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Upfront ASCT still preferred for young MM patients
Photo by Chad McNeeley
CHICAGO—An interim analysis of a large, phase 3 study has confirmed that upfront autologous stem cell transplantation (ASCT) is still the preferred
treatment for newly diagnosed, young multiple myeloma (MM) patients, even in the age of novel agents such as bortezomib.
Investigators compared 4 cycles of bortezomib-melphalan-prednisone (VMP) with high-dose melphalan (HDM) and single or double ASCT, depending upon the policy of the treating institution.
At a median follow-up of 24 months, the 3-year progression-free survival (PFS) was significantly better for patients who had received ASCT.
Michele Cavo, MD, of Seràgnoli Institute of Hematology in Bologna, Italy, reported the results of this first interim analysis of the European Myeloma Network trial (EMN/HO95 MM) at a press briefing preceding the 2016 ASCO Annual Meeting. More details will be presented at the meeting itself (abstract 8000).
Study investigators enrolled 1503 patients from February 2011 through April 2014. They performed the specified interim analysis in January 2016.
Patients were 65 years or younger, and all received bortezomib-based induction therapy followed by stem cell collection. Investigators then randomized 1266 patients to receive either VMP (n=754) or HDM plus single or double ASCT (n=512).
Patients underwent a second randomization to either 2 cycles of bortezomib-based consolidation or no consolidation therapy.
All patients received lenalidomide maintenance until disease progression. The primary endpoint was PFS after the first randomization.
Results
PFS was significantly longer in patients who had received a transplant, with a hazard ratio (HR) of 0.76, 95% confidence interval (CI) of 0.61-0.94, and P value of 0.01.
This benefit held true for patients with revised ISS stage III (HR=0.52, 95% CI 0.32-0.84, P=0.01).
And patients with high-risk cytogenetics also retained the benefit (HR=0.72, 95% CI 0.54-0.97, P=0.03). High-risk was defined as t(4;14), del(17p), del(1p), or gain of 1q.
Investigators also performed a multivariate analysis and found randomization to the HDM arm to be an independent predictor of prolonged PFS (HR=0.61, 95% CI 0.45-0.82, P=0.001).
There was no significant difference between the 2 arms in terms of stringent complete response and complete response.
However, when very good partial response was included in the best-response analysis, patients in the transplant arm fared significantly better (P<0.0001) than patients in the VMP arm—84% and 74%, respectively.
Investigators have not yet completed the interim data analysis related to the second randomization. The study is ongoing, and future analyses will include overall survival, toxicity, quality of life, and other measures.
This study was funded by the Haemato Oncology Foundation for Adults in the Netherlands (HOVON). 
Photo by Chad McNeeley
CHICAGO—An interim analysis of a large, phase 3 study has confirmed that upfront autologous stem cell transplantation (ASCT) is still the preferred
treatment for newly diagnosed, young multiple myeloma (MM) patients, even in the age of novel agents such as bortezomib.
Investigators compared 4 cycles of bortezomib-melphalan-prednisone (VMP) with high-dose melphalan (HDM) and single or double ASCT, depending upon the policy of the treating institution.
At a median follow-up of 24 months, the 3-year progression-free survival (PFS) was significantly better for patients who had received ASCT.
Michele Cavo, MD, of Seràgnoli Institute of Hematology in Bologna, Italy, reported the results of this first interim analysis of the European Myeloma Network trial (EMN/HO95 MM) at a press briefing preceding the 2016 ASCO Annual Meeting. More details will be presented at the meeting itself (abstract 8000).
Study investigators enrolled 1503 patients from February 2011 through April 2014. They performed the specified interim analysis in January 2016.
Patients were 65 years or younger, and all received bortezomib-based induction therapy followed by stem cell collection. Investigators then randomized 1266 patients to receive either VMP (n=754) or HDM plus single or double ASCT (n=512).
Patients underwent a second randomization to either 2 cycles of bortezomib-based consolidation or no consolidation therapy.
All patients received lenalidomide maintenance until disease progression. The primary endpoint was PFS after the first randomization.
Results
PFS was significantly longer in patients who had received a transplant, with a hazard ratio (HR) of 0.76, 95% confidence interval (CI) of 0.61-0.94, and P value of 0.01.
This benefit held true for patients with revised ISS stage III (HR=0.52, 95% CI 0.32-0.84, P=0.01).
And patients with high-risk cytogenetics also retained the benefit (HR=0.72, 95% CI 0.54-0.97, P=0.03). High-risk was defined as t(4;14), del(17p), del(1p), or gain of 1q.
Investigators also performed a multivariate analysis and found randomization to the HDM arm to be an independent predictor of prolonged PFS (HR=0.61, 95% CI 0.45-0.82, P=0.001).
There was no significant difference between the 2 arms in terms of stringent complete response and complete response.
However, when very good partial response was included in the best-response analysis, patients in the transplant arm fared significantly better (P<0.0001) than patients in the VMP arm—84% and 74%, respectively.
Investigators have not yet completed the interim data analysis related to the second randomization. The study is ongoing, and future analyses will include overall survival, toxicity, quality of life, and other measures.
This study was funded by the Haemato Oncology Foundation for Adults in the Netherlands (HOVON).
Photo by Chad McNeeley
CHICAGO—An interim analysis of a large, phase 3 study has confirmed that upfront autologous stem cell transplantation (ASCT) is still the preferred
treatment for newly diagnosed, young multiple myeloma (MM) patients, even in the age of novel agents such as bortezomib.
Investigators compared 4 cycles of bortezomib-melphalan-prednisone (VMP) with high-dose melphalan (HDM) and single or double ASCT, depending upon the policy of the treating institution.
At a median follow-up of 24 months, the 3-year progression-free survival (PFS) was significantly better for patients who had received ASCT.
Michele Cavo, MD, of Seràgnoli Institute of Hematology in Bologna, Italy, reported the results of this first interim analysis of the European Myeloma Network trial (EMN/HO95 MM) at a press briefing preceding the 2016 ASCO Annual Meeting. More details will be presented at the meeting itself (abstract 8000).
Study investigators enrolled 1503 patients from February 2011 through April 2014. They performed the specified interim analysis in January 2016.
Patients were 65 years or younger, and all received bortezomib-based induction therapy followed by stem cell collection. Investigators then randomized 1266 patients to receive either VMP (n=754) or HDM plus single or double ASCT (n=512).
Patients underwent a second randomization to either 2 cycles of bortezomib-based consolidation or no consolidation therapy.
All patients received lenalidomide maintenance until disease progression. The primary endpoint was PFS after the first randomization.
Results
PFS was significantly longer in patients who had received a transplant, with a hazard ratio (HR) of 0.76, 95% confidence interval (CI) of 0.61-0.94, and P value of 0.01.
This benefit held true for patients with revised ISS stage III (HR=0.52, 95% CI 0.32-0.84, P=0.01).
And patients with high-risk cytogenetics also retained the benefit (HR=0.72, 95% CI 0.54-0.97, P=0.03). High-risk was defined as t(4;14), del(17p), del(1p), or gain of 1q.
Investigators also performed a multivariate analysis and found randomization to the HDM arm to be an independent predictor of prolonged PFS (HR=0.61, 95% CI 0.45-0.82, P=0.001).
There was no significant difference between the 2 arms in terms of stringent complete response and complete response.
However, when very good partial response was included in the best-response analysis, patients in the transplant arm fared significantly better (P<0.0001) than patients in the VMP arm—84% and 74%, respectively.
Investigators have not yet completed the interim data analysis related to the second randomization. The study is ongoing, and future analyses will include overall survival, toxicity, quality of life, and other measures.
This study was funded by the Haemato Oncology Foundation for Adults in the Netherlands (HOVON).
Creating ‘real’ HSCs in the lab
in the bone marrow
Scientists believe they have come one step closer to creating hematopoietic stem cells (HSCs) that are just like the real thing.
“Our work focuses on finding a way to generate a supply of these life-saving hematopoietic stem cells in the lab so that they are a perfect match to the patient in need of a transplant,” said Hanna Mikkola, MD, PhD, of the University of California, Los Angeles.
“One big challenge is that when we try to create hematopoietic stem cells from pluripotent stem cells in the lab, they don’t acquire the same abilities of the real hematopoietic stem cells found in the body.”
Dr Mikkola and her colleagues described their attempts to overcome this challenge in Nature Cell Biology.
The researchers tried to create HSCs from pluripotent stem cells, but when they compared the lab-created cells to HSCs found in the body, they found that HOXA genes weren’t activated in the lab-created cells.
The team also discovered that HOXA genes help HSCs maintain their stem-cell attributes, such as the ability to self-renew.
“Without the ability to self-renew, hematopoietic stem cells cannot be used for transplantation therapies,” said Vincenzo Calvanese, PhD, an assistant project scientist in Dr Mikkola’s lab.
“Our findings show that the activation of HOXA genes can be used as a marker for hematopoietic stem cells that have acquired the capacity to renew themselves.”
The researchers’ next challenge was to pinpoint the naturally occurring process that activates HOXA genes so they could try to replicate the process in the lab.
They found that mimicking the effects of retinoic acid acts like a switch that turns on the HOXA genes during HSC development.
“Inducing retinoic acid activity at a very specific time in cell development makes our lab-created cells more similar to the real hematopoietic stem cells found in the body,” said Diana Dou, a graduate student in Dr Mikkola’s lab.
“This is an important step forward as we work to develop hematopoietic stem cells for transplantation therapies for life-threatening blood diseases.”
The researchers’ next step will be to refine the process they’ve developed in order to produce lab-created HSCs that have—and maintain—all the functions of human HSCs.
in the bone marrow
Scientists believe they have come one step closer to creating hematopoietic stem cells (HSCs) that are just like the real thing.
“Our work focuses on finding a way to generate a supply of these life-saving hematopoietic stem cells in the lab so that they are a perfect match to the patient in need of a transplant,” said Hanna Mikkola, MD, PhD, of the University of California, Los Angeles.
“One big challenge is that when we try to create hematopoietic stem cells from pluripotent stem cells in the lab, they don’t acquire the same abilities of the real hematopoietic stem cells found in the body.”
Dr Mikkola and her colleagues described their attempts to overcome this challenge in Nature Cell Biology.
The researchers tried to create HSCs from pluripotent stem cells, but when they compared the lab-created cells to HSCs found in the body, they found that HOXA genes weren’t activated in the lab-created cells.
The team also discovered that HOXA genes help HSCs maintain their stem-cell attributes, such as the ability to self-renew.
“Without the ability to self-renew, hematopoietic stem cells cannot be used for transplantation therapies,” said Vincenzo Calvanese, PhD, an assistant project scientist in Dr Mikkola’s lab.
“Our findings show that the activation of HOXA genes can be used as a marker for hematopoietic stem cells that have acquired the capacity to renew themselves.”
The researchers’ next challenge was to pinpoint the naturally occurring process that activates HOXA genes so they could try to replicate the process in the lab.
They found that mimicking the effects of retinoic acid acts like a switch that turns on the HOXA genes during HSC development.
“Inducing retinoic acid activity at a very specific time in cell development makes our lab-created cells more similar to the real hematopoietic stem cells found in the body,” said Diana Dou, a graduate student in Dr Mikkola’s lab.
“This is an important step forward as we work to develop hematopoietic stem cells for transplantation therapies for life-threatening blood diseases.”
The researchers’ next step will be to refine the process they’ve developed in order to produce lab-created HSCs that have—and maintain—all the functions of human HSCs.
in the bone marrow
Scientists believe they have come one step closer to creating hematopoietic stem cells (HSCs) that are just like the real thing.
“Our work focuses on finding a way to generate a supply of these life-saving hematopoietic stem cells in the lab so that they are a perfect match to the patient in need of a transplant,” said Hanna Mikkola, MD, PhD, of the University of California, Los Angeles.
“One big challenge is that when we try to create hematopoietic stem cells from pluripotent stem cells in the lab, they don’t acquire the same abilities of the real hematopoietic stem cells found in the body.”
Dr Mikkola and her colleagues described their attempts to overcome this challenge in Nature Cell Biology.
The researchers tried to create HSCs from pluripotent stem cells, but when they compared the lab-created cells to HSCs found in the body, they found that HOXA genes weren’t activated in the lab-created cells.
The team also discovered that HOXA genes help HSCs maintain their stem-cell attributes, such as the ability to self-renew.
“Without the ability to self-renew, hematopoietic stem cells cannot be used for transplantation therapies,” said Vincenzo Calvanese, PhD, an assistant project scientist in Dr Mikkola’s lab.
“Our findings show that the activation of HOXA genes can be used as a marker for hematopoietic stem cells that have acquired the capacity to renew themselves.”
The researchers’ next challenge was to pinpoint the naturally occurring process that activates HOXA genes so they could try to replicate the process in the lab.
They found that mimicking the effects of retinoic acid acts like a switch that turns on the HOXA genes during HSC development.
“Inducing retinoic acid activity at a very specific time in cell development makes our lab-created cells more similar to the real hematopoietic stem cells found in the body,” said Diana Dou, a graduate student in Dr Mikkola’s lab.
“This is an important step forward as we work to develop hematopoietic stem cells for transplantation therapies for life-threatening blood diseases.”
The researchers’ next step will be to refine the process they’ve developed in order to produce lab-created HSCs that have—and maintain—all the functions of human HSCs.
Company warns of counterfeit drug
Photo by Bill Branson
Heritage Pharmaceuticals Inc., has announced the existence of a counterfeit drug product labeled as BiCNU® (carmustine for injection) 100 mg.
The company said that, to the best of its knowledge, the counterfeit product has only been distributed in India, Ireland, and Israel.
However, Heritage is consulting with the US Food and Drug Administration (FDA) to aid the agency’s evaluations of this product, assist with determining the source of the counterfeit drug, and prevent the further distribution of this product or its introduction into the US.
BiCNU® is primarily used for chemotherapy in the treatment of lymphomas, multiple myeloma, and brain cancers. But the drug is also used for immunosuppression before organ transplant or hematopoietic stem cell transplant.
Heritage said it has directly notified all customers and provided detailed information that will help them identify a counterfeit BiCNU® product. Customers have been instructed to examine their inventory immediately and to quarantine, discontinue distribution of, and return any suspected counterfeit product.
Any customers who may have recently distributed the BiCNU® products to their own customers have been asked to convey this information to their customers so they will be able to carefully examine all BiCNU® products before use and identify the characteristics of a suspected counterfeit product.
Any end users who believe they may have received a counterfeit drug should return the product to the pharmacy that dispensed the medicine.
Any US health practitioners who determine they are in possession of a counterfeit product should contact the FDA through MedWatch. Instructions for such reporting are available on the FDA website.
Anyone with questions about the counterfeit product should contact the Heritage customer call center directly at (866) 901-3784, which is open Monday through Friday, from 9 am to 5 pm EST.
Photo by Bill Branson
Heritage Pharmaceuticals Inc., has announced the existence of a counterfeit drug product labeled as BiCNU® (carmustine for injection) 100 mg.
The company said that, to the best of its knowledge, the counterfeit product has only been distributed in India, Ireland, and Israel.
However, Heritage is consulting with the US Food and Drug Administration (FDA) to aid the agency’s evaluations of this product, assist with determining the source of the counterfeit drug, and prevent the further distribution of this product or its introduction into the US.
BiCNU® is primarily used for chemotherapy in the treatment of lymphomas, multiple myeloma, and brain cancers. But the drug is also used for immunosuppression before organ transplant or hematopoietic stem cell transplant.
Heritage said it has directly notified all customers and provided detailed information that will help them identify a counterfeit BiCNU® product. Customers have been instructed to examine their inventory immediately and to quarantine, discontinue distribution of, and return any suspected counterfeit product.
Any customers who may have recently distributed the BiCNU® products to their own customers have been asked to convey this information to their customers so they will be able to carefully examine all BiCNU® products before use and identify the characteristics of a suspected counterfeit product.
Any end users who believe they may have received a counterfeit drug should return the product to the pharmacy that dispensed the medicine.
Any US health practitioners who determine they are in possession of a counterfeit product should contact the FDA through MedWatch. Instructions for such reporting are available on the FDA website.
Anyone with questions about the counterfeit product should contact the Heritage customer call center directly at (866) 901-3784, which is open Monday through Friday, from 9 am to 5 pm EST.
Photo by Bill Branson
Heritage Pharmaceuticals Inc., has announced the existence of a counterfeit drug product labeled as BiCNU® (carmustine for injection) 100 mg.
The company said that, to the best of its knowledge, the counterfeit product has only been distributed in India, Ireland, and Israel.
However, Heritage is consulting with the US Food and Drug Administration (FDA) to aid the agency’s evaluations of this product, assist with determining the source of the counterfeit drug, and prevent the further distribution of this product or its introduction into the US.
BiCNU® is primarily used for chemotherapy in the treatment of lymphomas, multiple myeloma, and brain cancers. But the drug is also used for immunosuppression before organ transplant or hematopoietic stem cell transplant.
Heritage said it has directly notified all customers and provided detailed information that will help them identify a counterfeit BiCNU® product. Customers have been instructed to examine their inventory immediately and to quarantine, discontinue distribution of, and return any suspected counterfeit product.
Any customers who may have recently distributed the BiCNU® products to their own customers have been asked to convey this information to their customers so they will be able to carefully examine all BiCNU® products before use and identify the characteristics of a suspected counterfeit product.
Any end users who believe they may have received a counterfeit drug should return the product to the pharmacy that dispensed the medicine.
Any US health practitioners who determine they are in possession of a counterfeit product should contact the FDA through MedWatch. Instructions for such reporting are available on the FDA website.
Anyone with questions about the counterfeit product should contact the Heritage customer call center directly at (866) 901-3784, which is open Monday through Friday, from 9 am to 5 pm EST.
Group isolates Tregs to treat GVHD
Image by Kathryn T. Iacono
Researchers say they have devised a method for harvesting regulatory T cells (Tregs) on a large scale, and they are currently testing these Tregs in a trial of patients with graft-versus-host disease (GVHD).
The team described the harvesting method in the Journal of Immunotherapy.
“A Tregs-based therapy could help reduce the risk of GVHD, but Tregs are a very rare population amongst blood cells,” said study author Sebastian Bertin-Maghit, PhD, of the Agency for Science, Technology and Research (A*STAR) in Singapore.
“For our therapy to work, we needed a large supply of pure, ‘untouched’ Tregs that are uncontaminated with other cell types.”
However, when it came to isolating pure Tregs on a large scale, the researchers found existing isolation methods inefficient.
So rather than isolating the cells by “plucking” them out of a donor sample—a method that comes with the risk of unwanted modification or activation of some cells—the team devised a depletion method for selecting Tregs in their pure, untouched state.
“We depleted all unwanted cells in donor samples using isolation reagents,” Dr Bertin-Maghit said. “This allowed us to harvest Tregs in their natural state. We took great care to wash out the isolation reagents in the final product.”
The researchers have since proven that this single-step depletion process can be scaled up to harvest highly pure Tregs at levels suitable for clinical trials, and their procedure complies with current trial standards.
Furthermore, while previous attempts to collect Tregs produced a final product with 60% pure Tregs, this new method generates over 90% pure Tregs.
“The first clinical trial using our Treg product is currently ongoing at the Singapore General Hospital,” Dr Bertin-Maghit said. “We are assessing the safety of Tregs in the treatment of GVHD in 12 leukemia patients. We believe our procedure will open doors to a new era in cell therapy.”
Image by Kathryn T. Iacono
Researchers say they have devised a method for harvesting regulatory T cells (Tregs) on a large scale, and they are currently testing these Tregs in a trial of patients with graft-versus-host disease (GVHD).
The team described the harvesting method in the Journal of Immunotherapy.
“A Tregs-based therapy could help reduce the risk of GVHD, but Tregs are a very rare population amongst blood cells,” said study author Sebastian Bertin-Maghit, PhD, of the Agency for Science, Technology and Research (A*STAR) in Singapore.
“For our therapy to work, we needed a large supply of pure, ‘untouched’ Tregs that are uncontaminated with other cell types.”
However, when it came to isolating pure Tregs on a large scale, the researchers found existing isolation methods inefficient.
So rather than isolating the cells by “plucking” them out of a donor sample—a method that comes with the risk of unwanted modification or activation of some cells—the team devised a depletion method for selecting Tregs in their pure, untouched state.
“We depleted all unwanted cells in donor samples using isolation reagents,” Dr Bertin-Maghit said. “This allowed us to harvest Tregs in their natural state. We took great care to wash out the isolation reagents in the final product.”
The researchers have since proven that this single-step depletion process can be scaled up to harvest highly pure Tregs at levels suitable for clinical trials, and their procedure complies with current trial standards.
Furthermore, while previous attempts to collect Tregs produced a final product with 60% pure Tregs, this new method generates over 90% pure Tregs.
“The first clinical trial using our Treg product is currently ongoing at the Singapore General Hospital,” Dr Bertin-Maghit said. “We are assessing the safety of Tregs in the treatment of GVHD in 12 leukemia patients. We believe our procedure will open doors to a new era in cell therapy.”
Image by Kathryn T. Iacono
Researchers say they have devised a method for harvesting regulatory T cells (Tregs) on a large scale, and they are currently testing these Tregs in a trial of patients with graft-versus-host disease (GVHD).
The team described the harvesting method in the Journal of Immunotherapy.
“A Tregs-based therapy could help reduce the risk of GVHD, but Tregs are a very rare population amongst blood cells,” said study author Sebastian Bertin-Maghit, PhD, of the Agency for Science, Technology and Research (A*STAR) in Singapore.
“For our therapy to work, we needed a large supply of pure, ‘untouched’ Tregs that are uncontaminated with other cell types.”
However, when it came to isolating pure Tregs on a large scale, the researchers found existing isolation methods inefficient.
So rather than isolating the cells by “plucking” them out of a donor sample—a method that comes with the risk of unwanted modification or activation of some cells—the team devised a depletion method for selecting Tregs in their pure, untouched state.
“We depleted all unwanted cells in donor samples using isolation reagents,” Dr Bertin-Maghit said. “This allowed us to harvest Tregs in their natural state. We took great care to wash out the isolation reagents in the final product.”
The researchers have since proven that this single-step depletion process can be scaled up to harvest highly pure Tregs at levels suitable for clinical trials, and their procedure complies with current trial standards.
Furthermore, while previous attempts to collect Tregs produced a final product with 60% pure Tregs, this new method generates over 90% pure Tregs.
“The first clinical trial using our Treg product is currently ongoing at the Singapore General Hospital,” Dr Bertin-Maghit said. “We are assessing the safety of Tregs in the treatment of GVHD in 12 leukemia patients. We believe our procedure will open doors to a new era in cell therapy.”
Tools may aid transition from pediatric to adult care
Photo courtesy of the CDC
WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.
The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.
It includes 2 types of forms—a transition-readiness assessment and a clinical summary.
The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.
“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.
“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”
ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.
An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:
- generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
- specific forms for hemophilia
- specific forms for sickle cell disease.
For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.
The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.
This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.
The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.
More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.
Photo courtesy of the CDC
WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.
The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.
It includes 2 types of forms—a transition-readiness assessment and a clinical summary.
The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.
“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.
“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”
ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.
An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:
- generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
- specific forms for hemophilia
- specific forms for sickle cell disease.
For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.
The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.
This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.
The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.
More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.
Photo courtesy of the CDC
WASHINGTON, DC—The American Society of Hematology (ASH) has created a toolkit to help hematologists aid patients who are transitioning from pediatric to adult practices.
The toolkit contains general resources for all hematologic conditions, as well as specific resources for patients with hemophilia and sickle cell disease.
It includes 2 types of forms—a transition-readiness assessment and a clinical summary.
The toolkit was presented at the American College of Physicians (ACP) Internal Medicine Meeting 2016.
“Transitioning from pediatric to adult healthcare practices is often a challenge for patients with chronic medical issues because it can be difficult to adhere to a treatment regimen or attend regular appointments without the assistance of a parent or guardian,” said ASH President Charles S. Abrams, MD, of the University of Pennsylvania in Philadelphia.
“ASH recognizes that understanding a patient’s preparedness to take control of his or her medical condition in adulthood can make a huge difference in quality of care, which is why we are pleased to join the American College of Physicians and partner societies in this important initiative.”
ASH joined more than 2 dozen groups to participate in the ACP’s Pediatric to Adult Care Transition Initiative. The goal of this initiative was to develop guidance and tools that both primary care internal medicine and subspecialty practices can use for patients who are transitioning from pediatric/adolescent practices to adult care.
An ASH Transitions Work Group, made up of society members from pediatric and adult practices, developed 3 segments of the hematology-specific toolkit:
- generic forms for patients with any hematologic condition, with an addendum that includes links to additional condition-specific guidelines and resources
- specific forms for hemophilia
- specific forms for sickle cell disease.
For each segment, there are 2 types of forms— a transition-readiness assessment and a clinical summary.
The transition-readiness assessment should be completed by the patient. It assesses the patient’s readiness for the transition to adult care by evaluating the patient’s understanding of his or her condition and ability to manage medications, appointments, insurance, and medical privacy issues.
This assessment should be used by the adult care team to assess any remaining gaps in the patient’s self-care knowledge or additional issues that should be addressed to ensure optimal care.
The clinical summary is a medical record summary to be completed by the referring provider and the patient. The summary contains essential clinical information regarding the patient’s condition that is to be included in the patient’s medical record upon transfer to the adult practice.
More information on the ACP Pediatric to Adult Care Transitions Initiative is available on the ACP website. The forms for the ASH transitions toolkit are available in the “Hematology” section of the Condition-Specific Tools page.
Team creates bone marrow on a chip
Image by Daniel E. Sabath
Engineered bone marrow grown in a microfluidic chip device mimics living bone marrow, according to research published in Tissue Engineering.
Experiments showed the engineered bone marrow responded in a way similar to living bone marrow when exposed to damaging radiation followed by treatment with compounds that aid in blood cell recovery.
The researchers said this new bone marrow-on-a-chip device holds promise for testing and developing improved radiation countermeasures.
Yu-suke Torisawa, PhD, of Kyoto University in Japan, and his colleagues conducted this research.
The team used a tissue engineering approach to induce formation of new marrow-containing bone in mice. They then surgically removed the bone, placed it in a microfluidic device, and continuously perfused it with medium in vitro.
Next, the researchers set out to determine if the device would keep the engineered bone marrow alive so they could perform tests on it.
To test the system, the team analyzed the dynamics of blood cell production and evaluated the radiation-protecting effects of granulocyte-colony stimulating factor (G-CSF) and bactericidal/permeability-increasing protein (BPI).
Experiments showed the microfluidic device could maintain hematopoietic stem and progenitor cells in normal proportions for at least 2 weeks in culture.
Over time, the researchers observed increases in the number of leukocytes and red blood cells in the microfluidic circulation. And they found that adding erythropoietin induced a significant increase in erythrocyte production.
When the researchers exposed the engineered bone marrow to gamma radiation, they saw reduced leukocyte production.
And when they treated the engineered bone marrow with G-CSF or BPI, the team saw significant increases in the number of hematopoietic stem cells and myeloid cells in the fluidic outflow.
On the other hand, BPI did not have such an effect on static bone marrow cultures. But the researchers pointed out that previous work has shown BPI can accelerate recovery from radiation-induced toxicity in vivo.
The team therefore concluded that, unlike static bone marrow cultures, engineered bone marrow grown in a microfluidic device effectively mimics the recovery response of bone marrow in the body.
Image by Daniel E. Sabath
Engineered bone marrow grown in a microfluidic chip device mimics living bone marrow, according to research published in Tissue Engineering.
Experiments showed the engineered bone marrow responded in a way similar to living bone marrow when exposed to damaging radiation followed by treatment with compounds that aid in blood cell recovery.
The researchers said this new bone marrow-on-a-chip device holds promise for testing and developing improved radiation countermeasures.
Yu-suke Torisawa, PhD, of Kyoto University in Japan, and his colleagues conducted this research.
The team used a tissue engineering approach to induce formation of new marrow-containing bone in mice. They then surgically removed the bone, placed it in a microfluidic device, and continuously perfused it with medium in vitro.
Next, the researchers set out to determine if the device would keep the engineered bone marrow alive so they could perform tests on it.
To test the system, the team analyzed the dynamics of blood cell production and evaluated the radiation-protecting effects of granulocyte-colony stimulating factor (G-CSF) and bactericidal/permeability-increasing protein (BPI).
Experiments showed the microfluidic device could maintain hematopoietic stem and progenitor cells in normal proportions for at least 2 weeks in culture.
Over time, the researchers observed increases in the number of leukocytes and red blood cells in the microfluidic circulation. And they found that adding erythropoietin induced a significant increase in erythrocyte production.
When the researchers exposed the engineered bone marrow to gamma radiation, they saw reduced leukocyte production.
And when they treated the engineered bone marrow with G-CSF or BPI, the team saw significant increases in the number of hematopoietic stem cells and myeloid cells in the fluidic outflow.
On the other hand, BPI did not have such an effect on static bone marrow cultures. But the researchers pointed out that previous work has shown BPI can accelerate recovery from radiation-induced toxicity in vivo.
The team therefore concluded that, unlike static bone marrow cultures, engineered bone marrow grown in a microfluidic device effectively mimics the recovery response of bone marrow in the body.
Image by Daniel E. Sabath
Engineered bone marrow grown in a microfluidic chip device mimics living bone marrow, according to research published in Tissue Engineering.
Experiments showed the engineered bone marrow responded in a way similar to living bone marrow when exposed to damaging radiation followed by treatment with compounds that aid in blood cell recovery.
The researchers said this new bone marrow-on-a-chip device holds promise for testing and developing improved radiation countermeasures.
Yu-suke Torisawa, PhD, of Kyoto University in Japan, and his colleagues conducted this research.
The team used a tissue engineering approach to induce formation of new marrow-containing bone in mice. They then surgically removed the bone, placed it in a microfluidic device, and continuously perfused it with medium in vitro.
Next, the researchers set out to determine if the device would keep the engineered bone marrow alive so they could perform tests on it.
To test the system, the team analyzed the dynamics of blood cell production and evaluated the radiation-protecting effects of granulocyte-colony stimulating factor (G-CSF) and bactericidal/permeability-increasing protein (BPI).
Experiments showed the microfluidic device could maintain hematopoietic stem and progenitor cells in normal proportions for at least 2 weeks in culture.
Over time, the researchers observed increases in the number of leukocytes and red blood cells in the microfluidic circulation. And they found that adding erythropoietin induced a significant increase in erythrocyte production.
When the researchers exposed the engineered bone marrow to gamma radiation, they saw reduced leukocyte production.
And when they treated the engineered bone marrow with G-CSF or BPI, the team saw significant increases in the number of hematopoietic stem cells and myeloid cells in the fluidic outflow.
On the other hand, BPI did not have such an effect on static bone marrow cultures. But the researchers pointed out that previous work has shown BPI can accelerate recovery from radiation-induced toxicity in vivo.
The team therefore concluded that, unlike static bone marrow cultures, engineered bone marrow grown in a microfluidic device effectively mimics the recovery response of bone marrow in the body.
Pre-treatment gut bacteria may predict risk of BSI
A new study suggests the composition of a cancer patient’s intestinal microbiome before treatment may predict his risk of developing a bloodstream infection (BSI) after treatment.
Researchers analyzed fecal samples from patients with non-Hodgkin lymphoma who were set to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) with myeloablative conditioning.
The team found that patients with less diversity in their fecal samples before this treatment were more likely to develop a BSI after.
Emmanuel Montassier, MD, PhD, of Nantes University Hospital in France, and his colleagues conducted this study and reported the result in Genome Medicine.
A previous study suggested that intestinal domination—when a single bacterial taxon occupies at least 30% of the microbiota—is associated with BSIs in patients undergoing allo-HSCT. However, the role of the intestinal microbiome before treatment was not clear.
So Dr Montassier and his colleagues set out to characterize the fecal microbiome before treatment. To do this, they sequenced the bacterial DNA of fecal samples from 28 patients with non-Hodgkin lymphoma.
The team collected the samples before patients began a 5-day myeloablative conditioning regimen (high-dose carmustine, etoposide, aracytine, and melphalan), followed by allo-HSCT on the seventh day.
Eleven of these patients developed a BSI at a mean of 12 days after sample collection. Two patients (18.2%) developed Enterococcus BSI, 4 (36.4%) developed Escherichia coli BSI, and 5 (45.5%) developed other Gammaproteobacteria BSI.
The researchers said that alpha diversity in samples from these patients was significantly lower than alpha diversity from patients who did not develop a BSI, with reduced evenness (Shannon index, Monte Carlo permuted t-test two-sided P value = 0.004) and reduced richness (Observed species, Monte Carlo permuted t-test two-sided P value = 0.001)
The team also noted that, compared to patients who did not develop a BSI, those who did had decreased abundance of Barnesiellaceae, Coriobacteriaceae, Faecalibacterium, Christensenella, Dehalobacterium, Desulfovibrio, and Sutterella.
Using this information, the researchers developed a BSI risk index that could predict the likelihood of a BSI with 90% sensitivity and specificity.
“This method worked even better than we expected because we found a consistent difference between the gut bacteria in those who developed infections and those who did not,” said study author Dan Knights, PhD, of the University of Minnesota in Minneapolis.
“This research is an early demonstration that we may be able to use the bugs in our gut to predict infections and possibly develop new prognostic models in other diseases.”
Still, the researchers said these findings are based on a limited number of patients treated with the same regimen at a single clinic. So the next step for this research is to validate the findings in a much larger cohort including patients with different cancer types, different treatment types, and from multiple treatment centers.
“We still need to determine if these bacteria are playing any kind of causal role in the infections or if they are simply acting as biomarkers for some other predisposing condition in the patient,” Dr Montassier said.
A new study suggests the composition of a cancer patient’s intestinal microbiome before treatment may predict his risk of developing a bloodstream infection (BSI) after treatment.
Researchers analyzed fecal samples from patients with non-Hodgkin lymphoma who were set to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) with myeloablative conditioning.
The team found that patients with less diversity in their fecal samples before this treatment were more likely to develop a BSI after.
Emmanuel Montassier, MD, PhD, of Nantes University Hospital in France, and his colleagues conducted this study and reported the result in Genome Medicine.
A previous study suggested that intestinal domination—when a single bacterial taxon occupies at least 30% of the microbiota—is associated with BSIs in patients undergoing allo-HSCT. However, the role of the intestinal microbiome before treatment was not clear.
So Dr Montassier and his colleagues set out to characterize the fecal microbiome before treatment. To do this, they sequenced the bacterial DNA of fecal samples from 28 patients with non-Hodgkin lymphoma.
The team collected the samples before patients began a 5-day myeloablative conditioning regimen (high-dose carmustine, etoposide, aracytine, and melphalan), followed by allo-HSCT on the seventh day.
Eleven of these patients developed a BSI at a mean of 12 days after sample collection. Two patients (18.2%) developed Enterococcus BSI, 4 (36.4%) developed Escherichia coli BSI, and 5 (45.5%) developed other Gammaproteobacteria BSI.
The researchers said that alpha diversity in samples from these patients was significantly lower than alpha diversity from patients who did not develop a BSI, with reduced evenness (Shannon index, Monte Carlo permuted t-test two-sided P value = 0.004) and reduced richness (Observed species, Monte Carlo permuted t-test two-sided P value = 0.001)
The team also noted that, compared to patients who did not develop a BSI, those who did had decreased abundance of Barnesiellaceae, Coriobacteriaceae, Faecalibacterium, Christensenella, Dehalobacterium, Desulfovibrio, and Sutterella.
Using this information, the researchers developed a BSI risk index that could predict the likelihood of a BSI with 90% sensitivity and specificity.
“This method worked even better than we expected because we found a consistent difference between the gut bacteria in those who developed infections and those who did not,” said study author Dan Knights, PhD, of the University of Minnesota in Minneapolis.
“This research is an early demonstration that we may be able to use the bugs in our gut to predict infections and possibly develop new prognostic models in other diseases.”
Still, the researchers said these findings are based on a limited number of patients treated with the same regimen at a single clinic. So the next step for this research is to validate the findings in a much larger cohort including patients with different cancer types, different treatment types, and from multiple treatment centers.
“We still need to determine if these bacteria are playing any kind of causal role in the infections or if they are simply acting as biomarkers for some other predisposing condition in the patient,” Dr Montassier said.
A new study suggests the composition of a cancer patient’s intestinal microbiome before treatment may predict his risk of developing a bloodstream infection (BSI) after treatment.
Researchers analyzed fecal samples from patients with non-Hodgkin lymphoma who were set to receive an allogeneic hematopoietic stem cell transplant (allo-HSCT) with myeloablative conditioning.
The team found that patients with less diversity in their fecal samples before this treatment were more likely to develop a BSI after.
Emmanuel Montassier, MD, PhD, of Nantes University Hospital in France, and his colleagues conducted this study and reported the result in Genome Medicine.
A previous study suggested that intestinal domination—when a single bacterial taxon occupies at least 30% of the microbiota—is associated with BSIs in patients undergoing allo-HSCT. However, the role of the intestinal microbiome before treatment was not clear.
So Dr Montassier and his colleagues set out to characterize the fecal microbiome before treatment. To do this, they sequenced the bacterial DNA of fecal samples from 28 patients with non-Hodgkin lymphoma.
The team collected the samples before patients began a 5-day myeloablative conditioning regimen (high-dose carmustine, etoposide, aracytine, and melphalan), followed by allo-HSCT on the seventh day.
Eleven of these patients developed a BSI at a mean of 12 days after sample collection. Two patients (18.2%) developed Enterococcus BSI, 4 (36.4%) developed Escherichia coli BSI, and 5 (45.5%) developed other Gammaproteobacteria BSI.
The researchers said that alpha diversity in samples from these patients was significantly lower than alpha diversity from patients who did not develop a BSI, with reduced evenness (Shannon index, Monte Carlo permuted t-test two-sided P value = 0.004) and reduced richness (Observed species, Monte Carlo permuted t-test two-sided P value = 0.001)
The team also noted that, compared to patients who did not develop a BSI, those who did had decreased abundance of Barnesiellaceae, Coriobacteriaceae, Faecalibacterium, Christensenella, Dehalobacterium, Desulfovibrio, and Sutterella.
Using this information, the researchers developed a BSI risk index that could predict the likelihood of a BSI with 90% sensitivity and specificity.
“This method worked even better than we expected because we found a consistent difference between the gut bacteria in those who developed infections and those who did not,” said study author Dan Knights, PhD, of the University of Minnesota in Minneapolis.
“This research is an early demonstration that we may be able to use the bugs in our gut to predict infections and possibly develop new prognostic models in other diseases.”
Still, the researchers said these findings are based on a limited number of patients treated with the same regimen at a single clinic. So the next step for this research is to validate the findings in a much larger cohort including patients with different cancer types, different treatment types, and from multiple treatment centers.
“We still need to determine if these bacteria are playing any kind of causal role in the infections or if they are simply acting as biomarkers for some other predisposing condition in the patient,” Dr Montassier said.
Protein enables expansion of cord blood HSCs
Photo courtesy of NHS
New research suggests an RNA-binding protein can be used to expand hematopoietic stem cells (HSCs) derived from umbilical cord blood.
Investigators found the protein, Musashi-2 (MSI2), regulates the function and development of cord-blood derived HSCs, and overexpressing MSI2 can significantly expand both short-term and long-term repopulating HSCs.
“By expanding the stem cells as we have done, many more donated [cord blood] samples could now be used for transplants,” said Kristin Hope, PhD, of McMaster University in Hamilton, Ontario, Canada.
“Providing enhanced numbers of stem cells for transplantation could alleviate some of the current post-transplantation complications and allow for faster recoveries, in turn, reducing overall healthcare costs and wait times for newly diagnosed patients seeking treatment.”
Dr Hope and her colleagues described this exploration of HSC expansion in Nature.
The team first found that expression of MSI2 messenger RNA was elevated in primitive cord blood hematopoietic stem and progenitor cells (HSPCs), but it decreased during differentiation.
They then found that overexpressing MSI2 enhances the activity of cord blood progenitors in vitro and increases the number of short-term repopulating HSCs in vitro and in vivo.
During in vitro culture, MSI2-overexpressing cells were 2.3-fold more abundant than control cells at 7 days and 6-fold more abundant at 21 days. After 7 days, MSI2-overexpressing cells showed a cumulative 9.3-fold increase in colony-forming cells but no changes in cell cycling or death.
MSI2-overexpressing short-term repopulating cells (STRCs) yielded 1.8-fold more primitive CD34+ cells than control STRCs. And the MSI2-overexpressing STRCs prompted a 17-fold increase in functional STRCs.
Furthermore, 100% of mice transplanted with MSI2-overexpressing STRCs were engrafted at 6.5 weeks, compared to 50% of mice transplanted with control STRCs.
Additional transplant experiments showed that MSI2 overexpression also impacted long-term HSCs (LT-HSCs). Compared to control cells, MSI2-overexpressing cells increased the percentage of GFP+ HSCs in the bone marrow 4.6-fold and the frequency of LT-HSCs 3.5-fold.
The researchers said the increase in LT-HSC frequency corresponded to MSI2-overexpressing GFP+ HSCs having expanded in mice 2.4-fold over input. With control HSCs, on the other hand, there was a 1.5-fold decrease.
In ex vivo culture, MSI2 overexpression induced a cumulative 23-fold expansion of secondary LT-HSCs when compared to control LT-HSCs.
Finally, the researchers performed a global analysis of MSI2–RNA interactions and found that MSI2 mediates HSPC self-renewal and ex vivo expansion by coordinating the post-transcriptional regulation of proteins belonging to a shared self-renewal regulatory pathway.
“We’ve really shone a light on the way these stem cells work,” Dr Hope said. “We now understand how they operate at a completely new level, and that provides us with a serious advantage in determining how to maximize these stem cells in therapeutics. With this newfound ability to control the regeneration of these cells, more people will be able to get the treatment they need.”
Photo courtesy of NHS
New research suggests an RNA-binding protein can be used to expand hematopoietic stem cells (HSCs) derived from umbilical cord blood.
Investigators found the protein, Musashi-2 (MSI2), regulates the function and development of cord-blood derived HSCs, and overexpressing MSI2 can significantly expand both short-term and long-term repopulating HSCs.
“By expanding the stem cells as we have done, many more donated [cord blood] samples could now be used for transplants,” said Kristin Hope, PhD, of McMaster University in Hamilton, Ontario, Canada.
“Providing enhanced numbers of stem cells for transplantation could alleviate some of the current post-transplantation complications and allow for faster recoveries, in turn, reducing overall healthcare costs and wait times for newly diagnosed patients seeking treatment.”
Dr Hope and her colleagues described this exploration of HSC expansion in Nature.
The team first found that expression of MSI2 messenger RNA was elevated in primitive cord blood hematopoietic stem and progenitor cells (HSPCs), but it decreased during differentiation.
They then found that overexpressing MSI2 enhances the activity of cord blood progenitors in vitro and increases the number of short-term repopulating HSCs in vitro and in vivo.
During in vitro culture, MSI2-overexpressing cells were 2.3-fold more abundant than control cells at 7 days and 6-fold more abundant at 21 days. After 7 days, MSI2-overexpressing cells showed a cumulative 9.3-fold increase in colony-forming cells but no changes in cell cycling or death.
MSI2-overexpressing short-term repopulating cells (STRCs) yielded 1.8-fold more primitive CD34+ cells than control STRCs. And the MSI2-overexpressing STRCs prompted a 17-fold increase in functional STRCs.
Furthermore, 100% of mice transplanted with MSI2-overexpressing STRCs were engrafted at 6.5 weeks, compared to 50% of mice transplanted with control STRCs.
Additional transplant experiments showed that MSI2 overexpression also impacted long-term HSCs (LT-HSCs). Compared to control cells, MSI2-overexpressing cells increased the percentage of GFP+ HSCs in the bone marrow 4.6-fold and the frequency of LT-HSCs 3.5-fold.
The researchers said the increase in LT-HSC frequency corresponded to MSI2-overexpressing GFP+ HSCs having expanded in mice 2.4-fold over input. With control HSCs, on the other hand, there was a 1.5-fold decrease.
In ex vivo culture, MSI2 overexpression induced a cumulative 23-fold expansion of secondary LT-HSCs when compared to control LT-HSCs.
Finally, the researchers performed a global analysis of MSI2–RNA interactions and found that MSI2 mediates HSPC self-renewal and ex vivo expansion by coordinating the post-transcriptional regulation of proteins belonging to a shared self-renewal regulatory pathway.
“We’ve really shone a light on the way these stem cells work,” Dr Hope said. “We now understand how they operate at a completely new level, and that provides us with a serious advantage in determining how to maximize these stem cells in therapeutics. With this newfound ability to control the regeneration of these cells, more people will be able to get the treatment they need.”
Photo courtesy of NHS
New research suggests an RNA-binding protein can be used to expand hematopoietic stem cells (HSCs) derived from umbilical cord blood.
Investigators found the protein, Musashi-2 (MSI2), regulates the function and development of cord-blood derived HSCs, and overexpressing MSI2 can significantly expand both short-term and long-term repopulating HSCs.
“By expanding the stem cells as we have done, many more donated [cord blood] samples could now be used for transplants,” said Kristin Hope, PhD, of McMaster University in Hamilton, Ontario, Canada.
“Providing enhanced numbers of stem cells for transplantation could alleviate some of the current post-transplantation complications and allow for faster recoveries, in turn, reducing overall healthcare costs and wait times for newly diagnosed patients seeking treatment.”
Dr Hope and her colleagues described this exploration of HSC expansion in Nature.
The team first found that expression of MSI2 messenger RNA was elevated in primitive cord blood hematopoietic stem and progenitor cells (HSPCs), but it decreased during differentiation.
They then found that overexpressing MSI2 enhances the activity of cord blood progenitors in vitro and increases the number of short-term repopulating HSCs in vitro and in vivo.
During in vitro culture, MSI2-overexpressing cells were 2.3-fold more abundant than control cells at 7 days and 6-fold more abundant at 21 days. After 7 days, MSI2-overexpressing cells showed a cumulative 9.3-fold increase in colony-forming cells but no changes in cell cycling or death.
MSI2-overexpressing short-term repopulating cells (STRCs) yielded 1.8-fold more primitive CD34+ cells than control STRCs. And the MSI2-overexpressing STRCs prompted a 17-fold increase in functional STRCs.
Furthermore, 100% of mice transplanted with MSI2-overexpressing STRCs were engrafted at 6.5 weeks, compared to 50% of mice transplanted with control STRCs.
Additional transplant experiments showed that MSI2 overexpression also impacted long-term HSCs (LT-HSCs). Compared to control cells, MSI2-overexpressing cells increased the percentage of GFP+ HSCs in the bone marrow 4.6-fold and the frequency of LT-HSCs 3.5-fold.
The researchers said the increase in LT-HSC frequency corresponded to MSI2-overexpressing GFP+ HSCs having expanded in mice 2.4-fold over input. With control HSCs, on the other hand, there was a 1.5-fold decrease.
In ex vivo culture, MSI2 overexpression induced a cumulative 23-fold expansion of secondary LT-HSCs when compared to control LT-HSCs.
Finally, the researchers performed a global analysis of MSI2–RNA interactions and found that MSI2 mediates HSPC self-renewal and ex vivo expansion by coordinating the post-transcriptional regulation of proteins belonging to a shared self-renewal regulatory pathway.
“We’ve really shone a light on the way these stem cells work,” Dr Hope said. “We now understand how they operate at a completely new level, and that provides us with a serious advantage in determining how to maximize these stem cells in therapeutics. With this newfound ability to control the regeneration of these cells, more people will be able to get the treatment they need.”
Inflammation has negative effects on HSCs
in the bone marrow
Preclinical research suggests chronic inflammation leads to an imbalanced blood system, which may have an impact on hematopoietic stem cell (HSC) transplant.
The study showed that chronic exposure to an inflammatory “emergency” signal, interleukin-1 (IL-1), has a negative effect on HSCs—restricting differentiation, impairing self-renewal capacity, and priming HSCs to fail massive replicative challenges such as transplantation.
However, these effects proved to be fully reversible.
Eric M. Pietras, PhD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues recounted these findings in Nature Cell Biology.
While HSCs are usually dormant in the bone marrow, Dr Pietras said he and his colleagues showed that, “these cells are also exquisitely sensitive to changes in their environment and react accordingly.”
The team showed that HSCs are sensitive to the amount of IL-1 they encounter. Chronic IL-1 exposure prompts accelerated cell division and pushes HSCs toward myeloid differentiation through activation of the NF-κB pathway and engagement of a PU.1-dependent myeloid gene program.
So HSCs that are overexposed to IL-1 lose their ability to differentiate into lymphoid and erythroid cells.
“[The HSCs are] receiving a signal telling them they need to keep building myeloid cells, and, as a result, they don’t make the other blood cells you need,” Dr Pietras explained.
“You can end up with too few red blood cells, reducing the body’s ability to deliver oxygen to cells. Or we see decreased production of new lymphoid cells, leaving the system potentially immunodeficient. These are all common features of chronically inflamed, and even aged, blood systems.”
Chronic IL-1 exposure also led to decreased self-renewal activity and regenerative potential in HSCs in response to transplantation in mice. Dr Pietras and his colleagues believe these findings may translate to HSC transplant in humans.
“Our results show that not only should we be looking for markers of blood system compatibility [in HSC donors], but we may also want to explore whether a potential donor’s [HSCs] have been exposed to inflammation and may not be as effective at rebuilding the patient’s blood system,” Dr Pietras said.
“Likewise, the presence of inflammation in the individual receiving the [HSC transplant] could also be an important factor in how well the stem cells regenerate a new blood system once they are transplanted.”
Fortunately, Dr Pietras and his colleagues found the damaging effects of chronic IL-1 exposure could be reversed upon IL-1 withdrawal.
To test the durability of IL-1’s effects, the researchers treated mice with IL-1 for 20 days and then stopped for several weeks to see if the HSCs recovered.
“Our data suggest that it is possible to turn back the clock and reverse the effects of chronic inflammation on [HSCs], perhaps using therapies already available in the clinic to block inflammatory signals such as IL-1,” Dr Pietras said.
“Of course, we don’t yet know, on a human scale, how long it takes a stem cell to ‘remember’ these insults. It may be that, after a longer period of exposure to IL-1, these changes become more fixed.”
in the bone marrow
Preclinical research suggests chronic inflammation leads to an imbalanced blood system, which may have an impact on hematopoietic stem cell (HSC) transplant.
The study showed that chronic exposure to an inflammatory “emergency” signal, interleukin-1 (IL-1), has a negative effect on HSCs—restricting differentiation, impairing self-renewal capacity, and priming HSCs to fail massive replicative challenges such as transplantation.
However, these effects proved to be fully reversible.
Eric M. Pietras, PhD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues recounted these findings in Nature Cell Biology.
While HSCs are usually dormant in the bone marrow, Dr Pietras said he and his colleagues showed that, “these cells are also exquisitely sensitive to changes in their environment and react accordingly.”
The team showed that HSCs are sensitive to the amount of IL-1 they encounter. Chronic IL-1 exposure prompts accelerated cell division and pushes HSCs toward myeloid differentiation through activation of the NF-κB pathway and engagement of a PU.1-dependent myeloid gene program.
So HSCs that are overexposed to IL-1 lose their ability to differentiate into lymphoid and erythroid cells.
“[The HSCs are] receiving a signal telling them they need to keep building myeloid cells, and, as a result, they don’t make the other blood cells you need,” Dr Pietras explained.
“You can end up with too few red blood cells, reducing the body’s ability to deliver oxygen to cells. Or we see decreased production of new lymphoid cells, leaving the system potentially immunodeficient. These are all common features of chronically inflamed, and even aged, blood systems.”
Chronic IL-1 exposure also led to decreased self-renewal activity and regenerative potential in HSCs in response to transplantation in mice. Dr Pietras and his colleagues believe these findings may translate to HSC transplant in humans.
“Our results show that not only should we be looking for markers of blood system compatibility [in HSC donors], but we may also want to explore whether a potential donor’s [HSCs] have been exposed to inflammation and may not be as effective at rebuilding the patient’s blood system,” Dr Pietras said.
“Likewise, the presence of inflammation in the individual receiving the [HSC transplant] could also be an important factor in how well the stem cells regenerate a new blood system once they are transplanted.”
Fortunately, Dr Pietras and his colleagues found the damaging effects of chronic IL-1 exposure could be reversed upon IL-1 withdrawal.
To test the durability of IL-1’s effects, the researchers treated mice with IL-1 for 20 days and then stopped for several weeks to see if the HSCs recovered.
“Our data suggest that it is possible to turn back the clock and reverse the effects of chronic inflammation on [HSCs], perhaps using therapies already available in the clinic to block inflammatory signals such as IL-1,” Dr Pietras said.
“Of course, we don’t yet know, on a human scale, how long it takes a stem cell to ‘remember’ these insults. It may be that, after a longer period of exposure to IL-1, these changes become more fixed.”
in the bone marrow
Preclinical research suggests chronic inflammation leads to an imbalanced blood system, which may have an impact on hematopoietic stem cell (HSC) transplant.
The study showed that chronic exposure to an inflammatory “emergency” signal, interleukin-1 (IL-1), has a negative effect on HSCs—restricting differentiation, impairing self-renewal capacity, and priming HSCs to fail massive replicative challenges such as transplantation.
However, these effects proved to be fully reversible.
Eric M. Pietras, PhD, of the University of Colorado Anschutz Medical Campus in Aurora, and his colleagues recounted these findings in Nature Cell Biology.
While HSCs are usually dormant in the bone marrow, Dr Pietras said he and his colleagues showed that, “these cells are also exquisitely sensitive to changes in their environment and react accordingly.”
The team showed that HSCs are sensitive to the amount of IL-1 they encounter. Chronic IL-1 exposure prompts accelerated cell division and pushes HSCs toward myeloid differentiation through activation of the NF-κB pathway and engagement of a PU.1-dependent myeloid gene program.
So HSCs that are overexposed to IL-1 lose their ability to differentiate into lymphoid and erythroid cells.
“[The HSCs are] receiving a signal telling them they need to keep building myeloid cells, and, as a result, they don’t make the other blood cells you need,” Dr Pietras explained.
“You can end up with too few red blood cells, reducing the body’s ability to deliver oxygen to cells. Or we see decreased production of new lymphoid cells, leaving the system potentially immunodeficient. These are all common features of chronically inflamed, and even aged, blood systems.”
Chronic IL-1 exposure also led to decreased self-renewal activity and regenerative potential in HSCs in response to transplantation in mice. Dr Pietras and his colleagues believe these findings may translate to HSC transplant in humans.
“Our results show that not only should we be looking for markers of blood system compatibility [in HSC donors], but we may also want to explore whether a potential donor’s [HSCs] have been exposed to inflammation and may not be as effective at rebuilding the patient’s blood system,” Dr Pietras said.
“Likewise, the presence of inflammation in the individual receiving the [HSC transplant] could also be an important factor in how well the stem cells regenerate a new blood system once they are transplanted.”
Fortunately, Dr Pietras and his colleagues found the damaging effects of chronic IL-1 exposure could be reversed upon IL-1 withdrawal.
To test the durability of IL-1’s effects, the researchers treated mice with IL-1 for 20 days and then stopped for several weeks to see if the HSCs recovered.
“Our data suggest that it is possible to turn back the clock and reverse the effects of chronic inflammation on [HSCs], perhaps using therapies already available in the clinic to block inflammatory signals such as IL-1,” Dr Pietras said.
“Of course, we don’t yet know, on a human scale, how long it takes a stem cell to ‘remember’ these insults. It may be that, after a longer period of exposure to IL-1, these changes become more fixed.”
Low risk of complications with well-managed warfarin
Photo courtesy of NIGMS
Results of a retrospective study suggest that well-managed warfarin therapy confers a low risk of complications in patients with non-valvular atrial fibrillation (NVAF).
However, certain patients require close monitoring, including those with renal failure, those taking aspirin concomitantly, and those with an individual time in therapeutic range (iTTR) less than 70% or high international normalized ratio (INR) variability.
Fredrik Björck, MD, of Umea University in Umea, Sweden, and his colleagues conducted this research and reported the results in JAMA Cardiology.
The researchers noted that warfarin has been compared to non-vitamin K antagonist oral anticoagulants for stroke prevention in NVAF, but these studies were based on comparisons with warfarin arms that had TTRs of 55.2% to 64.9%, which makes the results less credible in healthcare systems with higher TTRs.
So the team wanted to evaluate the efficacy and safety of well-managed warfarin therapy in patients with NVAF. They analyzed data from Swedish registries to identify 40,449 patients who were starting warfarin due to NVAF.
The patients’ mean age was 72.5, 40% (n=16,201) were women, and their mean CHA2DS2-VASc score at baseline was 3.3. They were monitored until they stopped treatment, died, or the study ended.
Overall results
The annual incidence of all-cause mortality was 2.19%. The annual incidence of any major bleeding was 2.23%—0.76% gastrointestinal, 0.44% intracranial, and 1.23% other bleeding.
The annual incidence of any thromboembolism was 2.95%—1.73% arterial thromboembolism, 1.23% myocardial infarction, and 0.13% venous thromboembolism.
Aspirin and intracranial bleeding
When compared to patients who were only taking warfarin, those who were also taking aspirin had significantly higher rates of any major bleeding (2.04% vs 3.07%), gastrointestinal bleeding (0.67% vs 1.18%), and other major bleeding (1.13% vs 1.67%).
But there was no significant difference in intracranial bleeding (0.41% vs 0.62%).
Overall, patients had an increased risk of intracranial bleeding if they had renal failure (hazard ratio [HR]=2.25, P=0.003), stroke (HR=1.58, P=0.002), or hypertension (HR=1.37, P=0.03).
In addition, the risk of intracranial bleeding increased significantly with age (HR=1.03, P=0.002), and women had a lower risk than men (HR=0.71, P=0.01).
INR and iTTR
Patients with an iTTR of less than 70% had a significantly higher incidence of treatment complications than patients with an iTTR of 70% or greater.
This includes all-cause mortality (4.35% vs 1.29%), any major bleeding (3.81% vs 1.61%), intracranial bleeding (0.72% vs 0.34%), gastrointestinal bleeding (1.26% vs 0.56%), other bleeding (2.17% vs 0.84), any thromboembolism (4.41% vs 2.37%), arterial thromboembolism (2.52% vs 1.41%), myocardial infarction (1.90% vs 0.98%), and venous thromboembolism (0.24% vs 0.09%).
Similarly, patients with high INR variability had a significantly higher incidence of nearly all events when compared to patients with low INR variability (below the mean value of 0.83).
This includes all-cause mortality (2.94% vs 1.50%), any major bleeding (3.04% vs 1.47%), gastrointestinal bleeding (1.05% vs 0.50%), other bleeding (1.79% vs 0.71), any thromboembolism (3.48% vs 2.46%), arterial thromboembolism (1.98% vs 1.51%), and myocardial infarction (1.53% vs 0.96%).
The exceptions were intracranial bleeding (0.51% vs 0.38%) and venous thromboembolism (0.16% vs 0.11%).
For patients with an iTTR of 70% or greater, there was no significant difference in the cumulative incidence of complications when comparing groups according to INR variability.
Photo courtesy of NIGMS
Results of a retrospective study suggest that well-managed warfarin therapy confers a low risk of complications in patients with non-valvular atrial fibrillation (NVAF).
However, certain patients require close monitoring, including those with renal failure, those taking aspirin concomitantly, and those with an individual time in therapeutic range (iTTR) less than 70% or high international normalized ratio (INR) variability.
Fredrik Björck, MD, of Umea University in Umea, Sweden, and his colleagues conducted this research and reported the results in JAMA Cardiology.
The researchers noted that warfarin has been compared to non-vitamin K antagonist oral anticoagulants for stroke prevention in NVAF, but these studies were based on comparisons with warfarin arms that had TTRs of 55.2% to 64.9%, which makes the results less credible in healthcare systems with higher TTRs.
So the team wanted to evaluate the efficacy and safety of well-managed warfarin therapy in patients with NVAF. They analyzed data from Swedish registries to identify 40,449 patients who were starting warfarin due to NVAF.
The patients’ mean age was 72.5, 40% (n=16,201) were women, and their mean CHA2DS2-VASc score at baseline was 3.3. They were monitored until they stopped treatment, died, or the study ended.
Overall results
The annual incidence of all-cause mortality was 2.19%. The annual incidence of any major bleeding was 2.23%—0.76% gastrointestinal, 0.44% intracranial, and 1.23% other bleeding.
The annual incidence of any thromboembolism was 2.95%—1.73% arterial thromboembolism, 1.23% myocardial infarction, and 0.13% venous thromboembolism.
Aspirin and intracranial bleeding
When compared to patients who were only taking warfarin, those who were also taking aspirin had significantly higher rates of any major bleeding (2.04% vs 3.07%), gastrointestinal bleeding (0.67% vs 1.18%), and other major bleeding (1.13% vs 1.67%).
But there was no significant difference in intracranial bleeding (0.41% vs 0.62%).
Overall, patients had an increased risk of intracranial bleeding if they had renal failure (hazard ratio [HR]=2.25, P=0.003), stroke (HR=1.58, P=0.002), or hypertension (HR=1.37, P=0.03).
In addition, the risk of intracranial bleeding increased significantly with age (HR=1.03, P=0.002), and women had a lower risk than men (HR=0.71, P=0.01).
INR and iTTR
Patients with an iTTR of less than 70% had a significantly higher incidence of treatment complications than patients with an iTTR of 70% or greater.
This includes all-cause mortality (4.35% vs 1.29%), any major bleeding (3.81% vs 1.61%), intracranial bleeding (0.72% vs 0.34%), gastrointestinal bleeding (1.26% vs 0.56%), other bleeding (2.17% vs 0.84), any thromboembolism (4.41% vs 2.37%), arterial thromboembolism (2.52% vs 1.41%), myocardial infarction (1.90% vs 0.98%), and venous thromboembolism (0.24% vs 0.09%).
Similarly, patients with high INR variability had a significantly higher incidence of nearly all events when compared to patients with low INR variability (below the mean value of 0.83).
This includes all-cause mortality (2.94% vs 1.50%), any major bleeding (3.04% vs 1.47%), gastrointestinal bleeding (1.05% vs 0.50%), other bleeding (1.79% vs 0.71), any thromboembolism (3.48% vs 2.46%), arterial thromboembolism (1.98% vs 1.51%), and myocardial infarction (1.53% vs 0.96%).
The exceptions were intracranial bleeding (0.51% vs 0.38%) and venous thromboembolism (0.16% vs 0.11%).
For patients with an iTTR of 70% or greater, there was no significant difference in the cumulative incidence of complications when comparing groups according to INR variability.
Photo courtesy of NIGMS
Results of a retrospective study suggest that well-managed warfarin therapy confers a low risk of complications in patients with non-valvular atrial fibrillation (NVAF).
However, certain patients require close monitoring, including those with renal failure, those taking aspirin concomitantly, and those with an individual time in therapeutic range (iTTR) less than 70% or high international normalized ratio (INR) variability.
Fredrik Björck, MD, of Umea University in Umea, Sweden, and his colleagues conducted this research and reported the results in JAMA Cardiology.
The researchers noted that warfarin has been compared to non-vitamin K antagonist oral anticoagulants for stroke prevention in NVAF, but these studies were based on comparisons with warfarin arms that had TTRs of 55.2% to 64.9%, which makes the results less credible in healthcare systems with higher TTRs.
So the team wanted to evaluate the efficacy and safety of well-managed warfarin therapy in patients with NVAF. They analyzed data from Swedish registries to identify 40,449 patients who were starting warfarin due to NVAF.
The patients’ mean age was 72.5, 40% (n=16,201) were women, and their mean CHA2DS2-VASc score at baseline was 3.3. They were monitored until they stopped treatment, died, or the study ended.
Overall results
The annual incidence of all-cause mortality was 2.19%. The annual incidence of any major bleeding was 2.23%—0.76% gastrointestinal, 0.44% intracranial, and 1.23% other bleeding.
The annual incidence of any thromboembolism was 2.95%—1.73% arterial thromboembolism, 1.23% myocardial infarction, and 0.13% venous thromboembolism.
Aspirin and intracranial bleeding
When compared to patients who were only taking warfarin, those who were also taking aspirin had significantly higher rates of any major bleeding (2.04% vs 3.07%), gastrointestinal bleeding (0.67% vs 1.18%), and other major bleeding (1.13% vs 1.67%).
But there was no significant difference in intracranial bleeding (0.41% vs 0.62%).
Overall, patients had an increased risk of intracranial bleeding if they had renal failure (hazard ratio [HR]=2.25, P=0.003), stroke (HR=1.58, P=0.002), or hypertension (HR=1.37, P=0.03).
In addition, the risk of intracranial bleeding increased significantly with age (HR=1.03, P=0.002), and women had a lower risk than men (HR=0.71, P=0.01).
INR and iTTR
Patients with an iTTR of less than 70% had a significantly higher incidence of treatment complications than patients with an iTTR of 70% or greater.
This includes all-cause mortality (4.35% vs 1.29%), any major bleeding (3.81% vs 1.61%), intracranial bleeding (0.72% vs 0.34%), gastrointestinal bleeding (1.26% vs 0.56%), other bleeding (2.17% vs 0.84), any thromboembolism (4.41% vs 2.37%), arterial thromboembolism (2.52% vs 1.41%), myocardial infarction (1.90% vs 0.98%), and venous thromboembolism (0.24% vs 0.09%).
Similarly, patients with high INR variability had a significantly higher incidence of nearly all events when compared to patients with low INR variability (below the mean value of 0.83).
This includes all-cause mortality (2.94% vs 1.50%), any major bleeding (3.04% vs 1.47%), gastrointestinal bleeding (1.05% vs 0.50%), other bleeding (1.79% vs 0.71), any thromboembolism (3.48% vs 2.46%), arterial thromboembolism (1.98% vs 1.51%), and myocardial infarction (1.53% vs 0.96%).
The exceptions were intracranial bleeding (0.51% vs 0.38%) and venous thromboembolism (0.16% vs 0.11%).
For patients with an iTTR of 70% or greater, there was no significant difference in the cumulative incidence of complications when comparing groups according to INR variability.