User login
Two definitions of Gulf War illness recommended
An Institute of Medicine committee could not reach consensus on a single definition of Gulf War illness and recommended in a new report that clinicians and researchers at least narrow it down to two definitions.
That’s the preferred term – Gulf War illness – for a slew of health problems that occur at a higher rate in the approximately 697,000 U.S. veterans who served in the 1990-1991 Gulf War than in other veterans, the committee said. Gulf War illness is widely used and is more accurate than other terms used over the years for the same problems, including Gulf War syndrome, chronic multisystem illness, unexplained illness, medically unexplained symptoms, and medically unexplained physical symptoms, the report stated.
The Institute of Medicine (IOM) drafted a committee of 16 experts at the request of the Department of Veterans Affairs to try to develop a case definition for what's now called Gulf War illness in order to help standardize diagnosis, inclusion in research studies, and treatments. The committee's 120-page report, "Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined," is available on the IOM website.
Unable to find validation for one definition because of methodologic limitations in the studies, the committee recommended using either a broader definition from the Centers for Disease Control and Prevention (CDC) or a more restrictive one from studies of Kansas veterans, depending on the situation. Between the two of them, the definitions capture the most common symptoms of Gulf War illness and provide a framework for more focused research and treatment, the report said.
The committee found 2,033 articles in the literature focused on Gulf War illness symptoms and closely reviewed 718 of them. It found no objective diagnostic criteria but saw cumulative evidence that Gulf War illness is real. Fatigue, pain, and neurocognitive, gastrointestinal, respiratory, and/or dermatologic symptoms were reported with higher frequency in Gulf War veterans than in veterans of the same era who had not been deployed or were deployed elsewhere.
To identify the illness in a Gulf War veteran, the CDC definition requires one or more symptoms in at least two of the following categories: fatigue, pain, or mood and cognition. The Kansas definition requires symptoms in at least three of the following domains: fatigue or sleep, pain, neurologic or cognitive or mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms.
The CDC definition identified the illness in 29%-60% of Gulf War veterans, depending on the population studied. The Kansas definition identified the illness in 34% of Kansas veterans of the Gulf War.
The reason the committee couldn’t compile a single case definition is that the studies in the literature do not report on key features of the illness including onset, duration, severity, frequency of symptoms, and exclusionary criteria. The Department of Veterans Affairs should boost efforts to collect these kinds of data, conduct earlier in-depth assessments after deployment when unexpected complaints occur, and track troops’ exposures to vaccinations, drugs, and environmental factors, the report recommends.
The name Gulf War illness won out over Gulf War syndrome because "syndrome" indicates a new group of signs and symptoms, while the types and patterns of symptoms in this illness commonly are seen with other illnesses. The committee rejected "chronic multisymptom illness" because the phrase is not specific to Gulf War veterans.
The committee included experts in clinical medicine, toxicology, psychiatry, neurology, gastroenterology, epidemiology, sociology, psychometrics, biostatistics, occupational medicine, and basic science.
The report does not include potential disclosures of conflicts of interest.
On Twitter @sherryboschert
There has long been debate about whether Gulf War syndrome or Gulf War illness existed. If you remember the time of the Gulf War and shortly afterwards, there were a lot of questions about whether this was "all in their heads." Nobody ever found the sources of the illness. This report says to me that it’s final – that this august institution says, yes, this illness does exist. Whether you use the wider or narrower definition, this is to be taken seriously. That’s very important for physicians to know.
In terms of the two definitions – one narrower to be used for research and one broader to be used clinically – I think this gives people a little bit of latitude, depending on where they fit. The take-home piece is that, since there has been such a smorgasbord of opinions, thoughts, and descriptions, this should help the field by solidifying it further. We do still have two working definitions and we still don’t know a lot such as onset, duration, severity, frequency, and exclusionary criteria. Certainly, more needs to be done, but I think this is a very important step.
|
|
Finally, I think it’s also important that they said "Gulf War illness" rather than "chronic multisymptom illness." Again, I think that lends credibility to the claims of the veterans who have been there. This committee is willing to say, yes, there is something about having been deployed to the first Gulf War at a particular time that helps us understand your medical history. That’s not as far as we’d like to go, but it’s certainly some steps in the right direction.
That was a very short war a long time ago. Now, we’ve had 12 years of a very long war with multiple deployments, yet we haven’t really seen Gulf War illness or its equivalent in this generation of Iraq and Afghanistan veterans. I have expected that at some point we’re going to see these psychosomatic, vague symptoms coming out of this current war. I definitely think there’s time. Traumatic brain injury seems like the cardinal disorder from these wars, but I think we’re going to see some psychosomatic reactions over time.
Dr. Elspeth Cameron Ritchie is an expert on military health issues who retired as a colonel after 28 years in the U.S. Army. These are excerpts of an interview in which she spoke as an individual, not in her current roles as chief clinical officer of the Department of Behavioral Health for the District of Columbia and professor of psychiatry at the Uniformed Services University of the Health Sciences, Bethesda, Md., and at Georgetown University, Washington. She reported having no financial disclosures.
There has long been debate about whether Gulf War syndrome or Gulf War illness existed. If you remember the time of the Gulf War and shortly afterwards, there were a lot of questions about whether this was "all in their heads." Nobody ever found the sources of the illness. This report says to me that it’s final – that this august institution says, yes, this illness does exist. Whether you use the wider or narrower definition, this is to be taken seriously. That’s very important for physicians to know.
In terms of the two definitions – one narrower to be used for research and one broader to be used clinically – I think this gives people a little bit of latitude, depending on where they fit. The take-home piece is that, since there has been such a smorgasbord of opinions, thoughts, and descriptions, this should help the field by solidifying it further. We do still have two working definitions and we still don’t know a lot such as onset, duration, severity, frequency, and exclusionary criteria. Certainly, more needs to be done, but I think this is a very important step.
|
|
|
Finally, I think it’s also important that they said "Gulf War illness" rather than "chronic multisymptom illness." Again, I think that lends credibility to the claims of the veterans who have been there. This committee is willing to say, yes, there is something about having been deployed to the first Gulf War at a particular time that helps us understand your medical history. That’s not as far as we’d like to go, but it’s certainly some steps in the right direction.
That was a very short war a long time ago. Now, we’ve had 12 years of a very long war with multiple deployments, yet we haven’t really seen Gulf War illness or its equivalent in this generation of Iraq and Afghanistan veterans. I have expected that at some point we’re going to see these psychosomatic, vague symptoms coming out of this current war. I definitely think there’s time. Traumatic brain injury seems like the cardinal disorder from these wars, but I think we’re going to see some psychosomatic reactions over time.
Dr. Elspeth Cameron Ritchie is an expert on military health issues who retired as a colonel after 28 years in the U.S. Army. These are excerpts of an interview in which she spoke as an individual, not in her current roles as chief clinical officer of the Department of Behavioral Health for the District of Columbia and professor of psychiatry at the Uniformed Services University of the Health Sciences, Bethesda, Md., and at Georgetown University, Washington. She reported having no financial disclosures.
There has long been debate about whether Gulf War syndrome or Gulf War illness existed. If you remember the time of the Gulf War and shortly afterwards, there were a lot of questions about whether this was "all in their heads." Nobody ever found the sources of the illness. This report says to me that it’s final – that this august institution says, yes, this illness does exist. Whether you use the wider or narrower definition, this is to be taken seriously. That’s very important for physicians to know.
In terms of the two definitions – one narrower to be used for research and one broader to be used clinically – I think this gives people a little bit of latitude, depending on where they fit. The take-home piece is that, since there has been such a smorgasbord of opinions, thoughts, and descriptions, this should help the field by solidifying it further. We do still have two working definitions and we still don’t know a lot such as onset, duration, severity, frequency, and exclusionary criteria. Certainly, more needs to be done, but I think this is a very important step.
|
|
|
Finally, I think it’s also important that they said "Gulf War illness" rather than "chronic multisymptom illness." Again, I think that lends credibility to the claims of the veterans who have been there. This committee is willing to say, yes, there is something about having been deployed to the first Gulf War at a particular time that helps us understand your medical history. That’s not as far as we’d like to go, but it’s certainly some steps in the right direction.
That was a very short war a long time ago. Now, we’ve had 12 years of a very long war with multiple deployments, yet we haven’t really seen Gulf War illness or its equivalent in this generation of Iraq and Afghanistan veterans. I have expected that at some point we’re going to see these psychosomatic, vague symptoms coming out of this current war. I definitely think there’s time. Traumatic brain injury seems like the cardinal disorder from these wars, but I think we’re going to see some psychosomatic reactions over time.
Dr. Elspeth Cameron Ritchie is an expert on military health issues who retired as a colonel after 28 years in the U.S. Army. These are excerpts of an interview in which she spoke as an individual, not in her current roles as chief clinical officer of the Department of Behavioral Health for the District of Columbia and professor of psychiatry at the Uniformed Services University of the Health Sciences, Bethesda, Md., and at Georgetown University, Washington. She reported having no financial disclosures.
An Institute of Medicine committee could not reach consensus on a single definition of Gulf War illness and recommended in a new report that clinicians and researchers at least narrow it down to two definitions.
That’s the preferred term – Gulf War illness – for a slew of health problems that occur at a higher rate in the approximately 697,000 U.S. veterans who served in the 1990-1991 Gulf War than in other veterans, the committee said. Gulf War illness is widely used and is more accurate than other terms used over the years for the same problems, including Gulf War syndrome, chronic multisystem illness, unexplained illness, medically unexplained symptoms, and medically unexplained physical symptoms, the report stated.
The Institute of Medicine (IOM) drafted a committee of 16 experts at the request of the Department of Veterans Affairs to try to develop a case definition for what's now called Gulf War illness in order to help standardize diagnosis, inclusion in research studies, and treatments. The committee's 120-page report, "Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined," is available on the IOM website.
Unable to find validation for one definition because of methodologic limitations in the studies, the committee recommended using either a broader definition from the Centers for Disease Control and Prevention (CDC) or a more restrictive one from studies of Kansas veterans, depending on the situation. Between the two of them, the definitions capture the most common symptoms of Gulf War illness and provide a framework for more focused research and treatment, the report said.
The committee found 2,033 articles in the literature focused on Gulf War illness symptoms and closely reviewed 718 of them. It found no objective diagnostic criteria but saw cumulative evidence that Gulf War illness is real. Fatigue, pain, and neurocognitive, gastrointestinal, respiratory, and/or dermatologic symptoms were reported with higher frequency in Gulf War veterans than in veterans of the same era who had not been deployed or were deployed elsewhere.
To identify the illness in a Gulf War veteran, the CDC definition requires one or more symptoms in at least two of the following categories: fatigue, pain, or mood and cognition. The Kansas definition requires symptoms in at least three of the following domains: fatigue or sleep, pain, neurologic or cognitive or mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms.
The CDC definition identified the illness in 29%-60% of Gulf War veterans, depending on the population studied. The Kansas definition identified the illness in 34% of Kansas veterans of the Gulf War.
The reason the committee couldn’t compile a single case definition is that the studies in the literature do not report on key features of the illness including onset, duration, severity, frequency of symptoms, and exclusionary criteria. The Department of Veterans Affairs should boost efforts to collect these kinds of data, conduct earlier in-depth assessments after deployment when unexpected complaints occur, and track troops’ exposures to vaccinations, drugs, and environmental factors, the report recommends.
The name Gulf War illness won out over Gulf War syndrome because "syndrome" indicates a new group of signs and symptoms, while the types and patterns of symptoms in this illness commonly are seen with other illnesses. The committee rejected "chronic multisymptom illness" because the phrase is not specific to Gulf War veterans.
The committee included experts in clinical medicine, toxicology, psychiatry, neurology, gastroenterology, epidemiology, sociology, psychometrics, biostatistics, occupational medicine, and basic science.
The report does not include potential disclosures of conflicts of interest.
On Twitter @sherryboschert
An Institute of Medicine committee could not reach consensus on a single definition of Gulf War illness and recommended in a new report that clinicians and researchers at least narrow it down to two definitions.
That’s the preferred term – Gulf War illness – for a slew of health problems that occur at a higher rate in the approximately 697,000 U.S. veterans who served in the 1990-1991 Gulf War than in other veterans, the committee said. Gulf War illness is widely used and is more accurate than other terms used over the years for the same problems, including Gulf War syndrome, chronic multisystem illness, unexplained illness, medically unexplained symptoms, and medically unexplained physical symptoms, the report stated.
The Institute of Medicine (IOM) drafted a committee of 16 experts at the request of the Department of Veterans Affairs to try to develop a case definition for what's now called Gulf War illness in order to help standardize diagnosis, inclusion in research studies, and treatments. The committee's 120-page report, "Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined," is available on the IOM website.
Unable to find validation for one definition because of methodologic limitations in the studies, the committee recommended using either a broader definition from the Centers for Disease Control and Prevention (CDC) or a more restrictive one from studies of Kansas veterans, depending on the situation. Between the two of them, the definitions capture the most common symptoms of Gulf War illness and provide a framework for more focused research and treatment, the report said.
The committee found 2,033 articles in the literature focused on Gulf War illness symptoms and closely reviewed 718 of them. It found no objective diagnostic criteria but saw cumulative evidence that Gulf War illness is real. Fatigue, pain, and neurocognitive, gastrointestinal, respiratory, and/or dermatologic symptoms were reported with higher frequency in Gulf War veterans than in veterans of the same era who had not been deployed or were deployed elsewhere.
To identify the illness in a Gulf War veteran, the CDC definition requires one or more symptoms in at least two of the following categories: fatigue, pain, or mood and cognition. The Kansas definition requires symptoms in at least three of the following domains: fatigue or sleep, pain, neurologic or cognitive or mood symptoms, gastrointestinal symptoms, respiratory symptoms, and skin symptoms.
The CDC definition identified the illness in 29%-60% of Gulf War veterans, depending on the population studied. The Kansas definition identified the illness in 34% of Kansas veterans of the Gulf War.
The reason the committee couldn’t compile a single case definition is that the studies in the literature do not report on key features of the illness including onset, duration, severity, frequency of symptoms, and exclusionary criteria. The Department of Veterans Affairs should boost efforts to collect these kinds of data, conduct earlier in-depth assessments after deployment when unexpected complaints occur, and track troops’ exposures to vaccinations, drugs, and environmental factors, the report recommends.
The name Gulf War illness won out over Gulf War syndrome because "syndrome" indicates a new group of signs and symptoms, while the types and patterns of symptoms in this illness commonly are seen with other illnesses. The committee rejected "chronic multisymptom illness" because the phrase is not specific to Gulf War veterans.
The committee included experts in clinical medicine, toxicology, psychiatry, neurology, gastroenterology, epidemiology, sociology, psychometrics, biostatistics, occupational medicine, and basic science.
The report does not include potential disclosures of conflicts of interest.
On Twitter @sherryboschert
Many discontinued RCTs go unpublished, unreported
for use in a clinical trial
Credit: Esther Dyson
Too many discontinued clinical trials go unreported to ethics committees and remain unpublished, according to a paper published in JAMA.
Investigators evaluated more than 1000 randomized clinical trials (RCTs) initiated in 3 countries between 2000 and 2003. And they found that roughly a quarter of these trials were ultimately discontinued.
Although all of these RCTs had been approved by research ethics committees, less than 40% of the discontinuations were reported to the committees.
And discontinued trials were significantly more likely than completed trials to remain unpublished.
The most common reason for discontinuation was insufficient subject enrollment.
Benjamin Kasenda, MD, of University Hospital Basel in Switzerland, and his colleagues conducted this research. They examined the characteristics of 1017 RCTs approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. The last follow-up of these trials was April 27, 2013.
Overall, 253 RCTs (24.9%) were discontinued, but only 38% of these discontinuations were reported to ethics committees.
Discontinued trials were more likely than completed trials to remain unpublished—55.1% vs 33.6% (P<0.001).
The most common reasons for discontinuation were poor recruitment (9.9%, 101/1017), administrative reasons (3.8%, 39/1017), and futility (3.6%, 37/1017).
A multivariate analysis revealed that industry sponsorship, compared to investigator sponsorship, and a larger planned sample size in increments of 100 were associated with lower rates of discontinuation due to poor recruitment. The adjusted odds ratios were 0.25 (P<0.001) and 0.96 (P=0.04), respectively.
Dr Kasenda and his colleagues said these results suggest researchers must put forth more effort to ensure that trial discontinuation is reported to ethics committees and that results of discontinued trials are published.
They said failure to publish these results is “a waste of valid data that could contribute to systematic reviews and meta-analyses.” In addition, taking steps to improve subject recruitment could greatly reduce RCT discontinuation. 
for use in a clinical trial
Credit: Esther Dyson
Too many discontinued clinical trials go unreported to ethics committees and remain unpublished, according to a paper published in JAMA.
Investigators evaluated more than 1000 randomized clinical trials (RCTs) initiated in 3 countries between 2000 and 2003. And they found that roughly a quarter of these trials were ultimately discontinued.
Although all of these RCTs had been approved by research ethics committees, less than 40% of the discontinuations were reported to the committees.
And discontinued trials were significantly more likely than completed trials to remain unpublished.
The most common reason for discontinuation was insufficient subject enrollment.
Benjamin Kasenda, MD, of University Hospital Basel in Switzerland, and his colleagues conducted this research. They examined the characteristics of 1017 RCTs approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. The last follow-up of these trials was April 27, 2013.
Overall, 253 RCTs (24.9%) were discontinued, but only 38% of these discontinuations were reported to ethics committees.
Discontinued trials were more likely than completed trials to remain unpublished—55.1% vs 33.6% (P<0.001).
The most common reasons for discontinuation were poor recruitment (9.9%, 101/1017), administrative reasons (3.8%, 39/1017), and futility (3.6%, 37/1017).
A multivariate analysis revealed that industry sponsorship, compared to investigator sponsorship, and a larger planned sample size in increments of 100 were associated with lower rates of discontinuation due to poor recruitment. The adjusted odds ratios were 0.25 (P<0.001) and 0.96 (P=0.04), respectively.
Dr Kasenda and his colleagues said these results suggest researchers must put forth more effort to ensure that trial discontinuation is reported to ethics committees and that results of discontinued trials are published.
They said failure to publish these results is “a waste of valid data that could contribute to systematic reviews and meta-analyses.” In addition, taking steps to improve subject recruitment could greatly reduce RCT discontinuation.
for use in a clinical trial
Credit: Esther Dyson
Too many discontinued clinical trials go unreported to ethics committees and remain unpublished, according to a paper published in JAMA.
Investigators evaluated more than 1000 randomized clinical trials (RCTs) initiated in 3 countries between 2000 and 2003. And they found that roughly a quarter of these trials were ultimately discontinued.
Although all of these RCTs had been approved by research ethics committees, less than 40% of the discontinuations were reported to the committees.
And discontinued trials were significantly more likely than completed trials to remain unpublished.
The most common reason for discontinuation was insufficient subject enrollment.
Benjamin Kasenda, MD, of University Hospital Basel in Switzerland, and his colleagues conducted this research. They examined the characteristics of 1017 RCTs approved by 6 research ethics committees in Switzerland, Germany, and Canada between 2000 and 2003. The last follow-up of these trials was April 27, 2013.
Overall, 253 RCTs (24.9%) were discontinued, but only 38% of these discontinuations were reported to ethics committees.
Discontinued trials were more likely than completed trials to remain unpublished—55.1% vs 33.6% (P<0.001).
The most common reasons for discontinuation were poor recruitment (9.9%, 101/1017), administrative reasons (3.8%, 39/1017), and futility (3.6%, 37/1017).
A multivariate analysis revealed that industry sponsorship, compared to investigator sponsorship, and a larger planned sample size in increments of 100 were associated with lower rates of discontinuation due to poor recruitment. The adjusted odds ratios were 0.25 (P<0.001) and 0.96 (P=0.04), respectively.
Dr Kasenda and his colleagues said these results suggest researchers must put forth more effort to ensure that trial discontinuation is reported to ethics committees and that results of discontinued trials are published.
They said failure to publish these results is “a waste of valid data that could contribute to systematic reviews and meta-analyses.” In addition, taking steps to improve subject recruitment could greatly reduce RCT discontinuation.
T cells protect from GVHD, preserve GVT effect
GRAPEVINE, TEXAS—Adding specialized T cells to allogeneic bone marrow transplants can prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect, preclinical research suggests.
Donor-derived CD4+ invariant natural killer T cells (iNKT cells) helped protect mice from developing GVHD and lymphoma, thereby improving their survival.
As human CD4+ iNKT cells can be expanded in vitro, these findings may translate to the clinic, said study investigator Dominik Schneidawind, MD, of Stanford University in California.
Dr Schneidawind discussed this research at the 2014 BMT Tandem Meetings as abstract 2*, which was designated one of the meeting’s “Best Abstracts.”
Improved survival
Dr Schneidawind and his colleagues created a model of allogeneic bone marrow transplant in Balb/c (H-2Kd) mice. The mice were first irradiated with 8 Gy and then received T cell-depleted bone marrow, along with 1 x 106 CD4/CD8 T cells (Tcon) from C57Bl/6 (H-2Kb) donor mice and varying doses of CD4+ iNKT cells: 1 x 104 to 1 x 105.
Mice that received 100,000 CD4+ iNKT cells had significantly improved survival (P=0.002)—and better weight and GVHD scores—compared to mice that received bone marrow grafts alone. But a CD4+ iNKT dose as low as 10,000 cells also conferred a significant improvement in survival (P=0.03).
“In contrast, you need roughly 500,000 to 1 million donor-derived regulatory T cells to achieve a comparable survival benefit in this model of bone marrow transplantation,” Dr Schneidawind noted.
GVT effect
Dr Schneidawind and his colleagues also evaluated the impact of CD4+ iNKT cells on the GVT effect. They used luciferase-transfected BCL1 cells to induce lymphoma development, injecting the cells into mice 1 day before transplant.
Mice that received BCL1 cells, with or without CD4+ iNKT cells, showed increasing bioluminescence imaging (BLI) signals and all died from progressive lymphoma. The mice that received BLC1 and Tcon did not show an increase in BLI signals, but they all died from GVHD.
However, the mice that received BCL1, Tcon, and CD4+ iNKT cells didn’t show any sign of lymphoma or GVHD and survived through the whole experiment (P=0.002).
The investigators conducted the same experiment with the luciferase-positive A20 cell line. And they observed similar results. Mice that received A20 cells, Tcon, and CD4+ iNKT cells showed no sign of lymphoma and had significantly improved survival (P=0.002) over animals that received A20 and Tcon.
“Interestingly, animals that received A20 cells and 50,000 CD4+ iNKT cells only, without Tcon, showed a significant decrease in BLI signal and significantly improved survival,” Dr Schneidawind noted.
“So we conclude from these experiments that CD4+ iNKT cells do not abrogate the Tcon-mediated [GVT] effect but might exert some distinct antitumor activity by themselves.”
Mechanism of GVHD prevention
Lastly, Dr Schneidawind and his colleagues wanted to determine exactly how CD4+ iNKT cells prevent GVHD. The group’s experiments showed that the cells inhibit the proliferation of alloreactive T cells and promote the expansion of donor-derived CD4+ FoxP3+ Tregs.
The investigators decided to take a closer look at the Tregs, evaluating their role in GVHD-related death.
To do this, the team evaluated survival in 4 groups of mice: (1) irradiated controls; (2) mice that received only bone marrow; (3) mice that received Tcon, CD4+ iNKT cells, and a graft depleted of CD4+ FoxP3+ Tregs; and (4) mice that received Tcon, CD4+ iNKT cells, and a non-depleted graft.
“Animals that received a Treg-depleted graft and were treated with CD4+ iNKT [plus Tcon] did not show a significant improvement in survival [over controls],” Dr Schneidawind said.
“In contrast, animals that received a Treg-non-depleted graft showed a significant improvement in survival [P=0.006]. So we conclude that the expansion of these Tregs is necessary to protect from GVHD lethality and that they are required in this context.”
In closing, Dr Schneidawind noted that, although human CD4+ iNKT cells are rare, they can be isolated from peripheral blood and expanded in vitro. This suggests his group’s findings might ultimately prove useful for patients.
*Information in the abstract differs from that presented.
GRAPEVINE, TEXAS—Adding specialized T cells to allogeneic bone marrow transplants can prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect, preclinical research suggests.
Donor-derived CD4+ invariant natural killer T cells (iNKT cells) helped protect mice from developing GVHD and lymphoma, thereby improving their survival.
As human CD4+ iNKT cells can be expanded in vitro, these findings may translate to the clinic, said study investigator Dominik Schneidawind, MD, of Stanford University in California.
Dr Schneidawind discussed this research at the 2014 BMT Tandem Meetings as abstract 2*, which was designated one of the meeting’s “Best Abstracts.”
Improved survival
Dr Schneidawind and his colleagues created a model of allogeneic bone marrow transplant in Balb/c (H-2Kd) mice. The mice were first irradiated with 8 Gy and then received T cell-depleted bone marrow, along with 1 x 106 CD4/CD8 T cells (Tcon) from C57Bl/6 (H-2Kb) donor mice and varying doses of CD4+ iNKT cells: 1 x 104 to 1 x 105.
Mice that received 100,000 CD4+ iNKT cells had significantly improved survival (P=0.002)—and better weight and GVHD scores—compared to mice that received bone marrow grafts alone. But a CD4+ iNKT dose as low as 10,000 cells also conferred a significant improvement in survival (P=0.03).
“In contrast, you need roughly 500,000 to 1 million donor-derived regulatory T cells to achieve a comparable survival benefit in this model of bone marrow transplantation,” Dr Schneidawind noted.
GVT effect
Dr Schneidawind and his colleagues also evaluated the impact of CD4+ iNKT cells on the GVT effect. They used luciferase-transfected BCL1 cells to induce lymphoma development, injecting the cells into mice 1 day before transplant.
Mice that received BCL1 cells, with or without CD4+ iNKT cells, showed increasing bioluminescence imaging (BLI) signals and all died from progressive lymphoma. The mice that received BLC1 and Tcon did not show an increase in BLI signals, but they all died from GVHD.
However, the mice that received BCL1, Tcon, and CD4+ iNKT cells didn’t show any sign of lymphoma or GVHD and survived through the whole experiment (P=0.002).
The investigators conducted the same experiment with the luciferase-positive A20 cell line. And they observed similar results. Mice that received A20 cells, Tcon, and CD4+ iNKT cells showed no sign of lymphoma and had significantly improved survival (P=0.002) over animals that received A20 and Tcon.
“Interestingly, animals that received A20 cells and 50,000 CD4+ iNKT cells only, without Tcon, showed a significant decrease in BLI signal and significantly improved survival,” Dr Schneidawind noted.
“So we conclude from these experiments that CD4+ iNKT cells do not abrogate the Tcon-mediated [GVT] effect but might exert some distinct antitumor activity by themselves.”
Mechanism of GVHD prevention
Lastly, Dr Schneidawind and his colleagues wanted to determine exactly how CD4+ iNKT cells prevent GVHD. The group’s experiments showed that the cells inhibit the proliferation of alloreactive T cells and promote the expansion of donor-derived CD4+ FoxP3+ Tregs.
The investigators decided to take a closer look at the Tregs, evaluating their role in GVHD-related death.
To do this, the team evaluated survival in 4 groups of mice: (1) irradiated controls; (2) mice that received only bone marrow; (3) mice that received Tcon, CD4+ iNKT cells, and a graft depleted of CD4+ FoxP3+ Tregs; and (4) mice that received Tcon, CD4+ iNKT cells, and a non-depleted graft.
“Animals that received a Treg-depleted graft and were treated with CD4+ iNKT [plus Tcon] did not show a significant improvement in survival [over controls],” Dr Schneidawind said.
“In contrast, animals that received a Treg-non-depleted graft showed a significant improvement in survival [P=0.006]. So we conclude that the expansion of these Tregs is necessary to protect from GVHD lethality and that they are required in this context.”
In closing, Dr Schneidawind noted that, although human CD4+ iNKT cells are rare, they can be isolated from peripheral blood and expanded in vitro. This suggests his group’s findings might ultimately prove useful for patients.
*Information in the abstract differs from that presented.
GRAPEVINE, TEXAS—Adding specialized T cells to allogeneic bone marrow transplants can prevent graft-vs-host disease (GVHD) while preserving the graft-vs-tumor (GVT) effect, preclinical research suggests.
Donor-derived CD4+ invariant natural killer T cells (iNKT cells) helped protect mice from developing GVHD and lymphoma, thereby improving their survival.
As human CD4+ iNKT cells can be expanded in vitro, these findings may translate to the clinic, said study investigator Dominik Schneidawind, MD, of Stanford University in California.
Dr Schneidawind discussed this research at the 2014 BMT Tandem Meetings as abstract 2*, which was designated one of the meeting’s “Best Abstracts.”
Improved survival
Dr Schneidawind and his colleagues created a model of allogeneic bone marrow transplant in Balb/c (H-2Kd) mice. The mice were first irradiated with 8 Gy and then received T cell-depleted bone marrow, along with 1 x 106 CD4/CD8 T cells (Tcon) from C57Bl/6 (H-2Kb) donor mice and varying doses of CD4+ iNKT cells: 1 x 104 to 1 x 105.
Mice that received 100,000 CD4+ iNKT cells had significantly improved survival (P=0.002)—and better weight and GVHD scores—compared to mice that received bone marrow grafts alone. But a CD4+ iNKT dose as low as 10,000 cells also conferred a significant improvement in survival (P=0.03).
“In contrast, you need roughly 500,000 to 1 million donor-derived regulatory T cells to achieve a comparable survival benefit in this model of bone marrow transplantation,” Dr Schneidawind noted.
GVT effect
Dr Schneidawind and his colleagues also evaluated the impact of CD4+ iNKT cells on the GVT effect. They used luciferase-transfected BCL1 cells to induce lymphoma development, injecting the cells into mice 1 day before transplant.
Mice that received BCL1 cells, with or without CD4+ iNKT cells, showed increasing bioluminescence imaging (BLI) signals and all died from progressive lymphoma. The mice that received BLC1 and Tcon did not show an increase in BLI signals, but they all died from GVHD.
However, the mice that received BCL1, Tcon, and CD4+ iNKT cells didn’t show any sign of lymphoma or GVHD and survived through the whole experiment (P=0.002).
The investigators conducted the same experiment with the luciferase-positive A20 cell line. And they observed similar results. Mice that received A20 cells, Tcon, and CD4+ iNKT cells showed no sign of lymphoma and had significantly improved survival (P=0.002) over animals that received A20 and Tcon.
“Interestingly, animals that received A20 cells and 50,000 CD4+ iNKT cells only, without Tcon, showed a significant decrease in BLI signal and significantly improved survival,” Dr Schneidawind noted.
“So we conclude from these experiments that CD4+ iNKT cells do not abrogate the Tcon-mediated [GVT] effect but might exert some distinct antitumor activity by themselves.”
Mechanism of GVHD prevention
Lastly, Dr Schneidawind and his colleagues wanted to determine exactly how CD4+ iNKT cells prevent GVHD. The group’s experiments showed that the cells inhibit the proliferation of alloreactive T cells and promote the expansion of donor-derived CD4+ FoxP3+ Tregs.
The investigators decided to take a closer look at the Tregs, evaluating their role in GVHD-related death.
To do this, the team evaluated survival in 4 groups of mice: (1) irradiated controls; (2) mice that received only bone marrow; (3) mice that received Tcon, CD4+ iNKT cells, and a graft depleted of CD4+ FoxP3+ Tregs; and (4) mice that received Tcon, CD4+ iNKT cells, and a non-depleted graft.
“Animals that received a Treg-depleted graft and were treated with CD4+ iNKT [plus Tcon] did not show a significant improvement in survival [over controls],” Dr Schneidawind said.
“In contrast, animals that received a Treg-non-depleted graft showed a significant improvement in survival [P=0.006]. So we conclude that the expansion of these Tregs is necessary to protect from GVHD lethality and that they are required in this context.”
In closing, Dr Schneidawind noted that, although human CD4+ iNKT cells are rare, they can be isolated from peripheral blood and expanded in vitro. This suggests his group’s findings might ultimately prove useful for patients.
*Information in the abstract differs from that presented.
Trial registry info differs from journal publication
Credit: CDC/James Gathany
New research has revealed discrepancies between information posted on the ClinicalTrials.gov website and information published in journals.
During a 1-year period, nearly all of the trials published in “high-impact” journals and listed on ClinicalTrials.gov had at least 1 discrepancy between the 2 sources.
This included differences in study group data, intervention information, and primary and secondary endpoints.
Jessica E. Becker, of the Yale University School of Medicine in New Haven, Connecticut, and her colleagues disclosed these findings in a letter to JAMA.
The researchers identified 96 trials reporting results on ClinicalTrials.gov that were also published in 19 “high-impact” journals from July 1, 2010, to June 30, 2011. The trials were most frequently published in NEJM (n=23; 24%), The Lancet (n=18; 19%), and JAMA (n=11; 12%).
Common conditions investigated in these studies included cardiovascular disease, diabetes, and hyperlipidemia (n=21; 23%); cancer (n=20; 21%); and infectious disease (n=19; 20%). Seventy-three percent of the trials (n=70) were primarily funded by industry.
Cohort, intervention, and efficacy endpoint information was reported in both the journal and on ClinicalTrials.gov for most of the trials—ranging from 93% to 100%.
For 97% of the trials (93/96), there was at least 1 difference in information between the registry and the journal article. The level of discordance between the sources was lowest for enrollment numbers—2%—and highest for completion rates—22%.
Discordance was also quite high for the trial interventions (16%). This included differences in dosage descriptions, frequencies, and duration of the intervention.
There were 132 primary efficacy endpoints described in both sources. Fifty-two percent of these endpoints could be compared between the 2 sources and had concordant results. Results for 23% (n=30) could not be compared, and 16% (n=21) were discordant.
The majority (n=15) of discordant results did not alter the interpretation of the trial. But for 6 trials, the discordance did affect interpretation.
These trials had differences in time to disease progression, rate of disease recurrence, time to resolution of a condition, progression-free survival, and results of statistical analyses.
Among the 619 secondary efficacy endpoints that were described in both sources, results for 37% (n=228) could not be compared, and 9% (n=53) were discordant. Overall, 16% of secondary efficacy endpoints were described in both sources and reported concordant results.
The researchers said this study raises questions about the accuracy of information published on ClinicalTrials.gov and in journals.
Furthermore, because the journals studied have rigorous peer review processes, the trials in this sample may represent best-case scenarios with regard to the quality of results reporting.
Credit: CDC/James Gathany
New research has revealed discrepancies between information posted on the ClinicalTrials.gov website and information published in journals.
During a 1-year period, nearly all of the trials published in “high-impact” journals and listed on ClinicalTrials.gov had at least 1 discrepancy between the 2 sources.
This included differences in study group data, intervention information, and primary and secondary endpoints.
Jessica E. Becker, of the Yale University School of Medicine in New Haven, Connecticut, and her colleagues disclosed these findings in a letter to JAMA.
The researchers identified 96 trials reporting results on ClinicalTrials.gov that were also published in 19 “high-impact” journals from July 1, 2010, to June 30, 2011. The trials were most frequently published in NEJM (n=23; 24%), The Lancet (n=18; 19%), and JAMA (n=11; 12%).
Common conditions investigated in these studies included cardiovascular disease, diabetes, and hyperlipidemia (n=21; 23%); cancer (n=20; 21%); and infectious disease (n=19; 20%). Seventy-three percent of the trials (n=70) were primarily funded by industry.
Cohort, intervention, and efficacy endpoint information was reported in both the journal and on ClinicalTrials.gov for most of the trials—ranging from 93% to 100%.
For 97% of the trials (93/96), there was at least 1 difference in information between the registry and the journal article. The level of discordance between the sources was lowest for enrollment numbers—2%—and highest for completion rates—22%.
Discordance was also quite high for the trial interventions (16%). This included differences in dosage descriptions, frequencies, and duration of the intervention.
There were 132 primary efficacy endpoints described in both sources. Fifty-two percent of these endpoints could be compared between the 2 sources and had concordant results. Results for 23% (n=30) could not be compared, and 16% (n=21) were discordant.
The majority (n=15) of discordant results did not alter the interpretation of the trial. But for 6 trials, the discordance did affect interpretation.
These trials had differences in time to disease progression, rate of disease recurrence, time to resolution of a condition, progression-free survival, and results of statistical analyses.
Among the 619 secondary efficacy endpoints that were described in both sources, results for 37% (n=228) could not be compared, and 9% (n=53) were discordant. Overall, 16% of secondary efficacy endpoints were described in both sources and reported concordant results.
The researchers said this study raises questions about the accuracy of information published on ClinicalTrials.gov and in journals.
Furthermore, because the journals studied have rigorous peer review processes, the trials in this sample may represent best-case scenarios with regard to the quality of results reporting.
Credit: CDC/James Gathany
New research has revealed discrepancies between information posted on the ClinicalTrials.gov website and information published in journals.
During a 1-year period, nearly all of the trials published in “high-impact” journals and listed on ClinicalTrials.gov had at least 1 discrepancy between the 2 sources.
This included differences in study group data, intervention information, and primary and secondary endpoints.
Jessica E. Becker, of the Yale University School of Medicine in New Haven, Connecticut, and her colleagues disclosed these findings in a letter to JAMA.
The researchers identified 96 trials reporting results on ClinicalTrials.gov that were also published in 19 “high-impact” journals from July 1, 2010, to June 30, 2011. The trials were most frequently published in NEJM (n=23; 24%), The Lancet (n=18; 19%), and JAMA (n=11; 12%).
Common conditions investigated in these studies included cardiovascular disease, diabetes, and hyperlipidemia (n=21; 23%); cancer (n=20; 21%); and infectious disease (n=19; 20%). Seventy-three percent of the trials (n=70) were primarily funded by industry.
Cohort, intervention, and efficacy endpoint information was reported in both the journal and on ClinicalTrials.gov for most of the trials—ranging from 93% to 100%.
For 97% of the trials (93/96), there was at least 1 difference in information between the registry and the journal article. The level of discordance between the sources was lowest for enrollment numbers—2%—and highest for completion rates—22%.
Discordance was also quite high for the trial interventions (16%). This included differences in dosage descriptions, frequencies, and duration of the intervention.
There were 132 primary efficacy endpoints described in both sources. Fifty-two percent of these endpoints could be compared between the 2 sources and had concordant results. Results for 23% (n=30) could not be compared, and 16% (n=21) were discordant.
The majority (n=15) of discordant results did not alter the interpretation of the trial. But for 6 trials, the discordance did affect interpretation.
These trials had differences in time to disease progression, rate of disease recurrence, time to resolution of a condition, progression-free survival, and results of statistical analyses.
Among the 619 secondary efficacy endpoints that were described in both sources, results for 37% (n=228) could not be compared, and 9% (n=53) were discordant. Overall, 16% of secondary efficacy endpoints were described in both sources and reported concordant results.
The researchers said this study raises questions about the accuracy of information published on ClinicalTrials.gov and in journals.
Furthermore, because the journals studied have rigorous peer review processes, the trials in this sample may represent best-case scenarios with regard to the quality of results reporting.
PODCAST: Highlights of the March 2014 Issue of The Hospitalist
This month in our issue, we look at the challenges and rewards of global health work. Hospitalist Dr. Brett Hendel-Paterson, who participates in HealthPartners’ Travel and Tropical Medicine Center in St. Paul, Minnesota discusses how humility, curiosity, and hope are at the root of clinicians’ experiences in global health work, and the long-term commitment and social contract needed to do the job. Dr. Evan Lyon, head of the University of Chicago’s Global Hospital Medicine Fellowship program, shares how global health work has influenced his interactions with his patients.
For those attending the Society of Hospital Medicine’s annual conference, HM14, we offer tips on using the HM14 In Hand mobile app to navigate the courses, events, and must-sees at this year’s convention.
Also in this issue, we look at what makes a hospital medicine group effective, offer Dr. Win Whitcomb’s primer on the relative value unit and its place in the shift from volume-to-value reimbursement, look at CMS’s efforts to increase participation in the physician quality reporting system, and our Key Clinical Question covers which patients undergoing gastrointestinal endoscopic procedures should receive antibiotic prophylaxis.
Click here to listen to the March highlights podcast.
This month in our issue, we look at the challenges and rewards of global health work. Hospitalist Dr. Brett Hendel-Paterson, who participates in HealthPartners’ Travel and Tropical Medicine Center in St. Paul, Minnesota discusses how humility, curiosity, and hope are at the root of clinicians’ experiences in global health work, and the long-term commitment and social contract needed to do the job. Dr. Evan Lyon, head of the University of Chicago’s Global Hospital Medicine Fellowship program, shares how global health work has influenced his interactions with his patients.
For those attending the Society of Hospital Medicine’s annual conference, HM14, we offer tips on using the HM14 In Hand mobile app to navigate the courses, events, and must-sees at this year’s convention.
Also in this issue, we look at what makes a hospital medicine group effective, offer Dr. Win Whitcomb’s primer on the relative value unit and its place in the shift from volume-to-value reimbursement, look at CMS’s efforts to increase participation in the physician quality reporting system, and our Key Clinical Question covers which patients undergoing gastrointestinal endoscopic procedures should receive antibiotic prophylaxis.
Click here to listen to the March highlights podcast.
This month in our issue, we look at the challenges and rewards of global health work. Hospitalist Dr. Brett Hendel-Paterson, who participates in HealthPartners’ Travel and Tropical Medicine Center in St. Paul, Minnesota discusses how humility, curiosity, and hope are at the root of clinicians’ experiences in global health work, and the long-term commitment and social contract needed to do the job. Dr. Evan Lyon, head of the University of Chicago’s Global Hospital Medicine Fellowship program, shares how global health work has influenced his interactions with his patients.
For those attending the Society of Hospital Medicine’s annual conference, HM14, we offer tips on using the HM14 In Hand mobile app to navigate the courses, events, and must-sees at this year’s convention.
Also in this issue, we look at what makes a hospital medicine group effective, offer Dr. Win Whitcomb’s primer on the relative value unit and its place in the shift from volume-to-value reimbursement, look at CMS’s efforts to increase participation in the physician quality reporting system, and our Key Clinical Question covers which patients undergoing gastrointestinal endoscopic procedures should receive antibiotic prophylaxis.
Click here to listen to the March highlights podcast.
University of Chicago Hospitalist Evan Lyon, MD, Chats about Rational Testing and Social Context in Low-Resource Areas
Hospitalists Are Uniquely Qualified for Global Health Initiatives
Hospitalist Vincent DeGennaro, Jr., MD, MPH, didn’t train as an oncologist. But during the course of his daily duties at the Hospital Bernard Mevs in Port-au-Prince, Haiti, he administers chemotherapy at the hospital’s women’s cancer center.
“Chemotherapy was outside the realm of my specialty, but under the training and remote consultation of U.S. oncologists, I have become more comfortable with it,” says Dr. DeGennaro, an assistant professor in the division of hospital medicine at the University of Florida College of Medicine in Gainesville. Along with performing echocardiograms and working in Haiti’s only ICU, it’s an example of how global health forces him to be a “true generalist.” That’s also true of hospital medicine. In fact, the flexible schedule hospital medicine offers was a deciding factor in his career choice. Shift work in a discrete time period would allow him, he reasoned, to also follow his passion of global health.
Volunteering in low-resource settings was something that “felt right to me from the beginning,” Dr. DeGennaro says. He worked in Honduras and the Dominican Republic during medical school, mostly through medical missions organizations. Work with Partners in Health during medical school and in Rwanda after residency exposed him to the capacity-building goals of that organization. He now spends seven months of the academic year in Haiti, where he is helping Project Medishare (www.projectmedishare.org) in its efforts to build capacity and infrastructure at the country’s major trauma hospital. In July, he will be supervising clinical fellows as the director of the University of Florida’s first HM global health fellowship program.
Haitian patients have to pay for their own tests, so Dr. DeGennaro must carefully choose those that will guide his management decisions for patients. “Low-resource utilization forces you to become a better clinician,” he says. “I think we have gotten intellectually lazy in the United States, where we can order a dozen tests and let the results guide us instead of using our clinical skills to narrow what tests to order.”
Delivering care in under-resourced countries, he adds, has changed him: “I’m a much better doctor for it.”
Gretchen Henkel is a freelance writer in California.
Hospitalist Vincent DeGennaro, Jr., MD, MPH, didn’t train as an oncologist. But during the course of his daily duties at the Hospital Bernard Mevs in Port-au-Prince, Haiti, he administers chemotherapy at the hospital’s women’s cancer center.
“Chemotherapy was outside the realm of my specialty, but under the training and remote consultation of U.S. oncologists, I have become more comfortable with it,” says Dr. DeGennaro, an assistant professor in the division of hospital medicine at the University of Florida College of Medicine in Gainesville. Along with performing echocardiograms and working in Haiti’s only ICU, it’s an example of how global health forces him to be a “true generalist.” That’s also true of hospital medicine. In fact, the flexible schedule hospital medicine offers was a deciding factor in his career choice. Shift work in a discrete time period would allow him, he reasoned, to also follow his passion of global health.
Volunteering in low-resource settings was something that “felt right to me from the beginning,” Dr. DeGennaro says. He worked in Honduras and the Dominican Republic during medical school, mostly through medical missions organizations. Work with Partners in Health during medical school and in Rwanda after residency exposed him to the capacity-building goals of that organization. He now spends seven months of the academic year in Haiti, where he is helping Project Medishare (www.projectmedishare.org) in its efforts to build capacity and infrastructure at the country’s major trauma hospital. In July, he will be supervising clinical fellows as the director of the University of Florida’s first HM global health fellowship program.
Haitian patients have to pay for their own tests, so Dr. DeGennaro must carefully choose those that will guide his management decisions for patients. “Low-resource utilization forces you to become a better clinician,” he says. “I think we have gotten intellectually lazy in the United States, where we can order a dozen tests and let the results guide us instead of using our clinical skills to narrow what tests to order.”
Delivering care in under-resourced countries, he adds, has changed him: “I’m a much better doctor for it.”
Gretchen Henkel is a freelance writer in California.
Hospitalist Vincent DeGennaro, Jr., MD, MPH, didn’t train as an oncologist. But during the course of his daily duties at the Hospital Bernard Mevs in Port-au-Prince, Haiti, he administers chemotherapy at the hospital’s women’s cancer center.
“Chemotherapy was outside the realm of my specialty, but under the training and remote consultation of U.S. oncologists, I have become more comfortable with it,” says Dr. DeGennaro, an assistant professor in the division of hospital medicine at the University of Florida College of Medicine in Gainesville. Along with performing echocardiograms and working in Haiti’s only ICU, it’s an example of how global health forces him to be a “true generalist.” That’s also true of hospital medicine. In fact, the flexible schedule hospital medicine offers was a deciding factor in his career choice. Shift work in a discrete time period would allow him, he reasoned, to also follow his passion of global health.
Volunteering in low-resource settings was something that “felt right to me from the beginning,” Dr. DeGennaro says. He worked in Honduras and the Dominican Republic during medical school, mostly through medical missions organizations. Work with Partners in Health during medical school and in Rwanda after residency exposed him to the capacity-building goals of that organization. He now spends seven months of the academic year in Haiti, where he is helping Project Medishare (www.projectmedishare.org) in its efforts to build capacity and infrastructure at the country’s major trauma hospital. In July, he will be supervising clinical fellows as the director of the University of Florida’s first HM global health fellowship program.
Haitian patients have to pay for their own tests, so Dr. DeGennaro must carefully choose those that will guide his management decisions for patients. “Low-resource utilization forces you to become a better clinician,” he says. “I think we have gotten intellectually lazy in the United States, where we can order a dozen tests and let the results guide us instead of using our clinical skills to narrow what tests to order.”
Delivering care in under-resourced countries, he adds, has changed him: “I’m a much better doctor for it.”
Gretchen Henkel is a freelance writer in California.
Patient-Specific Instrumentation: Incorporating New Technology in Total Knee Arthroplasty
Some consider denosumab standard treatment for unresectable giant cell tumor of bone
MILAN – Denosumab, a drug originally developed to treat patients with osteoporosis, can halt progression of giant cell tumor of the bone and is now considered by some experts to be standard treatment for patients with tumors that cannot be surgically removed without causing significant morbidity.
The Food and Drug Administration added this indication to the labeling for denosumab (Xgeva) in June 2013, and current management recommendations from the National Comprehensive Cancer Network list denosumab treatment as an option for patients with unresectable giant cell tumor of the bone (GCTB).
But experience with denosumab for this indication is limited and of relatively short duration, and questions remain about its optimal use.
"Does treatment need to be lifelong, if so what is the optimal schedule, and what are the long-term sequelae?" Dr. David Thomas said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "If surgical resection is an option that is absolutely the first option. This is not an antitumor drug. It contains the tumor’s progression, and it does that very well," said Dr. Thomas, head of the sarcoma genomics and genetics laboratory at Peter MacCallum Cancer Centre in Melbourne.
"It’s clearly a good idea for patients with GCTB, where you would have to do a mutilating operation" to remove the tumor. But you’d be crazy to use it for a GCTB of the proximal tibia that is curable by resection and curettage and packing with cement," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at University of Texas M.D. Anderson Cancer Center, Houston. About 90% of GCTB are resectable in a way that is acceptable to patients, he estimated during an interview.
"For the 10% for whom surgery is not a good option, denosumab is fantastic, and it’s being used, but most medical oncologists never see these patients" because GCTB is relatively rare, Dr. Benjamin said.
The largest reported experience with denosumab in patients with GCTB was an international, multicenter, open-label study with 282 patients and a 13-month median follow-up reported last year by Dr. Thomas and his associates (Lancet Onc. 2013;14:901-8). Although this experience provided evidence for the drug’s efficacy and reasonable safety for many patients, the documented experience remains relatively short for a drug that may need to be taken lifelong to keep the tumor in check. And many patients would start treatment relatively early in life because when GCTB occurs, it is often in adolescents or young adults.
"We really don’t know what will happen long term," Dr. Thomas cautioned in an interview.
The published experience also highlighted some potential adverse effects from denosumab that warrant close monitoring of patients. Three of the 281 patients (1%) available for the safety analysis developed osteonecrosis of the jaw; 15 patients (5%) developed hypocalcemia, although none were considered serious; 5 patients (2%) had a serious infection; and 3 patients (1%) had a new primary malignancy. In addition, women should not become pregnant while on denosumab. So far, follow-up produced no suggestion of an increased rate of malignant transformation of the GCTB, he said.
"Because you may need to treat for a lifetime, it’s a big decision to start treatment. But before we had this, we couldn’t have a discussion," of a treatment option when surgery wasn’t possible, he said. "I had a patient in 2004, before denosumab was available, with multiple, recurrent giant cell tumors that spread up his spine" and hence were inoperable and the patient died from the "enormous morbidity" the tumor caused. "Denosumab would have likely saved his life," Dr. Thomas said.
The denosumab study was sponsored by Amgen, maker of the drug. Dr. Thomas said that he has received consulting fees and research support from Amgen. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
On Twitter @mitchelzoler
MILAN – Denosumab, a drug originally developed to treat patients with osteoporosis, can halt progression of giant cell tumor of the bone and is now considered by some experts to be standard treatment for patients with tumors that cannot be surgically removed without causing significant morbidity.
The Food and Drug Administration added this indication to the labeling for denosumab (Xgeva) in June 2013, and current management recommendations from the National Comprehensive Cancer Network list denosumab treatment as an option for patients with unresectable giant cell tumor of the bone (GCTB).
But experience with denosumab for this indication is limited and of relatively short duration, and questions remain about its optimal use.
"Does treatment need to be lifelong, if so what is the optimal schedule, and what are the long-term sequelae?" Dr. David Thomas said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "If surgical resection is an option that is absolutely the first option. This is not an antitumor drug. It contains the tumor’s progression, and it does that very well," said Dr. Thomas, head of the sarcoma genomics and genetics laboratory at Peter MacCallum Cancer Centre in Melbourne.
"It’s clearly a good idea for patients with GCTB, where you would have to do a mutilating operation" to remove the tumor. But you’d be crazy to use it for a GCTB of the proximal tibia that is curable by resection and curettage and packing with cement," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at University of Texas M.D. Anderson Cancer Center, Houston. About 90% of GCTB are resectable in a way that is acceptable to patients, he estimated during an interview.
"For the 10% for whom surgery is not a good option, denosumab is fantastic, and it’s being used, but most medical oncologists never see these patients" because GCTB is relatively rare, Dr. Benjamin said.
The largest reported experience with denosumab in patients with GCTB was an international, multicenter, open-label study with 282 patients and a 13-month median follow-up reported last year by Dr. Thomas and his associates (Lancet Onc. 2013;14:901-8). Although this experience provided evidence for the drug’s efficacy and reasonable safety for many patients, the documented experience remains relatively short for a drug that may need to be taken lifelong to keep the tumor in check. And many patients would start treatment relatively early in life because when GCTB occurs, it is often in adolescents or young adults.
"We really don’t know what will happen long term," Dr. Thomas cautioned in an interview.
The published experience also highlighted some potential adverse effects from denosumab that warrant close monitoring of patients. Three of the 281 patients (1%) available for the safety analysis developed osteonecrosis of the jaw; 15 patients (5%) developed hypocalcemia, although none were considered serious; 5 patients (2%) had a serious infection; and 3 patients (1%) had a new primary malignancy. In addition, women should not become pregnant while on denosumab. So far, follow-up produced no suggestion of an increased rate of malignant transformation of the GCTB, he said.
"Because you may need to treat for a lifetime, it’s a big decision to start treatment. But before we had this, we couldn’t have a discussion," of a treatment option when surgery wasn’t possible, he said. "I had a patient in 2004, before denosumab was available, with multiple, recurrent giant cell tumors that spread up his spine" and hence were inoperable and the patient died from the "enormous morbidity" the tumor caused. "Denosumab would have likely saved his life," Dr. Thomas said.
The denosumab study was sponsored by Amgen, maker of the drug. Dr. Thomas said that he has received consulting fees and research support from Amgen. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
On Twitter @mitchelzoler
MILAN – Denosumab, a drug originally developed to treat patients with osteoporosis, can halt progression of giant cell tumor of the bone and is now considered by some experts to be standard treatment for patients with tumors that cannot be surgically removed without causing significant morbidity.
The Food and Drug Administration added this indication to the labeling for denosumab (Xgeva) in June 2013, and current management recommendations from the National Comprehensive Cancer Network list denosumab treatment as an option for patients with unresectable giant cell tumor of the bone (GCTB).
But experience with denosumab for this indication is limited and of relatively short duration, and questions remain about its optimal use.
"Does treatment need to be lifelong, if so what is the optimal schedule, and what are the long-term sequelae?" Dr. David Thomas said at Sarcoma and GIST 2014, hosted by the European Society for Medical Oncology. "If surgical resection is an option that is absolutely the first option. This is not an antitumor drug. It contains the tumor’s progression, and it does that very well," said Dr. Thomas, head of the sarcoma genomics and genetics laboratory at Peter MacCallum Cancer Centre in Melbourne.
"It’s clearly a good idea for patients with GCTB, where you would have to do a mutilating operation" to remove the tumor. But you’d be crazy to use it for a GCTB of the proximal tibia that is curable by resection and curettage and packing with cement," said Dr. Robert S. Benjamin, professor and chairman of sarcoma medical oncology at University of Texas M.D. Anderson Cancer Center, Houston. About 90% of GCTB are resectable in a way that is acceptable to patients, he estimated during an interview.
"For the 10% for whom surgery is not a good option, denosumab is fantastic, and it’s being used, but most medical oncologists never see these patients" because GCTB is relatively rare, Dr. Benjamin said.
The largest reported experience with denosumab in patients with GCTB was an international, multicenter, open-label study with 282 patients and a 13-month median follow-up reported last year by Dr. Thomas and his associates (Lancet Onc. 2013;14:901-8). Although this experience provided evidence for the drug’s efficacy and reasonable safety for many patients, the documented experience remains relatively short for a drug that may need to be taken lifelong to keep the tumor in check. And many patients would start treatment relatively early in life because when GCTB occurs, it is often in adolescents or young adults.
"We really don’t know what will happen long term," Dr. Thomas cautioned in an interview.
The published experience also highlighted some potential adverse effects from denosumab that warrant close monitoring of patients. Three of the 281 patients (1%) available for the safety analysis developed osteonecrosis of the jaw; 15 patients (5%) developed hypocalcemia, although none were considered serious; 5 patients (2%) had a serious infection; and 3 patients (1%) had a new primary malignancy. In addition, women should not become pregnant while on denosumab. So far, follow-up produced no suggestion of an increased rate of malignant transformation of the GCTB, he said.
"Because you may need to treat for a lifetime, it’s a big decision to start treatment. But before we had this, we couldn’t have a discussion," of a treatment option when surgery wasn’t possible, he said. "I had a patient in 2004, before denosumab was available, with multiple, recurrent giant cell tumors that spread up his spine" and hence were inoperable and the patient died from the "enormous morbidity" the tumor caused. "Denosumab would have likely saved his life," Dr. Thomas said.
The denosumab study was sponsored by Amgen, maker of the drug. Dr. Thomas said that he has received consulting fees and research support from Amgen. Dr. Benjamin said that he has been a consultant to Johnson & Johnson, Merck, and Pfizer.
On Twitter @mitchelzoler
EXPERT ANALYSIS FROM SARCOMA AND GIST 2014
Order of Cy, TBI doesn’t impact HSCT outcome
GRAPEVINE, TEXAS—The order in which patients receive cyclophosphamide (Cy) and total body irradiation (TBI) does not affect the outcome of hematopoietic stem cell transplant (HSCT), researchers have reported.
In a large, retrospective study, the rates of relapse, survival, chronic graft-vs-host disease (GVHD), and other complications were similar whether patients received Cy-TBI or TBI-Cy.
However, receiving Cy-TBI was associated with a slight decrease in the risk of grade 2-4 acute GVHD.
Jennifer L. Holter-Chakrabarty, MD, of the University of Oklahoma in Oklahoma City, presented these findings at the 2014 BMT Tandem Meetings as abstract 13.
She noted that other researchers have investigated the impact of TBI/Cy order, but the results have not provided definitive answers.
“Mouse models show that TBI-Cy is superior, with reduced lung toxicity and increased incidence of bone marrow damage,” Dr Holter-Chakrabarty said.
“Cy-TBI, however, in a retrospective study, showed improved anti-leukemic effect, as well as increased incidence of sinusoidal obstructive syndrome. So for this reason, we wanted to look at the CIBMTR database and compare the order of cyclophosphamide and TBI.”
She and her colleagues analyzed data from 1769 HSCT recipients who were younger than 60 years of age and had been reported to the CIBMTR from 2003 to 2010. Patients had been diagnosed with acute myeloid leukemia (AML, n=945) or acute lymphoblastic leukemia (ALL, n=824) and were in their first or second remission.
They had received TBI doses of at least 1200 cGy, followed by related or unrelated bone marrow or peripheral blood stem cell grafts. Patients who had received cord blood, haploidentical, or T-cell-depleted grafts were excluded.
In all, 948 patients received Cy-TBI, and 821 received TBI-Cy. The 2 cohorts had comparable patient-, disease- and transplant-related characteristics.
The sequence of TBI and Cy did not significantly affect the rates of relapse, leukemia-free survival, or overall survival. And it had no significant impact on transplant-related complications, with the exception of acute grade 2-4 GVHD.
At 100 days, the rate of grade 2-4 acute GVHD was 39% in the Cy-TBI group and 45% in the TBI-Cy group (P=0.01). But the rates of grade 3-4 acute GVHD were 16% and 15%, respectively (P=0.62).
At 100 days, the incidence of veno-occlusive disease and sinusoidal obstructive syndrome was 4% in the Cy-TBI group and 6% in the TBI-Cy group (P=0.082). At 1 year, the incidence of interstitial pneumonia syndrome was 6% and 5%, respectively (P=0.370).
At 3 years, the relapse rate was 27% in the Cy-TBI group and 29% in the TBI-Cy group (P=0.34). Leukemia-free survival was 48% and 49%, respectively (P=0.27). And overall survival was 53% and 52%, respectively (P=0.62).
Transplant-related mortality at 3 years was 24% and 23%, respectively (P=0.67). And the rate of chronic GVHD was 45% and 47%, respectively (P=0.39).
“So, in this population, we see no difference,” Dr Holter-Chakrabarty said. “Cy-TBI or TBI-Cy—it seems to not make a difference either way in relapse, treatment-related mortality, [chronic] graft-vs-host disease, acute 3 and 4 [GVHD], and survival. However, it does give us an idea that 2-4 acute GVHD may be lower in Cy-TBI.”
GRAPEVINE, TEXAS—The order in which patients receive cyclophosphamide (Cy) and total body irradiation (TBI) does not affect the outcome of hematopoietic stem cell transplant (HSCT), researchers have reported.
In a large, retrospective study, the rates of relapse, survival, chronic graft-vs-host disease (GVHD), and other complications were similar whether patients received Cy-TBI or TBI-Cy.
However, receiving Cy-TBI was associated with a slight decrease in the risk of grade 2-4 acute GVHD.
Jennifer L. Holter-Chakrabarty, MD, of the University of Oklahoma in Oklahoma City, presented these findings at the 2014 BMT Tandem Meetings as abstract 13.
She noted that other researchers have investigated the impact of TBI/Cy order, but the results have not provided definitive answers.
“Mouse models show that TBI-Cy is superior, with reduced lung toxicity and increased incidence of bone marrow damage,” Dr Holter-Chakrabarty said.
“Cy-TBI, however, in a retrospective study, showed improved anti-leukemic effect, as well as increased incidence of sinusoidal obstructive syndrome. So for this reason, we wanted to look at the CIBMTR database and compare the order of cyclophosphamide and TBI.”
She and her colleagues analyzed data from 1769 HSCT recipients who were younger than 60 years of age and had been reported to the CIBMTR from 2003 to 2010. Patients had been diagnosed with acute myeloid leukemia (AML, n=945) or acute lymphoblastic leukemia (ALL, n=824) and were in their first or second remission.
They had received TBI doses of at least 1200 cGy, followed by related or unrelated bone marrow or peripheral blood stem cell grafts. Patients who had received cord blood, haploidentical, or T-cell-depleted grafts were excluded.
In all, 948 patients received Cy-TBI, and 821 received TBI-Cy. The 2 cohorts had comparable patient-, disease- and transplant-related characteristics.
The sequence of TBI and Cy did not significantly affect the rates of relapse, leukemia-free survival, or overall survival. And it had no significant impact on transplant-related complications, with the exception of acute grade 2-4 GVHD.
At 100 days, the rate of grade 2-4 acute GVHD was 39% in the Cy-TBI group and 45% in the TBI-Cy group (P=0.01). But the rates of grade 3-4 acute GVHD were 16% and 15%, respectively (P=0.62).
At 100 days, the incidence of veno-occlusive disease and sinusoidal obstructive syndrome was 4% in the Cy-TBI group and 6% in the TBI-Cy group (P=0.082). At 1 year, the incidence of interstitial pneumonia syndrome was 6% and 5%, respectively (P=0.370).
At 3 years, the relapse rate was 27% in the Cy-TBI group and 29% in the TBI-Cy group (P=0.34). Leukemia-free survival was 48% and 49%, respectively (P=0.27). And overall survival was 53% and 52%, respectively (P=0.62).
Transplant-related mortality at 3 years was 24% and 23%, respectively (P=0.67). And the rate of chronic GVHD was 45% and 47%, respectively (P=0.39).
“So, in this population, we see no difference,” Dr Holter-Chakrabarty said. “Cy-TBI or TBI-Cy—it seems to not make a difference either way in relapse, treatment-related mortality, [chronic] graft-vs-host disease, acute 3 and 4 [GVHD], and survival. However, it does give us an idea that 2-4 acute GVHD may be lower in Cy-TBI.”
GRAPEVINE, TEXAS—The order in which patients receive cyclophosphamide (Cy) and total body irradiation (TBI) does not affect the outcome of hematopoietic stem cell transplant (HSCT), researchers have reported.
In a large, retrospective study, the rates of relapse, survival, chronic graft-vs-host disease (GVHD), and other complications were similar whether patients received Cy-TBI or TBI-Cy.
However, receiving Cy-TBI was associated with a slight decrease in the risk of grade 2-4 acute GVHD.
Jennifer L. Holter-Chakrabarty, MD, of the University of Oklahoma in Oklahoma City, presented these findings at the 2014 BMT Tandem Meetings as abstract 13.
She noted that other researchers have investigated the impact of TBI/Cy order, but the results have not provided definitive answers.
“Mouse models show that TBI-Cy is superior, with reduced lung toxicity and increased incidence of bone marrow damage,” Dr Holter-Chakrabarty said.
“Cy-TBI, however, in a retrospective study, showed improved anti-leukemic effect, as well as increased incidence of sinusoidal obstructive syndrome. So for this reason, we wanted to look at the CIBMTR database and compare the order of cyclophosphamide and TBI.”
She and her colleagues analyzed data from 1769 HSCT recipients who were younger than 60 years of age and had been reported to the CIBMTR from 2003 to 2010. Patients had been diagnosed with acute myeloid leukemia (AML, n=945) or acute lymphoblastic leukemia (ALL, n=824) and were in their first or second remission.
They had received TBI doses of at least 1200 cGy, followed by related or unrelated bone marrow or peripheral blood stem cell grafts. Patients who had received cord blood, haploidentical, or T-cell-depleted grafts were excluded.
In all, 948 patients received Cy-TBI, and 821 received TBI-Cy. The 2 cohorts had comparable patient-, disease- and transplant-related characteristics.
The sequence of TBI and Cy did not significantly affect the rates of relapse, leukemia-free survival, or overall survival. And it had no significant impact on transplant-related complications, with the exception of acute grade 2-4 GVHD.
At 100 days, the rate of grade 2-4 acute GVHD was 39% in the Cy-TBI group and 45% in the TBI-Cy group (P=0.01). But the rates of grade 3-4 acute GVHD were 16% and 15%, respectively (P=0.62).
At 100 days, the incidence of veno-occlusive disease and sinusoidal obstructive syndrome was 4% in the Cy-TBI group and 6% in the TBI-Cy group (P=0.082). At 1 year, the incidence of interstitial pneumonia syndrome was 6% and 5%, respectively (P=0.370).
At 3 years, the relapse rate was 27% in the Cy-TBI group and 29% in the TBI-Cy group (P=0.34). Leukemia-free survival was 48% and 49%, respectively (P=0.27). And overall survival was 53% and 52%, respectively (P=0.62).
Transplant-related mortality at 3 years was 24% and 23%, respectively (P=0.67). And the rate of chronic GVHD was 45% and 47%, respectively (P=0.39).
“So, in this population, we see no difference,” Dr Holter-Chakrabarty said. “Cy-TBI or TBI-Cy—it seems to not make a difference either way in relapse, treatment-related mortality, [chronic] graft-vs-host disease, acute 3 and 4 [GVHD], and survival. However, it does give us an idea that 2-4 acute GVHD may be lower in Cy-TBI.”