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Combo may overcome drug resistance in ALL
Credit: Linda Bartlett
Adding the alkylating agent cyclophosphamide to treatment with a monoclonal antibody (mAb) can overcome drug resistance in mice with acute lymphoblastic leukemia (ALL), researchers have reported in Cell.
mAbs such as rituximab and alemtuzumab are designed to bind to proteins found on the surfaces of tumor cells.
Once the mAbs flag the tumor cells, macrophages destroy them. But the drugs have little effect on tumor cells that hide out in the bone marrow.
Experiments in mice with B-cell ALL revealed that cyclophosphamide stimulates the immune response in bone marrow, eliminating the reservoir of cancer cells that can produce new tumors after treatment with a mAb.
Finding hidden ALL cells
Michael Hemann, PhD, of MIT’s Koch Institute for Integrative Cancer Research in Cambridge, Massachusetts, and his colleagues began this research by administering alemtuzumab to the mice.
The drug successfully cleared most ALL cells, but some remained hidden in the bone marrow, which has been identified as a site of drug resistance in many cancers.
The researchers found that, within the bone marrow, alemtuzumab successfully binds to ALL cells. But macrophages do not attack the cells due to the presence of lipid compounds called prostaglandins, which repress macrophage activity.
Scientists believe the bone marrow naturally produces prostaglandins to help protect the immune cells maturing there. Tumor cells that reach the bone marrow can exploit this protective environment to aid their own survival.
The finding is an important contribution to scientists’ understanding of how mAbs act against ALL, according to Ravi Majeti, MD, PhD, of Stanford University in California, who was not involved in this research.
“There clearly has been a lack of understanding about why antibody therapies have been relatively unsuccessful as monotherapies,” Dr Majeti said.
Tricking the immune system
Dr Hemann and his colleagues then tested a variety of anticancer drugs in combination with alemtuzumab. And they discovered that cyclophosphamide can “rewire” the bone marrow microenvironment to make it much more receptive to macrophages, allowing them to destroy the tumor cells hiding there.
“After you treat with cyclophosphamide, you get this flux of macrophages into the bone marrow, and these macrophages are now active and very capable of consuming the targeted tumor cells,” Dr Hemann said.
“Essentially, we are tricking the immune system to suddenly recognize an entity that it wouldn’t typically recognize and aggressively go after antibody-bound tumor cells.”
Following treatment with this combination, the mice survived and remained free of ALL for the duration of the study, which was about 18 months.
However, the researchers found that timing of drug delivery was critical. Alemtuzumab and cyclophosphamide must be administered together so that cyclophosphamide can create the right type of environment for macrophages to become activated in the bone marrow.
The team also obtained good results by combining cyclophosphamide with rituximab.
They now plan to test cyclophosphamide with other mAbs and begin testing the alemtuzumab-cyclophosphamide combination in patients. 
Credit: Linda Bartlett
Adding the alkylating agent cyclophosphamide to treatment with a monoclonal antibody (mAb) can overcome drug resistance in mice with acute lymphoblastic leukemia (ALL), researchers have reported in Cell.
mAbs such as rituximab and alemtuzumab are designed to bind to proteins found on the surfaces of tumor cells.
Once the mAbs flag the tumor cells, macrophages destroy them. But the drugs have little effect on tumor cells that hide out in the bone marrow.
Experiments in mice with B-cell ALL revealed that cyclophosphamide stimulates the immune response in bone marrow, eliminating the reservoir of cancer cells that can produce new tumors after treatment with a mAb.
Finding hidden ALL cells
Michael Hemann, PhD, of MIT’s Koch Institute for Integrative Cancer Research in Cambridge, Massachusetts, and his colleagues began this research by administering alemtuzumab to the mice.
The drug successfully cleared most ALL cells, but some remained hidden in the bone marrow, which has been identified as a site of drug resistance in many cancers.
The researchers found that, within the bone marrow, alemtuzumab successfully binds to ALL cells. But macrophages do not attack the cells due to the presence of lipid compounds called prostaglandins, which repress macrophage activity.
Scientists believe the bone marrow naturally produces prostaglandins to help protect the immune cells maturing there. Tumor cells that reach the bone marrow can exploit this protective environment to aid their own survival.
The finding is an important contribution to scientists’ understanding of how mAbs act against ALL, according to Ravi Majeti, MD, PhD, of Stanford University in California, who was not involved in this research.
“There clearly has been a lack of understanding about why antibody therapies have been relatively unsuccessful as monotherapies,” Dr Majeti said.
Tricking the immune system
Dr Hemann and his colleagues then tested a variety of anticancer drugs in combination with alemtuzumab. And they discovered that cyclophosphamide can “rewire” the bone marrow microenvironment to make it much more receptive to macrophages, allowing them to destroy the tumor cells hiding there.
“After you treat with cyclophosphamide, you get this flux of macrophages into the bone marrow, and these macrophages are now active and very capable of consuming the targeted tumor cells,” Dr Hemann said.
“Essentially, we are tricking the immune system to suddenly recognize an entity that it wouldn’t typically recognize and aggressively go after antibody-bound tumor cells.”
Following treatment with this combination, the mice survived and remained free of ALL for the duration of the study, which was about 18 months.
However, the researchers found that timing of drug delivery was critical. Alemtuzumab and cyclophosphamide must be administered together so that cyclophosphamide can create the right type of environment for macrophages to become activated in the bone marrow.
The team also obtained good results by combining cyclophosphamide with rituximab.
They now plan to test cyclophosphamide with other mAbs and begin testing the alemtuzumab-cyclophosphamide combination in patients.
Credit: Linda Bartlett
Adding the alkylating agent cyclophosphamide to treatment with a monoclonal antibody (mAb) can overcome drug resistance in mice with acute lymphoblastic leukemia (ALL), researchers have reported in Cell.
mAbs such as rituximab and alemtuzumab are designed to bind to proteins found on the surfaces of tumor cells.
Once the mAbs flag the tumor cells, macrophages destroy them. But the drugs have little effect on tumor cells that hide out in the bone marrow.
Experiments in mice with B-cell ALL revealed that cyclophosphamide stimulates the immune response in bone marrow, eliminating the reservoir of cancer cells that can produce new tumors after treatment with a mAb.
Finding hidden ALL cells
Michael Hemann, PhD, of MIT’s Koch Institute for Integrative Cancer Research in Cambridge, Massachusetts, and his colleagues began this research by administering alemtuzumab to the mice.
The drug successfully cleared most ALL cells, but some remained hidden in the bone marrow, which has been identified as a site of drug resistance in many cancers.
The researchers found that, within the bone marrow, alemtuzumab successfully binds to ALL cells. But macrophages do not attack the cells due to the presence of lipid compounds called prostaglandins, which repress macrophage activity.
Scientists believe the bone marrow naturally produces prostaglandins to help protect the immune cells maturing there. Tumor cells that reach the bone marrow can exploit this protective environment to aid their own survival.
The finding is an important contribution to scientists’ understanding of how mAbs act against ALL, according to Ravi Majeti, MD, PhD, of Stanford University in California, who was not involved in this research.
“There clearly has been a lack of understanding about why antibody therapies have been relatively unsuccessful as monotherapies,” Dr Majeti said.
Tricking the immune system
Dr Hemann and his colleagues then tested a variety of anticancer drugs in combination with alemtuzumab. And they discovered that cyclophosphamide can “rewire” the bone marrow microenvironment to make it much more receptive to macrophages, allowing them to destroy the tumor cells hiding there.
“After you treat with cyclophosphamide, you get this flux of macrophages into the bone marrow, and these macrophages are now active and very capable of consuming the targeted tumor cells,” Dr Hemann said.
“Essentially, we are tricking the immune system to suddenly recognize an entity that it wouldn’t typically recognize and aggressively go after antibody-bound tumor cells.”
Following treatment with this combination, the mice survived and remained free of ALL for the duration of the study, which was about 18 months.
However, the researchers found that timing of drug delivery was critical. Alemtuzumab and cyclophosphamide must be administered together so that cyclophosphamide can create the right type of environment for macrophages to become activated in the bone marrow.
The team also obtained good results by combining cyclophosphamide with rituximab.
They now plan to test cyclophosphamide with other mAbs and begin testing the alemtuzumab-cyclophosphamide combination in patients.
Experts offer guidance for preventing drug shortages
with chemotherapy drugs
Credit: Bill Branson
A group of healthcare experts has created a “blueprint” for managing and preventing drug shortages.
They devised 6 recommendations for preempting shortages of pediatric oncology drugs, but the suggestions can be applied to other drugs as well.
Some of the recommendations would represent new norms for healthcare practice, such as sharing scarce drugs among healthcare institutions and not giving preferential access to patients participating in clinical trials.
The suggestions appear in a consensus statement published in Pediatrics.
“Although our recommendations were developed with pediatric oncology in mind, and serve as a blueprint for preventing children with cancer from lacking access to essential life-saving medications, we believe that they apply more broadly across medicine to include pediatrics and adult medicine in general,” said statement author Yoram Unguru, MD, of the Johns Hopkins Berman Institute of Bioethics in Baltimore, Maryland.
He and his coauthors developed the following recommendations:
- Support national polices—and develop new measures—to prevent drug shortages
- Use drug supplies efficiently to reduce the likelihood of shortages
- Give equal priority to evidence-based uses of drugs, whether they occur within or outside clinical trials
- Develop an improved clearinghouse for sharing drug shortage information
- Explore the sharing of drug supplies among institutions
- Develop strategies to engage stakeholders in the management of drug shortages.
For each recommendation, the authors included potential barriers to its implementation. A centralized information source of drug supply information, for instance, comes with the risk that such information will encourage hoarding of existing supplies. This includes “gray market” suppliers that sell scarce drugs for inflated prices.
The authors also pointed to the marketplace economy as an obstacle to implementing their recommendations and preventing drug shortages. Drug manufacturers do not like to disclose manufacturing problems that lead to shortages, nor are competitive healthcare institutions accustomed to cooperating to share resources.
Nonetheless, the authors called for an exploration of “ways to facilitate inter-institutional and inter-state transfer of drugs, especially during shortages,” as well as the ethical obligation to patients inside vs outside a healthcare institution when there is a drug shortage.
“The reasons for drug shortages are complex, but we must not lose sight of the fact that, without access to these life-saving drugs, children and adults with cancer will almost certainly die,” Dr Unguru said. “It is untenable for this situation to continue any longer. We have a clear moral obligation to act to address this critical issue.”
with chemotherapy drugs
Credit: Bill Branson
A group of healthcare experts has created a “blueprint” for managing and preventing drug shortages.
They devised 6 recommendations for preempting shortages of pediatric oncology drugs, but the suggestions can be applied to other drugs as well.
Some of the recommendations would represent new norms for healthcare practice, such as sharing scarce drugs among healthcare institutions and not giving preferential access to patients participating in clinical trials.
The suggestions appear in a consensus statement published in Pediatrics.
“Although our recommendations were developed with pediatric oncology in mind, and serve as a blueprint for preventing children with cancer from lacking access to essential life-saving medications, we believe that they apply more broadly across medicine to include pediatrics and adult medicine in general,” said statement author Yoram Unguru, MD, of the Johns Hopkins Berman Institute of Bioethics in Baltimore, Maryland.
He and his coauthors developed the following recommendations:
- Support national polices—and develop new measures—to prevent drug shortages
- Use drug supplies efficiently to reduce the likelihood of shortages
- Give equal priority to evidence-based uses of drugs, whether they occur within or outside clinical trials
- Develop an improved clearinghouse for sharing drug shortage information
- Explore the sharing of drug supplies among institutions
- Develop strategies to engage stakeholders in the management of drug shortages.
For each recommendation, the authors included potential barriers to its implementation. A centralized information source of drug supply information, for instance, comes with the risk that such information will encourage hoarding of existing supplies. This includes “gray market” suppliers that sell scarce drugs for inflated prices.
The authors also pointed to the marketplace economy as an obstacle to implementing their recommendations and preventing drug shortages. Drug manufacturers do not like to disclose manufacturing problems that lead to shortages, nor are competitive healthcare institutions accustomed to cooperating to share resources.
Nonetheless, the authors called for an exploration of “ways to facilitate inter-institutional and inter-state transfer of drugs, especially during shortages,” as well as the ethical obligation to patients inside vs outside a healthcare institution when there is a drug shortage.
“The reasons for drug shortages are complex, but we must not lose sight of the fact that, without access to these life-saving drugs, children and adults with cancer will almost certainly die,” Dr Unguru said. “It is untenable for this situation to continue any longer. We have a clear moral obligation to act to address this critical issue.”
with chemotherapy drugs
Credit: Bill Branson
A group of healthcare experts has created a “blueprint” for managing and preventing drug shortages.
They devised 6 recommendations for preempting shortages of pediatric oncology drugs, but the suggestions can be applied to other drugs as well.
Some of the recommendations would represent new norms for healthcare practice, such as sharing scarce drugs among healthcare institutions and not giving preferential access to patients participating in clinical trials.
The suggestions appear in a consensus statement published in Pediatrics.
“Although our recommendations were developed with pediatric oncology in mind, and serve as a blueprint for preventing children with cancer from lacking access to essential life-saving medications, we believe that they apply more broadly across medicine to include pediatrics and adult medicine in general,” said statement author Yoram Unguru, MD, of the Johns Hopkins Berman Institute of Bioethics in Baltimore, Maryland.
He and his coauthors developed the following recommendations:
- Support national polices—and develop new measures—to prevent drug shortages
- Use drug supplies efficiently to reduce the likelihood of shortages
- Give equal priority to evidence-based uses of drugs, whether they occur within or outside clinical trials
- Develop an improved clearinghouse for sharing drug shortage information
- Explore the sharing of drug supplies among institutions
- Develop strategies to engage stakeholders in the management of drug shortages.
For each recommendation, the authors included potential barriers to its implementation. A centralized information source of drug supply information, for instance, comes with the risk that such information will encourage hoarding of existing supplies. This includes “gray market” suppliers that sell scarce drugs for inflated prices.
The authors also pointed to the marketplace economy as an obstacle to implementing their recommendations and preventing drug shortages. Drug manufacturers do not like to disclose manufacturing problems that lead to shortages, nor are competitive healthcare institutions accustomed to cooperating to share resources.
Nonetheless, the authors called for an exploration of “ways to facilitate inter-institutional and inter-state transfer of drugs, especially during shortages,” as well as the ethical obligation to patients inside vs outside a healthcare institution when there is a drug shortage.
“The reasons for drug shortages are complex, but we must not lose sight of the fact that, without access to these life-saving drugs, children and adults with cancer will almost certainly die,” Dr Unguru said. “It is untenable for this situation to continue any longer. We have a clear moral obligation to act to address this critical issue.”
Antibody prevents thrombosis in rabbits
oxygenator membranes
Credit: Kjell Hultenby
A newly developed antibody can prevent thrombosis without increasing the risk of bleeding in rabbits, according to research published in Science Translational Medicine.
The antibody, called 3F7, works by blocking a protein that’s active in the coagulation system factor XII (FXII).
Scientists have long known that humans deficient in FXII do not bleed excessively.
And in 2005, Thomas Renné, MD, PhD, of the Karolinska Institutet in Stockholm, Sweden, and his colleagues discovered that mice lacking FXII could have neither a stroke nor a pulmonary embolism, even though they had normal bleeding patterns.
“Since then, our goal has been to find an effective way to block FXII,” Dr Renné said. “Now, we have developed an antibody that blocks FXII in human blood, mice, and rabbits. This provides protection against thrombosis without increasing the risk of bleeding.”
The researchers tested 3F7 in rabbits during extracorporeal membrane oxygenation (ECMO) treatment. ECMO is an advanced heart-lung machine used in life-threatening conditions, but contact with the plastic tubing causes the blood to clot.
The incidence of thrombosis in rabbits on ECMO receiving 3F7 was as low as in rabbits receiving heparin. There were significantly fewer fibrin clots in the oxygenators of 3F7-treated rabbits and heparin-treated rabbits than in saline-treated controls—4 ± 3%, 8 ± 6%, and 100 ± 19%, respectively.
However, bleeding was more severe in the heparin-treated rabbits than in 3F7-treated rabbits and controls. Incision-provoked skin bleeding time was more than 600 seconds in the heparin group, 160 ± 40 s in the 3F7 group, and 130 ± 15 s in controls.
Cuticle bleeding time was more than 600 s in the heparin group, 165 ± 40 s in the 3F7 group, and 120 ± 30 s in controls. The mean blood loss from cuticle wounds was 5.1 ± 1.1 mL/10 min, 0.3 ± 0.1 mL/10 min, and 0.2 ± 0.05 mL/10 min, respectively.
“Blocking FXII appears to be an effective strategy against thrombus formation, and we have shown this in experiments on rabbits in a clinically relevant context,” Dr Renné said in conclusion.
“We plan to test the antibody in a phase 1 study. It is possible that the antibody also blocks inflammation mediated by FXII, an interesting area for future studies.”
oxygenator membranes
Credit: Kjell Hultenby
A newly developed antibody can prevent thrombosis without increasing the risk of bleeding in rabbits, according to research published in Science Translational Medicine.
The antibody, called 3F7, works by blocking a protein that’s active in the coagulation system factor XII (FXII).
Scientists have long known that humans deficient in FXII do not bleed excessively.
And in 2005, Thomas Renné, MD, PhD, of the Karolinska Institutet in Stockholm, Sweden, and his colleagues discovered that mice lacking FXII could have neither a stroke nor a pulmonary embolism, even though they had normal bleeding patterns.
“Since then, our goal has been to find an effective way to block FXII,” Dr Renné said. “Now, we have developed an antibody that blocks FXII in human blood, mice, and rabbits. This provides protection against thrombosis without increasing the risk of bleeding.”
The researchers tested 3F7 in rabbits during extracorporeal membrane oxygenation (ECMO) treatment. ECMO is an advanced heart-lung machine used in life-threatening conditions, but contact with the plastic tubing causes the blood to clot.
The incidence of thrombosis in rabbits on ECMO receiving 3F7 was as low as in rabbits receiving heparin. There were significantly fewer fibrin clots in the oxygenators of 3F7-treated rabbits and heparin-treated rabbits than in saline-treated controls—4 ± 3%, 8 ± 6%, and 100 ± 19%, respectively.
However, bleeding was more severe in the heparin-treated rabbits than in 3F7-treated rabbits and controls. Incision-provoked skin bleeding time was more than 600 seconds in the heparin group, 160 ± 40 s in the 3F7 group, and 130 ± 15 s in controls.
Cuticle bleeding time was more than 600 s in the heparin group, 165 ± 40 s in the 3F7 group, and 120 ± 30 s in controls. The mean blood loss from cuticle wounds was 5.1 ± 1.1 mL/10 min, 0.3 ± 0.1 mL/10 min, and 0.2 ± 0.05 mL/10 min, respectively.
“Blocking FXII appears to be an effective strategy against thrombus formation, and we have shown this in experiments on rabbits in a clinically relevant context,” Dr Renné said in conclusion.
“We plan to test the antibody in a phase 1 study. It is possible that the antibody also blocks inflammation mediated by FXII, an interesting area for future studies.”
oxygenator membranes
Credit: Kjell Hultenby
A newly developed antibody can prevent thrombosis without increasing the risk of bleeding in rabbits, according to research published in Science Translational Medicine.
The antibody, called 3F7, works by blocking a protein that’s active in the coagulation system factor XII (FXII).
Scientists have long known that humans deficient in FXII do not bleed excessively.
And in 2005, Thomas Renné, MD, PhD, of the Karolinska Institutet in Stockholm, Sweden, and his colleagues discovered that mice lacking FXII could have neither a stroke nor a pulmonary embolism, even though they had normal bleeding patterns.
“Since then, our goal has been to find an effective way to block FXII,” Dr Renné said. “Now, we have developed an antibody that blocks FXII in human blood, mice, and rabbits. This provides protection against thrombosis without increasing the risk of bleeding.”
The researchers tested 3F7 in rabbits during extracorporeal membrane oxygenation (ECMO) treatment. ECMO is an advanced heart-lung machine used in life-threatening conditions, but contact with the plastic tubing causes the blood to clot.
The incidence of thrombosis in rabbits on ECMO receiving 3F7 was as low as in rabbits receiving heparin. There were significantly fewer fibrin clots in the oxygenators of 3F7-treated rabbits and heparin-treated rabbits than in saline-treated controls—4 ± 3%, 8 ± 6%, and 100 ± 19%, respectively.
However, bleeding was more severe in the heparin-treated rabbits than in 3F7-treated rabbits and controls. Incision-provoked skin bleeding time was more than 600 seconds in the heparin group, 160 ± 40 s in the 3F7 group, and 130 ± 15 s in controls.
Cuticle bleeding time was more than 600 s in the heparin group, 165 ± 40 s in the 3F7 group, and 120 ± 30 s in controls. The mean blood loss from cuticle wounds was 5.1 ± 1.1 mL/10 min, 0.3 ± 0.1 mL/10 min, and 0.2 ± 0.05 mL/10 min, respectively.
“Blocking FXII appears to be an effective strategy against thrombus formation, and we have shown this in experiments on rabbits in a clinically relevant context,” Dr Renné said in conclusion.
“We plan to test the antibody in a phase 1 study. It is possible that the antibody also blocks inflammation mediated by FXII, an interesting area for future studies.”
Polymer could improve blood cryopreservation
Credit: UAB Hospital
Scientists have found that a common polymer can help red blood cells (RBCs) survive storage at freezing temperatures, and it may offer benefits over current methods of cryopreservation.
The polymer, polyvinyl alcohol, mimics antifreeze properties found in cold-acclimatized fish, such as arctic cod.
And experiments revealed that using polyvinyl alcohol in blood cryopreservation can inhibit the growth of ice crystals, which damage RBCs and make them unusable.
Matthew Gibson, PhD, of the University of Warwick in the UK, and his colleagues conducted these experiments and reported the results in Nature Communications.
“We know that certain types of fish survive perfectly well in sub-zero sea temperatures without their blood freezing,” Dr Gibson said. “We used this as a starting point to search for synthetic substances which reflect what nature already does so well.”
“On closer examination, it turns out that polyvinyl alcohol, which is actually a derivative of wood glue, mimics the properties of the antifreeze proteins found in these kinds of fish.”
So Dr Gibson and his colleagues decided to see how polyvinyl alcohol fared in blood cryopreservation.
The team tested RBCs from sheep and humans and found that polyvinyl alcohol could inhibit ice crystal growth, even when used at concentrations as low as 0.01wt%.
The polymer was most effective at 0.1wt%, which allowed for 40% RBC recovery. Higher concentrations of polyvinyl alcohol did reduce the growth of ice crystals, but the benefits were counteracted by the secondary effects of ice shaping, which can pierce cell membranes.
The researchers noted that the current method of cryopreservation typically requires more than 20wt% of organic solvents to prevent ice formation. And the solvents must be removed before the blood can be used.
“Polyvinyl alcohol has 3 things in its favor when applied to freezing blood,” Dr Gibson said. “Firstly, it reduces the growth of ice crystals during thawing. Secondly, it reduces the need for organic solvents, and, crucially, it reduces the time between defrosting and having transfusion-ready blood by eliminating the need to remove solvent.”
Dr Gibson pointed out that, although polyvinyl alcohol appears to be a promising option for cryopreservation, additional research is needed. But if the polymer proves effective in subsequent studies, it could be used on other cell types as well.
Credit: UAB Hospital
Scientists have found that a common polymer can help red blood cells (RBCs) survive storage at freezing temperatures, and it may offer benefits over current methods of cryopreservation.
The polymer, polyvinyl alcohol, mimics antifreeze properties found in cold-acclimatized fish, such as arctic cod.
And experiments revealed that using polyvinyl alcohol in blood cryopreservation can inhibit the growth of ice crystals, which damage RBCs and make them unusable.
Matthew Gibson, PhD, of the University of Warwick in the UK, and his colleagues conducted these experiments and reported the results in Nature Communications.
“We know that certain types of fish survive perfectly well in sub-zero sea temperatures without their blood freezing,” Dr Gibson said. “We used this as a starting point to search for synthetic substances which reflect what nature already does so well.”
“On closer examination, it turns out that polyvinyl alcohol, which is actually a derivative of wood glue, mimics the properties of the antifreeze proteins found in these kinds of fish.”
So Dr Gibson and his colleagues decided to see how polyvinyl alcohol fared in blood cryopreservation.
The team tested RBCs from sheep and humans and found that polyvinyl alcohol could inhibit ice crystal growth, even when used at concentrations as low as 0.01wt%.
The polymer was most effective at 0.1wt%, which allowed for 40% RBC recovery. Higher concentrations of polyvinyl alcohol did reduce the growth of ice crystals, but the benefits were counteracted by the secondary effects of ice shaping, which can pierce cell membranes.
The researchers noted that the current method of cryopreservation typically requires more than 20wt% of organic solvents to prevent ice formation. And the solvents must be removed before the blood can be used.
“Polyvinyl alcohol has 3 things in its favor when applied to freezing blood,” Dr Gibson said. “Firstly, it reduces the growth of ice crystals during thawing. Secondly, it reduces the need for organic solvents, and, crucially, it reduces the time between defrosting and having transfusion-ready blood by eliminating the need to remove solvent.”
Dr Gibson pointed out that, although polyvinyl alcohol appears to be a promising option for cryopreservation, additional research is needed. But if the polymer proves effective in subsequent studies, it could be used on other cell types as well.
Credit: UAB Hospital
Scientists have found that a common polymer can help red blood cells (RBCs) survive storage at freezing temperatures, and it may offer benefits over current methods of cryopreservation.
The polymer, polyvinyl alcohol, mimics antifreeze properties found in cold-acclimatized fish, such as arctic cod.
And experiments revealed that using polyvinyl alcohol in blood cryopreservation can inhibit the growth of ice crystals, which damage RBCs and make them unusable.
Matthew Gibson, PhD, of the University of Warwick in the UK, and his colleagues conducted these experiments and reported the results in Nature Communications.
“We know that certain types of fish survive perfectly well in sub-zero sea temperatures without their blood freezing,” Dr Gibson said. “We used this as a starting point to search for synthetic substances which reflect what nature already does so well.”
“On closer examination, it turns out that polyvinyl alcohol, which is actually a derivative of wood glue, mimics the properties of the antifreeze proteins found in these kinds of fish.”
So Dr Gibson and his colleagues decided to see how polyvinyl alcohol fared in blood cryopreservation.
The team tested RBCs from sheep and humans and found that polyvinyl alcohol could inhibit ice crystal growth, even when used at concentrations as low as 0.01wt%.
The polymer was most effective at 0.1wt%, which allowed for 40% RBC recovery. Higher concentrations of polyvinyl alcohol did reduce the growth of ice crystals, but the benefits were counteracted by the secondary effects of ice shaping, which can pierce cell membranes.
The researchers noted that the current method of cryopreservation typically requires more than 20wt% of organic solvents to prevent ice formation. And the solvents must be removed before the blood can be used.
“Polyvinyl alcohol has 3 things in its favor when applied to freezing blood,” Dr Gibson said. “Firstly, it reduces the growth of ice crystals during thawing. Secondly, it reduces the need for organic solvents, and, crucially, it reduces the time between defrosting and having transfusion-ready blood by eliminating the need to remove solvent.”
Dr Gibson pointed out that, although polyvinyl alcohol appears to be a promising option for cryopreservation, additional research is needed. But if the polymer proves effective in subsequent studies, it could be used on other cell types as well.
ASCO explains how ACA impacts trial participation
patient and her father
Credit: Rhoda Baer
The Affordable Care Act (ACA) includes provisions that may make it easier for US cancer patients to participate in clinical trials.
But this aspect of the law has not received much attention and is not well understood, according to the American Society of Clinical Oncology (ASCO).
So the organization has created educational materials for providers and patients that explain ACA coverage as it relates to clinical trials.
“ASCO and other groups fought long and hard for this law requiring insurers nationwide to cover the routine costs of care for individuals participating in clinical trials,” said ASCO President Clifford A. Hudis, MD, FACP.
“Healthcare providers, financial counselors, and others involved in helping patients need to understand the law’s provisions so that their patients can benefit and we can make scientific progress.”
The law, which is effective for health plans newly issued or renewed after January 1, 2014, prohibits health plans or insurance issuers from:
- Denying participation of beneficiaries in clinical trials
- Denying or limiting coverage of routine patient care costs, subject to the plan’s out-of-network coverage policy
- Discriminating against the individual on the basis of participation in a trial.
The federal government has not yet issued regulations to guide implementation of the law. While much of the statutory language is clear, in the absence of federal guidance, payers will likely vary on the legal interpretation of each element of the provision.
Therefore, understanding the provisions can help patients and their healthcare providers seek the best available treatment options, which may include participation in a clinical trial.
Provider materials are available on ASCO’s Clinical Trials Coverage web page at www.ASCO.org/ClinicalTrialsCoverage.
Patient materials available on Cancer.Net include a detailed article explaining health insurance coverage of clinical trials at www.cancer.net/clinicaltrials and a fact sheet that provides an overview of the ACA provision at www.cancer.net/factsheets.
patient and her father
Credit: Rhoda Baer
The Affordable Care Act (ACA) includes provisions that may make it easier for US cancer patients to participate in clinical trials.
But this aspect of the law has not received much attention and is not well understood, according to the American Society of Clinical Oncology (ASCO).
So the organization has created educational materials for providers and patients that explain ACA coverage as it relates to clinical trials.
“ASCO and other groups fought long and hard for this law requiring insurers nationwide to cover the routine costs of care for individuals participating in clinical trials,” said ASCO President Clifford A. Hudis, MD, FACP.
“Healthcare providers, financial counselors, and others involved in helping patients need to understand the law’s provisions so that their patients can benefit and we can make scientific progress.”
The law, which is effective for health plans newly issued or renewed after January 1, 2014, prohibits health plans or insurance issuers from:
- Denying participation of beneficiaries in clinical trials
- Denying or limiting coverage of routine patient care costs, subject to the plan’s out-of-network coverage policy
- Discriminating against the individual on the basis of participation in a trial.
The federal government has not yet issued regulations to guide implementation of the law. While much of the statutory language is clear, in the absence of federal guidance, payers will likely vary on the legal interpretation of each element of the provision.
Therefore, understanding the provisions can help patients and their healthcare providers seek the best available treatment options, which may include participation in a clinical trial.
Provider materials are available on ASCO’s Clinical Trials Coverage web page at www.ASCO.org/ClinicalTrialsCoverage.
Patient materials available on Cancer.Net include a detailed article explaining health insurance coverage of clinical trials at www.cancer.net/clinicaltrials and a fact sheet that provides an overview of the ACA provision at www.cancer.net/factsheets.
patient and her father
Credit: Rhoda Baer
The Affordable Care Act (ACA) includes provisions that may make it easier for US cancer patients to participate in clinical trials.
But this aspect of the law has not received much attention and is not well understood, according to the American Society of Clinical Oncology (ASCO).
So the organization has created educational materials for providers and patients that explain ACA coverage as it relates to clinical trials.
“ASCO and other groups fought long and hard for this law requiring insurers nationwide to cover the routine costs of care for individuals participating in clinical trials,” said ASCO President Clifford A. Hudis, MD, FACP.
“Healthcare providers, financial counselors, and others involved in helping patients need to understand the law’s provisions so that their patients can benefit and we can make scientific progress.”
The law, which is effective for health plans newly issued or renewed after January 1, 2014, prohibits health plans or insurance issuers from:
- Denying participation of beneficiaries in clinical trials
- Denying or limiting coverage of routine patient care costs, subject to the plan’s out-of-network coverage policy
- Discriminating against the individual on the basis of participation in a trial.
The federal government has not yet issued regulations to guide implementation of the law. While much of the statutory language is clear, in the absence of federal guidance, payers will likely vary on the legal interpretation of each element of the provision.
Therefore, understanding the provisions can help patients and their healthcare providers seek the best available treatment options, which may include participation in a clinical trial.
Provider materials are available on ASCO’s Clinical Trials Coverage web page at www.ASCO.org/ClinicalTrialsCoverage.
Patient materials available on Cancer.Net include a detailed article explaining health insurance coverage of clinical trials at www.cancer.net/clinicaltrials and a fact sheet that provides an overview of the ACA provision at www.cancer.net/factsheets.
Affluence seems to affect CML survival in the UK
Credit: CDC
Results of population-based research suggest that financial status may affect survival in patients with chronic myeloid leukemia (CML) living in the UK.
The study showed that, despite equal access to the same clinical care and treatment, survival rates were significantly lower for patients living in more deprived areas.
The researchers said this difference might be explained by lower rates of treatment compliance in the less affluent population.
“These findings highlight the importance of conducting comprehensive, population-based studies to examine treatment pathways across the entire patient population, rather than solely concentrating on findings from clinical trials,” said study author Alexandra Smith, PhD, of the University of York in the UK.
She and her colleagues recounted their findings in BMJ Open.
The team analyzed data from 242 patients who were diagnosed with CML from September 2004 to August 2011. Ninety-seven percent of patients had chronic-phase disease at presentation, and 86% were Ph-positive.
Fifty-five percent of patients were younger than 60 at diagnosis, and 60% were male. Fifty-nine percent lived in deprivation quintiles 1 to 3, and 41% lived in the less affluent quintiles 4 and 5.
Ninety-seven percent of patients received treatment with tyrosine kinase inhibitors (TKIs)—94% imatinib and the rest dasatinib. Three percent of patients were not treated with TKIs due to death, relocation, refusal, a more serious competing comorbidity, or the use of supportive care alone.
Factors affecting survival
The minimum follow-up was 1.5 years, and the maximum was 8.5 years. The overall 5-year survival was 79%. And the relative survival, which took into account the background mortality in the general population, was 89%.
The relative survival curves did not differ significantly between the 2 age groups. Five-year relative survival was 90% for patients younger than 60 and 87% for those older than 60.
Gender also had little impact on relative survival. The 5-year rates were 90% for men and 89% for women.
However, relative survival differed significantly according to affluence. The 5-year relative survival was 95% for the most affluent patients (quintiles 1 to 3) and 80% for the least affluent (quintiles 4 and 5).
Although 41% of all patients lived in the less affluent areas, this group accounted for about 60% of the deaths.
The researchers said this finding could not be attributed to biological features of disease or access to therapy. But they believe a lack of treatment compliance could be the cause.
“We suspect a major factor is that we are not supporting patients sufficiently to allow them to be fully compliant with a treatment that needs to be taken every day to be effective,” said Russell Patmore, MD, of Castle Hill Hospital in the UK.
“We would encourage all teams treating patients with CML to use these findings to focus their resource where it is likely to be most beneficial. This includes helping patients to manage their CML by explaining fully the importance of daily treatment and providing easy access to ongoing support.”
Credit: CDC
Results of population-based research suggest that financial status may affect survival in patients with chronic myeloid leukemia (CML) living in the UK.
The study showed that, despite equal access to the same clinical care and treatment, survival rates were significantly lower for patients living in more deprived areas.
The researchers said this difference might be explained by lower rates of treatment compliance in the less affluent population.
“These findings highlight the importance of conducting comprehensive, population-based studies to examine treatment pathways across the entire patient population, rather than solely concentrating on findings from clinical trials,” said study author Alexandra Smith, PhD, of the University of York in the UK.
She and her colleagues recounted their findings in BMJ Open.
The team analyzed data from 242 patients who were diagnosed with CML from September 2004 to August 2011. Ninety-seven percent of patients had chronic-phase disease at presentation, and 86% were Ph-positive.
Fifty-five percent of patients were younger than 60 at diagnosis, and 60% were male. Fifty-nine percent lived in deprivation quintiles 1 to 3, and 41% lived in the less affluent quintiles 4 and 5.
Ninety-seven percent of patients received treatment with tyrosine kinase inhibitors (TKIs)—94% imatinib and the rest dasatinib. Three percent of patients were not treated with TKIs due to death, relocation, refusal, a more serious competing comorbidity, or the use of supportive care alone.
Factors affecting survival
The minimum follow-up was 1.5 years, and the maximum was 8.5 years. The overall 5-year survival was 79%. And the relative survival, which took into account the background mortality in the general population, was 89%.
The relative survival curves did not differ significantly between the 2 age groups. Five-year relative survival was 90% for patients younger than 60 and 87% for those older than 60.
Gender also had little impact on relative survival. The 5-year rates were 90% for men and 89% for women.
However, relative survival differed significantly according to affluence. The 5-year relative survival was 95% for the most affluent patients (quintiles 1 to 3) and 80% for the least affluent (quintiles 4 and 5).
Although 41% of all patients lived in the less affluent areas, this group accounted for about 60% of the deaths.
The researchers said this finding could not be attributed to biological features of disease or access to therapy. But they believe a lack of treatment compliance could be the cause.
“We suspect a major factor is that we are not supporting patients sufficiently to allow them to be fully compliant with a treatment that needs to be taken every day to be effective,” said Russell Patmore, MD, of Castle Hill Hospital in the UK.
“We would encourage all teams treating patients with CML to use these findings to focus their resource where it is likely to be most beneficial. This includes helping patients to manage their CML by explaining fully the importance of daily treatment and providing easy access to ongoing support.”
Credit: CDC
Results of population-based research suggest that financial status may affect survival in patients with chronic myeloid leukemia (CML) living in the UK.
The study showed that, despite equal access to the same clinical care and treatment, survival rates were significantly lower for patients living in more deprived areas.
The researchers said this difference might be explained by lower rates of treatment compliance in the less affluent population.
“These findings highlight the importance of conducting comprehensive, population-based studies to examine treatment pathways across the entire patient population, rather than solely concentrating on findings from clinical trials,” said study author Alexandra Smith, PhD, of the University of York in the UK.
She and her colleagues recounted their findings in BMJ Open.
The team analyzed data from 242 patients who were diagnosed with CML from September 2004 to August 2011. Ninety-seven percent of patients had chronic-phase disease at presentation, and 86% were Ph-positive.
Fifty-five percent of patients were younger than 60 at diagnosis, and 60% were male. Fifty-nine percent lived in deprivation quintiles 1 to 3, and 41% lived in the less affluent quintiles 4 and 5.
Ninety-seven percent of patients received treatment with tyrosine kinase inhibitors (TKIs)—94% imatinib and the rest dasatinib. Three percent of patients were not treated with TKIs due to death, relocation, refusal, a more serious competing comorbidity, or the use of supportive care alone.
Factors affecting survival
The minimum follow-up was 1.5 years, and the maximum was 8.5 years. The overall 5-year survival was 79%. And the relative survival, which took into account the background mortality in the general population, was 89%.
The relative survival curves did not differ significantly between the 2 age groups. Five-year relative survival was 90% for patients younger than 60 and 87% for those older than 60.
Gender also had little impact on relative survival. The 5-year rates were 90% for men and 89% for women.
However, relative survival differed significantly according to affluence. The 5-year relative survival was 95% for the most affluent patients (quintiles 1 to 3) and 80% for the least affluent (quintiles 4 and 5).
Although 41% of all patients lived in the less affluent areas, this group accounted for about 60% of the deaths.
The researchers said this finding could not be attributed to biological features of disease or access to therapy. But they believe a lack of treatment compliance could be the cause.
“We suspect a major factor is that we are not supporting patients sufficiently to allow them to be fully compliant with a treatment that needs to be taken every day to be effective,” said Russell Patmore, MD, of Castle Hill Hospital in the UK.
“We would encourage all teams treating patients with CML to use these findings to focus their resource where it is likely to be most beneficial. This includes helping patients to manage their CML by explaining fully the importance of daily treatment and providing easy access to ongoing support.”
Drug gets breakthrough designation for SAA
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the thrombopoietin receptor agonist eltrombopag (Promacta/Revolade) to treat patients with severe aplastic anemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST).
Eltrombopag is not approved in this setting anywhere in the world, and there are no approved therapies for SAA patients who are unresponsive to initial IST.
Of those patients who are unresponsive to initial IST, approximately 40% die from infection or bleeding within 5 years of their diagnosis.
Breakthrough therapy designation is the newest of the FDA’s programs aimed at accelerating the development and review of drugs for serious or life-threatening conditions. A drug receives the designation when preliminary clinical evidence suggests it may offer substantial improvement over available therapies on at least one clinically significant endpoint.
Eltrombopag was granted breakthrough designation based on results from an open-label, phase 2 study in 43 heavily pretreated SAA patients with an insufficient response to IST. Updated results of this trial were published in December (Desmond et al, Blood 2013).
Patients received varying doses of eltrombopag to improve blood counts. At 3 to 4 months of follow-up, the overall response rate was 40% (17/43), which included 1 tri-lineage and 5 bi-lineage responses.
Most of the 17 patients who remained on eltrombopag in an extension study continued to show improvement, but 3 lost their response. Ultimately, 7 patients had significant increases in neutrophil, red cell, and platelet counts.
Five patients who experienced robust near-normalization of blood counts discontinued the drug and maintained stable counts a median of 13 months after discontinuation (range, 1-15).
Eight patients, including 2 who responded, developed new cytogenetic abnormalities while on eltrombopag. But none have evolved to acute myeloid leukemia to date.
The only dose-limiting toxicity was reversible transaminitis. Two patients had reversible transaminitis related to treatment, and both required dose interruption.
There were no thrombotic events while patients were on treatment, but 1 responding patient developed deep-vein thrombosis 14 months after treatment discontinuation.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the thrombopoietin receptor agonist eltrombopag (Promacta/Revolade) to treat patients with severe aplastic anemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST).
Eltrombopag is not approved in this setting anywhere in the world, and there are no approved therapies for SAA patients who are unresponsive to initial IST.
Of those patients who are unresponsive to initial IST, approximately 40% die from infection or bleeding within 5 years of their diagnosis.
Breakthrough therapy designation is the newest of the FDA’s programs aimed at accelerating the development and review of drugs for serious or life-threatening conditions. A drug receives the designation when preliminary clinical evidence suggests it may offer substantial improvement over available therapies on at least one clinically significant endpoint.
Eltrombopag was granted breakthrough designation based on results from an open-label, phase 2 study in 43 heavily pretreated SAA patients with an insufficient response to IST. Updated results of this trial were published in December (Desmond et al, Blood 2013).
Patients received varying doses of eltrombopag to improve blood counts. At 3 to 4 months of follow-up, the overall response rate was 40% (17/43), which included 1 tri-lineage and 5 bi-lineage responses.
Most of the 17 patients who remained on eltrombopag in an extension study continued to show improvement, but 3 lost their response. Ultimately, 7 patients had significant increases in neutrophil, red cell, and platelet counts.
Five patients who experienced robust near-normalization of blood counts discontinued the drug and maintained stable counts a median of 13 months after discontinuation (range, 1-15).
Eight patients, including 2 who responded, developed new cytogenetic abnormalities while on eltrombopag. But none have evolved to acute myeloid leukemia to date.
The only dose-limiting toxicity was reversible transaminitis. Two patients had reversible transaminitis related to treatment, and both required dose interruption.
There were no thrombotic events while patients were on treatment, but 1 responding patient developed deep-vein thrombosis 14 months after treatment discontinuation.
The US Food and Drug Administration (FDA) has granted breakthrough therapy designation for the thrombopoietin receptor agonist eltrombopag (Promacta/Revolade) to treat patients with severe aplastic anemia (SAA) who have had an insufficient response to immunosuppressive therapy (IST).
Eltrombopag is not approved in this setting anywhere in the world, and there are no approved therapies for SAA patients who are unresponsive to initial IST.
Of those patients who are unresponsive to initial IST, approximately 40% die from infection or bleeding within 5 years of their diagnosis.
Breakthrough therapy designation is the newest of the FDA’s programs aimed at accelerating the development and review of drugs for serious or life-threatening conditions. A drug receives the designation when preliminary clinical evidence suggests it may offer substantial improvement over available therapies on at least one clinically significant endpoint.
Eltrombopag was granted breakthrough designation based on results from an open-label, phase 2 study in 43 heavily pretreated SAA patients with an insufficient response to IST. Updated results of this trial were published in December (Desmond et al, Blood 2013).
Patients received varying doses of eltrombopag to improve blood counts. At 3 to 4 months of follow-up, the overall response rate was 40% (17/43), which included 1 tri-lineage and 5 bi-lineage responses.
Most of the 17 patients who remained on eltrombopag in an extension study continued to show improvement, but 3 lost their response. Ultimately, 7 patients had significant increases in neutrophil, red cell, and platelet counts.
Five patients who experienced robust near-normalization of blood counts discontinued the drug and maintained stable counts a median of 13 months after discontinuation (range, 1-15).
Eight patients, including 2 who responded, developed new cytogenetic abnormalities while on eltrombopag. But none have evolved to acute myeloid leukemia to date.
The only dose-limiting toxicity was reversible transaminitis. Two patients had reversible transaminitis related to treatment, and both required dose interruption.
There were no thrombotic events while patients were on treatment, but 1 responding patient developed deep-vein thrombosis 14 months after treatment discontinuation.
Researcher status affects paper popularity, study suggests
Credit: Rhoda Baer
New research indicates that author status affects how frequently scientific papers are cited, but the size of that effect depends on a number of other factors.
Investigators found that, overall, citations increased 12% above the expected level when authors were awarded “prestigious investigator status” at the Howard Hughes Medical Institute (HHMI).
However, certain kinds of research papers benefitted more than others by this increased prestige.
“We find much more of an effect on recent papers published in a short window before the prize,” said study author Pierre Azoulay, PhD, of the MIT Sloan School of Management in Cambridge.
And the greatest gains came for papers in new areas of research and for papers published in lower-profile journals. Younger researchers who had lower profiles prior to receiving the HHMI award were more likely to see a change as well.
“The effect was much more pronounced when there was more reason to be uncertain about the quality of the science or the scientist before the prize,” Dr Azoulay noted.
This paper, titled “Matthew: Effect or Fable?,” was published in Management Science.
The “Matthew Effect” is a term coined by sociologist Robert K. Merton to describe the possibility that the work of those with high status receives greater attention than equivalent work by those who are not as well known.
Positively identifying this phenomenon in scientific paper citations is difficult, however, because it is hard to separate the status of the author from the quality of the paper. It is possible, after all, that better-known researchers are simply producing higher-quality papers, which get more attention as a result.
But Dr Azoulay and his colleagues said they’ve found a way to address this issue. They looked at papers first published before the authors became HHMI investigators, then examined the citation rates for those papers after the HHMI appointments occurred, compared to a baseline of similar papers whose authors did not receive HHMI appointments.
More specifically, each paper in the study was paired with what Dr Azoulay called a “fraternal twin,” that is, another paper published in the same journal, at the same time, with the same initial citation pattern. For good measure, the authors of the papers in this comparison group were all scientists who had received other early career awards.
In all, from 1984 through 2003, 443 scientists were named HHMI investigators. Dr Azoulay and his colleagues examined 3636 papers written by 424 of those scientists, comparing them to 3636 papers in the control group.
“You couldn’t tell [the 2 sets of papers] apart in terms of citation trajectories, up until the time of the prize,” Dr Azoulay said.
Beyond the overall 12% increase in citations, the effect was nearly twice as great for papers published in lower-profile journals.
Alternately, Dr Azoulay pointed out, “If your paper was published in Cell or Nature or Science, the HHMI [award] doesn’t add a lot.”
Credit: Rhoda Baer
New research indicates that author status affects how frequently scientific papers are cited, but the size of that effect depends on a number of other factors.
Investigators found that, overall, citations increased 12% above the expected level when authors were awarded “prestigious investigator status” at the Howard Hughes Medical Institute (HHMI).
However, certain kinds of research papers benefitted more than others by this increased prestige.
“We find much more of an effect on recent papers published in a short window before the prize,” said study author Pierre Azoulay, PhD, of the MIT Sloan School of Management in Cambridge.
And the greatest gains came for papers in new areas of research and for papers published in lower-profile journals. Younger researchers who had lower profiles prior to receiving the HHMI award were more likely to see a change as well.
“The effect was much more pronounced when there was more reason to be uncertain about the quality of the science or the scientist before the prize,” Dr Azoulay noted.
This paper, titled “Matthew: Effect or Fable?,” was published in Management Science.
The “Matthew Effect” is a term coined by sociologist Robert K. Merton to describe the possibility that the work of those with high status receives greater attention than equivalent work by those who are not as well known.
Positively identifying this phenomenon in scientific paper citations is difficult, however, because it is hard to separate the status of the author from the quality of the paper. It is possible, after all, that better-known researchers are simply producing higher-quality papers, which get more attention as a result.
But Dr Azoulay and his colleagues said they’ve found a way to address this issue. They looked at papers first published before the authors became HHMI investigators, then examined the citation rates for those papers after the HHMI appointments occurred, compared to a baseline of similar papers whose authors did not receive HHMI appointments.
More specifically, each paper in the study was paired with what Dr Azoulay called a “fraternal twin,” that is, another paper published in the same journal, at the same time, with the same initial citation pattern. For good measure, the authors of the papers in this comparison group were all scientists who had received other early career awards.
In all, from 1984 through 2003, 443 scientists were named HHMI investigators. Dr Azoulay and his colleagues examined 3636 papers written by 424 of those scientists, comparing them to 3636 papers in the control group.
“You couldn’t tell [the 2 sets of papers] apart in terms of citation trajectories, up until the time of the prize,” Dr Azoulay said.
Beyond the overall 12% increase in citations, the effect was nearly twice as great for papers published in lower-profile journals.
Alternately, Dr Azoulay pointed out, “If your paper was published in Cell or Nature or Science, the HHMI [award] doesn’t add a lot.”
Credit: Rhoda Baer
New research indicates that author status affects how frequently scientific papers are cited, but the size of that effect depends on a number of other factors.
Investigators found that, overall, citations increased 12% above the expected level when authors were awarded “prestigious investigator status” at the Howard Hughes Medical Institute (HHMI).
However, certain kinds of research papers benefitted more than others by this increased prestige.
“We find much more of an effect on recent papers published in a short window before the prize,” said study author Pierre Azoulay, PhD, of the MIT Sloan School of Management in Cambridge.
And the greatest gains came for papers in new areas of research and for papers published in lower-profile journals. Younger researchers who had lower profiles prior to receiving the HHMI award were more likely to see a change as well.
“The effect was much more pronounced when there was more reason to be uncertain about the quality of the science or the scientist before the prize,” Dr Azoulay noted.
This paper, titled “Matthew: Effect or Fable?,” was published in Management Science.
The “Matthew Effect” is a term coined by sociologist Robert K. Merton to describe the possibility that the work of those with high status receives greater attention than equivalent work by those who are not as well known.
Positively identifying this phenomenon in scientific paper citations is difficult, however, because it is hard to separate the status of the author from the quality of the paper. It is possible, after all, that better-known researchers are simply producing higher-quality papers, which get more attention as a result.
But Dr Azoulay and his colleagues said they’ve found a way to address this issue. They looked at papers first published before the authors became HHMI investigators, then examined the citation rates for those papers after the HHMI appointments occurred, compared to a baseline of similar papers whose authors did not receive HHMI appointments.
More specifically, each paper in the study was paired with what Dr Azoulay called a “fraternal twin,” that is, another paper published in the same journal, at the same time, with the same initial citation pattern. For good measure, the authors of the papers in this comparison group were all scientists who had received other early career awards.
In all, from 1984 through 2003, 443 scientists were named HHMI investigators. Dr Azoulay and his colleagues examined 3636 papers written by 424 of those scientists, comparing them to 3636 papers in the control group.
“You couldn’t tell [the 2 sets of papers] apart in terms of citation trajectories, up until the time of the prize,” Dr Azoulay said.
Beyond the overall 12% increase in citations, the effect was nearly twice as great for papers published in lower-profile journals.
Alternately, Dr Azoulay pointed out, “If your paper was published in Cell or Nature or Science, the HHMI [award] doesn’t add a lot.”
Methylation patterns can predict survival in AML, team says
Credit: Lance Liotta
Researchers have found evidence to suggest that methylation patterns in hematopoietic stem cells (HSCs) can be used to determine prognosis in patients with acute myeloid leukemia (AML).
The team discovered that patients with methylation patterns resembling those of healthy individuals lived longer than patients with substantially different patterns.
If validated in clinical trials, this finding could be used to help physicians tailor treatment according to a patient’s needs.
Ulrich Steidl, MD, PhD, of the Albert Einstein College of Medicine in New York, and his colleagues described this research in The Journal of Clinical Investigation.
The investigators knew that aberrations in HSC methylation can prevent the cells from differentiating into mature blood cells, which leads to AML.
So they speculated that comparing how closely the methylation patterns in cells from AML patients resemble the patterns found in healthy individuals’ HSCs might foretell the patients’ response to treatment.
To find out, the researchers first looked at methylation patterns in HSCs from healthy individuals. The team found that most cytosines are methylated in healthy HSCs.
And where demethylation occurs, it’s mainly limited to one particular stage of HSC differentiation—the commitment step from short-term HSC to common myeloid progenitor.
The investigators then set out to identify loci with the most significant methylation changes across differentiation stages. Their analysis revealed a set of 561 loci that distinguished between the 4 stages of HSC development they investigated.
The team next wanted to determine whether the methylation status of these loci was affected in AML. So they developed an epigenetic signature score based on loci methylation. A patient’s score increased the more his methylation pattern differed from that of a healthy individual.
The researchers tested their scoring method using data from 3 cohorts of AML patients. In each of these groups, patients with low scores had approximately twice the median survival time of patients with high scores.
Specifically, the investigators evaluated AML patients in a trial testing 2 different doses of daunorubicin (Fernandez et al, NEJM 2009).
Among patients receiving lower-dose daunorubicin, those with lower epigenetic signature scores had a median overall survival (OS) of 19 months, compared with 10.8 months for patients with higher scores (P=0.0165).
The researchers observed similar results in the patients receiving a higher dose of daunorubicin. The median OS in the group with low epigenetic signature scores was 25.4 months, compared with 13.2 months in the group with high scores (P=0.0062).
Likewise, in a third cohort of AML patients, those with a low epigenetic signature score had significantly better OS than those with a high score—a median of 28.1 months and 14.9 months, respectively (P=0.0150).
The investigators performed the same analyses using a commitment-associated gene-expression signature. And they found their epigenetic signature was more effective at predicting patient survival.
Dr Steidl and his colleagues are now studying the genes found in the aberrant epigenetic signatures to determine if they play a role in causing AML.
Credit: Lance Liotta
Researchers have found evidence to suggest that methylation patterns in hematopoietic stem cells (HSCs) can be used to determine prognosis in patients with acute myeloid leukemia (AML).
The team discovered that patients with methylation patterns resembling those of healthy individuals lived longer than patients with substantially different patterns.
If validated in clinical trials, this finding could be used to help physicians tailor treatment according to a patient’s needs.
Ulrich Steidl, MD, PhD, of the Albert Einstein College of Medicine in New York, and his colleagues described this research in The Journal of Clinical Investigation.
The investigators knew that aberrations in HSC methylation can prevent the cells from differentiating into mature blood cells, which leads to AML.
So they speculated that comparing how closely the methylation patterns in cells from AML patients resemble the patterns found in healthy individuals’ HSCs might foretell the patients’ response to treatment.
To find out, the researchers first looked at methylation patterns in HSCs from healthy individuals. The team found that most cytosines are methylated in healthy HSCs.
And where demethylation occurs, it’s mainly limited to one particular stage of HSC differentiation—the commitment step from short-term HSC to common myeloid progenitor.
The investigators then set out to identify loci with the most significant methylation changes across differentiation stages. Their analysis revealed a set of 561 loci that distinguished between the 4 stages of HSC development they investigated.
The team next wanted to determine whether the methylation status of these loci was affected in AML. So they developed an epigenetic signature score based on loci methylation. A patient’s score increased the more his methylation pattern differed from that of a healthy individual.
The researchers tested their scoring method using data from 3 cohorts of AML patients. In each of these groups, patients with low scores had approximately twice the median survival time of patients with high scores.
Specifically, the investigators evaluated AML patients in a trial testing 2 different doses of daunorubicin (Fernandez et al, NEJM 2009).
Among patients receiving lower-dose daunorubicin, those with lower epigenetic signature scores had a median overall survival (OS) of 19 months, compared with 10.8 months for patients with higher scores (P=0.0165).
The researchers observed similar results in the patients receiving a higher dose of daunorubicin. The median OS in the group with low epigenetic signature scores was 25.4 months, compared with 13.2 months in the group with high scores (P=0.0062).
Likewise, in a third cohort of AML patients, those with a low epigenetic signature score had significantly better OS than those with a high score—a median of 28.1 months and 14.9 months, respectively (P=0.0150).
The investigators performed the same analyses using a commitment-associated gene-expression signature. And they found their epigenetic signature was more effective at predicting patient survival.
Dr Steidl and his colleagues are now studying the genes found in the aberrant epigenetic signatures to determine if they play a role in causing AML.
Credit: Lance Liotta
Researchers have found evidence to suggest that methylation patterns in hematopoietic stem cells (HSCs) can be used to determine prognosis in patients with acute myeloid leukemia (AML).
The team discovered that patients with methylation patterns resembling those of healthy individuals lived longer than patients with substantially different patterns.
If validated in clinical trials, this finding could be used to help physicians tailor treatment according to a patient’s needs.
Ulrich Steidl, MD, PhD, of the Albert Einstein College of Medicine in New York, and his colleagues described this research in The Journal of Clinical Investigation.
The investigators knew that aberrations in HSC methylation can prevent the cells from differentiating into mature blood cells, which leads to AML.
So they speculated that comparing how closely the methylation patterns in cells from AML patients resemble the patterns found in healthy individuals’ HSCs might foretell the patients’ response to treatment.
To find out, the researchers first looked at methylation patterns in HSCs from healthy individuals. The team found that most cytosines are methylated in healthy HSCs.
And where demethylation occurs, it’s mainly limited to one particular stage of HSC differentiation—the commitment step from short-term HSC to common myeloid progenitor.
The investigators then set out to identify loci with the most significant methylation changes across differentiation stages. Their analysis revealed a set of 561 loci that distinguished between the 4 stages of HSC development they investigated.
The team next wanted to determine whether the methylation status of these loci was affected in AML. So they developed an epigenetic signature score based on loci methylation. A patient’s score increased the more his methylation pattern differed from that of a healthy individual.
The researchers tested their scoring method using data from 3 cohorts of AML patients. In each of these groups, patients with low scores had approximately twice the median survival time of patients with high scores.
Specifically, the investigators evaluated AML patients in a trial testing 2 different doses of daunorubicin (Fernandez et al, NEJM 2009).
Among patients receiving lower-dose daunorubicin, those with lower epigenetic signature scores had a median overall survival (OS) of 19 months, compared with 10.8 months for patients with higher scores (P=0.0165).
The researchers observed similar results in the patients receiving a higher dose of daunorubicin. The median OS in the group with low epigenetic signature scores was 25.4 months, compared with 13.2 months in the group with high scores (P=0.0062).
Likewise, in a third cohort of AML patients, those with a low epigenetic signature score had significantly better OS than those with a high score—a median of 28.1 months and 14.9 months, respectively (P=0.0150).
The investigators performed the same analyses using a commitment-associated gene-expression signature. And they found their epigenetic signature was more effective at predicting patient survival.
Dr Steidl and his colleagues are now studying the genes found in the aberrant epigenetic signatures to determine if they play a role in causing AML.
FDA approves system for GVHD prophylaxis
Credit: Miltenyi Biotec
The US Food and Drug Administration (FDA) has granted approval for a device system that can prevent graft-vs-host disease (GVHD).
The CliniMACS CD34 Reagent System is intended for use in patients with acute myeloid leukemia who are in first complete remission and undergoing stem cell transplant (SCT) from a matched, related donor.
This in vitro system enriches CD34+ hematopoietic stem cells from a donated apheresis product, while depleting other cells that can cause GVHD.
The system employs a reagent consisting of a CD34 antibody conjugated to an iron-containing nanoparticle. It enriches CD34+ cells by passing the antibody/nanoparticle-labeled cell suspension through a magnetic separation column, which is provided as part of a single-use, disposable tubing set.
Magnetically labeled CD34+ target cells are retained within the separation column, while the unlabeled cells flow through. The CD34+ cells can be recovered by removing the magnetic field and eluting the targeted CD34+ cells into a collection bag.
The FDA’s approval of this system was based on data from a phase 2 study (BMT CTN 0303) conducted by the Blood and Marrow Transplant Clinical Trials Network (Pasquini et al, JCO 2012).
The trial included 128 patients undergoing SCT from a matched, sibling donor. Forty-four patients received grafts that were T-cell depleted (TCD) using the CliniMACS system as the sole form of immune suppression. The other 84 patients received T-cell-replete grafts and pharmacologic immune suppression therapy (IST).
The 2 groups were largely similar, although more patients in the TCD arm received treatment regimens that included radiation—100% vs 50%.
Neutrophil engraftment was similar between the 2 groups. At 28 days, 96% of patients in the IST arm and 100% in the TCD arm had achieved engraftment.
Patients in the TCD arm had a significantly lower rate of chronic GVHD than those in the IST arm. The TCD patients also had a lower rate of acute GVHD, but the difference was not significant.
At 100 days, the rates of grade 2-4, acute GVHD were 39% with IST and 23% with TCD grafts (P=0.07). At 2 years, the rates of chronic GVHD were 19% with TCD grafts and 50% with IST (P<0.001).
There were no significant differences between the 2 groups with regard to graft rejection, leukemia relapse, treatment-related mortality, disease-free survival, or overall survival. However, patients in the TCD arm had a higher rate of GVHD-free survival at 2 years—41% vs 19% (P=0.006).
The CliniMACS CD34 Reagent System is manufactured by Miltenyi Biotec. For more information on the system, see the company’s website.
Credit: Miltenyi Biotec
The US Food and Drug Administration (FDA) has granted approval for a device system that can prevent graft-vs-host disease (GVHD).
The CliniMACS CD34 Reagent System is intended for use in patients with acute myeloid leukemia who are in first complete remission and undergoing stem cell transplant (SCT) from a matched, related donor.
This in vitro system enriches CD34+ hematopoietic stem cells from a donated apheresis product, while depleting other cells that can cause GVHD.
The system employs a reagent consisting of a CD34 antibody conjugated to an iron-containing nanoparticle. It enriches CD34+ cells by passing the antibody/nanoparticle-labeled cell suspension through a magnetic separation column, which is provided as part of a single-use, disposable tubing set.
Magnetically labeled CD34+ target cells are retained within the separation column, while the unlabeled cells flow through. The CD34+ cells can be recovered by removing the magnetic field and eluting the targeted CD34+ cells into a collection bag.
The FDA’s approval of this system was based on data from a phase 2 study (BMT CTN 0303) conducted by the Blood and Marrow Transplant Clinical Trials Network (Pasquini et al, JCO 2012).
The trial included 128 patients undergoing SCT from a matched, sibling donor. Forty-four patients received grafts that were T-cell depleted (TCD) using the CliniMACS system as the sole form of immune suppression. The other 84 patients received T-cell-replete grafts and pharmacologic immune suppression therapy (IST).
The 2 groups were largely similar, although more patients in the TCD arm received treatment regimens that included radiation—100% vs 50%.
Neutrophil engraftment was similar between the 2 groups. At 28 days, 96% of patients in the IST arm and 100% in the TCD arm had achieved engraftment.
Patients in the TCD arm had a significantly lower rate of chronic GVHD than those in the IST arm. The TCD patients also had a lower rate of acute GVHD, but the difference was not significant.
At 100 days, the rates of grade 2-4, acute GVHD were 39% with IST and 23% with TCD grafts (P=0.07). At 2 years, the rates of chronic GVHD were 19% with TCD grafts and 50% with IST (P<0.001).
There were no significant differences between the 2 groups with regard to graft rejection, leukemia relapse, treatment-related mortality, disease-free survival, or overall survival. However, patients in the TCD arm had a higher rate of GVHD-free survival at 2 years—41% vs 19% (P=0.006).
The CliniMACS CD34 Reagent System is manufactured by Miltenyi Biotec. For more information on the system, see the company’s website.
Credit: Miltenyi Biotec
The US Food and Drug Administration (FDA) has granted approval for a device system that can prevent graft-vs-host disease (GVHD).
The CliniMACS CD34 Reagent System is intended for use in patients with acute myeloid leukemia who are in first complete remission and undergoing stem cell transplant (SCT) from a matched, related donor.
This in vitro system enriches CD34+ hematopoietic stem cells from a donated apheresis product, while depleting other cells that can cause GVHD.
The system employs a reagent consisting of a CD34 antibody conjugated to an iron-containing nanoparticle. It enriches CD34+ cells by passing the antibody/nanoparticle-labeled cell suspension through a magnetic separation column, which is provided as part of a single-use, disposable tubing set.
Magnetically labeled CD34+ target cells are retained within the separation column, while the unlabeled cells flow through. The CD34+ cells can be recovered by removing the magnetic field and eluting the targeted CD34+ cells into a collection bag.
The FDA’s approval of this system was based on data from a phase 2 study (BMT CTN 0303) conducted by the Blood and Marrow Transplant Clinical Trials Network (Pasquini et al, JCO 2012).
The trial included 128 patients undergoing SCT from a matched, sibling donor. Forty-four patients received grafts that were T-cell depleted (TCD) using the CliniMACS system as the sole form of immune suppression. The other 84 patients received T-cell-replete grafts and pharmacologic immune suppression therapy (IST).
The 2 groups were largely similar, although more patients in the TCD arm received treatment regimens that included radiation—100% vs 50%.
Neutrophil engraftment was similar between the 2 groups. At 28 days, 96% of patients in the IST arm and 100% in the TCD arm had achieved engraftment.
Patients in the TCD arm had a significantly lower rate of chronic GVHD than those in the IST arm. The TCD patients also had a lower rate of acute GVHD, but the difference was not significant.
At 100 days, the rates of grade 2-4, acute GVHD were 39% with IST and 23% with TCD grafts (P=0.07). At 2 years, the rates of chronic GVHD were 19% with TCD grafts and 50% with IST (P<0.001).
There were no significant differences between the 2 groups with regard to graft rejection, leukemia relapse, treatment-related mortality, disease-free survival, or overall survival. However, patients in the TCD arm had a higher rate of GVHD-free survival at 2 years—41% vs 19% (P=0.006).
The CliniMACS CD34 Reagent System is manufactured by Miltenyi Biotec. For more information on the system, see the company’s website.