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Risk-directed therapy improves survival in ALL
Credit: St Jude Biomedical
Communications
Risk-directed therapy can level the playing field for patients with BCR-ABL1-like acute lymphoblastic leukemia (ALL), new research suggests.
Using minimal residual disease (MRD) and other risk factors to guide treatment intensity allowed patients withBCR-ABL1-like ALL to have survival rates comparable to those of other B-ALL patients.
The research also revealed that not all BCR-ABL1-like ALL patients have high-risk disease.
Ching-Hon Pui, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these results in the Journal of Clinical Oncology.
Patients with BCR-ABL1-like ALL tend to have poor outcomes, so Dr Pui and his colleagues evaluated the utility of risk-directed therapy in these and other B-ALL patients.
The team assessed patients enrolled in the Total Therapy XV study between 2000 and 2007. They were 1 to 18 years of age at diagnosis. There were 344 subjects with adequate samples for gene expression profiling.
Forty patients (11.6%) had BCR-ABL1-like ALL. They were significantly more likely than other study participants to be male, have Down syndrome, and have higher MRD levels on day 19 and at the end of induction.
The researchers monitored patients and adjusted their treatment intensity based on MRD at days 19 and 42. The treatment regimen was described in JAMA in 2009.
The MRD monitoring combined with conventional risk factors, such as patient age and white blood count at diagnosis, demonstrated that BCR-ABL1-like ALL is not a uniformly high-risk disease.
Forty percent of BCR-ABL1-like ALL patients were actually classified as having low-risk disease because they had other favorable clinical or biological features and no MRD at the end of remission induction.
The other 60% were classified as having standard-risk or high-risk disease. The group included 6 patients who underwent transplant.
There were no significant differences in event-free or overall survival in patients with BCR-ABL1-like ALL and the other ALL patients. At 5 years, event-free survival was 90.0% ± 4.7% and 88.4% ± 1.9%, respectively. And 5-year overall survival was 92.5% ± 4.2% and 95.1% ± 1.3%, respectively.
When available, more sophisticated genetic testing should be used to identify which of the B-ALL patients with high levels of MRD have the BCR-ABL1-like ALL subtype, Dr Pui said. Many of these patients have genetic alterations that make them responsive to tyrosine kinase inhibitors (TKIs) and possibly other targeted therapies.
For example, in this study, the researchers evaluated genetic abnormalities in 25 BCR-ABL1-like ALL patients. Eleven had a genomic rearrangement of CRLF2, 6 had fusion transcripts responsive to ABL TKIs or JAK inhibitors, and 7 had mutations involving the Ras signaling pathway.
“In the future, genetic testing will likely be used at diagnosis to identify [BCR-ABL1-like ALL] and direct patients to the best targeted therapy,” Dr Pui said, “possibly including some drugs that are currently experimental.” 
Credit: St Jude Biomedical
Communications
Risk-directed therapy can level the playing field for patients with BCR-ABL1-like acute lymphoblastic leukemia (ALL), new research suggests.
Using minimal residual disease (MRD) and other risk factors to guide treatment intensity allowed patients withBCR-ABL1-like ALL to have survival rates comparable to those of other B-ALL patients.
The research also revealed that not all BCR-ABL1-like ALL patients have high-risk disease.
Ching-Hon Pui, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these results in the Journal of Clinical Oncology.
Patients with BCR-ABL1-like ALL tend to have poor outcomes, so Dr Pui and his colleagues evaluated the utility of risk-directed therapy in these and other B-ALL patients.
The team assessed patients enrolled in the Total Therapy XV study between 2000 and 2007. They were 1 to 18 years of age at diagnosis. There were 344 subjects with adequate samples for gene expression profiling.
Forty patients (11.6%) had BCR-ABL1-like ALL. They were significantly more likely than other study participants to be male, have Down syndrome, and have higher MRD levels on day 19 and at the end of induction.
The researchers monitored patients and adjusted their treatment intensity based on MRD at days 19 and 42. The treatment regimen was described in JAMA in 2009.
The MRD monitoring combined with conventional risk factors, such as patient age and white blood count at diagnosis, demonstrated that BCR-ABL1-like ALL is not a uniformly high-risk disease.
Forty percent of BCR-ABL1-like ALL patients were actually classified as having low-risk disease because they had other favorable clinical or biological features and no MRD at the end of remission induction.
The other 60% were classified as having standard-risk or high-risk disease. The group included 6 patients who underwent transplant.
There were no significant differences in event-free or overall survival in patients with BCR-ABL1-like ALL and the other ALL patients. At 5 years, event-free survival was 90.0% ± 4.7% and 88.4% ± 1.9%, respectively. And 5-year overall survival was 92.5% ± 4.2% and 95.1% ± 1.3%, respectively.
When available, more sophisticated genetic testing should be used to identify which of the B-ALL patients with high levels of MRD have the BCR-ABL1-like ALL subtype, Dr Pui said. Many of these patients have genetic alterations that make them responsive to tyrosine kinase inhibitors (TKIs) and possibly other targeted therapies.
For example, in this study, the researchers evaluated genetic abnormalities in 25 BCR-ABL1-like ALL patients. Eleven had a genomic rearrangement of CRLF2, 6 had fusion transcripts responsive to ABL TKIs or JAK inhibitors, and 7 had mutations involving the Ras signaling pathway.
“In the future, genetic testing will likely be used at diagnosis to identify [BCR-ABL1-like ALL] and direct patients to the best targeted therapy,” Dr Pui said, “possibly including some drugs that are currently experimental.”
Credit: St Jude Biomedical
Communications
Risk-directed therapy can level the playing field for patients with BCR-ABL1-like acute lymphoblastic leukemia (ALL), new research suggests.
Using minimal residual disease (MRD) and other risk factors to guide treatment intensity allowed patients withBCR-ABL1-like ALL to have survival rates comparable to those of other B-ALL patients.
The research also revealed that not all BCR-ABL1-like ALL patients have high-risk disease.
Ching-Hon Pui, MD, of St Jude Children’s Research Hospital in Memphis, Tennessee, and his colleagues reported these results in the Journal of Clinical Oncology.
Patients with BCR-ABL1-like ALL tend to have poor outcomes, so Dr Pui and his colleagues evaluated the utility of risk-directed therapy in these and other B-ALL patients.
The team assessed patients enrolled in the Total Therapy XV study between 2000 and 2007. They were 1 to 18 years of age at diagnosis. There were 344 subjects with adequate samples for gene expression profiling.
Forty patients (11.6%) had BCR-ABL1-like ALL. They were significantly more likely than other study participants to be male, have Down syndrome, and have higher MRD levels on day 19 and at the end of induction.
The researchers monitored patients and adjusted their treatment intensity based on MRD at days 19 and 42. The treatment regimen was described in JAMA in 2009.
The MRD monitoring combined with conventional risk factors, such as patient age and white blood count at diagnosis, demonstrated that BCR-ABL1-like ALL is not a uniformly high-risk disease.
Forty percent of BCR-ABL1-like ALL patients were actually classified as having low-risk disease because they had other favorable clinical or biological features and no MRD at the end of remission induction.
The other 60% were classified as having standard-risk or high-risk disease. The group included 6 patients who underwent transplant.
There were no significant differences in event-free or overall survival in patients with BCR-ABL1-like ALL and the other ALL patients. At 5 years, event-free survival was 90.0% ± 4.7% and 88.4% ± 1.9%, respectively. And 5-year overall survival was 92.5% ± 4.2% and 95.1% ± 1.3%, respectively.
When available, more sophisticated genetic testing should be used to identify which of the B-ALL patients with high levels of MRD have the BCR-ABL1-like ALL subtype, Dr Pui said. Many of these patients have genetic alterations that make them responsive to tyrosine kinase inhibitors (TKIs) and possibly other targeted therapies.
For example, in this study, the researchers evaluated genetic abnormalities in 25 BCR-ABL1-like ALL patients. Eleven had a genomic rearrangement of CRLF2, 6 had fusion transcripts responsive to ABL TKIs or JAK inhibitors, and 7 had mutations involving the Ras signaling pathway.
“In the future, genetic testing will likely be used at diagnosis to identify [BCR-ABL1-like ALL] and direct patients to the best targeted therapy,” Dr Pui said, “possibly including some drugs that are currently experimental.”
Program for poor can boost hospital profits
Credit: Petr Kratochvil
A federal program designed to help the poor may actually be used to help US hospitals increase their profits, according to research published in Health Affairs.
Researchers examined enrollment in the 340B program, which provides deep discounts on outpatient drug purchases.
They found that hospitals and clinics that joined the program since 2004 currently serve more affluent and well-insured communities than those that qualified for the program in previous years.
This supports the idea that the program is changing from one that serves patients in need to one that enriches hospitals and their affiliated clinics, according to the researchers.
“This study provides the first nationally representative empirical evidence suggesting that the program’s original intent is being eroded by the actions of certain hospitals,” said study author Rena M. Conti, PhD, of the University of Chicago in Illinois.
This study follows work by Dr Conti and Peter B. Bach, MD, of Memorial Sloan-Kettering Cancer Center in New York, that was published in JAMA last year.
The JAMA study explained how 340B-qualified hospital-affiliated clinics can boost profits thanks to discounts on expensive anticancer drugs. The facilities receive the discounts under the expectation that the savings will be passed on to poor patients.
“Hospitals qualify for the program based on the poverty of their inpatient census only,” Dr Conti said. “The affiliated clinics are the only 340B institutions not required to pass the discounts off to patients or their insurers, nor do they have to report to the government exactly how these profits are used to serve the poor. Insurers’ and their patients’ payments for outpatient drug treatment don’t reflect the discounts the hospital receives.”
The 340B program, which began in 1992, was designed to help selected hospitals and their outpatient clinics serve low-income and uninsured patients by providing discounts of 30% to 50% on outpatient drugs.
About a decade ago, enrollment in 340B began to increase rapidly. Now, more than a third of the 4375 US non-federal hospitals are 340B-qualified. Recent Congressional and news reports suggest that, for selected hospitals, profits off the 340B program can be significant.
For their new study, Drs Conti and Bach examined the populations served by hospitals and clinics qualifying for 340B before and after the decade-long growth spurt. They matched data for all hospitals and clinics registered with the 340B program to socioeconomic data from the US Census Bureau.
The results showed that communities served by hospital-affiliated clinics joining the program in 2004 or later tended to have higher household incomes, much less unemployment, and higher rates of health insurance.
The researchers said their findings are consistent with recent complaints that, rather than serving vulnerable communities, the 340B program is being used to increase profits for hospitals and their affiliated clinics.
Credit: Petr Kratochvil
A federal program designed to help the poor may actually be used to help US hospitals increase their profits, according to research published in Health Affairs.
Researchers examined enrollment in the 340B program, which provides deep discounts on outpatient drug purchases.
They found that hospitals and clinics that joined the program since 2004 currently serve more affluent and well-insured communities than those that qualified for the program in previous years.
This supports the idea that the program is changing from one that serves patients in need to one that enriches hospitals and their affiliated clinics, according to the researchers.
“This study provides the first nationally representative empirical evidence suggesting that the program’s original intent is being eroded by the actions of certain hospitals,” said study author Rena M. Conti, PhD, of the University of Chicago in Illinois.
This study follows work by Dr Conti and Peter B. Bach, MD, of Memorial Sloan-Kettering Cancer Center in New York, that was published in JAMA last year.
The JAMA study explained how 340B-qualified hospital-affiliated clinics can boost profits thanks to discounts on expensive anticancer drugs. The facilities receive the discounts under the expectation that the savings will be passed on to poor patients.
“Hospitals qualify for the program based on the poverty of their inpatient census only,” Dr Conti said. “The affiliated clinics are the only 340B institutions not required to pass the discounts off to patients or their insurers, nor do they have to report to the government exactly how these profits are used to serve the poor. Insurers’ and their patients’ payments for outpatient drug treatment don’t reflect the discounts the hospital receives.”
The 340B program, which began in 1992, was designed to help selected hospitals and their outpatient clinics serve low-income and uninsured patients by providing discounts of 30% to 50% on outpatient drugs.
About a decade ago, enrollment in 340B began to increase rapidly. Now, more than a third of the 4375 US non-federal hospitals are 340B-qualified. Recent Congressional and news reports suggest that, for selected hospitals, profits off the 340B program can be significant.
For their new study, Drs Conti and Bach examined the populations served by hospitals and clinics qualifying for 340B before and after the decade-long growth spurt. They matched data for all hospitals and clinics registered with the 340B program to socioeconomic data from the US Census Bureau.
The results showed that communities served by hospital-affiliated clinics joining the program in 2004 or later tended to have higher household incomes, much less unemployment, and higher rates of health insurance.
The researchers said their findings are consistent with recent complaints that, rather than serving vulnerable communities, the 340B program is being used to increase profits for hospitals and their affiliated clinics.
Credit: Petr Kratochvil
A federal program designed to help the poor may actually be used to help US hospitals increase their profits, according to research published in Health Affairs.
Researchers examined enrollment in the 340B program, which provides deep discounts on outpatient drug purchases.
They found that hospitals and clinics that joined the program since 2004 currently serve more affluent and well-insured communities than those that qualified for the program in previous years.
This supports the idea that the program is changing from one that serves patients in need to one that enriches hospitals and their affiliated clinics, according to the researchers.
“This study provides the first nationally representative empirical evidence suggesting that the program’s original intent is being eroded by the actions of certain hospitals,” said study author Rena M. Conti, PhD, of the University of Chicago in Illinois.
This study follows work by Dr Conti and Peter B. Bach, MD, of Memorial Sloan-Kettering Cancer Center in New York, that was published in JAMA last year.
The JAMA study explained how 340B-qualified hospital-affiliated clinics can boost profits thanks to discounts on expensive anticancer drugs. The facilities receive the discounts under the expectation that the savings will be passed on to poor patients.
“Hospitals qualify for the program based on the poverty of their inpatient census only,” Dr Conti said. “The affiliated clinics are the only 340B institutions not required to pass the discounts off to patients or their insurers, nor do they have to report to the government exactly how these profits are used to serve the poor. Insurers’ and their patients’ payments for outpatient drug treatment don’t reflect the discounts the hospital receives.”
The 340B program, which began in 1992, was designed to help selected hospitals and their outpatient clinics serve low-income and uninsured patients by providing discounts of 30% to 50% on outpatient drugs.
About a decade ago, enrollment in 340B began to increase rapidly. Now, more than a third of the 4375 US non-federal hospitals are 340B-qualified. Recent Congressional and news reports suggest that, for selected hospitals, profits off the 340B program can be significant.
For their new study, Drs Conti and Bach examined the populations served by hospitals and clinics qualifying for 340B before and after the decade-long growth spurt. They matched data for all hospitals and clinics registered with the 340B program to socioeconomic data from the US Census Bureau.
The results showed that communities served by hospital-affiliated clinics joining the program in 2004 or later tended to have higher household incomes, much less unemployment, and higher rates of health insurance.
The researchers said their findings are consistent with recent complaints that, rather than serving vulnerable communities, the 340B program is being used to increase profits for hospitals and their affiliated clinics.
Mental health challenges fairly common in cancer patients
chemotherapy
Credit: Rhoda Baer
In a large German study, investigators found that nearly a third of cancer patients experienced some form of clinically relevant mental health
challenge.
Of the more than 2100 cancer patients interviewed, 32% had experienced a clinically meaningful level of mental or emotional distress in the previous 4 weeks.
This prevalence is higher than that observed in the general population, and the difference is primarily due to a higher rate of anxiety and adjustment disorders.
The incidence of mental health issues varied by cancer type. The highest was among patients with breast cancer (42%) and head and neck cancer (41%), followed by malignant melanoma (39%).
The lowest prevalence was seen among patients with prostate cancer (22%), stomach cancers (21%), and pancreatic cancer (20%).
These results appear in the Journal of Clinical Oncology.
“These findings reinforce that, as doctors, we need to be very aware of signs and symptoms of mental and emotional distress,” said lead study author Anja Mehnert, PhD, of the University of Leipzig in Germany.
“We must encourage patients to seek evaluation, support, and treatment if necessary, as there are long-term risks often associated with more severe, untreated mental health disorders. This research also sheds light on which patients we should watch more closely.”
Dr Mehnert and her colleagues conducted this study in 2141 cancer patients who were 18 to 75 years of age. The team conducted face-to-face interviews in hospitals, outpatient cancer care centers, and rehabilitation centers in Germany.
Interview answers were immediately entered into a computer based-diagnostic program. The test assessed various psychological symptoms over the previous 4-week period. Patients’ diagnoses were classified according to the Diagnostic and Statistical Manual of Mental Disorders, the standard classification used by mental health professionals.
The patients had a range of cancer types, with the most common being breast cancer (44%), prostate cancer (15%), and colorectal cancer (14%). The average time since cancer diagnosis was 13.5 months, and 51% of the participants were women.
The researchers found that 32% of patients experienced at least one clinically meaningful mental health issue (defined in the study as a mental health disorder). This is a higher prevalence than in the general population, in which 18% to 20% of people are estimated to have a clinically meaningful mental disorder.
In the 4-week period prior to the interview, 11.5% of patients experienced an anxiety disorder. Eleven percent met the criteria for an adjustment disorder, a predominantly mixed anxiety-depressive syndrome that persisted for at least 4 weeks in response to a significant life change. And 6.5% of patients had signs of a mood disorder such as major depression.
The 11.5% rate of anxiety disorders—such as phobia, panic, or generalized anxiety disorder—was slightly higher than in the general population (9%), while the prevalence of other mental health diagnoses was similar to rates in the general population.
It is likely that the prevalence of adjustment disorders (11%), which is rarely assessed in general population surveys, significantly contributed to the overall higher prevalence rate of mental disorders in this population of patients with cancer.
Dr Mehnert said it was surprising that patients with a more treatable malignancy, such as breast cancer, experienced more distress than people with cancers that are more challenging to treat, such as stomach and pancreatic cancers. So more research is needed to interpret these findings.
The investigators believe the study’s results may be useful for planning future support programs for cancer patients, and they can provide additional information to guide programs for people with specific cancer types.
The team also believes the findings can likely be generalized to patients in the US because the prevalence of mental health diagnoses is similar between the 2 countries.
chemotherapy
Credit: Rhoda Baer
In a large German study, investigators found that nearly a third of cancer patients experienced some form of clinically relevant mental health
challenge.
Of the more than 2100 cancer patients interviewed, 32% had experienced a clinically meaningful level of mental or emotional distress in the previous 4 weeks.
This prevalence is higher than that observed in the general population, and the difference is primarily due to a higher rate of anxiety and adjustment disorders.
The incidence of mental health issues varied by cancer type. The highest was among patients with breast cancer (42%) and head and neck cancer (41%), followed by malignant melanoma (39%).
The lowest prevalence was seen among patients with prostate cancer (22%), stomach cancers (21%), and pancreatic cancer (20%).
These results appear in the Journal of Clinical Oncology.
“These findings reinforce that, as doctors, we need to be very aware of signs and symptoms of mental and emotional distress,” said lead study author Anja Mehnert, PhD, of the University of Leipzig in Germany.
“We must encourage patients to seek evaluation, support, and treatment if necessary, as there are long-term risks often associated with more severe, untreated mental health disorders. This research also sheds light on which patients we should watch more closely.”
Dr Mehnert and her colleagues conducted this study in 2141 cancer patients who were 18 to 75 years of age. The team conducted face-to-face interviews in hospitals, outpatient cancer care centers, and rehabilitation centers in Germany.
Interview answers were immediately entered into a computer based-diagnostic program. The test assessed various psychological symptoms over the previous 4-week period. Patients’ diagnoses were classified according to the Diagnostic and Statistical Manual of Mental Disorders, the standard classification used by mental health professionals.
The patients had a range of cancer types, with the most common being breast cancer (44%), prostate cancer (15%), and colorectal cancer (14%). The average time since cancer diagnosis was 13.5 months, and 51% of the participants were women.
The researchers found that 32% of patients experienced at least one clinically meaningful mental health issue (defined in the study as a mental health disorder). This is a higher prevalence than in the general population, in which 18% to 20% of people are estimated to have a clinically meaningful mental disorder.
In the 4-week period prior to the interview, 11.5% of patients experienced an anxiety disorder. Eleven percent met the criteria for an adjustment disorder, a predominantly mixed anxiety-depressive syndrome that persisted for at least 4 weeks in response to a significant life change. And 6.5% of patients had signs of a mood disorder such as major depression.
The 11.5% rate of anxiety disorders—such as phobia, panic, or generalized anxiety disorder—was slightly higher than in the general population (9%), while the prevalence of other mental health diagnoses was similar to rates in the general population.
It is likely that the prevalence of adjustment disorders (11%), which is rarely assessed in general population surveys, significantly contributed to the overall higher prevalence rate of mental disorders in this population of patients with cancer.
Dr Mehnert said it was surprising that patients with a more treatable malignancy, such as breast cancer, experienced more distress than people with cancers that are more challenging to treat, such as stomach and pancreatic cancers. So more research is needed to interpret these findings.
The investigators believe the study’s results may be useful for planning future support programs for cancer patients, and they can provide additional information to guide programs for people with specific cancer types.
The team also believes the findings can likely be generalized to patients in the US because the prevalence of mental health diagnoses is similar between the 2 countries.
chemotherapy
Credit: Rhoda Baer
In a large German study, investigators found that nearly a third of cancer patients experienced some form of clinically relevant mental health
challenge.
Of the more than 2100 cancer patients interviewed, 32% had experienced a clinically meaningful level of mental or emotional distress in the previous 4 weeks.
This prevalence is higher than that observed in the general population, and the difference is primarily due to a higher rate of anxiety and adjustment disorders.
The incidence of mental health issues varied by cancer type. The highest was among patients with breast cancer (42%) and head and neck cancer (41%), followed by malignant melanoma (39%).
The lowest prevalence was seen among patients with prostate cancer (22%), stomach cancers (21%), and pancreatic cancer (20%).
These results appear in the Journal of Clinical Oncology.
“These findings reinforce that, as doctors, we need to be very aware of signs and symptoms of mental and emotional distress,” said lead study author Anja Mehnert, PhD, of the University of Leipzig in Germany.
“We must encourage patients to seek evaluation, support, and treatment if necessary, as there are long-term risks often associated with more severe, untreated mental health disorders. This research also sheds light on which patients we should watch more closely.”
Dr Mehnert and her colleagues conducted this study in 2141 cancer patients who were 18 to 75 years of age. The team conducted face-to-face interviews in hospitals, outpatient cancer care centers, and rehabilitation centers in Germany.
Interview answers were immediately entered into a computer based-diagnostic program. The test assessed various psychological symptoms over the previous 4-week period. Patients’ diagnoses were classified according to the Diagnostic and Statistical Manual of Mental Disorders, the standard classification used by mental health professionals.
The patients had a range of cancer types, with the most common being breast cancer (44%), prostate cancer (15%), and colorectal cancer (14%). The average time since cancer diagnosis was 13.5 months, and 51% of the participants were women.
The researchers found that 32% of patients experienced at least one clinically meaningful mental health issue (defined in the study as a mental health disorder). This is a higher prevalence than in the general population, in which 18% to 20% of people are estimated to have a clinically meaningful mental disorder.
In the 4-week period prior to the interview, 11.5% of patients experienced an anxiety disorder. Eleven percent met the criteria for an adjustment disorder, a predominantly mixed anxiety-depressive syndrome that persisted for at least 4 weeks in response to a significant life change. And 6.5% of patients had signs of a mood disorder such as major depression.
The 11.5% rate of anxiety disorders—such as phobia, panic, or generalized anxiety disorder—was slightly higher than in the general population (9%), while the prevalence of other mental health diagnoses was similar to rates in the general population.
It is likely that the prevalence of adjustment disorders (11%), which is rarely assessed in general population surveys, significantly contributed to the overall higher prevalence rate of mental disorders in this population of patients with cancer.
Dr Mehnert said it was surprising that patients with a more treatable malignancy, such as breast cancer, experienced more distress than people with cancers that are more challenging to treat, such as stomach and pancreatic cancers. So more research is needed to interpret these findings.
The investigators believe the study’s results may be useful for planning future support programs for cancer patients, and they can provide additional information to guide programs for people with specific cancer types.
The team also believes the findings can likely be generalized to patients in the US because the prevalence of mental health diagnoses is similar between the 2 countries.
FDA allows access to pathogen inactivation system
The US Food and Drug Administration (FDA) has authorized the use of a pathogen inactivation system in regions of the US and its territories affected by outbreaks of Chikungunya and dengue virus.
The INTERCEPT Blood System for platelets is used for the preparation and storage of whole blood-derived and apheresis platelets.
The system can inactivate a range of viruses, bacteria, and parasites to reduce the risk of transmission via platelet transfusion. It can also prevent transfusion-associated graft-vs-host disease and reduce the risk of other adverse effects due to transfusion of contaminating donor leukocytes.
The INTERCEPT Blood System for platelets has not been granted full FDA approval. The agency has approved use of the system via an investigational device exemption (IDE).
This allows for early access to a device not yet approved in the US when no satisfactory alternative is available to treat patients with serious or life-threatening conditions.
The INTERCEPT Blood System for platelets will initially be available to sites in Puerto Rico that agree to participate in a clinical study. Depending on the scope of participation there, the system may be made available to sites in other areas where cases of Chikungunya and dengue have been reported, such as Florida and Texas.
“We are pleased to provide US blood centers and hospitals early access to INTERCEPT for the treatment of platelet components in light of the escalating threat of Chikungunya and dengue transfusion-transmitted infections,” said Carol Moore, of Cerus Corporation, the company developing the INTERCEPT system.
“With this expeditious approval of our IDE, we hope to initiate our first study site before year-end.”
About the system
The INTERCEPT Blood System for platelets is based on the premise that platelets don’t require functional DNA or RNA, but pathogens and contaminating leukocytes do. The system deploys proprietary molecules that, when activated, bind to and block the replication of DNA and RNA in the blood.
The system uses amotosalen HCl (a photoactive compound) and long-wavelength ultraviolet illumination to photochemically treat platelet components, rendering susceptible pathogens incapable of replicating and causing disease.
Published studies have demonstrated INTERCEPT inactivation of >6.4 log of Chikungunya and >5.3 log of dengue infectious titers, both in excess of observed titers in asymptomatic donors.
The INTERCEPT platelet system has been approved in Europe since 2002 and is currently used at more than 100 blood centers in 20 countries. The system is under regulatory review in the US, Canada, Brazil, and China.
About dengue and Chikungunya
Dengue virus is endemic to the Caribbean region. Local transmission of Chikungunya virus was detected in the Caribbean for the first time in February 2014. Both viruses are spread by species of mosquitoes common in tropical climates and regions within the continental US.
As of September 30, 2014, the Centers for Disease Control and Prevention has reported 11 confirmed locally transmitted cases of Chikungunya in
Florida, 421 cases in Puerto Rico, and 45 cases in the US Virgin Islands. Local transmission of dengue has also been reported in Texas and Florida.
Chikungunya virus causes high fevers, joint pain and swelling, headaches, and a rash. Symptoms have been reported to persist for up to 2 years in chronic cases. Rarely, Chikungunya can be fatal.
Symptoms of dengue include high fever, headaches, joint and muscle pain, vomiting, and a rash. In some cases, dengue infection is life-threatening due to dengue hemorrhagic fever, which causes bleeding from the nose, gums, or under the skin.
The US Food and Drug Administration (FDA) has authorized the use of a pathogen inactivation system in regions of the US and its territories affected by outbreaks of Chikungunya and dengue virus.
The INTERCEPT Blood System for platelets is used for the preparation and storage of whole blood-derived and apheresis platelets.
The system can inactivate a range of viruses, bacteria, and parasites to reduce the risk of transmission via platelet transfusion. It can also prevent transfusion-associated graft-vs-host disease and reduce the risk of other adverse effects due to transfusion of contaminating donor leukocytes.
The INTERCEPT Blood System for platelets has not been granted full FDA approval. The agency has approved use of the system via an investigational device exemption (IDE).
This allows for early access to a device not yet approved in the US when no satisfactory alternative is available to treat patients with serious or life-threatening conditions.
The INTERCEPT Blood System for platelets will initially be available to sites in Puerto Rico that agree to participate in a clinical study. Depending on the scope of participation there, the system may be made available to sites in other areas where cases of Chikungunya and dengue have been reported, such as Florida and Texas.
“We are pleased to provide US blood centers and hospitals early access to INTERCEPT for the treatment of platelet components in light of the escalating threat of Chikungunya and dengue transfusion-transmitted infections,” said Carol Moore, of Cerus Corporation, the company developing the INTERCEPT system.
“With this expeditious approval of our IDE, we hope to initiate our first study site before year-end.”
About the system
The INTERCEPT Blood System for platelets is based on the premise that platelets don’t require functional DNA or RNA, but pathogens and contaminating leukocytes do. The system deploys proprietary molecules that, when activated, bind to and block the replication of DNA and RNA in the blood.
The system uses amotosalen HCl (a photoactive compound) and long-wavelength ultraviolet illumination to photochemically treat platelet components, rendering susceptible pathogens incapable of replicating and causing disease.
Published studies have demonstrated INTERCEPT inactivation of >6.4 log of Chikungunya and >5.3 log of dengue infectious titers, both in excess of observed titers in asymptomatic donors.
The INTERCEPT platelet system has been approved in Europe since 2002 and is currently used at more than 100 blood centers in 20 countries. The system is under regulatory review in the US, Canada, Brazil, and China.
About dengue and Chikungunya
Dengue virus is endemic to the Caribbean region. Local transmission of Chikungunya virus was detected in the Caribbean for the first time in February 2014. Both viruses are spread by species of mosquitoes common in tropical climates and regions within the continental US.
As of September 30, 2014, the Centers for Disease Control and Prevention has reported 11 confirmed locally transmitted cases of Chikungunya in
Florida, 421 cases in Puerto Rico, and 45 cases in the US Virgin Islands. Local transmission of dengue has also been reported in Texas and Florida.
Chikungunya virus causes high fevers, joint pain and swelling, headaches, and a rash. Symptoms have been reported to persist for up to 2 years in chronic cases. Rarely, Chikungunya can be fatal.
Symptoms of dengue include high fever, headaches, joint and muscle pain, vomiting, and a rash. In some cases, dengue infection is life-threatening due to dengue hemorrhagic fever, which causes bleeding from the nose, gums, or under the skin.
The US Food and Drug Administration (FDA) has authorized the use of a pathogen inactivation system in regions of the US and its territories affected by outbreaks of Chikungunya and dengue virus.
The INTERCEPT Blood System for platelets is used for the preparation and storage of whole blood-derived and apheresis platelets.
The system can inactivate a range of viruses, bacteria, and parasites to reduce the risk of transmission via platelet transfusion. It can also prevent transfusion-associated graft-vs-host disease and reduce the risk of other adverse effects due to transfusion of contaminating donor leukocytes.
The INTERCEPT Blood System for platelets has not been granted full FDA approval. The agency has approved use of the system via an investigational device exemption (IDE).
This allows for early access to a device not yet approved in the US when no satisfactory alternative is available to treat patients with serious or life-threatening conditions.
The INTERCEPT Blood System for platelets will initially be available to sites in Puerto Rico that agree to participate in a clinical study. Depending on the scope of participation there, the system may be made available to sites in other areas where cases of Chikungunya and dengue have been reported, such as Florida and Texas.
“We are pleased to provide US blood centers and hospitals early access to INTERCEPT for the treatment of platelet components in light of the escalating threat of Chikungunya and dengue transfusion-transmitted infections,” said Carol Moore, of Cerus Corporation, the company developing the INTERCEPT system.
“With this expeditious approval of our IDE, we hope to initiate our first study site before year-end.”
About the system
The INTERCEPT Blood System for platelets is based on the premise that platelets don’t require functional DNA or RNA, but pathogens and contaminating leukocytes do. The system deploys proprietary molecules that, when activated, bind to and block the replication of DNA and RNA in the blood.
The system uses amotosalen HCl (a photoactive compound) and long-wavelength ultraviolet illumination to photochemically treat platelet components, rendering susceptible pathogens incapable of replicating and causing disease.
Published studies have demonstrated INTERCEPT inactivation of >6.4 log of Chikungunya and >5.3 log of dengue infectious titers, both in excess of observed titers in asymptomatic donors.
The INTERCEPT platelet system has been approved in Europe since 2002 and is currently used at more than 100 blood centers in 20 countries. The system is under regulatory review in the US, Canada, Brazil, and China.
About dengue and Chikungunya
Dengue virus is endemic to the Caribbean region. Local transmission of Chikungunya virus was detected in the Caribbean for the first time in February 2014. Both viruses are spread by species of mosquitoes common in tropical climates and regions within the continental US.
As of September 30, 2014, the Centers for Disease Control and Prevention has reported 11 confirmed locally transmitted cases of Chikungunya in
Florida, 421 cases in Puerto Rico, and 45 cases in the US Virgin Islands. Local transmission of dengue has also been reported in Texas and Florida.
Chikungunya virus causes high fevers, joint pain and swelling, headaches, and a rash. Symptoms have been reported to persist for up to 2 years in chronic cases. Rarely, Chikungunya can be fatal.
Symptoms of dengue include high fever, headaches, joint and muscle pain, vomiting, and a rash. In some cases, dengue infection is life-threatening due to dengue hemorrhagic fever, which causes bleeding from the nose, gums, or under the skin.
A single cell can cause MPNs
Credit: Aaron Logan
Scientists have found that a single cell containing the JAK2-V617F mutation can cause myeloproliferative neoplasms (MPNs) in mice.
The team isolated hematopoietic stem cells (HSCs) from malignant MPNs and transplanted a single cell with mutated JAK2 into groups of healthy mice.
A subset of the mice developed MPNs, which also bore the JAK2 mutation.
The researchers described this work in The Journal of Experimental Medicine.
Pontus Lundberg, PhD, of University Hospital Basel in Switzerland, and his colleagues performed several sets of experiments in which they transplanted JAK2-V617F-expressing cells in dilutions of wild-type bone marrow cells.
In the 1:125 dilution experiment, 24% of mice (4/17) developed polycythemia vera (PV). In the 1:250 dilution experiment, 44% of mice developed either PV or essential thrombocythemia (ET).
The researchers were interested to find that erythrocytosis and thrombocytosis were mutually exclusive in individual mice.
Additional investigation revealed that MPN development did not depend on the acquisition of additional somatic mutations.
To confirm their findings, the researchers then transplanted a single JAK2-V617F-expressing HSC into a total of 113 mice in 4 independent experiments.
Only 1 mouse developed an ET phenotype. Two other mice had transient high chimerism in erythrocytes and/or platelets, but they did not develop ET or PV.
Furthermore, transplanting bone marrow from the mouse with the ET phenotype into secondary recipients did not result in an MPN phenotype.
The researchers also analyzed JAK2-V617F-expressing HSCs in further detail, and they found these HSCs promoted cell division and increased DNA damage.
Higher JAK2-V617F expression was associated with a short-term HSC signature and increased myeloid bias. Lower JAK2-V617F expression was associated with the capacity to stably engraft in secondary recipients.
Dr Lundberg and his colleagues said this research shows that JAK2-V617F has complex effects on HSC biology and that MPNs can develop from a single JAK2-V617F-expressing cell.
Credit: Aaron Logan
Scientists have found that a single cell containing the JAK2-V617F mutation can cause myeloproliferative neoplasms (MPNs) in mice.
The team isolated hematopoietic stem cells (HSCs) from malignant MPNs and transplanted a single cell with mutated JAK2 into groups of healthy mice.
A subset of the mice developed MPNs, which also bore the JAK2 mutation.
The researchers described this work in The Journal of Experimental Medicine.
Pontus Lundberg, PhD, of University Hospital Basel in Switzerland, and his colleagues performed several sets of experiments in which they transplanted JAK2-V617F-expressing cells in dilutions of wild-type bone marrow cells.
In the 1:125 dilution experiment, 24% of mice (4/17) developed polycythemia vera (PV). In the 1:250 dilution experiment, 44% of mice developed either PV or essential thrombocythemia (ET).
The researchers were interested to find that erythrocytosis and thrombocytosis were mutually exclusive in individual mice.
Additional investigation revealed that MPN development did not depend on the acquisition of additional somatic mutations.
To confirm their findings, the researchers then transplanted a single JAK2-V617F-expressing HSC into a total of 113 mice in 4 independent experiments.
Only 1 mouse developed an ET phenotype. Two other mice had transient high chimerism in erythrocytes and/or platelets, but they did not develop ET or PV.
Furthermore, transplanting bone marrow from the mouse with the ET phenotype into secondary recipients did not result in an MPN phenotype.
The researchers also analyzed JAK2-V617F-expressing HSCs in further detail, and they found these HSCs promoted cell division and increased DNA damage.
Higher JAK2-V617F expression was associated with a short-term HSC signature and increased myeloid bias. Lower JAK2-V617F expression was associated with the capacity to stably engraft in secondary recipients.
Dr Lundberg and his colleagues said this research shows that JAK2-V617F has complex effects on HSC biology and that MPNs can develop from a single JAK2-V617F-expressing cell.
Credit: Aaron Logan
Scientists have found that a single cell containing the JAK2-V617F mutation can cause myeloproliferative neoplasms (MPNs) in mice.
The team isolated hematopoietic stem cells (HSCs) from malignant MPNs and transplanted a single cell with mutated JAK2 into groups of healthy mice.
A subset of the mice developed MPNs, which also bore the JAK2 mutation.
The researchers described this work in The Journal of Experimental Medicine.
Pontus Lundberg, PhD, of University Hospital Basel in Switzerland, and his colleagues performed several sets of experiments in which they transplanted JAK2-V617F-expressing cells in dilutions of wild-type bone marrow cells.
In the 1:125 dilution experiment, 24% of mice (4/17) developed polycythemia vera (PV). In the 1:250 dilution experiment, 44% of mice developed either PV or essential thrombocythemia (ET).
The researchers were interested to find that erythrocytosis and thrombocytosis were mutually exclusive in individual mice.
Additional investigation revealed that MPN development did not depend on the acquisition of additional somatic mutations.
To confirm their findings, the researchers then transplanted a single JAK2-V617F-expressing HSC into a total of 113 mice in 4 independent experiments.
Only 1 mouse developed an ET phenotype. Two other mice had transient high chimerism in erythrocytes and/or platelets, but they did not develop ET or PV.
Furthermore, transplanting bone marrow from the mouse with the ET phenotype into secondary recipients did not result in an MPN phenotype.
The researchers also analyzed JAK2-V617F-expressing HSCs in further detail, and they found these HSCs promoted cell division and increased DNA damage.
Higher JAK2-V617F expression was associated with a short-term HSC signature and increased myeloid bias. Lower JAK2-V617F expression was associated with the capacity to stably engraft in secondary recipients.
Dr Lundberg and his colleagues said this research shows that JAK2-V617F has complex effects on HSC biology and that MPNs can develop from a single JAK2-V617F-expressing cell.
Survey shows lack of adherence to safety guidelines
Credit: Bill Branson
Healthcare professionals do not consistently follow the recommended safe handling practices for antineoplastic drugs, according to a survey published in the Journal of Occupational and Environmental Hygiene.
Researchers surveyed more than 2000 healthcare workers and found that a majority do not always use the recommended personal protective equipment when they are administering antineoplastic drugs.
Furthermore, some respondents reported spills or leaks of a drug during administration, and a small percentage said they had experienced skin
contact with an antineoplastic drug.
“Chemotherapy drugs save lives of cancer patients but also can result in adverse health outcomes in workers who are exposed to these drugs, including cancer, reproductive problems, and organ damage when recommended safe handling guidelines are not followed,” said John Howard, MD, director of the National Institute for Occupational Safety and Health (NIOSH).
NIOSH researchers conducted this study, which included 2069 healthcare personnel who completed the 2011 Health and Safety Practices Survey of Healthcare Workers.
Results showed that, despite the longstanding availability of authoritative safe handling guidelines (ASHP, NIOSH, ONS, OSHA), recommended exposure controls were not always used.
For example, 80% of respondents said they do not always wear 2 pairs of chemotherapy gloves, and 15% said they don’t always wear a single pair.
Forty-two percent of respondents said they don’t always wear a nonabsorbent gown with a closed front and tight-fitting cuffs, and 12% had taken home potentially contaminated clothing.
Twelve percent of respondents reported a spill or leak of an antineoplastic drug during administration, and 4% reported skin contact with an antineoplastic drug.
Six percent of respondents said they primed intravenous tubing with an antineoplastic drug instead of a non-drug containing liquid, and 12% said the pharmacy department followed this practice.
Taking these and other findings into account, the researchers concluded that better risk communication is needed to ensure that employers and employees are fully aware of the hazards and the availability of precautionary measures to minimize exposure to antineoplastic drugs.
Credit: Bill Branson
Healthcare professionals do not consistently follow the recommended safe handling practices for antineoplastic drugs, according to a survey published in the Journal of Occupational and Environmental Hygiene.
Researchers surveyed more than 2000 healthcare workers and found that a majority do not always use the recommended personal protective equipment when they are administering antineoplastic drugs.
Furthermore, some respondents reported spills or leaks of a drug during administration, and a small percentage said they had experienced skin
contact with an antineoplastic drug.
“Chemotherapy drugs save lives of cancer patients but also can result in adverse health outcomes in workers who are exposed to these drugs, including cancer, reproductive problems, and organ damage when recommended safe handling guidelines are not followed,” said John Howard, MD, director of the National Institute for Occupational Safety and Health (NIOSH).
NIOSH researchers conducted this study, which included 2069 healthcare personnel who completed the 2011 Health and Safety Practices Survey of Healthcare Workers.
Results showed that, despite the longstanding availability of authoritative safe handling guidelines (ASHP, NIOSH, ONS, OSHA), recommended exposure controls were not always used.
For example, 80% of respondents said they do not always wear 2 pairs of chemotherapy gloves, and 15% said they don’t always wear a single pair.
Forty-two percent of respondents said they don’t always wear a nonabsorbent gown with a closed front and tight-fitting cuffs, and 12% had taken home potentially contaminated clothing.
Twelve percent of respondents reported a spill or leak of an antineoplastic drug during administration, and 4% reported skin contact with an antineoplastic drug.
Six percent of respondents said they primed intravenous tubing with an antineoplastic drug instead of a non-drug containing liquid, and 12% said the pharmacy department followed this practice.
Taking these and other findings into account, the researchers concluded that better risk communication is needed to ensure that employers and employees are fully aware of the hazards and the availability of precautionary measures to minimize exposure to antineoplastic drugs.
Credit: Bill Branson
Healthcare professionals do not consistently follow the recommended safe handling practices for antineoplastic drugs, according to a survey published in the Journal of Occupational and Environmental Hygiene.
Researchers surveyed more than 2000 healthcare workers and found that a majority do not always use the recommended personal protective equipment when they are administering antineoplastic drugs.
Furthermore, some respondents reported spills or leaks of a drug during administration, and a small percentage said they had experienced skin
contact with an antineoplastic drug.
“Chemotherapy drugs save lives of cancer patients but also can result in adverse health outcomes in workers who are exposed to these drugs, including cancer, reproductive problems, and organ damage when recommended safe handling guidelines are not followed,” said John Howard, MD, director of the National Institute for Occupational Safety and Health (NIOSH).
NIOSH researchers conducted this study, which included 2069 healthcare personnel who completed the 2011 Health and Safety Practices Survey of Healthcare Workers.
Results showed that, despite the longstanding availability of authoritative safe handling guidelines (ASHP, NIOSH, ONS, OSHA), recommended exposure controls were not always used.
For example, 80% of respondents said they do not always wear 2 pairs of chemotherapy gloves, and 15% said they don’t always wear a single pair.
Forty-two percent of respondents said they don’t always wear a nonabsorbent gown with a closed front and tight-fitting cuffs, and 12% had taken home potentially contaminated clothing.
Twelve percent of respondents reported a spill or leak of an antineoplastic drug during administration, and 4% reported skin contact with an antineoplastic drug.
Six percent of respondents said they primed intravenous tubing with an antineoplastic drug instead of a non-drug containing liquid, and 12% said the pharmacy department followed this practice.
Taking these and other findings into account, the researchers concluded that better risk communication is needed to ensure that employers and employees are fully aware of the hazards and the availability of precautionary measures to minimize exposure to antineoplastic drugs.
Animal studies help explain chemo brain
californica
releasing inkafter being disturbed
Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.
Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.
This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.
“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.
He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.
Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.
The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.
To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.
Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.
The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term
synaptic depression.
They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.
However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.
Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.
The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.
californica
releasing inkafter being disturbed
Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.
Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.
This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.
“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.
He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.
Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.
The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.
To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.
Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.
The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term
synaptic depression.
They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.
However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.
Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.
The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.
californica
releasing inkafter being disturbed
Results of preclinical research appear to explain how the anticancer agent doxorubicin can cause chemo brain.
Neuroscientists conducted experiments in cells from rats and Aplysia californica, a marine mollusk that has many of the same memory mechanisms as humans.
This revealed memory mechanisms that are inhibited by doxorubicin, as well as a method of unblocking these mechanisms—administering a drug known as SB203580.
“Our research has implications in the care of people given to cognitive deficits following drug treatment for cancer,” said John H. Byrne, PhD, of the University of Texas Health Medical School.
He added that understanding how drugs like doxorubicin impact the brain is an important first step in alleviating chemo brain, which is characterized by forgetfulness, trouble concentrating, and difficulty multitasking.
Dr Byrne and his colleagues explained this first step in The Journal of Neuroscience.
The researchers knew that, in non-neuronal cells, doxorubicin inhibits the expression of MAPK phosphatases, thereby inhibiting the dephosphorylation of ERK and p38 MAPK, 2 MAPK isoforms that are important for long-term memory.
To evaluate doxorubicin’s effects on levels of phosphorylated ERK and p38 MAPK, the team used cultures of cortical neurons from rats and sensory neurons from Aplysia californica.
Experiments showed that doxorubicin elevated levels of phosphorylated ERK and phosphorylated p38 MAPK in sensory neurons and cortical neurons. In addition, the drug increased phosphorylation of the downstream transcriptional repressor CREB2 in sensory neurons.
The researchers also assessed doxorubicin’s effects on long-term enhanced excitability, long-term synaptic facilitation, and long-term
synaptic depression.
They found that doxorubicin enhanced long-term synaptic depression induced by the neuropeptide Phe-Met-Arg-Phe-NH2. And the drug inhibited long-term synaptic facilitation induced by serotonin.
However, the researchers were able to restore long-term synaptic facilitation with SB203580, an inhibitor of p38 MAPK.
Unfortunately, SB203580 would not be appropriate for human use, Dr Byrne noted, adding that his team would like to identify other drugs that might have the same effect as SB203580.
The researchers also hope to determine if doxorubicin works the same way in humans as it did in these experiments.
Combo can improve survival in certain AML patients
In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).
However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.
Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.
The results are set to be presented in more detail at an upcoming scientific conference.
The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.
The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).
However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).
Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.
In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).
Results according to age
For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.
For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).
The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.
For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).
The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.
Adverse events and mortality
In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.
The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.
All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.
Regulatory plans
Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.
The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.
In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).
However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.
Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.
The results are set to be presented in more detail at an upcoming scientific conference.
The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.
The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).
However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).
Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.
In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).
Results according to age
For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.
For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).
The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.
For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).
The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.
Adverse events and mortality
In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.
The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.
All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.
Regulatory plans
Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.
The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.
In a phase 3 trial, adding the quinolone derivative vosaroxin (Qinprezo) to treatment with cytarabine did not improve overall survival in patients with relapsed or refractory acute myeloid leukemia (AML).
However, the combination did confer a survival benefit when transplant patients were excluded from the analysis and in patients age 60 and older.
Results of this trial were recently announced by Sunesis Pharmaceuticals, the company developing vosaroxin.
The results are set to be presented in more detail at an upcoming scientific conference.
The trial, known as VALOR, enrolled 711 AML patients who had relapsed or become refractory to treatment for the first time. The patients were randomized to receive cytarabine plus vosaroxin or cytarabine plus placebo. They were stratified for age, geography, and disease status.
The trial did not meet its primary endpoint of demonstrating a significant improvement in overall survival. The median overall survival was 7.5 months in the vosaroxin-cytarabine arm and 6.1 months in the placebo-cytarabine arm (hazard ratio [HR]=0.865, P=0.06).
However, there was a significant benefit in complete response rate with vosaroxin over placebo—30.1% and 16.3%, respectively (P=0.0000148).
Because transplant could confound the primary analysis, the researchers planned a predefined analysis of overall survival censoring for stem cell transplant.
In this analysis, patients receiving the vosaroxin combination had a median overall survival of 6.7 months, compared to 5.3 months for placebo and cytarabine (HR=0.809, P=0.02).
Results according to age
For age, the researchers stratified patients into those age 60 years and older and those younger than 60 years at enrollment.
For the younger patients (n=260), the median overall survival was 9.1 months in the vosaroxin-cytarabine arm and 7.9 months in the placebo-cytarabine arm (HR=1.079, not significant).
The complete response rates were 26.9% and 20.8%, respectively (P=0.24). The rate of stem cell transplant was 45.8% in this age group.
For patients aged 60 years and older (n=451), the median overall survival was 7.1 months in the vosaroxin-cytarabine arm and 5.0 months in the placebo-cytarabine arm (HR=0.755, P=0.006).
The complete response rates were 31.9% and 13.8%, respectively (P=0.0000048). The rate of stem cell transplant was 20.2% for this age group.
Adverse events and mortality
In the intent-to-treat population, grade 3 or higher non-hematologic adverse events that were more common in the vosaroxin arm were gastrointestinal and infection-related toxicities. This is consistent with events observed in previous company trials.
The rate of serious adverse events was 55.5% in the vosaroxin-cytarabine arm and 35.7% in the placebo-cytarabine arm.
All-cause mortality rates were similar between the arms. Thirty-day mortality rates were 7.9% in the vosaroxin-cytarabine arm and 6.6% in the placebo-cytarabine arm. And 60-day mortality rates were 19.7% and 19.4%, respectively.
Regulatory plans
Based on the results of the trial, Sunesis plans to submit a marketing authorization application for vosaroxin to the European Medicines Agency. The company also plans to meet with the US Food and Drug Administration (FDA) to determine the appropriate regulatory path forward.
The FDA and the European Commission have already granted orphan designation to vosaroxin for the treatment of AML. The drug has been granted fast track designation by the FDA as well, for the potential treatment of relapsed or refractory AML in combination with cytarabine.
New insight into HSCs’ role in hematopoiesis
allows scientists to identify
differences in blood cell origin
Credit: Camargo Lab
By developing a tracking system for stem cells, researchers may have discovered previously unrecognized features of hematopoiesis.
Their work suggests the main drivers of steady-state hematopoiesis are not hematopoietic stem cells (HSCs) but their less pluripotent descendants, progenitor cells.
The team speculates that stable populations of long-lived progenitor cells are responsible for giving rise to specific blood cell types, while HSCs likely act as essential reserves.
The research, published in Nature, indicates that progenitor cells could be just as valuable as HSCs for blood regeneration therapies.
The work challenges what textbooks have long read: that HSCs maintain the day-to-day renewal of blood, a conclusion drawn from their importance in re-establishing blood cell populations after bone marrow transplants.
Due to a lack of tools to study how blood forms in a normal context, no one was able to track the origin of blood cells without doing a transplant.
Fernando Camargo, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues addressed this problem with a tool that generates a unique barcode in the DNA of all HSCs and their progenitor cells in a mouse.
When a tagged cell divides, all of its descendant cells possess the same barcode. This biological inventory system makes it possible to determine the number of HSCs/progenitors being used to make blood and how long they live, as well as answer fundamental questions about where individual blood cells come from.
“There’s never been such a robust experimental method that could allow people to look at lineage relationships between mature cell types in the body without doing transplantation,” said study author Jianlong Sun, PhD, also of Boston Children’s Hospital.
“One of the major directions we can now go is to revisit the entire blood cell hierarchy and see how the current knowledge holds true when we use this internal labeling system.”
“People have tried using viruses to tag blood cells in the past, but the cells needed to be taken out of the body, infected, and re-transplanted, which raised a number of issues,” Dr Camargo noted. “I wanted to figure out a way to label blood cells inside of the body, and the best idea I had was to use mobile genetic elements called transposons.”
A transposon is a piece of genetic code that can jump to a random point in DNA when exposed to the enzyme transposase. Dr Camargo’s approach works using transgenic mice that possess a single fish-derived transposon in all of their blood cells.
When one of these mice is exposed to transposase, each of its blood cells’ transposons changes location. The location in the DNA where a transposon moves acts as an individual cell’s barcode, so that if the mouse’s blood is taken a few months later, any cell with the same transposon location can be linked back to its parent cell.
Now, the researchers are planning to explore more applications for their barcode tool.
“We are also tremendously excited to use this tool to barcode and track descendants of different stem cells or progenitor cells for a range of conditions, from aging to the normal immune response,” Dr Sun said.
“We first used this technology for blood analysis. However, this system can also help address basic questions about cell populations in solid tissue. You can imagine being able to look at tumor progression or identify the precise origins of cancer cells that have broken off from a tumor and are now circulating in the blood.”
allows scientists to identify
differences in blood cell origin
Credit: Camargo Lab
By developing a tracking system for stem cells, researchers may have discovered previously unrecognized features of hematopoiesis.
Their work suggests the main drivers of steady-state hematopoiesis are not hematopoietic stem cells (HSCs) but their less pluripotent descendants, progenitor cells.
The team speculates that stable populations of long-lived progenitor cells are responsible for giving rise to specific blood cell types, while HSCs likely act as essential reserves.
The research, published in Nature, indicates that progenitor cells could be just as valuable as HSCs for blood regeneration therapies.
The work challenges what textbooks have long read: that HSCs maintain the day-to-day renewal of blood, a conclusion drawn from their importance in re-establishing blood cell populations after bone marrow transplants.
Due to a lack of tools to study how blood forms in a normal context, no one was able to track the origin of blood cells without doing a transplant.
Fernando Camargo, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues addressed this problem with a tool that generates a unique barcode in the DNA of all HSCs and their progenitor cells in a mouse.
When a tagged cell divides, all of its descendant cells possess the same barcode. This biological inventory system makes it possible to determine the number of HSCs/progenitors being used to make blood and how long they live, as well as answer fundamental questions about where individual blood cells come from.
“There’s never been such a robust experimental method that could allow people to look at lineage relationships between mature cell types in the body without doing transplantation,” said study author Jianlong Sun, PhD, also of Boston Children’s Hospital.
“One of the major directions we can now go is to revisit the entire blood cell hierarchy and see how the current knowledge holds true when we use this internal labeling system.”
“People have tried using viruses to tag blood cells in the past, but the cells needed to be taken out of the body, infected, and re-transplanted, which raised a number of issues,” Dr Camargo noted. “I wanted to figure out a way to label blood cells inside of the body, and the best idea I had was to use mobile genetic elements called transposons.”
A transposon is a piece of genetic code that can jump to a random point in DNA when exposed to the enzyme transposase. Dr Camargo’s approach works using transgenic mice that possess a single fish-derived transposon in all of their blood cells.
When one of these mice is exposed to transposase, each of its blood cells’ transposons changes location. The location in the DNA where a transposon moves acts as an individual cell’s barcode, so that if the mouse’s blood is taken a few months later, any cell with the same transposon location can be linked back to its parent cell.
Now, the researchers are planning to explore more applications for their barcode tool.
“We are also tremendously excited to use this tool to barcode and track descendants of different stem cells or progenitor cells for a range of conditions, from aging to the normal immune response,” Dr Sun said.
“We first used this technology for blood analysis. However, this system can also help address basic questions about cell populations in solid tissue. You can imagine being able to look at tumor progression or identify the precise origins of cancer cells that have broken off from a tumor and are now circulating in the blood.”
allows scientists to identify
differences in blood cell origin
Credit: Camargo Lab
By developing a tracking system for stem cells, researchers may have discovered previously unrecognized features of hematopoiesis.
Their work suggests the main drivers of steady-state hematopoiesis are not hematopoietic stem cells (HSCs) but their less pluripotent descendants, progenitor cells.
The team speculates that stable populations of long-lived progenitor cells are responsible for giving rise to specific blood cell types, while HSCs likely act as essential reserves.
The research, published in Nature, indicates that progenitor cells could be just as valuable as HSCs for blood regeneration therapies.
The work challenges what textbooks have long read: that HSCs maintain the day-to-day renewal of blood, a conclusion drawn from their importance in re-establishing blood cell populations after bone marrow transplants.
Due to a lack of tools to study how blood forms in a normal context, no one was able to track the origin of blood cells without doing a transplant.
Fernando Camargo, PhD, of Boston Children’s Hospital in Massachusetts, and his colleagues addressed this problem with a tool that generates a unique barcode in the DNA of all HSCs and their progenitor cells in a mouse.
When a tagged cell divides, all of its descendant cells possess the same barcode. This biological inventory system makes it possible to determine the number of HSCs/progenitors being used to make blood and how long they live, as well as answer fundamental questions about where individual blood cells come from.
“There’s never been such a robust experimental method that could allow people to look at lineage relationships between mature cell types in the body without doing transplantation,” said study author Jianlong Sun, PhD, also of Boston Children’s Hospital.
“One of the major directions we can now go is to revisit the entire blood cell hierarchy and see how the current knowledge holds true when we use this internal labeling system.”
“People have tried using viruses to tag blood cells in the past, but the cells needed to be taken out of the body, infected, and re-transplanted, which raised a number of issues,” Dr Camargo noted. “I wanted to figure out a way to label blood cells inside of the body, and the best idea I had was to use mobile genetic elements called transposons.”
A transposon is a piece of genetic code that can jump to a random point in DNA when exposed to the enzyme transposase. Dr Camargo’s approach works using transgenic mice that possess a single fish-derived transposon in all of their blood cells.
When one of these mice is exposed to transposase, each of its blood cells’ transposons changes location. The location in the DNA where a transposon moves acts as an individual cell’s barcode, so that if the mouse’s blood is taken a few months later, any cell with the same transposon location can be linked back to its parent cell.
Now, the researchers are planning to explore more applications for their barcode tool.
“We are also tremendously excited to use this tool to barcode and track descendants of different stem cells or progenitor cells for a range of conditions, from aging to the normal immune response,” Dr Sun said.
“We first used this technology for blood analysis. However, this system can also help address basic questions about cell populations in solid tissue. You can imagine being able to look at tumor progression or identify the precise origins of cancer cells that have broken off from a tumor and are now circulating in the blood.”
NICE rejects obinutuzumab for CLL
Credit: Linda Bartlett
In a new draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend obinutuzumab (Gazyvaro) to treat chronic lymphocytic leukemia (CLL).
NICE CEO Sir Andrew Dillon said that although data suggest obinutuzumab is effective, there were too many “uncertainties” in the information submitted by Roche, the company developing the drug.
So NICE cannot be sure obinutuzumab would be an effective use of the National Health Service’s resources.
This is despite the fact that Roche offered to discount the drug’s list price of £26,496 per treatment course.
NICE is accepting comments on the draft guidance until 5 pm on October 23.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells. The drug induces antibody-dependent cellular cytotoxicity and caspase-independent apoptosis.
The European Commission approved obinutuzumab in July for use in combination with chlorambucil to treat patients with previously untreated CLL who have comorbidities that make them ineligible to receive fludarabine-based therapy.
Obinutuzumab was approved for this indication in the US in November 2013.
Obinutuzumab is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the US and the rest of the world.
Credit: Linda Bartlett
In a new draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend obinutuzumab (Gazyvaro) to treat chronic lymphocytic leukemia (CLL).
NICE CEO Sir Andrew Dillon said that although data suggest obinutuzumab is effective, there were too many “uncertainties” in the information submitted by Roche, the company developing the drug.
So NICE cannot be sure obinutuzumab would be an effective use of the National Health Service’s resources.
This is despite the fact that Roche offered to discount the drug’s list price of £26,496 per treatment course.
NICE is accepting comments on the draft guidance until 5 pm on October 23.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells. The drug induces antibody-dependent cellular cytotoxicity and caspase-independent apoptosis.
The European Commission approved obinutuzumab in July for use in combination with chlorambucil to treat patients with previously untreated CLL who have comorbidities that make them ineligible to receive fludarabine-based therapy.
Obinutuzumab was approved for this indication in the US in November 2013.
Obinutuzumab is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the US and the rest of the world.
Credit: Linda Bartlett
In a new draft guidance, the UK’s National Institute for Health and Care Excellence (NICE) has said it cannot recommend obinutuzumab (Gazyvaro) to treat chronic lymphocytic leukemia (CLL).
NICE CEO Sir Andrew Dillon said that although data suggest obinutuzumab is effective, there were too many “uncertainties” in the information submitted by Roche, the company developing the drug.
So NICE cannot be sure obinutuzumab would be an effective use of the National Health Service’s resources.
This is despite the fact that Roche offered to discount the drug’s list price of £26,496 per treatment course.
NICE is accepting comments on the draft guidance until 5 pm on October 23.
Obinutuzumab is a glycoengineered, humanized, monoclonal antibody that selectively binds to the extracellular domain of the CD20 antigen on B cells. The drug induces antibody-dependent cellular cytotoxicity and caspase-independent apoptosis.
The European Commission approved obinutuzumab in July for use in combination with chlorambucil to treat patients with previously untreated CLL who have comorbidities that make them ineligible to receive fludarabine-based therapy.
Obinutuzumab was approved for this indication in the US in November 2013.
Obinutuzumab is marketed as Gazyvaro in the European Union and Switzerland but as Gazyva in the US and the rest of the world.