User login
SGR repeal dubbed ‘victory’ for cancer patients
chemotherapy
Photo by Rhoda Baer
A bill that repeals the sustainable growth rate (SGR) formula for physician reimbursement under Medicare is a victory for cancer patients, according to oncologist groups.
The bill—known as H.R.2—passed both the US House of Representatives and the Senate with an overwhelming majority. It must still be signed into law by President Obama, but he has indicated he will sign it.
By repealing the SGR payment methodology, the bill will prevent a 21.2% reduction in physician reimbursement rates.
“Today’s courageous vote by the US Senate to finally end the sustainable growth rate formula is a vote for the millions of patients with cancer who depend on Medicare to help them fight their disease,” said Peter Paul Yu, MD, president of the American Society of Clinical Oncology.
“With Congress passing this historic legislation to finally end the 13-year SGR roller coaster ride, Medicare beneficiaries and their physicians can breathe easier knowing that they will no longer face the perennial threat of payment cuts that risk disruption of care and cause anxiety among patients.”
Under H.R. 2, Medicare’s physician reimbursements will increase by 0.5% in the second half of 2015, then an additional 0.5% annually from 2016 through the end of 2019. The 2019 rates will be maintained through 2025 with no additional increases.
The bill also includes comprehensive structural changes to Medicare’s reimbursement model that aim to promote physician participation in clinical quality improvement activities and value-based care that will take full effect in 2019.
Current Medicare programs that reward electronic health records, quality reporting, the value-based modifier, and meaningful use will be merged by 2019 to encourage participation and to reduce the administrative burden.
The bill also ensures the Children’s Health Insurance Program will receive funding for 2 more years and allocates $7.2 billion for community health centers.
“[P]assage of this legislation represents a long-awaited, historic victory for our patients,” said Bruce G. Haffty, MD, chair of the American Society for Radiation Oncology’s board of directors.
“Permanently repealing the SGR and replacing it with a stabilized reimbursement plan focused on quality will strengthen Medicare and allow us to enhance cancer care for the more than 1 million patients treated with radiation therapy each year.” 
chemotherapy
Photo by Rhoda Baer
A bill that repeals the sustainable growth rate (SGR) formula for physician reimbursement under Medicare is a victory for cancer patients, according to oncologist groups.
The bill—known as H.R.2—passed both the US House of Representatives and the Senate with an overwhelming majority. It must still be signed into law by President Obama, but he has indicated he will sign it.
By repealing the SGR payment methodology, the bill will prevent a 21.2% reduction in physician reimbursement rates.
“Today’s courageous vote by the US Senate to finally end the sustainable growth rate formula is a vote for the millions of patients with cancer who depend on Medicare to help them fight their disease,” said Peter Paul Yu, MD, president of the American Society of Clinical Oncology.
“With Congress passing this historic legislation to finally end the 13-year SGR roller coaster ride, Medicare beneficiaries and their physicians can breathe easier knowing that they will no longer face the perennial threat of payment cuts that risk disruption of care and cause anxiety among patients.”
Under H.R. 2, Medicare’s physician reimbursements will increase by 0.5% in the second half of 2015, then an additional 0.5% annually from 2016 through the end of 2019. The 2019 rates will be maintained through 2025 with no additional increases.
The bill also includes comprehensive structural changes to Medicare’s reimbursement model that aim to promote physician participation in clinical quality improvement activities and value-based care that will take full effect in 2019.
Current Medicare programs that reward electronic health records, quality reporting, the value-based modifier, and meaningful use will be merged by 2019 to encourage participation and to reduce the administrative burden.
The bill also ensures the Children’s Health Insurance Program will receive funding for 2 more years and allocates $7.2 billion for community health centers.
“[P]assage of this legislation represents a long-awaited, historic victory for our patients,” said Bruce G. Haffty, MD, chair of the American Society for Radiation Oncology’s board of directors.
“Permanently repealing the SGR and replacing it with a stabilized reimbursement plan focused on quality will strengthen Medicare and allow us to enhance cancer care for the more than 1 million patients treated with radiation therapy each year.”
chemotherapy
Photo by Rhoda Baer
A bill that repeals the sustainable growth rate (SGR) formula for physician reimbursement under Medicare is a victory for cancer patients, according to oncologist groups.
The bill—known as H.R.2—passed both the US House of Representatives and the Senate with an overwhelming majority. It must still be signed into law by President Obama, but he has indicated he will sign it.
By repealing the SGR payment methodology, the bill will prevent a 21.2% reduction in physician reimbursement rates.
“Today’s courageous vote by the US Senate to finally end the sustainable growth rate formula is a vote for the millions of patients with cancer who depend on Medicare to help them fight their disease,” said Peter Paul Yu, MD, president of the American Society of Clinical Oncology.
“With Congress passing this historic legislation to finally end the 13-year SGR roller coaster ride, Medicare beneficiaries and their physicians can breathe easier knowing that they will no longer face the perennial threat of payment cuts that risk disruption of care and cause anxiety among patients.”
Under H.R. 2, Medicare’s physician reimbursements will increase by 0.5% in the second half of 2015, then an additional 0.5% annually from 2016 through the end of 2019. The 2019 rates will be maintained through 2025 with no additional increases.
The bill also includes comprehensive structural changes to Medicare’s reimbursement model that aim to promote physician participation in clinical quality improvement activities and value-based care that will take full effect in 2019.
Current Medicare programs that reward electronic health records, quality reporting, the value-based modifier, and meaningful use will be merged by 2019 to encourage participation and to reduce the administrative burden.
The bill also ensures the Children’s Health Insurance Program will receive funding for 2 more years and allocates $7.2 billion for community health centers.
“[P]assage of this legislation represents a long-awaited, historic victory for our patients,” said Bruce G. Haffty, MD, chair of the American Society for Radiation Oncology’s board of directors.
“Permanently repealing the SGR and replacing it with a stabilized reimbursement plan focused on quality will strengthen Medicare and allow us to enhance cancer care for the more than 1 million patients treated with radiation therapy each year.”
Pharmacists can improve anticoagulant adherence
Photo by Rhoda Baer
Pharmacists can greatly improve patients’ adherence to the anticoagulant dabigatran, according to a study published in JAMA.
When patients with atrial fibrillation had their dabigatran prescriptions filled by pharmacists who educated them about the drug and monitored them on a regular basis, these individuals were 80% more likely to adhere to medication guidelines than patients who didn’t receive this kind of support.
“Although pharmacist-led management of [dabigatran and other new oral anticoagulants] is uncommon in the US, the findings make the case that it is still important and can ultimately impact clinical outcomes,” said study author Mintu Turakhia, MD, of Stanford University School of Medicine in California.
Previous studies had suggested that some patients were not adhering well to treatment guidelines for dabigatran. So Dr Turakhia and his colleagues set out to determine if this lack of adherence could be explained by where patients were filling their prescriptions.
The team looked at Veterans Health Administration sites where 20 or more outpatients had dabigatran prescriptions filled between 2010 and 2012.
“Surprisingly, we found that treatment adherence varied not by individual, but by site,” Dr Turakhia said. “We didn’t expect to see that much variation by site.”
So the researchers conducted in-depth telephone interviews with the managers, usually pharmacists, at 41 of these sites.
“We rolled up our sleeves and looked at what each site was doing,” Dr Turakhia said.
At the sites with the highest patient adherence, there was usually a pharmacist actively educating patients on medication adherence, reviewing any possible drug interactions, and following up to make sure patients were taking the medication when they were supposed to and that prescriptions were being refilled on time.
The sites with patients who had the highest adherence levels had some key features in common, among them this type of “pharmacist-led patient management.”
“We determined there was a high level of scrutiny and review to make sure patients were getting the drugs,” Dr Turakhia said. “There was a lot of consideration of the dose, interaction with chronic kidney disease, and review to make sure that patients should be getting these drugs.”
These results suggest an unintended side effect of atrial fibrillation patients switching from warfarin to dabigatran or other new oral anticoagulants may be poorer adherence to medication guidelines because most patients no longer make routine visits to a lab for monitoring.
“This finding challenges the entire framework of healthcare delivery of these new agents,” Dr Turakhia said. “These medicines were pitched as easier for patients and for healthcare providers.”
Since patients on new oral anticoagulants are no longer required to visit labs regularly, in most cases, the physician and/or practice nurses are responsible for checking on adherence. And most doctors’ offices don’t have a system in place to verify how well patients take their medication or get patients their refills promptly before medications run out.
“We’re suggesting that greater structured management of these patients, beyond the doctor just prescribing medications for them, is a good idea,” Dr Turakhia said. “Extra support, like that provided in the VA anticoagulation clinics with supportive pharmacist care, greatly improves medication adherence.”
Photo by Rhoda Baer
Pharmacists can greatly improve patients’ adherence to the anticoagulant dabigatran, according to a study published in JAMA.
When patients with atrial fibrillation had their dabigatran prescriptions filled by pharmacists who educated them about the drug and monitored them on a regular basis, these individuals were 80% more likely to adhere to medication guidelines than patients who didn’t receive this kind of support.
“Although pharmacist-led management of [dabigatran and other new oral anticoagulants] is uncommon in the US, the findings make the case that it is still important and can ultimately impact clinical outcomes,” said study author Mintu Turakhia, MD, of Stanford University School of Medicine in California.
Previous studies had suggested that some patients were not adhering well to treatment guidelines for dabigatran. So Dr Turakhia and his colleagues set out to determine if this lack of adherence could be explained by where patients were filling their prescriptions.
The team looked at Veterans Health Administration sites where 20 or more outpatients had dabigatran prescriptions filled between 2010 and 2012.
“Surprisingly, we found that treatment adherence varied not by individual, but by site,” Dr Turakhia said. “We didn’t expect to see that much variation by site.”
So the researchers conducted in-depth telephone interviews with the managers, usually pharmacists, at 41 of these sites.
“We rolled up our sleeves and looked at what each site was doing,” Dr Turakhia said.
At the sites with the highest patient adherence, there was usually a pharmacist actively educating patients on medication adherence, reviewing any possible drug interactions, and following up to make sure patients were taking the medication when they were supposed to and that prescriptions were being refilled on time.
The sites with patients who had the highest adherence levels had some key features in common, among them this type of “pharmacist-led patient management.”
“We determined there was a high level of scrutiny and review to make sure patients were getting the drugs,” Dr Turakhia said. “There was a lot of consideration of the dose, interaction with chronic kidney disease, and review to make sure that patients should be getting these drugs.”
These results suggest an unintended side effect of atrial fibrillation patients switching from warfarin to dabigatran or other new oral anticoagulants may be poorer adherence to medication guidelines because most patients no longer make routine visits to a lab for monitoring.
“This finding challenges the entire framework of healthcare delivery of these new agents,” Dr Turakhia said. “These medicines were pitched as easier for patients and for healthcare providers.”
Since patients on new oral anticoagulants are no longer required to visit labs regularly, in most cases, the physician and/or practice nurses are responsible for checking on adherence. And most doctors’ offices don’t have a system in place to verify how well patients take their medication or get patients their refills promptly before medications run out.
“We’re suggesting that greater structured management of these patients, beyond the doctor just prescribing medications for them, is a good idea,” Dr Turakhia said. “Extra support, like that provided in the VA anticoagulation clinics with supportive pharmacist care, greatly improves medication adherence.”
Photo by Rhoda Baer
Pharmacists can greatly improve patients’ adherence to the anticoagulant dabigatran, according to a study published in JAMA.
When patients with atrial fibrillation had their dabigatran prescriptions filled by pharmacists who educated them about the drug and monitored them on a regular basis, these individuals were 80% more likely to adhere to medication guidelines than patients who didn’t receive this kind of support.
“Although pharmacist-led management of [dabigatran and other new oral anticoagulants] is uncommon in the US, the findings make the case that it is still important and can ultimately impact clinical outcomes,” said study author Mintu Turakhia, MD, of Stanford University School of Medicine in California.
Previous studies had suggested that some patients were not adhering well to treatment guidelines for dabigatran. So Dr Turakhia and his colleagues set out to determine if this lack of adherence could be explained by where patients were filling their prescriptions.
The team looked at Veterans Health Administration sites where 20 or more outpatients had dabigatran prescriptions filled between 2010 and 2012.
“Surprisingly, we found that treatment adherence varied not by individual, but by site,” Dr Turakhia said. “We didn’t expect to see that much variation by site.”
So the researchers conducted in-depth telephone interviews with the managers, usually pharmacists, at 41 of these sites.
“We rolled up our sleeves and looked at what each site was doing,” Dr Turakhia said.
At the sites with the highest patient adherence, there was usually a pharmacist actively educating patients on medication adherence, reviewing any possible drug interactions, and following up to make sure patients were taking the medication when they were supposed to and that prescriptions were being refilled on time.
The sites with patients who had the highest adherence levels had some key features in common, among them this type of “pharmacist-led patient management.”
“We determined there was a high level of scrutiny and review to make sure patients were getting the drugs,” Dr Turakhia said. “There was a lot of consideration of the dose, interaction with chronic kidney disease, and review to make sure that patients should be getting these drugs.”
These results suggest an unintended side effect of atrial fibrillation patients switching from warfarin to dabigatran or other new oral anticoagulants may be poorer adherence to medication guidelines because most patients no longer make routine visits to a lab for monitoring.
“This finding challenges the entire framework of healthcare delivery of these new agents,” Dr Turakhia said. “These medicines were pitched as easier for patients and for healthcare providers.”
Since patients on new oral anticoagulants are no longer required to visit labs regularly, in most cases, the physician and/or practice nurses are responsible for checking on adherence. And most doctors’ offices don’t have a system in place to verify how well patients take their medication or get patients their refills promptly before medications run out.
“We’re suggesting that greater structured management of these patients, beyond the doctor just prescribing medications for them, is a good idea,” Dr Turakhia said. “Extra support, like that provided in the VA anticoagulation clinics with supportive pharmacist care, greatly improves medication adherence.”
Study reveals how ATRA fights APL
Image courtesy of AFIP
New research suggests the vitamin A derivative all-trans retinoic acid (ATRA) inhibits multiple oncogenic pathways and, at the same time, eliminates cancer stem cells by degrading the Pin1 enzyme.
Investigators said this discovery explains how ATRA successfully treats acute promyelocytic leukemia (APL), and it likely has implications for the treatment of other aggressive or drug-resistant cancers.
The team detailed their discovery in Nature Medicine.
“Pin1 changes protein shape through proline-directed phosphorylation, which is a major control mechanism for disease,” said study author Kun Ping Lu, MD, PhD, of Beth Israel Deaconess Medical Center at Harvard Medical School in Boston, Massachusetts.
“Pin1 is a common, key regulator in many types of cancer and, as a result, can control over 50 oncogenes and tumor suppressors, many of which are known to also control cancer stem cells.”
Until now, agents that inhibit Pin1 have been developed mainly through rational drug design. These inhibitors have proven active against Pin1 in the test tube, but, when tested in a cell model or in vivo, they are unable to efficiently enter cells to successfully inhibit Pin1 function.
In this new work, the investigators decided to take a different approach to identify Pin1 inhibitors. They developed a mechanism-based, high-throughput screen to identify compounds that were targeting active Pin1.
“We had previously identified Pin1 substrate-mimicking peptide inhibitors,” said Xiao Zhen Zhou, MD, also of Beth Israel Deaconess Medical Center.
“We therefore used these as a probe in a competition binding assay and screened approximately 8200 chemical compounds, including both approved drugs and other known bioactive compounds.”
To increase screening success, the investigators chose a probe that specifically binds to the Pin1 enzyme active site very tightly, an approach that is not commonly used for this kind of screen.
“Initially, it appeared that the screening results had no positive hits, so we had to manually sift through them looking for the one that would bind to Pin1,” Dr Zhou said. “We eventually spotted cis retinoic acid, which has the same chemical formula as all-trans retinoic acid but with a different chemical structure.”
It turned out that Pin1 prefers binding to ATRA, and cis retinoic acid needs to convert to ATRA in order to bind Pin1.
ATRA in APL and other cancers
ATRA was first discovered for the treatment of APL in 1987. It was originally thought that ATRA was treating APL by inducing cell differentiation, causing cancer cells to change into normal cells by activating the cellular retinoic acid receptors.
But these new findings suggest that is not the mechanism that is actually behind ATRA’s successful outcomes in treating APL.
“While it has been previously shown that ATRA’s ability to degrade the leukemia-causing fusion oncogene PML-RAR causes ATRA to stop the leukemia stem cells that drive APL, the underlying mechanism has remained elusive,” Dr Lu said.
“Our new, high-throughput drug screening has revealed the ATRA drug target, unexpectedly showing that ATRA directly binds, inhibits, and ultimately degrades active Pin1 selectively in cancer cells. The Pin1-ATRA complex structure suggests that ATRA is trapped in the Pin1 active site by mimicking an unreleasable enzyme substrate. Importantly, ATRA-induced Pin1 ablation degrades the fusion oncogene PML-RAR and treats APL in cell and animal models as well as in human patients.”
The investigators discovered that ATRA-induced Pin1 ablation inhibits triple-negative breast cancer growth as well. The drug proved active in human cells and in animal models, simultaneously turning off many oncogenes and turning on many tumor suppressors.
The team said these results provide a rationale for trying to extend ATRA’s half-life and for developing more potent, Pin1-targeted ATRA variants for cancer treatment.
“The current ATRA drug has a very short half-life of only 45 minutes in humans,” Dr Lu said. “We think that a more potent Pin1 inhibitor will be able to target many ‘dream targets’ that are not currently druggable.”
“ATRA appears to be well tolerated, with minimal side effects, and offers a promising new approach for targeting a Pin1-dependent, common oncogenic mechanism in numerous cancer-driving pathways in cancer and cancer stem cells. This is especially critical for treating aggressive or drug-resistant cancers.”
Image courtesy of AFIP
New research suggests the vitamin A derivative all-trans retinoic acid (ATRA) inhibits multiple oncogenic pathways and, at the same time, eliminates cancer stem cells by degrading the Pin1 enzyme.
Investigators said this discovery explains how ATRA successfully treats acute promyelocytic leukemia (APL), and it likely has implications for the treatment of other aggressive or drug-resistant cancers.
The team detailed their discovery in Nature Medicine.
“Pin1 changes protein shape through proline-directed phosphorylation, which is a major control mechanism for disease,” said study author Kun Ping Lu, MD, PhD, of Beth Israel Deaconess Medical Center at Harvard Medical School in Boston, Massachusetts.
“Pin1 is a common, key regulator in many types of cancer and, as a result, can control over 50 oncogenes and tumor suppressors, many of which are known to also control cancer stem cells.”
Until now, agents that inhibit Pin1 have been developed mainly through rational drug design. These inhibitors have proven active against Pin1 in the test tube, but, when tested in a cell model or in vivo, they are unable to efficiently enter cells to successfully inhibit Pin1 function.
In this new work, the investigators decided to take a different approach to identify Pin1 inhibitors. They developed a mechanism-based, high-throughput screen to identify compounds that were targeting active Pin1.
“We had previously identified Pin1 substrate-mimicking peptide inhibitors,” said Xiao Zhen Zhou, MD, also of Beth Israel Deaconess Medical Center.
“We therefore used these as a probe in a competition binding assay and screened approximately 8200 chemical compounds, including both approved drugs and other known bioactive compounds.”
To increase screening success, the investigators chose a probe that specifically binds to the Pin1 enzyme active site very tightly, an approach that is not commonly used for this kind of screen.
“Initially, it appeared that the screening results had no positive hits, so we had to manually sift through them looking for the one that would bind to Pin1,” Dr Zhou said. “We eventually spotted cis retinoic acid, which has the same chemical formula as all-trans retinoic acid but with a different chemical structure.”
It turned out that Pin1 prefers binding to ATRA, and cis retinoic acid needs to convert to ATRA in order to bind Pin1.
ATRA in APL and other cancers
ATRA was first discovered for the treatment of APL in 1987. It was originally thought that ATRA was treating APL by inducing cell differentiation, causing cancer cells to change into normal cells by activating the cellular retinoic acid receptors.
But these new findings suggest that is not the mechanism that is actually behind ATRA’s successful outcomes in treating APL.
“While it has been previously shown that ATRA’s ability to degrade the leukemia-causing fusion oncogene PML-RAR causes ATRA to stop the leukemia stem cells that drive APL, the underlying mechanism has remained elusive,” Dr Lu said.
“Our new, high-throughput drug screening has revealed the ATRA drug target, unexpectedly showing that ATRA directly binds, inhibits, and ultimately degrades active Pin1 selectively in cancer cells. The Pin1-ATRA complex structure suggests that ATRA is trapped in the Pin1 active site by mimicking an unreleasable enzyme substrate. Importantly, ATRA-induced Pin1 ablation degrades the fusion oncogene PML-RAR and treats APL in cell and animal models as well as in human patients.”
The investigators discovered that ATRA-induced Pin1 ablation inhibits triple-negative breast cancer growth as well. The drug proved active in human cells and in animal models, simultaneously turning off many oncogenes and turning on many tumor suppressors.
The team said these results provide a rationale for trying to extend ATRA’s half-life and for developing more potent, Pin1-targeted ATRA variants for cancer treatment.
“The current ATRA drug has a very short half-life of only 45 minutes in humans,” Dr Lu said. “We think that a more potent Pin1 inhibitor will be able to target many ‘dream targets’ that are not currently druggable.”
“ATRA appears to be well tolerated, with minimal side effects, and offers a promising new approach for targeting a Pin1-dependent, common oncogenic mechanism in numerous cancer-driving pathways in cancer and cancer stem cells. This is especially critical for treating aggressive or drug-resistant cancers.”
Image courtesy of AFIP
New research suggests the vitamin A derivative all-trans retinoic acid (ATRA) inhibits multiple oncogenic pathways and, at the same time, eliminates cancer stem cells by degrading the Pin1 enzyme.
Investigators said this discovery explains how ATRA successfully treats acute promyelocytic leukemia (APL), and it likely has implications for the treatment of other aggressive or drug-resistant cancers.
The team detailed their discovery in Nature Medicine.
“Pin1 changes protein shape through proline-directed phosphorylation, which is a major control mechanism for disease,” said study author Kun Ping Lu, MD, PhD, of Beth Israel Deaconess Medical Center at Harvard Medical School in Boston, Massachusetts.
“Pin1 is a common, key regulator in many types of cancer and, as a result, can control over 50 oncogenes and tumor suppressors, many of which are known to also control cancer stem cells.”
Until now, agents that inhibit Pin1 have been developed mainly through rational drug design. These inhibitors have proven active against Pin1 in the test tube, but, when tested in a cell model or in vivo, they are unable to efficiently enter cells to successfully inhibit Pin1 function.
In this new work, the investigators decided to take a different approach to identify Pin1 inhibitors. They developed a mechanism-based, high-throughput screen to identify compounds that were targeting active Pin1.
“We had previously identified Pin1 substrate-mimicking peptide inhibitors,” said Xiao Zhen Zhou, MD, also of Beth Israel Deaconess Medical Center.
“We therefore used these as a probe in a competition binding assay and screened approximately 8200 chemical compounds, including both approved drugs and other known bioactive compounds.”
To increase screening success, the investigators chose a probe that specifically binds to the Pin1 enzyme active site very tightly, an approach that is not commonly used for this kind of screen.
“Initially, it appeared that the screening results had no positive hits, so we had to manually sift through them looking for the one that would bind to Pin1,” Dr Zhou said. “We eventually spotted cis retinoic acid, which has the same chemical formula as all-trans retinoic acid but with a different chemical structure.”
It turned out that Pin1 prefers binding to ATRA, and cis retinoic acid needs to convert to ATRA in order to bind Pin1.
ATRA in APL and other cancers
ATRA was first discovered for the treatment of APL in 1987. It was originally thought that ATRA was treating APL by inducing cell differentiation, causing cancer cells to change into normal cells by activating the cellular retinoic acid receptors.
But these new findings suggest that is not the mechanism that is actually behind ATRA’s successful outcomes in treating APL.
“While it has been previously shown that ATRA’s ability to degrade the leukemia-causing fusion oncogene PML-RAR causes ATRA to stop the leukemia stem cells that drive APL, the underlying mechanism has remained elusive,” Dr Lu said.
“Our new, high-throughput drug screening has revealed the ATRA drug target, unexpectedly showing that ATRA directly binds, inhibits, and ultimately degrades active Pin1 selectively in cancer cells. The Pin1-ATRA complex structure suggests that ATRA is trapped in the Pin1 active site by mimicking an unreleasable enzyme substrate. Importantly, ATRA-induced Pin1 ablation degrades the fusion oncogene PML-RAR and treats APL in cell and animal models as well as in human patients.”
The investigators discovered that ATRA-induced Pin1 ablation inhibits triple-negative breast cancer growth as well. The drug proved active in human cells and in animal models, simultaneously turning off many oncogenes and turning on many tumor suppressors.
The team said these results provide a rationale for trying to extend ATRA’s half-life and for developing more potent, Pin1-targeted ATRA variants for cancer treatment.
“The current ATRA drug has a very short half-life of only 45 minutes in humans,” Dr Lu said. “We think that a more potent Pin1 inhibitor will be able to target many ‘dream targets’ that are not currently druggable.”
“ATRA appears to be well tolerated, with minimal side effects, and offers a promising new approach for targeting a Pin1-dependent, common oncogenic mechanism in numerous cancer-driving pathways in cancer and cancer stem cells. This is especially critical for treating aggressive or drug-resistant cancers.”
Data breaches of health information on the rise
Photo courtesy of NIH
A new study suggests data breaches of protected health information are on the rise in the US.
Researchers found that, between 2010 and 2013, there were data breaches affecting approximately 29 million records of health information covered
under the Health Insurance Portability and Accountability Act (HIPAA).
Breaches were reported in every state, tended to occur via electronic media, and largely resulted from overt criminal activity.
Vincent Liu, MD, of the Kaiser Permanente Division of Research in Oakland, California, and his colleagues published these findings in JAMA.
The researchers evaluated an online database maintained by the US Department of Health and Human Services that describes data breaches of unencrypted, protected health information (ie, individually identifiable information) reported by entities (health plans and clinicians) covered under HIPAA.
The team included breaches affecting 500 individuals or more that were reported as occurring from 2010 through 2013, accounting for 82% of all reports.
The research revealed 949 breaches affecting 29.1 million records. Six breaches involved more than 1 million records each.
The number of reported breaches increased over time, from 214 in 2010 to 265 in 2013.
Breaches were reported in every state, the District of Columbia, and Puerto Rico. Five states (California, Texas, Florida, New York, and Illinois) accounted for 34% of all breaches. However, when adjusted by population estimates, the states with the highest adjusted number of breaches and affected records varied.
Most breaches occurred via electronic media (67%), frequently involving laptop computers or portable electronic devices (33%). Most breaches also occurred via theft (58%).
The combined frequency of breaches resulting from hacking and unauthorized access or disclosure increased during the study period, from 12% in 2010 to 27% in 2013. Breaches involved external vendors in 29% of reports.
The researchers noted that this study was limited to breaches that were already recognized, reported, and affected at least 500 individuals. Therefore, the team likely underestimated the true number of healthcare data breaches occurring in the US each year.
Photo courtesy of NIH
A new study suggests data breaches of protected health information are on the rise in the US.
Researchers found that, between 2010 and 2013, there were data breaches affecting approximately 29 million records of health information covered
under the Health Insurance Portability and Accountability Act (HIPAA).
Breaches were reported in every state, tended to occur via electronic media, and largely resulted from overt criminal activity.
Vincent Liu, MD, of the Kaiser Permanente Division of Research in Oakland, California, and his colleagues published these findings in JAMA.
The researchers evaluated an online database maintained by the US Department of Health and Human Services that describes data breaches of unencrypted, protected health information (ie, individually identifiable information) reported by entities (health plans and clinicians) covered under HIPAA.
The team included breaches affecting 500 individuals or more that were reported as occurring from 2010 through 2013, accounting for 82% of all reports.
The research revealed 949 breaches affecting 29.1 million records. Six breaches involved more than 1 million records each.
The number of reported breaches increased over time, from 214 in 2010 to 265 in 2013.
Breaches were reported in every state, the District of Columbia, and Puerto Rico. Five states (California, Texas, Florida, New York, and Illinois) accounted for 34% of all breaches. However, when adjusted by population estimates, the states with the highest adjusted number of breaches and affected records varied.
Most breaches occurred via electronic media (67%), frequently involving laptop computers or portable electronic devices (33%). Most breaches also occurred via theft (58%).
The combined frequency of breaches resulting from hacking and unauthorized access or disclosure increased during the study period, from 12% in 2010 to 27% in 2013. Breaches involved external vendors in 29% of reports.
The researchers noted that this study was limited to breaches that were already recognized, reported, and affected at least 500 individuals. Therefore, the team likely underestimated the true number of healthcare data breaches occurring in the US each year.
Photo courtesy of NIH
A new study suggests data breaches of protected health information are on the rise in the US.
Researchers found that, between 2010 and 2013, there were data breaches affecting approximately 29 million records of health information covered
under the Health Insurance Portability and Accountability Act (HIPAA).
Breaches were reported in every state, tended to occur via electronic media, and largely resulted from overt criminal activity.
Vincent Liu, MD, of the Kaiser Permanente Division of Research in Oakland, California, and his colleagues published these findings in JAMA.
The researchers evaluated an online database maintained by the US Department of Health and Human Services that describes data breaches of unencrypted, protected health information (ie, individually identifiable information) reported by entities (health plans and clinicians) covered under HIPAA.
The team included breaches affecting 500 individuals or more that were reported as occurring from 2010 through 2013, accounting for 82% of all reports.
The research revealed 949 breaches affecting 29.1 million records. Six breaches involved more than 1 million records each.
The number of reported breaches increased over time, from 214 in 2010 to 265 in 2013.
Breaches were reported in every state, the District of Columbia, and Puerto Rico. Five states (California, Texas, Florida, New York, and Illinois) accounted for 34% of all breaches. However, when adjusted by population estimates, the states with the highest adjusted number of breaches and affected records varied.
Most breaches occurred via electronic media (67%), frequently involving laptop computers or portable electronic devices (33%). Most breaches also occurred via theft (58%).
The combined frequency of breaches resulting from hacking and unauthorized access or disclosure increased during the study period, from 12% in 2010 to 27% in 2013. Breaches involved external vendors in 29% of reports.
The researchers noted that this study was limited to breaches that were already recognized, reported, and affected at least 500 individuals. Therefore, the team likely underestimated the true number of healthcare data breaches occurring in the US each year.
System can diagnose lymphoma, other diseases
Photo by Daniel Sone
Scientists say a smartphone-based system could bring rapid, accurate molecular diagnosis of cancers and other diseases to locations lacking the latest medical technology.
In PNAS, the group explained how the digital diffraction diagnosis (D3) system collects detailed microscopic images for digital analysis of the molecular composition of cells and tissues.
In pilot experiments, the system enabled accurate diagnoses of lymphoma and cervical cancer.
“The emerging genomic and biological data for various cancers, which can be essential to choosing the most appropriate therapy, supports the need for molecular profiling strategies that are more accessible to providers, clinical investigators, and patients,” said study author Cesar Castro, MD, of Massachusetts General Hospital in Boston.
“And we believe the platform we have developed provides essential features at an extraordinarily low cost.”
The D3 system features an imaging module with a battery-powered LED light clipped onto a standard smartphone that records high-resolution imaging data with its camera.
With a greater field of view than traditional microscopy, the D3 system is capable of recording data on more than 100,000 cells from a blood or tissue sample in a single image. The data can then be transmitted for analysis to a remote graphic-processing server via a secure, encrypted cloud service, and the results returned to the point of care.
For molecular analysis of tumors, a sample of blood or tissue is labeled with microbeads that bind to known cancer-related molecules and loaded into the D3 imaging module.
After the image is recorded and data transmitted to the server, the presence of specific molecules is detected by analyzing the diffraction patterns generated by the microbeads. The use of variously sized or coated beads may offer unique diffraction signatures to facilitate detection.
A numerical algorithm the researchers developed can distinguish cells from beads and analyze as much as 10 MB of data in less than nine hundredths of a second.
In a pilot test with cancer cell lines, the D3 system detected the presence of tumor proteins with an accuracy matching that of the current gold standard for molecular profiling. And the system’s larger field of view enabled simultaneous analysis of more than 100,000 cells at a time.
The researchers also conducted analyses of cervical biopsy samples from 25 women with abnormal PAP smears—samples collected along with those used for clinical diagnosis—using microbeads tagged with antibodies against 3 published markers of cervical cancer.
Based on the number of antibody-tagged microbeads binding to cells, D3 analysis promptly and reliably categorized biopsy samples as high-risk, low-risk, or benign. Results matched those of conventional pathologic analysis.
In addition, D3 analysis of fine-needle lymph node biopsy samples was accurately able to differentiate 4 patients whose lymphoma diagnosis was confirmed by conventional pathology from another 4 patients with benign lymph node enlargement.
Along with protein analyses, the D3 system was enhanced to successfully detect DNA—in this instance, from human papilloma virus—with great sensitivity.
In all of these tests, results were available in under an hour and at a cost of $1.80 per assay, a price that would be expected to drop with further refinement of the D3 system.
“We expect that the D3 platform will enhance the breadth and depth of cancer screening in a way that is feasible and sustainable for resource limited-settings,” said Ralph Weissleder, MD, PhD, also of Massachusetts General Hospital.
“By taking advantage of the increased penetration of mobile phone technology worldwide, the system should allow the prompt triaging of suspicious or high-risk cases that could help to offset delays caused by limited pathology services in those regions and reduce the need for patients to return for follow-up care, which is often challenging for them.”
The researchers’ next steps are to investigate D3’s ability to analyze protein and DNA markers of other disease catalysts, integrate the software with larger databases, and conduct clinical studies in settings such as care-delivery sites in developing countries or rural areas.
Massachusetts General Hospital has filed a patent application covering the D3 technology.
Photo by Daniel Sone
Scientists say a smartphone-based system could bring rapid, accurate molecular diagnosis of cancers and other diseases to locations lacking the latest medical technology.
In PNAS, the group explained how the digital diffraction diagnosis (D3) system collects detailed microscopic images for digital analysis of the molecular composition of cells and tissues.
In pilot experiments, the system enabled accurate diagnoses of lymphoma and cervical cancer.
“The emerging genomic and biological data for various cancers, which can be essential to choosing the most appropriate therapy, supports the need for molecular profiling strategies that are more accessible to providers, clinical investigators, and patients,” said study author Cesar Castro, MD, of Massachusetts General Hospital in Boston.
“And we believe the platform we have developed provides essential features at an extraordinarily low cost.”
The D3 system features an imaging module with a battery-powered LED light clipped onto a standard smartphone that records high-resolution imaging data with its camera.
With a greater field of view than traditional microscopy, the D3 system is capable of recording data on more than 100,000 cells from a blood or tissue sample in a single image. The data can then be transmitted for analysis to a remote graphic-processing server via a secure, encrypted cloud service, and the results returned to the point of care.
For molecular analysis of tumors, a sample of blood or tissue is labeled with microbeads that bind to known cancer-related molecules and loaded into the D3 imaging module.
After the image is recorded and data transmitted to the server, the presence of specific molecules is detected by analyzing the diffraction patterns generated by the microbeads. The use of variously sized or coated beads may offer unique diffraction signatures to facilitate detection.
A numerical algorithm the researchers developed can distinguish cells from beads and analyze as much as 10 MB of data in less than nine hundredths of a second.
In a pilot test with cancer cell lines, the D3 system detected the presence of tumor proteins with an accuracy matching that of the current gold standard for molecular profiling. And the system’s larger field of view enabled simultaneous analysis of more than 100,000 cells at a time.
The researchers also conducted analyses of cervical biopsy samples from 25 women with abnormal PAP smears—samples collected along with those used for clinical diagnosis—using microbeads tagged with antibodies against 3 published markers of cervical cancer.
Based on the number of antibody-tagged microbeads binding to cells, D3 analysis promptly and reliably categorized biopsy samples as high-risk, low-risk, or benign. Results matched those of conventional pathologic analysis.
In addition, D3 analysis of fine-needle lymph node biopsy samples was accurately able to differentiate 4 patients whose lymphoma diagnosis was confirmed by conventional pathology from another 4 patients with benign lymph node enlargement.
Along with protein analyses, the D3 system was enhanced to successfully detect DNA—in this instance, from human papilloma virus—with great sensitivity.
In all of these tests, results were available in under an hour and at a cost of $1.80 per assay, a price that would be expected to drop with further refinement of the D3 system.
“We expect that the D3 platform will enhance the breadth and depth of cancer screening in a way that is feasible and sustainable for resource limited-settings,” said Ralph Weissleder, MD, PhD, also of Massachusetts General Hospital.
“By taking advantage of the increased penetration of mobile phone technology worldwide, the system should allow the prompt triaging of suspicious or high-risk cases that could help to offset delays caused by limited pathology services in those regions and reduce the need for patients to return for follow-up care, which is often challenging for them.”
The researchers’ next steps are to investigate D3’s ability to analyze protein and DNA markers of other disease catalysts, integrate the software with larger databases, and conduct clinical studies in settings such as care-delivery sites in developing countries or rural areas.
Massachusetts General Hospital has filed a patent application covering the D3 technology.
Photo by Daniel Sone
Scientists say a smartphone-based system could bring rapid, accurate molecular diagnosis of cancers and other diseases to locations lacking the latest medical technology.
In PNAS, the group explained how the digital diffraction diagnosis (D3) system collects detailed microscopic images for digital analysis of the molecular composition of cells and tissues.
In pilot experiments, the system enabled accurate diagnoses of lymphoma and cervical cancer.
“The emerging genomic and biological data for various cancers, which can be essential to choosing the most appropriate therapy, supports the need for molecular profiling strategies that are more accessible to providers, clinical investigators, and patients,” said study author Cesar Castro, MD, of Massachusetts General Hospital in Boston.
“And we believe the platform we have developed provides essential features at an extraordinarily low cost.”
The D3 system features an imaging module with a battery-powered LED light clipped onto a standard smartphone that records high-resolution imaging data with its camera.
With a greater field of view than traditional microscopy, the D3 system is capable of recording data on more than 100,000 cells from a blood or tissue sample in a single image. The data can then be transmitted for analysis to a remote graphic-processing server via a secure, encrypted cloud service, and the results returned to the point of care.
For molecular analysis of tumors, a sample of blood or tissue is labeled with microbeads that bind to known cancer-related molecules and loaded into the D3 imaging module.
After the image is recorded and data transmitted to the server, the presence of specific molecules is detected by analyzing the diffraction patterns generated by the microbeads. The use of variously sized or coated beads may offer unique diffraction signatures to facilitate detection.
A numerical algorithm the researchers developed can distinguish cells from beads and analyze as much as 10 MB of data in less than nine hundredths of a second.
In a pilot test with cancer cell lines, the D3 system detected the presence of tumor proteins with an accuracy matching that of the current gold standard for molecular profiling. And the system’s larger field of view enabled simultaneous analysis of more than 100,000 cells at a time.
The researchers also conducted analyses of cervical biopsy samples from 25 women with abnormal PAP smears—samples collected along with those used for clinical diagnosis—using microbeads tagged with antibodies against 3 published markers of cervical cancer.
Based on the number of antibody-tagged microbeads binding to cells, D3 analysis promptly and reliably categorized biopsy samples as high-risk, low-risk, or benign. Results matched those of conventional pathologic analysis.
In addition, D3 analysis of fine-needle lymph node biopsy samples was accurately able to differentiate 4 patients whose lymphoma diagnosis was confirmed by conventional pathology from another 4 patients with benign lymph node enlargement.
Along with protein analyses, the D3 system was enhanced to successfully detect DNA—in this instance, from human papilloma virus—with great sensitivity.
In all of these tests, results were available in under an hour and at a cost of $1.80 per assay, a price that would be expected to drop with further refinement of the D3 system.
“We expect that the D3 platform will enhance the breadth and depth of cancer screening in a way that is feasible and sustainable for resource limited-settings,” said Ralph Weissleder, MD, PhD, also of Massachusetts General Hospital.
“By taking advantage of the increased penetration of mobile phone technology worldwide, the system should allow the prompt triaging of suspicious or high-risk cases that could help to offset delays caused by limited pathology services in those regions and reduce the need for patients to return for follow-up care, which is often challenging for them.”
The researchers’ next steps are to investigate D3’s ability to analyze protein and DNA markers of other disease catalysts, integrate the software with larger databases, and conduct clinical studies in settings such as care-delivery sites in developing countries or rural areas.
Massachusetts General Hospital has filed a patent application covering the D3 technology.
Gene appears key to HSC regulation
in the bone marrow
The gene Ash1l plays a key role in regulating the maintenance and self-renewal of hematopoietic stem cells (HSCs), according to a study published in The Journal of Clinical Investigation.
The research provides new insight into how the body creates and maintains a healthy blood supply and immune system. It also opens new lines of inquiry about Ash1l’s potential role in cancers—like leukemia—that involve other members of the same gene family.
“If we find that Ash1l plays a role [in leukemia], that would open up avenues to try to block or slow down its activity pharmacologically,” said study author Ivan Maillard, MD, of the University of Michigan Medical School in Ann Arbor.
The Ash1l gene regulates the expression of multiple downstream homeotic genes, which help ensure the correct anatomical structure of a developing organism. And Ash1l is part of a family of genes that includes MLL1.
The researchers found that both Ash1l and MLL1 contribute to blood renewal. They observed mild defects in mice missing one gene or the other, but lacking both genes led to catastrophic deficiencies.
“We now have clear evidence that these genes cooperate to develop a healthy blood system,” Dr Maillard said.
He and his colleagues also found that Ash1l-deficient mice had normal numbers of HSCs during early development but a lack of HSCs in maturity—an indication the cells were not able to properly maintain themselves in the bone marrow.
Ash1l-deficient HSCs were unable to establish normal blood renewal after an HSC transplant. Moreover, Ash1l-deficient stem cells competed poorly with normal HSCs in the bone marrow and could easily be dislodged.
“By continuing to investigate the basic, underlying mechanisms [of blood renewal], we are helping to untangle the complex machinery . . . that may lay the foundation for new human treatments 5, 10, or 20 years from now,” Dr Maillard said.
in the bone marrow
The gene Ash1l plays a key role in regulating the maintenance and self-renewal of hematopoietic stem cells (HSCs), according to a study published in The Journal of Clinical Investigation.
The research provides new insight into how the body creates and maintains a healthy blood supply and immune system. It also opens new lines of inquiry about Ash1l’s potential role in cancers—like leukemia—that involve other members of the same gene family.
“If we find that Ash1l plays a role [in leukemia], that would open up avenues to try to block or slow down its activity pharmacologically,” said study author Ivan Maillard, MD, of the University of Michigan Medical School in Ann Arbor.
The Ash1l gene regulates the expression of multiple downstream homeotic genes, which help ensure the correct anatomical structure of a developing organism. And Ash1l is part of a family of genes that includes MLL1.
The researchers found that both Ash1l and MLL1 contribute to blood renewal. They observed mild defects in mice missing one gene or the other, but lacking both genes led to catastrophic deficiencies.
“We now have clear evidence that these genes cooperate to develop a healthy blood system,” Dr Maillard said.
He and his colleagues also found that Ash1l-deficient mice had normal numbers of HSCs during early development but a lack of HSCs in maturity—an indication the cells were not able to properly maintain themselves in the bone marrow.
Ash1l-deficient HSCs were unable to establish normal blood renewal after an HSC transplant. Moreover, Ash1l-deficient stem cells competed poorly with normal HSCs in the bone marrow and could easily be dislodged.
“By continuing to investigate the basic, underlying mechanisms [of blood renewal], we are helping to untangle the complex machinery . . . that may lay the foundation for new human treatments 5, 10, or 20 years from now,” Dr Maillard said.
in the bone marrow
The gene Ash1l plays a key role in regulating the maintenance and self-renewal of hematopoietic stem cells (HSCs), according to a study published in The Journal of Clinical Investigation.
The research provides new insight into how the body creates and maintains a healthy blood supply and immune system. It also opens new lines of inquiry about Ash1l’s potential role in cancers—like leukemia—that involve other members of the same gene family.
“If we find that Ash1l plays a role [in leukemia], that would open up avenues to try to block or slow down its activity pharmacologically,” said study author Ivan Maillard, MD, of the University of Michigan Medical School in Ann Arbor.
The Ash1l gene regulates the expression of multiple downstream homeotic genes, which help ensure the correct anatomical structure of a developing organism. And Ash1l is part of a family of genes that includes MLL1.
The researchers found that both Ash1l and MLL1 contribute to blood renewal. They observed mild defects in mice missing one gene or the other, but lacking both genes led to catastrophic deficiencies.
“We now have clear evidence that these genes cooperate to develop a healthy blood system,” Dr Maillard said.
He and his colleagues also found that Ash1l-deficient mice had normal numbers of HSCs during early development but a lack of HSCs in maturity—an indication the cells were not able to properly maintain themselves in the bone marrow.
Ash1l-deficient HSCs were unable to establish normal blood renewal after an HSC transplant. Moreover, Ash1l-deficient stem cells competed poorly with normal HSCs in the bone marrow and could easily be dislodged.
“By continuing to investigate the basic, underlying mechanisms [of blood renewal], we are helping to untangle the complex machinery . . . that may lay the foundation for new human treatments 5, 10, or 20 years from now,” Dr Maillard said.
How telomere length affects cancer mortality
with telomeres in green
Image by Claus Azzalin
New research suggests telomere length is associated with cancer mortality—but not in the way researchers expected.
The study showed that short telomeres in peripheral blood leukocytes were associated with high mortality from all causes.
But genetically determined short telomeres were associated with low cancer mortality.
Line Rode, MD, PhD, of Herlev Hospital in Denmark, and colleagues reported these findings in JNCI: Journal of the National Cancer Institute.
Some previous studies have suggested an association between short telomeres and high mortality, including cancer mortality, while others have not. A possible explanation for the conflicting evidence may be that the association was correlational, but other factors that were not adjusted for (such as age and lifestyle) were the real causes.
Genetic variation in genes associated with telomere length (TERC, TERT, and OBFC1) is independent of age and lifestyle factors. So researchers speculated that a genetic analysis called a Mendelian randomization could eliminate some of the confounding and allow them to confirm the association between telomere length and cancer mortality.
To perform this analysis, the team used data from 2 prospective cohort studies. The Copenhagen City Heart Study and the Copenhagen General Population Study included 64,637 individuals who were followed from 1991 to 2011.
Participants completed a questionnaire, underwent a physical examination, and had blood drawn for biochemistry, genotyping, and telomere length assays.
For each subject, the researchers had information on physical characteristics such as body mass index (BMI), blood pressure, and cholesterol measurements, as well as smoking status, alcohol consumption, physical activity, and socioeconomic variables.
In addition to measuring telomere length for each subject, the researchers used 3 single nucleotide polymorphisms of TERC, TERT, and OBFC1 to construct a score for the presence of telomere-shortening alleles.
A total of 7607 individuals died during the study period, 2420 of cancer. Overall, decreasing telomere length was associated with age, variables such as BMI and smoking, and death from all causes, including cancer.
In contrast, a higher genetic score for telomere shortening was associated with decreased cancer mortality but not with any other causes of death.
The researchers said this suggests the slightly shorter telomeres in cancer patients with the higher genetic score for telomere shortening might be beneficial because uncontrolled cancer cell replication is reduced.
And long telomeres may confer a survival advantage for cancer cells, as they allow for multiple cell divisions that lead to high cancer mortality.
with telomeres in green
Image by Claus Azzalin
New research suggests telomere length is associated with cancer mortality—but not in the way researchers expected.
The study showed that short telomeres in peripheral blood leukocytes were associated with high mortality from all causes.
But genetically determined short telomeres were associated with low cancer mortality.
Line Rode, MD, PhD, of Herlev Hospital in Denmark, and colleagues reported these findings in JNCI: Journal of the National Cancer Institute.
Some previous studies have suggested an association between short telomeres and high mortality, including cancer mortality, while others have not. A possible explanation for the conflicting evidence may be that the association was correlational, but other factors that were not adjusted for (such as age and lifestyle) were the real causes.
Genetic variation in genes associated with telomere length (TERC, TERT, and OBFC1) is independent of age and lifestyle factors. So researchers speculated that a genetic analysis called a Mendelian randomization could eliminate some of the confounding and allow them to confirm the association between telomere length and cancer mortality.
To perform this analysis, the team used data from 2 prospective cohort studies. The Copenhagen City Heart Study and the Copenhagen General Population Study included 64,637 individuals who were followed from 1991 to 2011.
Participants completed a questionnaire, underwent a physical examination, and had blood drawn for biochemistry, genotyping, and telomere length assays.
For each subject, the researchers had information on physical characteristics such as body mass index (BMI), blood pressure, and cholesterol measurements, as well as smoking status, alcohol consumption, physical activity, and socioeconomic variables.
In addition to measuring telomere length for each subject, the researchers used 3 single nucleotide polymorphisms of TERC, TERT, and OBFC1 to construct a score for the presence of telomere-shortening alleles.
A total of 7607 individuals died during the study period, 2420 of cancer. Overall, decreasing telomere length was associated with age, variables such as BMI and smoking, and death from all causes, including cancer.
In contrast, a higher genetic score for telomere shortening was associated with decreased cancer mortality but not with any other causes of death.
The researchers said this suggests the slightly shorter telomeres in cancer patients with the higher genetic score for telomere shortening might be beneficial because uncontrolled cancer cell replication is reduced.
And long telomeres may confer a survival advantage for cancer cells, as they allow for multiple cell divisions that lead to high cancer mortality.
with telomeres in green
Image by Claus Azzalin
New research suggests telomere length is associated with cancer mortality—but not in the way researchers expected.
The study showed that short telomeres in peripheral blood leukocytes were associated with high mortality from all causes.
But genetically determined short telomeres were associated with low cancer mortality.
Line Rode, MD, PhD, of Herlev Hospital in Denmark, and colleagues reported these findings in JNCI: Journal of the National Cancer Institute.
Some previous studies have suggested an association between short telomeres and high mortality, including cancer mortality, while others have not. A possible explanation for the conflicting evidence may be that the association was correlational, but other factors that were not adjusted for (such as age and lifestyle) were the real causes.
Genetic variation in genes associated with telomere length (TERC, TERT, and OBFC1) is independent of age and lifestyle factors. So researchers speculated that a genetic analysis called a Mendelian randomization could eliminate some of the confounding and allow them to confirm the association between telomere length and cancer mortality.
To perform this analysis, the team used data from 2 prospective cohort studies. The Copenhagen City Heart Study and the Copenhagen General Population Study included 64,637 individuals who were followed from 1991 to 2011.
Participants completed a questionnaire, underwent a physical examination, and had blood drawn for biochemistry, genotyping, and telomere length assays.
For each subject, the researchers had information on physical characteristics such as body mass index (BMI), blood pressure, and cholesterol measurements, as well as smoking status, alcohol consumption, physical activity, and socioeconomic variables.
In addition to measuring telomere length for each subject, the researchers used 3 single nucleotide polymorphisms of TERC, TERT, and OBFC1 to construct a score for the presence of telomere-shortening alleles.
A total of 7607 individuals died during the study period, 2420 of cancer. Overall, decreasing telomere length was associated with age, variables such as BMI and smoking, and death from all causes, including cancer.
In contrast, a higher genetic score for telomere shortening was associated with decreased cancer mortality but not with any other causes of death.
The researchers said this suggests the slightly shorter telomeres in cancer patients with the higher genetic score for telomere shortening might be beneficial because uncontrolled cancer cell replication is reduced.
And long telomeres may confer a survival advantage for cancer cells, as they allow for multiple cell divisions that lead to high cancer mortality.
Oral anticoagulants overprescribed in AF
Results of a large study indicate that patients with atrial fibrillation (AF) and a low risk of thromboembolism are sometimes prescribed oral
anticoagulants even though guidelines recommend against it.
“The irony is that there is a general push to get providers to prescribe these drugs, and they are also generally underprescribed among many AF
patients who actually need them,” said study author Gregory Marcus, MD, of the University of California San Francisco.
“Our study suggests people are trying to do the right thing but, due to a lack of understanding of some of the critical nuances, go too far in that direction in low-risk patients.”
Dr Marcus and his colleagues described this study in JAMA Internal Medicine.
The team noted that previous AF guidelines recommend against the use of oral anticoagulants in patients younger than 60 years of age without heart disease or other known risk factors for thromboembolism, and updated guidelines do not recommend the use of oral anticoagulants in patients without any established risk factor for stroke.
The researchers wanted to determine the frequency with which oral anticoagulant prescriptions are made outside of guideline recommendations. So they assessed 10,995 AF patients ages 60 and under from the overall Practice Innovation and Clinical Excellence (PINNACLE) Registry of the National Cardiovascular Data Registry who were treated in the US between 2008 and 2012.
About 23% (n=2561) of patients with a CHADS2 score of 0 and about 27% (n=1787) of patients with a CHA2DS2-VASc score of 0 were prescribed oral anticoagulant therapy contrary to guideline recommendations.
In a multivariable analysis of patients with a CHADS2 score of 0, several factors were associated with a higher likelihood of being prescribed oral anticoagulants. These included older age (relative risk [RR]=1.48 per 10 years; P<0.001), male sex (RR=1.34; P<0.001), higher body mass index (RR=1.18 per 5kg/m2; P<0.001), and having Medicare rather than private insurance (RR=1.32; P<0.001).
On the other hand, being treated in the South rather than the Northeast was associated with a lower likelihood of being prescribed oral anticoagulants (RR=0.69; P=0.04).
The researchers observed similar results in a multivariable analysis of patients with a CHA2DS2-VASc score of 0. Being treated in the South rather than the Northeast was associated with a lower likelihood of being prescribed oral anticoagulants (RR=0.67; P=0.03).
And older age (RR=1.44 per 10 years; P<0.001), higher body mass index (RR=1.19 per 5 kg/m2; P<0.001), having Medicare rather than private insurance (RR=1.29; P<0.001), and having no insurance rather than private insurance (RR=1.19; P=0.02) were all associated with a higher likelihood of being prescribed oral anticoagulants.
The researchers said these results suggest providers may not be fully aware of the potential risks of these drugs or the particularly low risk of thromboembolism in certain populations.
“Practitioners who prescribe blood thinners need to be diligent about weighing the risks and benefits of these medications,” said study author Jonathan C. Hsu, MD, of the University of California San Diego.
“In those patients with no risk factors for stroke, the risk of bleeding likely outweighs the benefit of stroke reduction. The fact that blood thinners were prescribed to so many patients with no risk factors for stroke is a wake-up call that we need to do better for our patients.”
Results of a large study indicate that patients with atrial fibrillation (AF) and a low risk of thromboembolism are sometimes prescribed oral
anticoagulants even though guidelines recommend against it.
“The irony is that there is a general push to get providers to prescribe these drugs, and they are also generally underprescribed among many AF
patients who actually need them,” said study author Gregory Marcus, MD, of the University of California San Francisco.
“Our study suggests people are trying to do the right thing but, due to a lack of understanding of some of the critical nuances, go too far in that direction in low-risk patients.”
Dr Marcus and his colleagues described this study in JAMA Internal Medicine.
The team noted that previous AF guidelines recommend against the use of oral anticoagulants in patients younger than 60 years of age without heart disease or other known risk factors for thromboembolism, and updated guidelines do not recommend the use of oral anticoagulants in patients without any established risk factor for stroke.
The researchers wanted to determine the frequency with which oral anticoagulant prescriptions are made outside of guideline recommendations. So they assessed 10,995 AF patients ages 60 and under from the overall Practice Innovation and Clinical Excellence (PINNACLE) Registry of the National Cardiovascular Data Registry who were treated in the US between 2008 and 2012.
About 23% (n=2561) of patients with a CHADS2 score of 0 and about 27% (n=1787) of patients with a CHA2DS2-VASc score of 0 were prescribed oral anticoagulant therapy contrary to guideline recommendations.
In a multivariable analysis of patients with a CHADS2 score of 0, several factors were associated with a higher likelihood of being prescribed oral anticoagulants. These included older age (relative risk [RR]=1.48 per 10 years; P<0.001), male sex (RR=1.34; P<0.001), higher body mass index (RR=1.18 per 5kg/m2; P<0.001), and having Medicare rather than private insurance (RR=1.32; P<0.001).
On the other hand, being treated in the South rather than the Northeast was associated with a lower likelihood of being prescribed oral anticoagulants (RR=0.69; P=0.04).
The researchers observed similar results in a multivariable analysis of patients with a CHA2DS2-VASc score of 0. Being treated in the South rather than the Northeast was associated with a lower likelihood of being prescribed oral anticoagulants (RR=0.67; P=0.03).
And older age (RR=1.44 per 10 years; P<0.001), higher body mass index (RR=1.19 per 5 kg/m2; P<0.001), having Medicare rather than private insurance (RR=1.29; P<0.001), and having no insurance rather than private insurance (RR=1.19; P=0.02) were all associated with a higher likelihood of being prescribed oral anticoagulants.
The researchers said these results suggest providers may not be fully aware of the potential risks of these drugs or the particularly low risk of thromboembolism in certain populations.
“Practitioners who prescribe blood thinners need to be diligent about weighing the risks and benefits of these medications,” said study author Jonathan C. Hsu, MD, of the University of California San Diego.
“In those patients with no risk factors for stroke, the risk of bleeding likely outweighs the benefit of stroke reduction. The fact that blood thinners were prescribed to so many patients with no risk factors for stroke is a wake-up call that we need to do better for our patients.”
Results of a large study indicate that patients with atrial fibrillation (AF) and a low risk of thromboembolism are sometimes prescribed oral
anticoagulants even though guidelines recommend against it.
“The irony is that there is a general push to get providers to prescribe these drugs, and they are also generally underprescribed among many AF
patients who actually need them,” said study author Gregory Marcus, MD, of the University of California San Francisco.
“Our study suggests people are trying to do the right thing but, due to a lack of understanding of some of the critical nuances, go too far in that direction in low-risk patients.”
Dr Marcus and his colleagues described this study in JAMA Internal Medicine.
The team noted that previous AF guidelines recommend against the use of oral anticoagulants in patients younger than 60 years of age without heart disease or other known risk factors for thromboembolism, and updated guidelines do not recommend the use of oral anticoagulants in patients without any established risk factor for stroke.
The researchers wanted to determine the frequency with which oral anticoagulant prescriptions are made outside of guideline recommendations. So they assessed 10,995 AF patients ages 60 and under from the overall Practice Innovation and Clinical Excellence (PINNACLE) Registry of the National Cardiovascular Data Registry who were treated in the US between 2008 and 2012.
About 23% (n=2561) of patients with a CHADS2 score of 0 and about 27% (n=1787) of patients with a CHA2DS2-VASc score of 0 were prescribed oral anticoagulant therapy contrary to guideline recommendations.
In a multivariable analysis of patients with a CHADS2 score of 0, several factors were associated with a higher likelihood of being prescribed oral anticoagulants. These included older age (relative risk [RR]=1.48 per 10 years; P<0.001), male sex (RR=1.34; P<0.001), higher body mass index (RR=1.18 per 5kg/m2; P<0.001), and having Medicare rather than private insurance (RR=1.32; P<0.001).
On the other hand, being treated in the South rather than the Northeast was associated with a lower likelihood of being prescribed oral anticoagulants (RR=0.69; P=0.04).
The researchers observed similar results in a multivariable analysis of patients with a CHA2DS2-VASc score of 0. Being treated in the South rather than the Northeast was associated with a lower likelihood of being prescribed oral anticoagulants (RR=0.67; P=0.03).
And older age (RR=1.44 per 10 years; P<0.001), higher body mass index (RR=1.19 per 5 kg/m2; P<0.001), having Medicare rather than private insurance (RR=1.29; P<0.001), and having no insurance rather than private insurance (RR=1.19; P=0.02) were all associated with a higher likelihood of being prescribed oral anticoagulants.
The researchers said these results suggest providers may not be fully aware of the potential risks of these drugs or the particularly low risk of thromboembolism in certain populations.
“Practitioners who prescribe blood thinners need to be diligent about weighing the risks and benefits of these medications,” said study author Jonathan C. Hsu, MD, of the University of California San Diego.
“In those patients with no risk factors for stroke, the risk of bleeding likely outweighs the benefit of stroke reduction. The fact that blood thinners were prescribed to so many patients with no risk factors for stroke is a wake-up call that we need to do better for our patients.”
Gene therapy superior to partially matched HSCT for SCID-X1
Photo by Chad McNeeley
Children with X-linked severe combined immunodeficiency (SCID-X1) who undergo gene therapy have fewer infections and hospitalizations than those who receive a hematopoietic stem cell transplant (HSCT) from a partially matched donor, according to a study published in Blood.
“Over the last decade, gene therapy has emerged as a viable alternative to a partial matched stem cell transplant for infants with SCID-X1,” said study author Fabien Touzot, MD, PhD, of Necker Children’s Hospital in Paris, France.
“To ensure that we are providing the best alternative therapy possible, we wanted to compare outcomes among infants treated with gene therapy and infants receiving partial matched transplants.”
Dr Touzot and his colleagues studied the medical records of 27 children who received either a partially matched HSCT (n=13) or gene therapy (n=14) for SCID-X1 at Necker Children’s Hospital between 1999 and 2013.
The children receiving half-matched transplants and the children receiving gene therapy had been followed for a median of 6 years and 12 years, respectively.
The researchers compared T-cell development among the patients, as well as key clinical outcomes such as infections and hospitalization.
The 14 children in the gene therapy group developed healthy immune cells faster than the 13 children in the half-matched transplant group. In fact, in the first 6 months after therapy, T-cell counts had reached normal values in 78% of the gene therapy patients, compared to 26% of the HSCT patients.
The more rapid growth of the immune system in gene therapy patients was also associated with faster resolution of disseminated BDG infections. These infections resolved in a median of 11 months in the gene therapy group, compared to 25.5 months in the half-matched transplant group.
Gene therapy patients also had fewer infection-related hospitalizations—3 hospitalizations in 3 patients, compared to 15 hospitalizations in 5 patients from the half-matched HSCT group.
“Our analysis suggests that gene therapy can put these incredibly sick children on the road to defending themselves against infection faster than a half-matched transplant,” Dr Touzot said. “These results suggest that, for patients without a fully matched stem cell donor, gene therapy is the next-best approach.”
Photo by Chad McNeeley
Children with X-linked severe combined immunodeficiency (SCID-X1) who undergo gene therapy have fewer infections and hospitalizations than those who receive a hematopoietic stem cell transplant (HSCT) from a partially matched donor, according to a study published in Blood.
“Over the last decade, gene therapy has emerged as a viable alternative to a partial matched stem cell transplant for infants with SCID-X1,” said study author Fabien Touzot, MD, PhD, of Necker Children’s Hospital in Paris, France.
“To ensure that we are providing the best alternative therapy possible, we wanted to compare outcomes among infants treated with gene therapy and infants receiving partial matched transplants.”
Dr Touzot and his colleagues studied the medical records of 27 children who received either a partially matched HSCT (n=13) or gene therapy (n=14) for SCID-X1 at Necker Children’s Hospital between 1999 and 2013.
The children receiving half-matched transplants and the children receiving gene therapy had been followed for a median of 6 years and 12 years, respectively.
The researchers compared T-cell development among the patients, as well as key clinical outcomes such as infections and hospitalization.
The 14 children in the gene therapy group developed healthy immune cells faster than the 13 children in the half-matched transplant group. In fact, in the first 6 months after therapy, T-cell counts had reached normal values in 78% of the gene therapy patients, compared to 26% of the HSCT patients.
The more rapid growth of the immune system in gene therapy patients was also associated with faster resolution of disseminated BDG infections. These infections resolved in a median of 11 months in the gene therapy group, compared to 25.5 months in the half-matched transplant group.
Gene therapy patients also had fewer infection-related hospitalizations—3 hospitalizations in 3 patients, compared to 15 hospitalizations in 5 patients from the half-matched HSCT group.
“Our analysis suggests that gene therapy can put these incredibly sick children on the road to defending themselves against infection faster than a half-matched transplant,” Dr Touzot said. “These results suggest that, for patients without a fully matched stem cell donor, gene therapy is the next-best approach.”
Photo by Chad McNeeley
Children with X-linked severe combined immunodeficiency (SCID-X1) who undergo gene therapy have fewer infections and hospitalizations than those who receive a hematopoietic stem cell transplant (HSCT) from a partially matched donor, according to a study published in Blood.
“Over the last decade, gene therapy has emerged as a viable alternative to a partial matched stem cell transplant for infants with SCID-X1,” said study author Fabien Touzot, MD, PhD, of Necker Children’s Hospital in Paris, France.
“To ensure that we are providing the best alternative therapy possible, we wanted to compare outcomes among infants treated with gene therapy and infants receiving partial matched transplants.”
Dr Touzot and his colleagues studied the medical records of 27 children who received either a partially matched HSCT (n=13) or gene therapy (n=14) for SCID-X1 at Necker Children’s Hospital between 1999 and 2013.
The children receiving half-matched transplants and the children receiving gene therapy had been followed for a median of 6 years and 12 years, respectively.
The researchers compared T-cell development among the patients, as well as key clinical outcomes such as infections and hospitalization.
The 14 children in the gene therapy group developed healthy immune cells faster than the 13 children in the half-matched transplant group. In fact, in the first 6 months after therapy, T-cell counts had reached normal values in 78% of the gene therapy patients, compared to 26% of the HSCT patients.
The more rapid growth of the immune system in gene therapy patients was also associated with faster resolution of disseminated BDG infections. These infections resolved in a median of 11 months in the gene therapy group, compared to 25.5 months in the half-matched transplant group.
Gene therapy patients also had fewer infection-related hospitalizations—3 hospitalizations in 3 patients, compared to 15 hospitalizations in 5 patients from the half-matched HSCT group.
“Our analysis suggests that gene therapy can put these incredibly sick children on the road to defending themselves against infection faster than a half-matched transplant,” Dr Touzot said. “These results suggest that, for patients without a fully matched stem cell donor, gene therapy is the next-best approach.”
Inhibitor controls WM long-term
Photo by Sam Odgen
Updated results of a phase 2 trial suggest the Bruton’s tyrosine kinase inhibitor ibrutinib can control Waldenstrom’s macroglobulinemia (WM) long-term.
In previously treated WM patients, ibrutinib produced an overall response rate of 91%.
The 2-year overall survival rate was 95%, and 69% of patients had not progressed at 2 years.
Researchers reported these results in NEJM. The research was supported by Pharmacyclics, Janssen Pharmaceuticals, and several foundations.
An earlier analysis of data from this trial supported the US Food and Drug Administration’s approval of ibrutinib as the first treatment for WM.
“These findings herald a new era for the treatment of Waldenstrom’s macroglobulinemia and show how genome sequencing can lead to the discovery of cancer mutations that can be specifically targeted by new therapies,” said study author Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
Dr Treon and his colleagues enrolled 63 WM patients on this trial. The patients had received a median of 2 prior therapies (range, 1-9), 56 patients (89%) had the MYD88L265P mutation, and 21 (34%) had the CXCR4WHIM mutation.
Patients received ibrutinib at 420 mg once daily until disease progression or unacceptable toxicity. After a median treatment duration of 19.1 months (range, 0.5-29.7 months), the overall response rate was 91%. The median time to response was 4 weeks.
Investigator-determined responses were impacted by the MYD88 and CXCR4 mutations. Patients carrying MYD88L265P and CXCR4WT achieved the highest responses, with a 100% overall response rate and 91% major response rate.
For all patients, the estimated progression-free and overall survival rates at 24 months were 69% and 95%, respectively.
“The results are remarkable when you consider that patients had received an average of 2 prior therapies, and 40% showed no response to the previous treatments,” Dr Treon said. “The findings herald a new era for the treatment of Waldenstrom’s macroglobulinemia.”
Dr Treon and his colleagues also said ibrutinib was well-tolerated. At the time of analysis, 68% of patients remained on therapy.
The most common grade 2-4 adverse events were neutropenia (22%) and thrombocytopenia (14%). Grade 3 or higher neutropenia and thrombocytopenia occurred in 9 (14%) and 8 (13%) patients, respectively.
Ibrutinib-related neutropenia and thrombocytopenia were reversible but required a dose reduction in 3 patients and treatment discontinuation in 4 patients.
Grade 2 or higher bleeding events occurred in 4 patients, and there were 15 infections considered possibly related to ibrutinib.
Treatment-related atrial fibrillation (AFib) occurred in 3 patients, all of whom had a prior history of paroxysmal AFib. AFib resolved when treatment was withheld, and all 3 patients were able to continue on therapy per protocol without an additional event.
Photo by Sam Odgen
Updated results of a phase 2 trial suggest the Bruton’s tyrosine kinase inhibitor ibrutinib can control Waldenstrom’s macroglobulinemia (WM) long-term.
In previously treated WM patients, ibrutinib produced an overall response rate of 91%.
The 2-year overall survival rate was 95%, and 69% of patients had not progressed at 2 years.
Researchers reported these results in NEJM. The research was supported by Pharmacyclics, Janssen Pharmaceuticals, and several foundations.
An earlier analysis of data from this trial supported the US Food and Drug Administration’s approval of ibrutinib as the first treatment for WM.
“These findings herald a new era for the treatment of Waldenstrom’s macroglobulinemia and show how genome sequencing can lead to the discovery of cancer mutations that can be specifically targeted by new therapies,” said study author Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
Dr Treon and his colleagues enrolled 63 WM patients on this trial. The patients had received a median of 2 prior therapies (range, 1-9), 56 patients (89%) had the MYD88L265P mutation, and 21 (34%) had the CXCR4WHIM mutation.
Patients received ibrutinib at 420 mg once daily until disease progression or unacceptable toxicity. After a median treatment duration of 19.1 months (range, 0.5-29.7 months), the overall response rate was 91%. The median time to response was 4 weeks.
Investigator-determined responses were impacted by the MYD88 and CXCR4 mutations. Patients carrying MYD88L265P and CXCR4WT achieved the highest responses, with a 100% overall response rate and 91% major response rate.
For all patients, the estimated progression-free and overall survival rates at 24 months were 69% and 95%, respectively.
“The results are remarkable when you consider that patients had received an average of 2 prior therapies, and 40% showed no response to the previous treatments,” Dr Treon said. “The findings herald a new era for the treatment of Waldenstrom’s macroglobulinemia.”
Dr Treon and his colleagues also said ibrutinib was well-tolerated. At the time of analysis, 68% of patients remained on therapy.
The most common grade 2-4 adverse events were neutropenia (22%) and thrombocytopenia (14%). Grade 3 or higher neutropenia and thrombocytopenia occurred in 9 (14%) and 8 (13%) patients, respectively.
Ibrutinib-related neutropenia and thrombocytopenia were reversible but required a dose reduction in 3 patients and treatment discontinuation in 4 patients.
Grade 2 or higher bleeding events occurred in 4 patients, and there were 15 infections considered possibly related to ibrutinib.
Treatment-related atrial fibrillation (AFib) occurred in 3 patients, all of whom had a prior history of paroxysmal AFib. AFib resolved when treatment was withheld, and all 3 patients were able to continue on therapy per protocol without an additional event.
Photo by Sam Odgen
Updated results of a phase 2 trial suggest the Bruton’s tyrosine kinase inhibitor ibrutinib can control Waldenstrom’s macroglobulinemia (WM) long-term.
In previously treated WM patients, ibrutinib produced an overall response rate of 91%.
The 2-year overall survival rate was 95%, and 69% of patients had not progressed at 2 years.
Researchers reported these results in NEJM. The research was supported by Pharmacyclics, Janssen Pharmaceuticals, and several foundations.
An earlier analysis of data from this trial supported the US Food and Drug Administration’s approval of ibrutinib as the first treatment for WM.
“These findings herald a new era for the treatment of Waldenstrom’s macroglobulinemia and show how genome sequencing can lead to the discovery of cancer mutations that can be specifically targeted by new therapies,” said study author Steven Treon, MD, PhD, of the Dana-Farber Cancer Institute in Boston, Massachusetts.
Dr Treon and his colleagues enrolled 63 WM patients on this trial. The patients had received a median of 2 prior therapies (range, 1-9), 56 patients (89%) had the MYD88L265P mutation, and 21 (34%) had the CXCR4WHIM mutation.
Patients received ibrutinib at 420 mg once daily until disease progression or unacceptable toxicity. After a median treatment duration of 19.1 months (range, 0.5-29.7 months), the overall response rate was 91%. The median time to response was 4 weeks.
Investigator-determined responses were impacted by the MYD88 and CXCR4 mutations. Patients carrying MYD88L265P and CXCR4WT achieved the highest responses, with a 100% overall response rate and 91% major response rate.
For all patients, the estimated progression-free and overall survival rates at 24 months were 69% and 95%, respectively.
“The results are remarkable when you consider that patients had received an average of 2 prior therapies, and 40% showed no response to the previous treatments,” Dr Treon said. “The findings herald a new era for the treatment of Waldenstrom’s macroglobulinemia.”
Dr Treon and his colleagues also said ibrutinib was well-tolerated. At the time of analysis, 68% of patients remained on therapy.
The most common grade 2-4 adverse events were neutropenia (22%) and thrombocytopenia (14%). Grade 3 or higher neutropenia and thrombocytopenia occurred in 9 (14%) and 8 (13%) patients, respectively.
Ibrutinib-related neutropenia and thrombocytopenia were reversible but required a dose reduction in 3 patients and treatment discontinuation in 4 patients.
Grade 2 or higher bleeding events occurred in 4 patients, and there were 15 infections considered possibly related to ibrutinib.
Treatment-related atrial fibrillation (AFib) occurred in 3 patients, all of whom had a prior history of paroxysmal AFib. AFib resolved when treatment was withheld, and all 3 patients were able to continue on therapy per protocol without an additional event.