defined as high-risk, with a 5-year failure-free survival (FFS) rate of 38.29%.
And 72% of patients (108/151) were defined as low-risk, with a 5-year FFS of 77.21%. The hazard ratio was 4.14 (P<0.0001).
The positive predictive value for 5-year FFS was 64%, and the negative predictive value was 78%. The m7-FLIPI outperformed a prognostic model of only gene mutations and the FLIPI-2.
Validation cohort
The validation cohort consisted of 107 patients who received R-CVP. The median follow-up for these patients was 6.7 years.
When the researchers applied the m7-FLIPI to this cohort, they found that 22% of patients (24/107) were defined as high-risk, with a 5-year FFS of 25%.
And 78% of patients (83/107) were defined as low-risk, with a 5-year FFS of 68.24%. The hazard ratio was 3.58 (P<0.0001).
The positive predictive value for 5-year FFS was 72%, and the negative predictive value was 68%. The m7-FLIPI outperformed the FLIPI alone and the FLIPI combined with ECOG performance status.
Overall survival
Although the m7-FLIPI was designed specifically for FFS, the researchers also tested its prognostic utility for overall survival (OS).
In the training cohort, high-risk disease according to the m7-FLIPI was associated with a 5-year OS of 65.25%, compared to 89.98% for low-risk disease (P=0.00031).
In the validation cohort, 5-year OS was 41.67% for patients with high-risk disease and 84.01% for patients with low-risk disease (P<0.0001). In both cohorts, the m7-FLIPI outperformed the FLIPI alone.
Based on these results, the researchers believe the m7-FLIPI could be utilized in a clinical setting to test all new FL patients at diagnosis and identify patients who harbor the most aggressive disease.
“The m7-FLIPI could be extremely significant for the medical community,” Dr Gascoyne said, “changing the story for high-risk patients who are currently destined to not respond well to standard treatment.”
Photo courtesy of NIH
A newly developed prognostic model can identify follicular lymphoma (FL) patients at the highest risk for treatment failure, according to researchers.
To create this model, called m7-FLIPI, the team combined the Follicular Lymphoma International Prognostic Index (FLIPI), Eastern Cooperative Oncology Group (ECOG) performance status, and the mutation status of 7 genes—EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11.
The researchers said this is the first prognostic model for FL that accounts for both clinical factors and genetic mutations.
They described the creation and testing of the model in The Lancet Oncology.
“We set out to determine, at the time of diagnosis, which patients’ disease will have sustained responses after treatment and whether new genetic data could help inform which patients are at risk for developing progressive lymphoma so clinicians would be able to offer these high-risk patients more effective therapies,” said Randy Gascoyne, MD, of the British Columbia Cancer Agency in Vancouver, Canada.
He and his colleagues created the m7-FLIPI by conducting a retrospective analysis of genetic mutations and clinical risk factors in 2 cohorts of patients with symptomatic, advanced stage, or bulky FL grade 1, 2, or 3A.
The patients had a biopsy specimen collected 12 months or less before they began first-line treatment with an immunochemotherapy regimen containing rituximab.
Training cohort
The training cohort consisted of 151 FL patients who received R-CHOP. The median follow-up for these patients was 7.7 years.
When the researchers applied the m7-FLIPI to this cohort, they found 28% of patients (43/151) were defined as high-risk, with a 5-year failure-free survival (FFS) rate of 38.29%.
And 72% of patients (108/151) were defined as low-risk, with a 5-year FFS of 77.21%. The hazard ratio was 4.14 (P<0.0001).
The positive predictive value for 5-year FFS was 64%, and the negative predictive value was 78%. The m7-FLIPI outperformed a prognostic model of only gene mutations and the FLIPI-2.
Validation cohort
The validation cohort consisted of 107 patients who received R-CVP. The median follow-up for these patients was 6.7 years.
When the researchers applied the m7-FLIPI to this cohort, they found that 22% of patients (24/107) were defined as high-risk, with a 5-year FFS of 25%.
And 78% of patients (83/107) were defined as low-risk, with a 5-year FFS of 68.24%. The hazard ratio was 3.58 (P<0.0001).
The positive predictive value for 5-year FFS was 72%, and the negative predictive value was 68%. The m7-FLIPI outperformed the FLIPI alone and the FLIPI combined with ECOG performance status.
Overall survival
Although the m7-FLIPI was designed specifically for FFS, the researchers also tested its prognostic utility for overall survival (OS).
In the training cohort, high-risk disease according to the m7-FLIPI was associated with a 5-year OS of 65.25%, compared to 89.98% for low-risk disease (P=0.00031).
In the validation cohort, 5-year OS was 41.67% for patients with high-risk disease and 84.01% for patients with low-risk disease (P<0.0001). In both cohorts, the m7-FLIPI outperformed the FLIPI alone.
Based on these results, the researchers believe the m7-FLIPI could be utilized in a clinical setting to test all new FL patients at diagnosis and identify patients who harbor the most aggressive disease.
“The m7-FLIPI could be extremely significant for the medical community,” Dr Gascoyne said, “changing the story for high-risk patients who are currently destined to not respond well to standard treatment.”
Photo courtesy of NIH
A newly developed prognostic model can identify follicular lymphoma (FL) patients at the highest risk for treatment failure, according to researchers.
To create this model, called m7-FLIPI, the team combined the Follicular Lymphoma International Prognostic Index (FLIPI), Eastern Cooperative Oncology Group (ECOG) performance status, and the mutation status of 7 genes—EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11.
The researchers said this is the first prognostic model for FL that accounts for both clinical factors and genetic mutations.
They described the creation and testing of the model in The Lancet Oncology.
“We set out to determine, at the time of diagnosis, which patients’ disease will have sustained responses after treatment and whether new genetic data could help inform which patients are at risk for developing progressive lymphoma so clinicians would be able to offer these high-risk patients more effective therapies,” said Randy Gascoyne, MD, of the British Columbia Cancer Agency in Vancouver, Canada.
He and his colleagues created the m7-FLIPI by conducting a retrospective analysis of genetic mutations and clinical risk factors in 2 cohorts of patients with symptomatic, advanced stage, or bulky FL grade 1, 2, or 3A.
The patients had a biopsy specimen collected 12 months or less before they began first-line treatment with an immunochemotherapy regimen containing rituximab.
Training cohort
The training cohort consisted of 151 FL patients who received R-CHOP. The median follow-up for these patients was 7.7 years.
When the researchers applied the m7-FLIPI to this cohort, they found 28% of patients (43/151) were defined as high-risk, with a 5-year failure-free survival (FFS) rate of 38.29%.
And 72% of patients (108/151) were defined as low-risk, with a 5-year FFS of 77.21%. The hazard ratio was 4.14 (P<0.0001).
The positive predictive value for 5-year FFS was 64%, and the negative predictive value was 78%. The m7-FLIPI outperformed a prognostic model of only gene mutations and the FLIPI-2.
Validation cohort
The validation cohort consisted of 107 patients who received R-CVP. The median follow-up for these patients was 6.7 years.
When the researchers applied the m7-FLIPI to this cohort, they found that 22% of patients (24/107) were defined as high-risk, with a 5-year FFS of 25%.
And 78% of patients (83/107) were defined as low-risk, with a 5-year FFS of 68.24%. The hazard ratio was 3.58 (P<0.0001).
The positive predictive value for 5-year FFS was 72%, and the negative predictive value was 68%. The m7-FLIPI outperformed the FLIPI alone and the FLIPI combined with ECOG performance status.
Overall survival
Although the m7-FLIPI was designed specifically for FFS, the researchers also tested its prognostic utility for overall survival (OS).
In the training cohort, high-risk disease according to the m7-FLIPI was associated with a 5-year OS of 65.25%, compared to 89.98% for low-risk disease (P=0.00031).
In the validation cohort, 5-year OS was 41.67% for patients with high-risk disease and 84.01% for patients with low-risk disease (P<0.0001). In both cohorts, the m7-FLIPI outperformed the FLIPI alone.
Based on these results, the researchers believe the m7-FLIPI could be utilized in a clinical setting to test all new FL patients at diagnosis and identify patients who harbor the most aggressive disease.
“The m7-FLIPI could be extremely significant for the medical community,” Dr Gascoyne said, “changing the story for high-risk patients who are currently destined to not respond well to standard treatment.”
Rivaroxaban monitoring kit launched in Europe
Instrumentation Laboratory, a company that develops in vitro diagnostic instruments, has announced the commercialization of the HemosIL Rivaroxaban Testing Solution in Europe.
This testing kit consists of the HemosIL Liquid Anti-Xa Assay, Rivaroxaban Calibrators, and Rivaroxaban Controls, which can be used with ACL TOP Hemostasis Testing Systems to monitor patients taking the oral anticoagulant rivaroxaban (Xarelto).
The assay, calibrators, and controls are now CE IVD Marked under the European IVD Directive 98/79/EC.
This allows Instrumentation Laboratory to distribute the HemosIL Rivaroxaban Testing Solution in the European Union and other international territories.
Although monitoring is generally not required for patients on rivaroxaban, there are cases in which measuring rivaroxaban may be necessary.
This includes patients who present with bleeding, require reversal of anticoagulation, experience deteriorating renal function, or must undergo surgery or an invasive procedure and have taken rivaroxaban within 24 hours or longer if creatinine clearance is < 50 mL min-1.
Liquid Anti-Xa Assay
The HemosIL Liquid Anti-Xa kit is a one-stage chromogenic assay based on a synthetic chromogenic substrate and factor Xa inactivation. Rivaroxaban levels in patient plasma are measured automatically on an ACL TOP Hemostasis Testing System when this assay is calibrated with the HemosIL Rivaroxaban Calibrators.
The Anti-Xa Assay kit consists of:
- Factor Xa reagent: 5 x 2.5 mL vial of a liquid preparation containing purified bovine factor Xa (approximately 5.5 nkat/mL), Tris-Buffer, EDTA, dextran sulfate, sodium chloride, and bovine serum albumin.
- Chromogenic substrate: 5 x 3 mL vial of liquid chromogenic substrate S-2732 (approximately 1.2 mg/mL) and bulking agent.
Rivaroxaban Calibrators
The HemosIL Rivaroxaban Calibrators are intended for the calibration of the Liquid Anti-Xa Assay when testing for rivaroxaban on an ACL TOP Hemostasis Testing System.
Two levels of lyophilized calibrators prepared from human citrated plasma by means of a dedicated process at 2 different concentrations of rivaroxaban are used by the instrument to automatically prepare a calibration curve.
The Rivaroxaban Calibrator kit consists of:
- Rivaroxaban Calibrator 1: 5 x 1 mL vials of a lyophilized human plasma containing buffers and stabilizers.
- Rivaroxaban Calibrator 2: 5 x 1 mL vials of a lyophilized human plasma containing rivaroxaban, buffers, and stabilizers.
Rivaroxaban Controls
HemosIL Rivaroxaban Controls are intended for the quality control of the Liquid Anti-Xa Assay when testing for rivaroxaban on an ACL TOP Hemostasis Testing System.
Two levels of lyophilized controls are prepared from human citrated plasma by means of a dedicated process at 2 different concentrations of rivaroxaban. Use of both controls is recommended for a complete quality control program.
The Rivaroxaban Controls kit consists of:
- Rivaroxaban Low Control: 5 x 1 mL vials of a lyophilized human plasma containing rivaroxaban, stabilizers, and buffer solution.
- Rivaroxaban High Control: 5 x 1 mL vials of a lyophilized human plasma containing rivaroxaban, stabilizers, and buffer solution.
Instrumentation Laboratory, a company that develops in vitro diagnostic instruments, has announced the commercialization of the HemosIL Rivaroxaban Testing Solution in Europe.
This testing kit consists of the HemosIL Liquid Anti-Xa Assay, Rivaroxaban Calibrators, and Rivaroxaban Controls, which can be used with ACL TOP Hemostasis Testing Systems to monitor patients taking the oral anticoagulant rivaroxaban (Xarelto).
The assay, calibrators, and controls are now CE IVD Marked under the European IVD Directive 98/79/EC.
This allows Instrumentation Laboratory to distribute the HemosIL Rivaroxaban Testing Solution in the European Union and other international territories.
Although monitoring is generally not required for patients on rivaroxaban, there are cases in which measuring rivaroxaban may be necessary.
This includes patients who present with bleeding, require reversal of anticoagulation, experience deteriorating renal function, or must undergo surgery or an invasive procedure and have taken rivaroxaban within 24 hours or longer if creatinine clearance is < 50 mL min-1.
Liquid Anti-Xa Assay
The HemosIL Liquid Anti-Xa kit is a one-stage chromogenic assay based on a synthetic chromogenic substrate and factor Xa inactivation. Rivaroxaban levels in patient plasma are measured automatically on an ACL TOP Hemostasis Testing System when this assay is calibrated with the HemosIL Rivaroxaban Calibrators.
The Anti-Xa Assay kit consists of:
- Factor Xa reagent: 5 x 2.5 mL vial of a liquid preparation containing purified bovine factor Xa (approximately 5.5 nkat/mL), Tris-Buffer, EDTA, dextran sulfate, sodium chloride, and bovine serum albumin.
- Chromogenic substrate: 5 x 3 mL vial of liquid chromogenic substrate S-2732 (approximately 1.2 mg/mL) and bulking agent.
Rivaroxaban Calibrators
The HemosIL Rivaroxaban Calibrators are intended for the calibration of the Liquid Anti-Xa Assay when testing for rivaroxaban on an ACL TOP Hemostasis Testing System.
Two levels of lyophilized calibrators prepared from human citrated plasma by means of a dedicated process at 2 different concentrations of rivaroxaban are used by the instrument to automatically prepare a calibration curve.
The Rivaroxaban Calibrator kit consists of:
- Rivaroxaban Calibrator 1: 5 x 1 mL vials of a lyophilized human plasma containing buffers and stabilizers.
- Rivaroxaban Calibrator 2: 5 x 1 mL vials of a lyophilized human plasma containing rivaroxaban, buffers, and stabilizers.
Rivaroxaban Controls
HemosIL Rivaroxaban Controls are intended for the quality control of the Liquid Anti-Xa Assay when testing for rivaroxaban on an ACL TOP Hemostasis Testing System.
Two levels of lyophilized controls are prepared from human citrated plasma by means of a dedicated process at 2 different concentrations of rivaroxaban. Use of both controls is recommended for a complete quality control program.
The Rivaroxaban Controls kit consists of:
- Rivaroxaban Low Control: 5 x 1 mL vials of a lyophilized human plasma containing rivaroxaban, stabilizers, and buffer solution.
- Rivaroxaban High Control: 5 x 1 mL vials of a lyophilized human plasma containing rivaroxaban, stabilizers, and buffer solution.
Instrumentation Laboratory, a company that develops in vitro diagnostic instruments, has announced the commercialization of the HemosIL Rivaroxaban Testing Solution in Europe.
This testing kit consists of the HemosIL Liquid Anti-Xa Assay, Rivaroxaban Calibrators, and Rivaroxaban Controls, which can be used with ACL TOP Hemostasis Testing Systems to monitor patients taking the oral anticoagulant rivaroxaban (Xarelto).
The assay, calibrators, and controls are now CE IVD Marked under the European IVD Directive 98/79/EC.
This allows Instrumentation Laboratory to distribute the HemosIL Rivaroxaban Testing Solution in the European Union and other international territories.
Although monitoring is generally not required for patients on rivaroxaban, there are cases in which measuring rivaroxaban may be necessary.
This includes patients who present with bleeding, require reversal of anticoagulation, experience deteriorating renal function, or must undergo surgery or an invasive procedure and have taken rivaroxaban within 24 hours or longer if creatinine clearance is < 50 mL min-1.
Liquid Anti-Xa Assay
The HemosIL Liquid Anti-Xa kit is a one-stage chromogenic assay based on a synthetic chromogenic substrate and factor Xa inactivation. Rivaroxaban levels in patient plasma are measured automatically on an ACL TOP Hemostasis Testing System when this assay is calibrated with the HemosIL Rivaroxaban Calibrators.
The Anti-Xa Assay kit consists of:
- Factor Xa reagent: 5 x 2.5 mL vial of a liquid preparation containing purified bovine factor Xa (approximately 5.5 nkat/mL), Tris-Buffer, EDTA, dextran sulfate, sodium chloride, and bovine serum albumin.
- Chromogenic substrate: 5 x 3 mL vial of liquid chromogenic substrate S-2732 (approximately 1.2 mg/mL) and bulking agent.
Rivaroxaban Calibrators
The HemosIL Rivaroxaban Calibrators are intended for the calibration of the Liquid Anti-Xa Assay when testing for rivaroxaban on an ACL TOP Hemostasis Testing System.
Two levels of lyophilized calibrators prepared from human citrated plasma by means of a dedicated process at 2 different concentrations of rivaroxaban are used by the instrument to automatically prepare a calibration curve.
The Rivaroxaban Calibrator kit consists of:
- Rivaroxaban Calibrator 1: 5 x 1 mL vials of a lyophilized human plasma containing buffers and stabilizers.
- Rivaroxaban Calibrator 2: 5 x 1 mL vials of a lyophilized human plasma containing rivaroxaban, buffers, and stabilizers.
Rivaroxaban Controls
HemosIL Rivaroxaban Controls are intended for the quality control of the Liquid Anti-Xa Assay when testing for rivaroxaban on an ACL TOP Hemostasis Testing System.
Two levels of lyophilized controls are prepared from human citrated plasma by means of a dedicated process at 2 different concentrations of rivaroxaban. Use of both controls is recommended for a complete quality control program.
The Rivaroxaban Controls kit consists of:
- Rivaroxaban Low Control: 5 x 1 mL vials of a lyophilized human plasma containing rivaroxaban, stabilizers, and buffer solution.
- Rivaroxaban High Control: 5 x 1 mL vials of a lyophilized human plasma containing rivaroxaban, stabilizers, and buffer solution.
Platform simplifies data analysis, team says
Photo by Rhoda Baer
Researchers say they have developed a user-friendly platform for analyzing transcriptomic and epigenomic sequencing data.
This platform, BioWardrobe, was designed to help biomedical researchers analyze data that might answer questions about diseases and basic biology.
“Although biologists can perform experiments and obtain the data, they often lack the programming expertise required to perform computational data analysis,” said Artem Barski, PhD, of the University of Cincinnati in Ohio.
“BioWardrobe aims to empower researchers by bridging this gap between data and knowledge.”
Dr Barski and Andrey Kartashov, also of the University of Cincinnati, described BioWardrobe in Genome Biology.
The pair said the recent proliferation of sequencing-based methods for analysis of gene expression, chromatin structure, and protein-DNA interactions has widened our horizons, but the volume of data obtained from sequencing requires computational data analysis.
Unfortunately, the bioinformatics and programming expertise required for this analysis may be absent in biomedical laboratories. And this can result in data inaccessibility or delays in applying modern sequencing-based technologies to pressing questions in basic and health-related research.
Dr Barski and Kartashov believe BioWardrobe can solve those problems by providing a “biologist-friendly” web interface.
BioWardrobe users can download data from institutional facilities or public databases, map reads, and visualize results on a genome browser. The platform also allows for differential gene expression and binding analysis, and it can create average tag-density profiles and heatmaps.
Dr Barski and Kartashov plan to continue improving BioWardrobe and continue using the platform in their own research on epigenetic regulation in the immune system, as well as in collaborative projects with other investigators.
Photo by Rhoda Baer
Researchers say they have developed a user-friendly platform for analyzing transcriptomic and epigenomic sequencing data.
This platform, BioWardrobe, was designed to help biomedical researchers analyze data that might answer questions about diseases and basic biology.
“Although biologists can perform experiments and obtain the data, they often lack the programming expertise required to perform computational data analysis,” said Artem Barski, PhD, of the University of Cincinnati in Ohio.
“BioWardrobe aims to empower researchers by bridging this gap between data and knowledge.”
Dr Barski and Andrey Kartashov, also of the University of Cincinnati, described BioWardrobe in Genome Biology.
The pair said the recent proliferation of sequencing-based methods for analysis of gene expression, chromatin structure, and protein-DNA interactions has widened our horizons, but the volume of data obtained from sequencing requires computational data analysis.
Unfortunately, the bioinformatics and programming expertise required for this analysis may be absent in biomedical laboratories. And this can result in data inaccessibility or delays in applying modern sequencing-based technologies to pressing questions in basic and health-related research.
Dr Barski and Kartashov believe BioWardrobe can solve those problems by providing a “biologist-friendly” web interface.
BioWardrobe users can download data from institutional facilities or public databases, map reads, and visualize results on a genome browser. The platform also allows for differential gene expression and binding analysis, and it can create average tag-density profiles and heatmaps.
Dr Barski and Kartashov plan to continue improving BioWardrobe and continue using the platform in their own research on epigenetic regulation in the immune system, as well as in collaborative projects with other investigators.
Photo by Rhoda Baer
Researchers say they have developed a user-friendly platform for analyzing transcriptomic and epigenomic sequencing data.
This platform, BioWardrobe, was designed to help biomedical researchers analyze data that might answer questions about diseases and basic biology.
“Although biologists can perform experiments and obtain the data, they often lack the programming expertise required to perform computational data analysis,” said Artem Barski, PhD, of the University of Cincinnati in Ohio.
“BioWardrobe aims to empower researchers by bridging this gap between data and knowledge.”
Dr Barski and Andrey Kartashov, also of the University of Cincinnati, described BioWardrobe in Genome Biology.
The pair said the recent proliferation of sequencing-based methods for analysis of gene expression, chromatin structure, and protein-DNA interactions has widened our horizons, but the volume of data obtained from sequencing requires computational data analysis.
Unfortunately, the bioinformatics and programming expertise required for this analysis may be absent in biomedical laboratories. And this can result in data inaccessibility or delays in applying modern sequencing-based technologies to pressing questions in basic and health-related research.
Dr Barski and Kartashov believe BioWardrobe can solve those problems by providing a “biologist-friendly” web interface.
BioWardrobe users can download data from institutional facilities or public databases, map reads, and visualize results on a genome browser. The platform also allows for differential gene expression and binding analysis, and it can create average tag-density profiles and heatmaps.
Dr Barski and Kartashov plan to continue improving BioWardrobe and continue using the platform in their own research on epigenetic regulation in the immune system, as well as in collaborative projects with other investigators.
How CLL evades the immune system
Photo courtesy of
Monash University
A study published in Leukemia has revealed a mechanism by which chronic lymphocytic leukemia (CLL) evades the immune system.
“It turns out that cancer cells are very good at sabotaging the immune system, using various tricks that confuse immune cells and ‘smoke screens’ preventing immune cells from recognizing the cancer,” said study author Fabienne Mackay, PhD, of Monash University in Melbourne, Victoria, Australia.
She and her colleagues believe they have determined exactly how CLL confuses the immune system and devised a way to stop it without destroying the patient’s immune system.
The team noted that B cells rely on the protein BAFF to survive. And each B cell has 3 different kinds of receptors that detect the presence of BAFF in the blood—TACI, BAFF-R, and BCMA.
The researchers discovered that, in CLL patients, the TACI receptors of cancerous B cells over-produce interleukin-10 (IL-10), which tricks the immune system into thinking nothing is wrong, allowing CLL to thrive undetected.
“We found that, when the receptor called TACI was blocked, it prevented the secretion of IL-10 without eliminating normal B cells,” Dr Mackay said. “Without IL-10, the tumor can no longer keep the immune system at bay, which means the patient’s immune system can be ‘kick-started’ again to fight infections and cancers.”
“This is very exciting because it means that B cells stay alive and well to do their job in the immune system fighting other infections. It also means the over-production of IL-10 is stopped, and the CLL cells are now exposed to immune cells specialized in fighting cancers.”
Dr Mackay said her team’s discovery may be relevant for cancers other than CLL and could change the way they are treated.
“The best weapon we have for fighting cancer is the immune system itself,” Dr Mackay noted. “It can sense the presence of an infection but also the emergence of a cancer.”
Photo courtesy of
Monash University
A study published in Leukemia has revealed a mechanism by which chronic lymphocytic leukemia (CLL) evades the immune system.
“It turns out that cancer cells are very good at sabotaging the immune system, using various tricks that confuse immune cells and ‘smoke screens’ preventing immune cells from recognizing the cancer,” said study author Fabienne Mackay, PhD, of Monash University in Melbourne, Victoria, Australia.
She and her colleagues believe they have determined exactly how CLL confuses the immune system and devised a way to stop it without destroying the patient’s immune system.
The team noted that B cells rely on the protein BAFF to survive. And each B cell has 3 different kinds of receptors that detect the presence of BAFF in the blood—TACI, BAFF-R, and BCMA.
The researchers discovered that, in CLL patients, the TACI receptors of cancerous B cells over-produce interleukin-10 (IL-10), which tricks the immune system into thinking nothing is wrong, allowing CLL to thrive undetected.
“We found that, when the receptor called TACI was blocked, it prevented the secretion of IL-10 without eliminating normal B cells,” Dr Mackay said. “Without IL-10, the tumor can no longer keep the immune system at bay, which means the patient’s immune system can be ‘kick-started’ again to fight infections and cancers.”
“This is very exciting because it means that B cells stay alive and well to do their job in the immune system fighting other infections. It also means the over-production of IL-10 is stopped, and the CLL cells are now exposed to immune cells specialized in fighting cancers.”
Dr Mackay said her team’s discovery may be relevant for cancers other than CLL and could change the way they are treated.
“The best weapon we have for fighting cancer is the immune system itself,” Dr Mackay noted. “It can sense the presence of an infection but also the emergence of a cancer.”
Photo courtesy of
Monash University
A study published in Leukemia has revealed a mechanism by which chronic lymphocytic leukemia (CLL) evades the immune system.
“It turns out that cancer cells are very good at sabotaging the immune system, using various tricks that confuse immune cells and ‘smoke screens’ preventing immune cells from recognizing the cancer,” said study author Fabienne Mackay, PhD, of Monash University in Melbourne, Victoria, Australia.
She and her colleagues believe they have determined exactly how CLL confuses the immune system and devised a way to stop it without destroying the patient’s immune system.
The team noted that B cells rely on the protein BAFF to survive. And each B cell has 3 different kinds of receptors that detect the presence of BAFF in the blood—TACI, BAFF-R, and BCMA.
The researchers discovered that, in CLL patients, the TACI receptors of cancerous B cells over-produce interleukin-10 (IL-10), which tricks the immune system into thinking nothing is wrong, allowing CLL to thrive undetected.
“We found that, when the receptor called TACI was blocked, it prevented the secretion of IL-10 without eliminating normal B cells,” Dr Mackay said. “Without IL-10, the tumor can no longer keep the immune system at bay, which means the patient’s immune system can be ‘kick-started’ again to fight infections and cancers.”
“This is very exciting because it means that B cells stay alive and well to do their job in the immune system fighting other infections. It also means the over-production of IL-10 is stopped, and the CLL cells are now exposed to immune cells specialized in fighting cancers.”
Dr Mackay said her team’s discovery may be relevant for cancers other than CLL and could change the way they are treated.
“The best weapon we have for fighting cancer is the immune system itself,” Dr Mackay noted. “It can sense the presence of an infection but also the emergence of a cancer.”
FDA extends storage of platelets in plasma
Photo by Charles Haymond
The US Food and Drug Administration (FDA) has cleared a labeling change for the Terumo BCT Trima Accel Automated Blood Collection System.
The change means platelets in plasma that are collected via this system can now be stored for 7 days instead of 5, but the blood products must be tested for bacterial contamination.
The label change also allows for use of a wireless feature designed to enhance the mobility and flexibility of the system.
The Trima Accel system includes the Trima Accel device, a tubing set, and Trima Accel software. The system uses a centrifuge to separate whole blood into platelets, plasma, and red blood cells. It then collects the components based on customer-configured priorities and the donor’s physiology and blood count.
Platelet storage
The FDA is now allowing platelets in 100% plasma that are collected via the Trima Accel system to be stored for up to 7 days post-collection. But platelets in isoplate solution can only be stored for up to 5 days.
For platelet storage up to 7 days, the FDA requires that every product be tested with a bacterial detection device cleared by the FDA and labeled as a “safety measure.”
Wireless feature
The newly cleared wireless feature connects the Trima Accel system to software applications such as the Cadence Data Collection System or the Vista Information System through the blood center’s or hospital’s existing wireless network.
This enables access to electronic donor information and reporting capabilities, with the goals of streamlining collections, simplifying data management, and allowing operators to focus on donor care, even when a wired connection is unavailable.
The wireless feature enables blood centers to either purchase a compatible wireless appliance from Terumo BCT or choose an appliance of their own for attachment to the Trima Accel system using a mounting bracket on the back of the system.
Photo by Charles Haymond
The US Food and Drug Administration (FDA) has cleared a labeling change for the Terumo BCT Trima Accel Automated Blood Collection System.
The change means platelets in plasma that are collected via this system can now be stored for 7 days instead of 5, but the blood products must be tested for bacterial contamination.
The label change also allows for use of a wireless feature designed to enhance the mobility and flexibility of the system.
The Trima Accel system includes the Trima Accel device, a tubing set, and Trima Accel software. The system uses a centrifuge to separate whole blood into platelets, plasma, and red blood cells. It then collects the components based on customer-configured priorities and the donor’s physiology and blood count.
Platelet storage
The FDA is now allowing platelets in 100% plasma that are collected via the Trima Accel system to be stored for up to 7 days post-collection. But platelets in isoplate solution can only be stored for up to 5 days.
For platelet storage up to 7 days, the FDA requires that every product be tested with a bacterial detection device cleared by the FDA and labeled as a “safety measure.”
Wireless feature
The newly cleared wireless feature connects the Trima Accel system to software applications such as the Cadence Data Collection System or the Vista Information System through the blood center’s or hospital’s existing wireless network.
This enables access to electronic donor information and reporting capabilities, with the goals of streamlining collections, simplifying data management, and allowing operators to focus on donor care, even when a wired connection is unavailable.
The wireless feature enables blood centers to either purchase a compatible wireless appliance from Terumo BCT or choose an appliance of their own for attachment to the Trima Accel system using a mounting bracket on the back of the system.
Photo by Charles Haymond
The US Food and Drug Administration (FDA) has cleared a labeling change for the Terumo BCT Trima Accel Automated Blood Collection System.
The change means platelets in plasma that are collected via this system can now be stored for 7 days instead of 5, but the blood products must be tested for bacterial contamination.
The label change also allows for use of a wireless feature designed to enhance the mobility and flexibility of the system.
The Trima Accel system includes the Trima Accel device, a tubing set, and Trima Accel software. The system uses a centrifuge to separate whole blood into platelets, plasma, and red blood cells. It then collects the components based on customer-configured priorities and the donor’s physiology and blood count.
Platelet storage
The FDA is now allowing platelets in 100% plasma that are collected via the Trima Accel system to be stored for up to 7 days post-collection. But platelets in isoplate solution can only be stored for up to 5 days.
For platelet storage up to 7 days, the FDA requires that every product be tested with a bacterial detection device cleared by the FDA and labeled as a “safety measure.”
Wireless feature
The newly cleared wireless feature connects the Trima Accel system to software applications such as the Cadence Data Collection System or the Vista Information System through the blood center’s or hospital’s existing wireless network.
This enables access to electronic donor information and reporting capabilities, with the goals of streamlining collections, simplifying data management, and allowing operators to focus on donor care, even when a wired connection is unavailable.
The wireless feature enables blood centers to either purchase a compatible wireless appliance from Terumo BCT or choose an appliance of their own for attachment to the Trima Accel system using a mounting bracket on the back of the system.
NICE recommends edoxaban for NVAF
Photo courtesy of the CDC
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).
The patients must have 1 or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.
Such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.
NICE said it wants to add edoxaban to that list because the drug is a clinically and cost-effective treatment option for these patients.
NICE’s draft guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.
For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.
Clinical effectiveness
NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.
Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.
A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.
The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.
The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other newer oral anticoagulants.
However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.
The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.
Cost-effectiveness
Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.
The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the newer oral anticoagulants.
Nevertheless, the committee recommended edoxaban as a cost-effective treatment for patients with NVAF who have 1 or more risk factors for stroke.
NICE’s draft guidance is now with consultees, who have the opportunity to appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.
Photo courtesy of the CDC
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).
The patients must have 1 or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.
Such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.
NICE said it wants to add edoxaban to that list because the drug is a clinically and cost-effective treatment option for these patients.
NICE’s draft guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.
For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.
Clinical effectiveness
NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.
Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.
A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.
The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.
The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other newer oral anticoagulants.
However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.
The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.
Cost-effectiveness
Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.
The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the newer oral anticoagulants.
Nevertheless, the committee recommended edoxaban as a cost-effective treatment for patients with NVAF who have 1 or more risk factors for stroke.
NICE’s draft guidance is now with consultees, who have the opportunity to appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.
Photo courtesy of the CDC
The UK’s National Institute for Health and Care Excellence (NICE) has issued a draft guidance recommending the oral anticoagulant edoxaban tosylate (Lixiana) as an option for preventing stroke and systemic embolism in adults with non-valvular atrial fibrillation (NVAF).
The patients must have 1 or more risk factors for stroke, including congestive heart failure, hypertension, diabetes, prior stroke or transient ischemic attack, and age of 75 years or older.
Such patients are generally treated with warfarin or the newer oral anticoagulants dabigatran, rivaroxaban, and apixaban.
NICE said it wants to add edoxaban to that list because the drug is a clinically and cost-effective treatment option for these patients.
NICE’s draft guidance says the decision about whether to start treatment with edoxaban should be made after an informed discussion between the clinician and the patient about the risks and benefits of edoxaban compared with warfarin, apixaban, dabigatran, and rivaroxaban.
For patients considering switching from warfarin, edoxaban’s potential benefits should be weighed against its potential risks, taking into account the patient’s level of international normalized ratio control.
Clinical effectiveness
NICE’s conclusion that edoxaban is clinically effective was based primarily on results of the ENGAGE AF-TIMI 48 trial. In this trial, researchers compared edoxaban and warfarin as prophylaxis for stroke or systemic embolism in patients with NVAF.
Results suggested edoxaban was at least non-inferior to warfarin with regard to efficacy, and edoxaban was associated with a significantly lower rate of major and fatal bleeding.
A committee advising NICE also reviewed a meta-analysis prepared by Daiichi Sankyo Co., Ltd., the company developing edoxaban.
The goal of the meta-analysis was to compare edoxaban with rivaroxaban, apixaban, and dabigatran. The analysis included 4 trials: ENGAGE AF-TIMI 48, ARISTOTLE (apixaban), RE-LY (dabigatran), and ROCKET-AF (rivaroxaban). All 4 trials had a warfarin comparator arm.
The results of the meta-analysis indicated that, for the composite endpoint of stroke and systemic embolism, efficacy was similar for high-dose edoxaban and the other newer oral anticoagulants.
However, edoxaban significantly reduced major bleeding risk by 24% compared to rivaroxaban, 28% compared to dabigatran at 150 mg, and 17% compared to dabigatran at 110 mg. Major bleeding rates were similar for high-dose edoxaban and apixaban.
The committee advising NICE said these results should be interpreted with caution, but edoxaban is unlikely to be different from rivaroxaban, apixaban, and dabigatran in clinical practice.
Cost-effectiveness
Edoxaban costs £58.80 for a 28-tablet pack (60 mg or 30 mg), and the daily cost of treatment is £2.10 (excluding value-added tax). However, costs may vary in different settings because of negotiated procurement discounts.
The committee advising NICE analyzed cost information and concluded that edoxaban is cost-effective compared with warfarin, but there is insufficient evidence to distinguish between the clinical and cost-effectiveness of edoxaban and the newer oral anticoagulants.
Nevertheless, the committee recommended edoxaban as a cost-effective treatment for patients with NVAF who have 1 or more risk factors for stroke.
NICE’s draft guidance is now with consultees, who have the opportunity to appeal against it. Once NICE issues its final guidance on a technology, it replaces local recommendations.