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New insight into T-cell development
Credit: NIAID
A fundamental theory about how the thymus “educates” T cells appears to be wrong, according to research published in Nature Communications.
It’s known that stem cells leave the bone marrow and travel to the thymus to become one of two CD4 T-cell types: effector cells or regulatory T cells (Tregs).
One widely held concept of why the cells become one type or the other is that they are exposed to different ligands in the thymus, said Leszek Ignatowicz, PhD, of Georgia Regents University in Augusta.
But when he and his colleagues limited the cells’ exposure to only one ligand, the same mix of T cells still emerged.
“We asked a simple question, ‘Is it going to affect their development,’ and the answer was ‘no,’” Dr Ignatowicz said. “The cells still mature in the thymus, so something else must be determining it.”
The finding provides more insight into immunity that could one day enable a new approach to vaccines that steer the thymus to produce more of whatever T-cell type a patient needs: more effector cells if they have an infection or cancer, more Tregs if they have autoimmune diseases such as arthritis and multiple sclerosis.
“We could help steer the education process in the desired direction,” Dr Ignatowicz said.
To uncover their findings, he and his colleagues studied two types of mice, each expressing a single ligand in the thymus. The researchers thought one would prompt strong ligand binding and favor Treg development, and the other would favor a weaker ligand bond and effector cell development.
The mix of resulting T cells was the same as if both were exposed to the usual thousands of ligands, although the experiment did reveal one difference.
Ligands—and, eventually, bacteria and other invaders—get the attention of T cells by activating their receptors. Both CD4 T-cell types generally have the same receptors, but they are organized differently.
The researchers found that as long as the binding was weak, as it was in the first mouse, there was a lot of overlap in the receptors the ligand bound to in both T-cell types. However, in the second mouse, where the ligand prompted strong binding, there was far less overlap.
“We are now trying to find what causes that difference,” Dr Ignatowicz said. 
Credit: NIAID
A fundamental theory about how the thymus “educates” T cells appears to be wrong, according to research published in Nature Communications.
It’s known that stem cells leave the bone marrow and travel to the thymus to become one of two CD4 T-cell types: effector cells or regulatory T cells (Tregs).
One widely held concept of why the cells become one type or the other is that they are exposed to different ligands in the thymus, said Leszek Ignatowicz, PhD, of Georgia Regents University in Augusta.
But when he and his colleagues limited the cells’ exposure to only one ligand, the same mix of T cells still emerged.
“We asked a simple question, ‘Is it going to affect their development,’ and the answer was ‘no,’” Dr Ignatowicz said. “The cells still mature in the thymus, so something else must be determining it.”
The finding provides more insight into immunity that could one day enable a new approach to vaccines that steer the thymus to produce more of whatever T-cell type a patient needs: more effector cells if they have an infection or cancer, more Tregs if they have autoimmune diseases such as arthritis and multiple sclerosis.
“We could help steer the education process in the desired direction,” Dr Ignatowicz said.
To uncover their findings, he and his colleagues studied two types of mice, each expressing a single ligand in the thymus. The researchers thought one would prompt strong ligand binding and favor Treg development, and the other would favor a weaker ligand bond and effector cell development.
The mix of resulting T cells was the same as if both were exposed to the usual thousands of ligands, although the experiment did reveal one difference.
Ligands—and, eventually, bacteria and other invaders—get the attention of T cells by activating their receptors. Both CD4 T-cell types generally have the same receptors, but they are organized differently.
The researchers found that as long as the binding was weak, as it was in the first mouse, there was a lot of overlap in the receptors the ligand bound to in both T-cell types. However, in the second mouse, where the ligand prompted strong binding, there was far less overlap.
“We are now trying to find what causes that difference,” Dr Ignatowicz said.
Credit: NIAID
A fundamental theory about how the thymus “educates” T cells appears to be wrong, according to research published in Nature Communications.
It’s known that stem cells leave the bone marrow and travel to the thymus to become one of two CD4 T-cell types: effector cells or regulatory T cells (Tregs).
One widely held concept of why the cells become one type or the other is that they are exposed to different ligands in the thymus, said Leszek Ignatowicz, PhD, of Georgia Regents University in Augusta.
But when he and his colleagues limited the cells’ exposure to only one ligand, the same mix of T cells still emerged.
“We asked a simple question, ‘Is it going to affect their development,’ and the answer was ‘no,’” Dr Ignatowicz said. “The cells still mature in the thymus, so something else must be determining it.”
The finding provides more insight into immunity that could one day enable a new approach to vaccines that steer the thymus to produce more of whatever T-cell type a patient needs: more effector cells if they have an infection or cancer, more Tregs if they have autoimmune diseases such as arthritis and multiple sclerosis.
“We could help steer the education process in the desired direction,” Dr Ignatowicz said.
To uncover their findings, he and his colleagues studied two types of mice, each expressing a single ligand in the thymus. The researchers thought one would prompt strong ligand binding and favor Treg development, and the other would favor a weaker ligand bond and effector cell development.
The mix of resulting T cells was the same as if both were exposed to the usual thousands of ligands, although the experiment did reveal one difference.
Ligands—and, eventually, bacteria and other invaders—get the attention of T cells by activating their receptors. Both CD4 T-cell types generally have the same receptors, but they are organized differently.
The researchers found that as long as the binding was weak, as it was in the first mouse, there was a lot of overlap in the receptors the ligand bound to in both T-cell types. However, in the second mouse, where the ligand prompted strong binding, there was far less overlap.
“We are now trying to find what causes that difference,” Dr Ignatowicz said.
Insurance–Readmission Paradox
The Affordable Care Act has made hospital readmissions a major public policy target by tying Medicare hospital payments to readmission rates for certain diseases. Since then, debate has spiked over the factors contributing to hospital readmissions, with particular attention being paid to the impact of socioeconomic status and access to care. The Massachusetts healthcare reform of 2006 is a useful natural experiment to help disentangle some of these effects. Although reform did little to change patients' income, education, health literacy, or other determinants of socioeconomic status, it did dramatically reduce uninsurance rates. State‐wide uninsurance rates dropped from 8.4% prereform to 3.4% postreform.[1] Most important, a gain in insurance appeared to translate to genuine improvements in access to outpatient and preventive care. Massachusetts residents postreform were more likely to report a usual source of care, were more likely to have had outpatient office visits, and less likely to use the emergency department.[1, 2, 3, 4] Thus, the 2006 Massachusetts health reform legislation appears to have genuinely increased access both to insurance and to outpatient care, while reducing the need for preventable hospital‐based care.
Contrary to popular belief, patients without insurance have low unadjusted readmission rates for most conditions, often even lower than rates among those who have private insurance, perhaps because uninsured patients tend to be younger and healthier than the general population, or perhaps because they avoid costly healthcare services such as hospitalizations and rehospitalizations.[5, 6] A priori, it is therefore possible that obtaining insurance would encourage such patients to seek care, increasing readmission rates. On the other hand, access to insurance might increase use of outpatient preventive and follow‐up care and treatments that would reduce readmission risk. A recent study by Lasser et al. found that, on a patient level, healthcare reform was associated with fairly minimal changes in readmission rates in Massachusetts, compared with trends in states not adopting health insurance reform.[7] The authors further found that there was no improvement in readmission rates among Hispanic and black patients in Massachusetts compared with other states, nor was there differential improvement in counties with the highest baseline uninsurance rates compared to other Massachusetts counties.
The question raised by Chen et al. in this issue of the Journal of Hospital Medicine, however, is whether the Massachusetts reform affected hospital‐level aggregate readmission rates, not individual patient‐level risk of readmission.[8] Because public policy regarding readmissions is directed at hospitals, not patients, a hospital‐level examination can shed light on likely implications for hospitals of new insurance gains prompted by the Affordable Care Act. Some commentators have expressed concern that payment penalty programs for excess readmissions may harm safety‐net hospitals.[9] Although uninsured patients may have low readmission rates, hospitals with high proportions of uninsured patients (safety‐net hospitals) tend to have slightly higher readmission rates than other hospitals, probably because they also have higher proportions of highreadmission‐risk Medicaid patients. Reducing the rate of uninsurance at these hospitals could theoretically have a number of different hospital‐level effects. Patients obtaining insurance might elect to seek care elsewhere, changing the distribution of patients among hospitals, and potentially affecting readmission rates. Hospitals might be more prone to readmit insured patients, increasing their readmission rate if more of their patients gain insurance. They might use new revenue from newly insured patients to provide better care‐coordination services, potentially reducing readmission risk, or as happened in Massachusetts, safety‐net hospitals may find themselves unexpectedly losing revenue because of elimination of other subsidies, potentially reducing their ability to provide care transition services.[10]
Examining the effect of health insurance reform on hospital readmission rates empirically, Chen et al. find that readmission rates rose 0.6 percentage points in the group of hospitals with the highest prereform rates of uninsurance, but that after risk adjustment for age, gender, race, and comorbidity, there was no significant change relative to other hospitals. What accounts for these results? One possibility is that some patients gaining health insurance who previously received care at safety‐net hospitals began to seek care at other institutions, but that the redistribution of patients occurred more among healthier newly insured patients than among the more chronically ill newly insured. In such a case, the hospitals with the highest prereform uninsurance rates might be left with a sicker population, increasing their unadjusted readmission rates but leaving adjusted readmission rates unchanged. One study did show a 2.3% decrease in the annual volume at Massachusetts safety‐net hospitals, compared to a 1.9% increase at nonsafety‐net hospitals postreform. The relative difference, however, was not statistically significant.[10] Nonetheless, Chen et al. did find that the comorbidity index increased postreform only for patients in the highest prereform uninsurance quartile, suggesting that their patient population might have become sicker. An alternate hypothesis is that safety‐net hospitals were the most financially adversely affected by the Massachusetts reform and may therefore have cut services that would have reduced readmission risk. However, the fact that risk‐adjusted readmission rates were unchanged makes that hypothesis less probable. Finally, the authors suggest that the population who were newly insured were themselves sicker than the general population, as illustrated by the increase in comorbidity postreform. Given the national profile of uninsured patients as generally healthier than insured patients, however, it is unlikely that Massachusetts' newly insured patients were much less healthy than previously insured patients, especially because Massachusetts enrolled a very large fraction of its previously uninsured patients. It is more probable that either there was a shift of healthier patients out of the safety‐net hospitals, that hospital billing departments began paying more attention to documenting comorbidity in patients for whom hospitalizations would now be reimbursed, or that new access to care enabled preexisting conditions to be diagnosed and documented.
So what does Chen et al.'s study mean for hospitals as they face an influx of newly insured patients through the Affordable Care Act health exchanges or Medicaid expansions? First, it is important to note that although risk adjustment eliminated any change in readmission rates postreform, the risk adjustment model used by these investigators is not the same as that used by Medicare. Medicare does not adjust for race, as the investigators did. Therefore, if some of the change in readmission rate is driven by changes in patient population at safety‐net hospitals, and if such moves occur differentially in different patient populations, increases in readmission rates at safety‐net hospitals might still be present even after Medicare‐type risk adjustment. Even so, the impact on Medicare‐driven readmission penalties for hospitals is likely to be fairly minimal, because Medicare coverage is relatively unaffected by the Affordable Care Act and by the Massachusetts reforms. Medicare enrollment rates are driven by age and disability, neither of which is directly relevant to universal coverage schemes. Studies of Massachusetts reform found very little change in Medicare enrollment postreform despite large declines in uninsurance.[2] Because payment penalties are determined based purely on readmission rates among Medicare patients over 65 years old, changes in overall hospital readmissions have little financial consequences for hospitals at the present moment. In the future, however, if private insurers and state Medicaid programs begin to focus on readmissions as well, then the situation may change.
Overall, Chen et al.'s study lends heartening support to accumulating evidence that the lessons of the RAND Corporation's health insurance experiment may not apply to high‐intensity care such as hospitalizationsat least in Massachusetts.[2, 11] Increasingly, it is becoming clear that gaining insurance does not necessarily mean receipt of more inpatient care. If you build it, they may not come.
Disclosures: Nothing to report.
- , . Access and affordability: an update on health reform in Massachusetts, fall 2008. Health Aff (Millwood). 2009;28(4):w578–w587.
- , . The impact of health care reform on hospital and preventive care: evidence from Massachusetts. J Public Econ. 2012;96(11‐12):909–929.
- , , . Massachusetts health reforms: uninsurance remains low, self‐reported health status improves as state prepares to tackle costs. Health Aff (Millwood). 2012;31(2):444–451.
- . The effect of the Massachusetts reform on health care utilization. Inquiry. 2012;49(4):317–326.
- Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project. Statistical brief #154. 2013. Available at: http://www.hcup‐us.ahrq.gov/reports/statbriefs/sb154.pdf. Accessed September 11, 2014.
- Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project. Statistical brief #153. 2013. Available at: http://www.hcup‐us.ahrq.gov/reports/statbriefs/sb153.pdf. Accessed September 11, 2014.
- , , , , , . The effect of Massachusetts health reform on 30 day hospital readmissions: retrospective analysis of hospital episode statistics. BMJ. 2014;348:g2329.
- , , . Readmission penalties and health insurance expansions: a dispatch from Massachusetts. J Hosp Med. 2014;9(11):681–687.
- , . Characteristics of hospitals receiving penalties under the Hospital Readmissions Reduction Program. JAMA. 2013;309(4):342–343.
- , , , . The health of safety net hospitals following Massachusetts health care reform: changes in volume, revenue, costs, and operating margins from 2006 to 2009. Int J Health Serv. 2013;43(2):321–335.
- , , , , , . Use of hospital‐based services among young adults with behavioral health diagnoses before and after health insurance expansions. JAMA Psychiatry. 2014;71(4):404–411.
The Affordable Care Act has made hospital readmissions a major public policy target by tying Medicare hospital payments to readmission rates for certain diseases. Since then, debate has spiked over the factors contributing to hospital readmissions, with particular attention being paid to the impact of socioeconomic status and access to care. The Massachusetts healthcare reform of 2006 is a useful natural experiment to help disentangle some of these effects. Although reform did little to change patients' income, education, health literacy, or other determinants of socioeconomic status, it did dramatically reduce uninsurance rates. State‐wide uninsurance rates dropped from 8.4% prereform to 3.4% postreform.[1] Most important, a gain in insurance appeared to translate to genuine improvements in access to outpatient and preventive care. Massachusetts residents postreform were more likely to report a usual source of care, were more likely to have had outpatient office visits, and less likely to use the emergency department.[1, 2, 3, 4] Thus, the 2006 Massachusetts health reform legislation appears to have genuinely increased access both to insurance and to outpatient care, while reducing the need for preventable hospital‐based care.
Contrary to popular belief, patients without insurance have low unadjusted readmission rates for most conditions, often even lower than rates among those who have private insurance, perhaps because uninsured patients tend to be younger and healthier than the general population, or perhaps because they avoid costly healthcare services such as hospitalizations and rehospitalizations.[5, 6] A priori, it is therefore possible that obtaining insurance would encourage such patients to seek care, increasing readmission rates. On the other hand, access to insurance might increase use of outpatient preventive and follow‐up care and treatments that would reduce readmission risk. A recent study by Lasser et al. found that, on a patient level, healthcare reform was associated with fairly minimal changes in readmission rates in Massachusetts, compared with trends in states not adopting health insurance reform.[7] The authors further found that there was no improvement in readmission rates among Hispanic and black patients in Massachusetts compared with other states, nor was there differential improvement in counties with the highest baseline uninsurance rates compared to other Massachusetts counties.
The question raised by Chen et al. in this issue of the Journal of Hospital Medicine, however, is whether the Massachusetts reform affected hospital‐level aggregate readmission rates, not individual patient‐level risk of readmission.[8] Because public policy regarding readmissions is directed at hospitals, not patients, a hospital‐level examination can shed light on likely implications for hospitals of new insurance gains prompted by the Affordable Care Act. Some commentators have expressed concern that payment penalty programs for excess readmissions may harm safety‐net hospitals.[9] Although uninsured patients may have low readmission rates, hospitals with high proportions of uninsured patients (safety‐net hospitals) tend to have slightly higher readmission rates than other hospitals, probably because they also have higher proportions of highreadmission‐risk Medicaid patients. Reducing the rate of uninsurance at these hospitals could theoretically have a number of different hospital‐level effects. Patients obtaining insurance might elect to seek care elsewhere, changing the distribution of patients among hospitals, and potentially affecting readmission rates. Hospitals might be more prone to readmit insured patients, increasing their readmission rate if more of their patients gain insurance. They might use new revenue from newly insured patients to provide better care‐coordination services, potentially reducing readmission risk, or as happened in Massachusetts, safety‐net hospitals may find themselves unexpectedly losing revenue because of elimination of other subsidies, potentially reducing their ability to provide care transition services.[10]
Examining the effect of health insurance reform on hospital readmission rates empirically, Chen et al. find that readmission rates rose 0.6 percentage points in the group of hospitals with the highest prereform rates of uninsurance, but that after risk adjustment for age, gender, race, and comorbidity, there was no significant change relative to other hospitals. What accounts for these results? One possibility is that some patients gaining health insurance who previously received care at safety‐net hospitals began to seek care at other institutions, but that the redistribution of patients occurred more among healthier newly insured patients than among the more chronically ill newly insured. In such a case, the hospitals with the highest prereform uninsurance rates might be left with a sicker population, increasing their unadjusted readmission rates but leaving adjusted readmission rates unchanged. One study did show a 2.3% decrease in the annual volume at Massachusetts safety‐net hospitals, compared to a 1.9% increase at nonsafety‐net hospitals postreform. The relative difference, however, was not statistically significant.[10] Nonetheless, Chen et al. did find that the comorbidity index increased postreform only for patients in the highest prereform uninsurance quartile, suggesting that their patient population might have become sicker. An alternate hypothesis is that safety‐net hospitals were the most financially adversely affected by the Massachusetts reform and may therefore have cut services that would have reduced readmission risk. However, the fact that risk‐adjusted readmission rates were unchanged makes that hypothesis less probable. Finally, the authors suggest that the population who were newly insured were themselves sicker than the general population, as illustrated by the increase in comorbidity postreform. Given the national profile of uninsured patients as generally healthier than insured patients, however, it is unlikely that Massachusetts' newly insured patients were much less healthy than previously insured patients, especially because Massachusetts enrolled a very large fraction of its previously uninsured patients. It is more probable that either there was a shift of healthier patients out of the safety‐net hospitals, that hospital billing departments began paying more attention to documenting comorbidity in patients for whom hospitalizations would now be reimbursed, or that new access to care enabled preexisting conditions to be diagnosed and documented.
So what does Chen et al.'s study mean for hospitals as they face an influx of newly insured patients through the Affordable Care Act health exchanges or Medicaid expansions? First, it is important to note that although risk adjustment eliminated any change in readmission rates postreform, the risk adjustment model used by these investigators is not the same as that used by Medicare. Medicare does not adjust for race, as the investigators did. Therefore, if some of the change in readmission rate is driven by changes in patient population at safety‐net hospitals, and if such moves occur differentially in different patient populations, increases in readmission rates at safety‐net hospitals might still be present even after Medicare‐type risk adjustment. Even so, the impact on Medicare‐driven readmission penalties for hospitals is likely to be fairly minimal, because Medicare coverage is relatively unaffected by the Affordable Care Act and by the Massachusetts reforms. Medicare enrollment rates are driven by age and disability, neither of which is directly relevant to universal coverage schemes. Studies of Massachusetts reform found very little change in Medicare enrollment postreform despite large declines in uninsurance.[2] Because payment penalties are determined based purely on readmission rates among Medicare patients over 65 years old, changes in overall hospital readmissions have little financial consequences for hospitals at the present moment. In the future, however, if private insurers and state Medicaid programs begin to focus on readmissions as well, then the situation may change.
Overall, Chen et al.'s study lends heartening support to accumulating evidence that the lessons of the RAND Corporation's health insurance experiment may not apply to high‐intensity care such as hospitalizationsat least in Massachusetts.[2, 11] Increasingly, it is becoming clear that gaining insurance does not necessarily mean receipt of more inpatient care. If you build it, they may not come.
Disclosures: Nothing to report.
The Affordable Care Act has made hospital readmissions a major public policy target by tying Medicare hospital payments to readmission rates for certain diseases. Since then, debate has spiked over the factors contributing to hospital readmissions, with particular attention being paid to the impact of socioeconomic status and access to care. The Massachusetts healthcare reform of 2006 is a useful natural experiment to help disentangle some of these effects. Although reform did little to change patients' income, education, health literacy, or other determinants of socioeconomic status, it did dramatically reduce uninsurance rates. State‐wide uninsurance rates dropped from 8.4% prereform to 3.4% postreform.[1] Most important, a gain in insurance appeared to translate to genuine improvements in access to outpatient and preventive care. Massachusetts residents postreform were more likely to report a usual source of care, were more likely to have had outpatient office visits, and less likely to use the emergency department.[1, 2, 3, 4] Thus, the 2006 Massachusetts health reform legislation appears to have genuinely increased access both to insurance and to outpatient care, while reducing the need for preventable hospital‐based care.
Contrary to popular belief, patients without insurance have low unadjusted readmission rates for most conditions, often even lower than rates among those who have private insurance, perhaps because uninsured patients tend to be younger and healthier than the general population, or perhaps because they avoid costly healthcare services such as hospitalizations and rehospitalizations.[5, 6] A priori, it is therefore possible that obtaining insurance would encourage such patients to seek care, increasing readmission rates. On the other hand, access to insurance might increase use of outpatient preventive and follow‐up care and treatments that would reduce readmission risk. A recent study by Lasser et al. found that, on a patient level, healthcare reform was associated with fairly minimal changes in readmission rates in Massachusetts, compared with trends in states not adopting health insurance reform.[7] The authors further found that there was no improvement in readmission rates among Hispanic and black patients in Massachusetts compared with other states, nor was there differential improvement in counties with the highest baseline uninsurance rates compared to other Massachusetts counties.
The question raised by Chen et al. in this issue of the Journal of Hospital Medicine, however, is whether the Massachusetts reform affected hospital‐level aggregate readmission rates, not individual patient‐level risk of readmission.[8] Because public policy regarding readmissions is directed at hospitals, not patients, a hospital‐level examination can shed light on likely implications for hospitals of new insurance gains prompted by the Affordable Care Act. Some commentators have expressed concern that payment penalty programs for excess readmissions may harm safety‐net hospitals.[9] Although uninsured patients may have low readmission rates, hospitals with high proportions of uninsured patients (safety‐net hospitals) tend to have slightly higher readmission rates than other hospitals, probably because they also have higher proportions of highreadmission‐risk Medicaid patients. Reducing the rate of uninsurance at these hospitals could theoretically have a number of different hospital‐level effects. Patients obtaining insurance might elect to seek care elsewhere, changing the distribution of patients among hospitals, and potentially affecting readmission rates. Hospitals might be more prone to readmit insured patients, increasing their readmission rate if more of their patients gain insurance. They might use new revenue from newly insured patients to provide better care‐coordination services, potentially reducing readmission risk, or as happened in Massachusetts, safety‐net hospitals may find themselves unexpectedly losing revenue because of elimination of other subsidies, potentially reducing their ability to provide care transition services.[10]
Examining the effect of health insurance reform on hospital readmission rates empirically, Chen et al. find that readmission rates rose 0.6 percentage points in the group of hospitals with the highest prereform rates of uninsurance, but that after risk adjustment for age, gender, race, and comorbidity, there was no significant change relative to other hospitals. What accounts for these results? One possibility is that some patients gaining health insurance who previously received care at safety‐net hospitals began to seek care at other institutions, but that the redistribution of patients occurred more among healthier newly insured patients than among the more chronically ill newly insured. In such a case, the hospitals with the highest prereform uninsurance rates might be left with a sicker population, increasing their unadjusted readmission rates but leaving adjusted readmission rates unchanged. One study did show a 2.3% decrease in the annual volume at Massachusetts safety‐net hospitals, compared to a 1.9% increase at nonsafety‐net hospitals postreform. The relative difference, however, was not statistically significant.[10] Nonetheless, Chen et al. did find that the comorbidity index increased postreform only for patients in the highest prereform uninsurance quartile, suggesting that their patient population might have become sicker. An alternate hypothesis is that safety‐net hospitals were the most financially adversely affected by the Massachusetts reform and may therefore have cut services that would have reduced readmission risk. However, the fact that risk‐adjusted readmission rates were unchanged makes that hypothesis less probable. Finally, the authors suggest that the population who were newly insured were themselves sicker than the general population, as illustrated by the increase in comorbidity postreform. Given the national profile of uninsured patients as generally healthier than insured patients, however, it is unlikely that Massachusetts' newly insured patients were much less healthy than previously insured patients, especially because Massachusetts enrolled a very large fraction of its previously uninsured patients. It is more probable that either there was a shift of healthier patients out of the safety‐net hospitals, that hospital billing departments began paying more attention to documenting comorbidity in patients for whom hospitalizations would now be reimbursed, or that new access to care enabled preexisting conditions to be diagnosed and documented.
So what does Chen et al.'s study mean for hospitals as they face an influx of newly insured patients through the Affordable Care Act health exchanges or Medicaid expansions? First, it is important to note that although risk adjustment eliminated any change in readmission rates postreform, the risk adjustment model used by these investigators is not the same as that used by Medicare. Medicare does not adjust for race, as the investigators did. Therefore, if some of the change in readmission rate is driven by changes in patient population at safety‐net hospitals, and if such moves occur differentially in different patient populations, increases in readmission rates at safety‐net hospitals might still be present even after Medicare‐type risk adjustment. Even so, the impact on Medicare‐driven readmission penalties for hospitals is likely to be fairly minimal, because Medicare coverage is relatively unaffected by the Affordable Care Act and by the Massachusetts reforms. Medicare enrollment rates are driven by age and disability, neither of which is directly relevant to universal coverage schemes. Studies of Massachusetts reform found very little change in Medicare enrollment postreform despite large declines in uninsurance.[2] Because payment penalties are determined based purely on readmission rates among Medicare patients over 65 years old, changes in overall hospital readmissions have little financial consequences for hospitals at the present moment. In the future, however, if private insurers and state Medicaid programs begin to focus on readmissions as well, then the situation may change.
Overall, Chen et al.'s study lends heartening support to accumulating evidence that the lessons of the RAND Corporation's health insurance experiment may not apply to high‐intensity care such as hospitalizationsat least in Massachusetts.[2, 11] Increasingly, it is becoming clear that gaining insurance does not necessarily mean receipt of more inpatient care. If you build it, they may not come.
Disclosures: Nothing to report.
- , . Access and affordability: an update on health reform in Massachusetts, fall 2008. Health Aff (Millwood). 2009;28(4):w578–w587.
- , . The impact of health care reform on hospital and preventive care: evidence from Massachusetts. J Public Econ. 2012;96(11‐12):909–929.
- , , . Massachusetts health reforms: uninsurance remains low, self‐reported health status improves as state prepares to tackle costs. Health Aff (Millwood). 2012;31(2):444–451.
- . The effect of the Massachusetts reform on health care utilization. Inquiry. 2012;49(4):317–326.
- Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project. Statistical brief #154. 2013. Available at: http://www.hcup‐us.ahrq.gov/reports/statbriefs/sb154.pdf. Accessed September 11, 2014.
- Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project. Statistical brief #153. 2013. Available at: http://www.hcup‐us.ahrq.gov/reports/statbriefs/sb153.pdf. Accessed September 11, 2014.
- , , , , , . The effect of Massachusetts health reform on 30 day hospital readmissions: retrospective analysis of hospital episode statistics. BMJ. 2014;348:g2329.
- , , . Readmission penalties and health insurance expansions: a dispatch from Massachusetts. J Hosp Med. 2014;9(11):681–687.
- , . Characteristics of hospitals receiving penalties under the Hospital Readmissions Reduction Program. JAMA. 2013;309(4):342–343.
- , , , . The health of safety net hospitals following Massachusetts health care reform: changes in volume, revenue, costs, and operating margins from 2006 to 2009. Int J Health Serv. 2013;43(2):321–335.
- , , , , , . Use of hospital‐based services among young adults with behavioral health diagnoses before and after health insurance expansions. JAMA Psychiatry. 2014;71(4):404–411.
- , . Access and affordability: an update on health reform in Massachusetts, fall 2008. Health Aff (Millwood). 2009;28(4):w578–w587.
- , . The impact of health care reform on hospital and preventive care: evidence from Massachusetts. J Public Econ. 2012;96(11‐12):909–929.
- , , . Massachusetts health reforms: uninsurance remains low, self‐reported health status improves as state prepares to tackle costs. Health Aff (Millwood). 2012;31(2):444–451.
- . The effect of the Massachusetts reform on health care utilization. Inquiry. 2012;49(4):317–326.
- Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project. Statistical brief #154. 2013. Available at: http://www.hcup‐us.ahrq.gov/reports/statbriefs/sb154.pdf. Accessed September 11, 2014.
- Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project. Statistical brief #153. 2013. Available at: http://www.hcup‐us.ahrq.gov/reports/statbriefs/sb153.pdf. Accessed September 11, 2014.
- , , , , , . The effect of Massachusetts health reform on 30 day hospital readmissions: retrospective analysis of hospital episode statistics. BMJ. 2014;348:g2329.
- , , . Readmission penalties and health insurance expansions: a dispatch from Massachusetts. J Hosp Med. 2014;9(11):681–687.
- , . Characteristics of hospitals receiving penalties under the Hospital Readmissions Reduction Program. JAMA. 2013;309(4):342–343.
- , , , . The health of safety net hospitals following Massachusetts health care reform: changes in volume, revenue, costs, and operating margins from 2006 to 2009. Int J Health Serv. 2013;43(2):321–335.
- , , , , , . Use of hospital‐based services among young adults with behavioral health diagnoses before and after health insurance expansions. JAMA Psychiatry. 2014;71(4):404–411.
Ebola: Essential facts for ObGyns
As Ebola virus spreads from West Africa, it has become apparent that ObGyns in the United States may need to evaluate patients who have been exposed to the disease. The Centers for Disease Control and Prevention (CDC) has a dedicated Web site for Ebola that outlines signs and symptoms, transmission, risk of exposure, diagnosis and treatment options, and clinical guidance for health-care workers.1
What are the symptoms of Ebola?
If a woman from West Africa presents with a fever, the CDC advises that she be asked specifically about recent travel to affected areas (currently Liberia, Sierra Leone, Guinea, and Nigeria). Clinical signs and symptoms of Ebola include a fever of 38.6°C [101.5°F] or higher with additional symptoms1:
- severe headache
- muscle pain
- weakness
- vomiting
- diarrhea
- abdominal (stomach) pain
- unexplained hemorrhage.
Symptoms may appear from 2–21 days after exposure to Ebola. If a person with early symptoms of Ebola has had contact with the blood or body fluids of a person sick with Ebola, objects contaminated with the blood or body fluids of a person sick with Ebola, or with Ebola-infected animals, the patient should be isolated and public health professionals immediately notified, says the CDC. Blood samples from the patient should be tested to confirm infection (visit the CDC’s Ebola Web site for a list of diagnostic tests).1
More women than men infected
In a recently published perspective from the CDC on what ObGyns should be aware of regarding Ebola, Jamieson and colleagues reported that, according to UNICEF data, in this current outbreak more women than men are infected.2 They say this is most likely because women in West Africa are the primary caregivers for sick relatives, as well as make up the majority of health-care providers and birth attendants.
Pregnancy and Ebola
Based on limited, historic data from other Ebola outbreaks in Africa, there is no evidence suggesting that pregnant women are more susceptible to Ebola, although say Jamieson and colleagues, there is limited evidence suggesting that pregnant women are more at risk for severe illness and death from Ebola.2 It also appears that pregnant women with Ebola are at increased risk for spontaneous abortion and pregnancy-related hemorrhage. In 1996 in Kikwit, Democratic Republic of the Congo, pregnant women were more likely than the overall patient population with Ebola to have hemorrhagic complications, specifically vaginal and uterine bleeding associated with abortion or delivery. Children born to mothers with Ebola have not survived, though the cause of death has not been identified specifically.2
Breastfeeding and Ebola
The CDC has issued recommendations for breastfeeding or infant feeding by women with suspected or confirmed exposure to Ebola. Two key points are made3:
- Mothers with probable or confirmed Ebola virus disease should not have close contact with their infants when safe alternatives to breastfeeding and infant care exist
- Where resources are limited, non−breastfed infants are at increased risk of death from starvation and other infectious diseases. These risks must be carefully weighed against the risk of Ebola virus disease.
CDC recommends that decisions about how to best feed an infant whose mother has probable or confirmed Ebola be made on a case-by-case basis, balancing nutritional needs with the risk of contracting the disease. There is not enough evidence to suggest when it is safe to resume breastfeeding after a mother’s recovery, unless her breast milk can be shown to be Ebola-free.3
Protecting health-care personnel
The CDC Ebola Web site1 provides specific protocols designed to keep health-care workers safe. These include detailed guidelines for evaluating returned travelers, instructions for specimen collection, transport, testing, submission, use of protective equipment, and isolation procedures.
Share your thoughts on this news! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name, and the city and state in which you practice
- The Centers for Disease Control and Prevention. Ebola (Ebola Virus Disease). http://www.cdc.gov/vhf/ebola/. Updated October 5, 2014. Accessed October 6, 2014.
- Jamieson DJ, Uyeko TM, Callaghan WM, Meaney-Delman D, Rasmussen SA. What obstetrician-gynecologists should know about Ebola: A perspective from the Centers from Disease Control and Prevention [published online ahead of print September 8, 2014]. http://journals.lww.com/greenjournal/Abstract/publishahead/What_Obstetrician_Gynecologists_Should_Know_About.99324.aspx. Obstet Gynecol. doi:10.1097/AOG.0000000000000533.
- The Centers for Disease Control and Prevention. Recommendations for breastfeeding/infant feeding in the context of Ebola. http://www.cdc.gov/vhf/ebola/hcp/recommendations-breastfeeding-infant-feeding-ebola.html. Updated September 19, 2014. Accessed October 6, 2014.
As Ebola virus spreads from West Africa, it has become apparent that ObGyns in the United States may need to evaluate patients who have been exposed to the disease. The Centers for Disease Control and Prevention (CDC) has a dedicated Web site for Ebola that outlines signs and symptoms, transmission, risk of exposure, diagnosis and treatment options, and clinical guidance for health-care workers.1
What are the symptoms of Ebola?
If a woman from West Africa presents with a fever, the CDC advises that she be asked specifically about recent travel to affected areas (currently Liberia, Sierra Leone, Guinea, and Nigeria). Clinical signs and symptoms of Ebola include a fever of 38.6°C [101.5°F] or higher with additional symptoms1:
- severe headache
- muscle pain
- weakness
- vomiting
- diarrhea
- abdominal (stomach) pain
- unexplained hemorrhage.
Symptoms may appear from 2–21 days after exposure to Ebola. If a person with early symptoms of Ebola has had contact with the blood or body fluids of a person sick with Ebola, objects contaminated with the blood or body fluids of a person sick with Ebola, or with Ebola-infected animals, the patient should be isolated and public health professionals immediately notified, says the CDC. Blood samples from the patient should be tested to confirm infection (visit the CDC’s Ebola Web site for a list of diagnostic tests).1
More women than men infected
In a recently published perspective from the CDC on what ObGyns should be aware of regarding Ebola, Jamieson and colleagues reported that, according to UNICEF data, in this current outbreak more women than men are infected.2 They say this is most likely because women in West Africa are the primary caregivers for sick relatives, as well as make up the majority of health-care providers and birth attendants.
Pregnancy and Ebola
Based on limited, historic data from other Ebola outbreaks in Africa, there is no evidence suggesting that pregnant women are more susceptible to Ebola, although say Jamieson and colleagues, there is limited evidence suggesting that pregnant women are more at risk for severe illness and death from Ebola.2 It also appears that pregnant women with Ebola are at increased risk for spontaneous abortion and pregnancy-related hemorrhage. In 1996 in Kikwit, Democratic Republic of the Congo, pregnant women were more likely than the overall patient population with Ebola to have hemorrhagic complications, specifically vaginal and uterine bleeding associated with abortion or delivery. Children born to mothers with Ebola have not survived, though the cause of death has not been identified specifically.2
Breastfeeding and Ebola
The CDC has issued recommendations for breastfeeding or infant feeding by women with suspected or confirmed exposure to Ebola. Two key points are made3:
- Mothers with probable or confirmed Ebola virus disease should not have close contact with their infants when safe alternatives to breastfeeding and infant care exist
- Where resources are limited, non−breastfed infants are at increased risk of death from starvation and other infectious diseases. These risks must be carefully weighed against the risk of Ebola virus disease.
CDC recommends that decisions about how to best feed an infant whose mother has probable or confirmed Ebola be made on a case-by-case basis, balancing nutritional needs with the risk of contracting the disease. There is not enough evidence to suggest when it is safe to resume breastfeeding after a mother’s recovery, unless her breast milk can be shown to be Ebola-free.3
Protecting health-care personnel
The CDC Ebola Web site1 provides specific protocols designed to keep health-care workers safe. These include detailed guidelines for evaluating returned travelers, instructions for specimen collection, transport, testing, submission, use of protective equipment, and isolation procedures.
Share your thoughts on this news! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name, and the city and state in which you practice
As Ebola virus spreads from West Africa, it has become apparent that ObGyns in the United States may need to evaluate patients who have been exposed to the disease. The Centers for Disease Control and Prevention (CDC) has a dedicated Web site for Ebola that outlines signs and symptoms, transmission, risk of exposure, diagnosis and treatment options, and clinical guidance for health-care workers.1
What are the symptoms of Ebola?
If a woman from West Africa presents with a fever, the CDC advises that she be asked specifically about recent travel to affected areas (currently Liberia, Sierra Leone, Guinea, and Nigeria). Clinical signs and symptoms of Ebola include a fever of 38.6°C [101.5°F] or higher with additional symptoms1:
- severe headache
- muscle pain
- weakness
- vomiting
- diarrhea
- abdominal (stomach) pain
- unexplained hemorrhage.
Symptoms may appear from 2–21 days after exposure to Ebola. If a person with early symptoms of Ebola has had contact with the blood or body fluids of a person sick with Ebola, objects contaminated with the blood or body fluids of a person sick with Ebola, or with Ebola-infected animals, the patient should be isolated and public health professionals immediately notified, says the CDC. Blood samples from the patient should be tested to confirm infection (visit the CDC’s Ebola Web site for a list of diagnostic tests).1
More women than men infected
In a recently published perspective from the CDC on what ObGyns should be aware of regarding Ebola, Jamieson and colleagues reported that, according to UNICEF data, in this current outbreak more women than men are infected.2 They say this is most likely because women in West Africa are the primary caregivers for sick relatives, as well as make up the majority of health-care providers and birth attendants.
Pregnancy and Ebola
Based on limited, historic data from other Ebola outbreaks in Africa, there is no evidence suggesting that pregnant women are more susceptible to Ebola, although say Jamieson and colleagues, there is limited evidence suggesting that pregnant women are more at risk for severe illness and death from Ebola.2 It also appears that pregnant women with Ebola are at increased risk for spontaneous abortion and pregnancy-related hemorrhage. In 1996 in Kikwit, Democratic Republic of the Congo, pregnant women were more likely than the overall patient population with Ebola to have hemorrhagic complications, specifically vaginal and uterine bleeding associated with abortion or delivery. Children born to mothers with Ebola have not survived, though the cause of death has not been identified specifically.2
Breastfeeding and Ebola
The CDC has issued recommendations for breastfeeding or infant feeding by women with suspected or confirmed exposure to Ebola. Two key points are made3:
- Mothers with probable or confirmed Ebola virus disease should not have close contact with their infants when safe alternatives to breastfeeding and infant care exist
- Where resources are limited, non−breastfed infants are at increased risk of death from starvation and other infectious diseases. These risks must be carefully weighed against the risk of Ebola virus disease.
CDC recommends that decisions about how to best feed an infant whose mother has probable or confirmed Ebola be made on a case-by-case basis, balancing nutritional needs with the risk of contracting the disease. There is not enough evidence to suggest when it is safe to resume breastfeeding after a mother’s recovery, unless her breast milk can be shown to be Ebola-free.3
Protecting health-care personnel
The CDC Ebola Web site1 provides specific protocols designed to keep health-care workers safe. These include detailed guidelines for evaluating returned travelers, instructions for specimen collection, transport, testing, submission, use of protective equipment, and isolation procedures.
Share your thoughts on this news! Send your Letter to the Editor to rbarbieri@frontlinemedcom.com. Please include your name, and the city and state in which you practice
- The Centers for Disease Control and Prevention. Ebola (Ebola Virus Disease). http://www.cdc.gov/vhf/ebola/. Updated October 5, 2014. Accessed October 6, 2014.
- Jamieson DJ, Uyeko TM, Callaghan WM, Meaney-Delman D, Rasmussen SA. What obstetrician-gynecologists should know about Ebola: A perspective from the Centers from Disease Control and Prevention [published online ahead of print September 8, 2014]. http://journals.lww.com/greenjournal/Abstract/publishahead/What_Obstetrician_Gynecologists_Should_Know_About.99324.aspx. Obstet Gynecol. doi:10.1097/AOG.0000000000000533.
- The Centers for Disease Control and Prevention. Recommendations for breastfeeding/infant feeding in the context of Ebola. http://www.cdc.gov/vhf/ebola/hcp/recommendations-breastfeeding-infant-feeding-ebola.html. Updated September 19, 2014. Accessed October 6, 2014.
- The Centers for Disease Control and Prevention. Ebola (Ebola Virus Disease). http://www.cdc.gov/vhf/ebola/. Updated October 5, 2014. Accessed October 6, 2014.
- Jamieson DJ, Uyeko TM, Callaghan WM, Meaney-Delman D, Rasmussen SA. What obstetrician-gynecologists should know about Ebola: A perspective from the Centers from Disease Control and Prevention [published online ahead of print September 8, 2014]. http://journals.lww.com/greenjournal/Abstract/publishahead/What_Obstetrician_Gynecologists_Should_Know_About.99324.aspx. Obstet Gynecol. doi:10.1097/AOG.0000000000000533.
- The Centers for Disease Control and Prevention. Recommendations for breastfeeding/infant feeding in the context of Ebola. http://www.cdc.gov/vhf/ebola/hcp/recommendations-breastfeeding-infant-feeding-ebola.html. Updated September 19, 2014. Accessed October 6, 2014.
Weighing self-determination against blissful ignorance at death’s door
I had a young cousin with thalassemia major. She had the textbook chipmunk facies, but you otherwise would not have known she was ill. Despite requiring blood transfusions every 3 weeks, she led a fairly normal life, graduating from college and holding down a good job.
In 2012, we found out that she had hepatitis C. She received treatment, but it did not succeed. By this point, she’d already developed cardiomyopathy, and she would later develop atrial fibrillation and heart failure. Earlier this year, Gilead was kind enough to give her its new drug sofosbuvir for free, but given her comorbidities, she could not tolerate it.
Recently, she was discharged after a protracted admission for heart failure. At that point, her hematologist, cardiologist, and hepatologist held a family meeting with her parents and siblings and pointed out the futility of her situation. Her family brought her home. They did what Filipino families in desperation do. They prayed and reached out to a “faith healer” – someone who uses poultices made from taro leaves, mutters incantations, and provides homemade remedies for any ailment. From a patient’s perspective, they provide hope where no one else will; from an outsider’s perspective, they are simply preying on the vulnerable.
Despite her family’s efforts, my cousin died about a month after coming home. She was only 27 years old. She woke up one morning feeling short of breath, weighed down by anasarca. She was brought to the hospital. Surrounded by her family, she asked her brother why he was crying. She asked her family not to bother calling her boyfriend; she’d talk to him when he came around. Then she fell asleep for the last time.
She did not know that she was dying. Her family had chosen to keep this from her.
When I learned about the circumstances of her passing I was angry and indignant at first. Why wouldn’t they tell her? What about patient self-determination and letting her be the judge of whether she wanted to be taken back to the hospital? Why would they deprive her of the opportunity to say goodbye? How is it that this sort of paternalistic, “I know what’s best for you” attitude still exists?
But I tried to put myself in her shoes, and it didn’t take long for me to question my certitude.
We romanticize the last moments of our lives. We imagine it to be filled with equanimity, a dignified acceptance of the inevitable. But that cannot always be the case. I can just as easily imagine myself to be angry, bitter, and, worst of all, fearful. Overwhelmed with sadness that it makes my last moments joyless rather than joyful.
Dying is intensely personal. Billions of people have led lives and reached endings unique to them. We may make noise about patient self-determination, but really, what is that if not just another manifestation of our arrogance that we know best? Is not insisting on patient self-determination just the other side of the same protect-the-patient-by-withholding-information coin?
I was humbled by my own ambivalence toward how her family handled her death, and a bit ashamed that I would be so quick to judge them. They did what they thought was best; who am I to question that? I may understand the science of life and death, but I cannot claim to understand living and dying.
Dr. Chan practices rheumatology in Pawtucket, R.I.
I had a young cousin with thalassemia major. She had the textbook chipmunk facies, but you otherwise would not have known she was ill. Despite requiring blood transfusions every 3 weeks, she led a fairly normal life, graduating from college and holding down a good job.
In 2012, we found out that she had hepatitis C. She received treatment, but it did not succeed. By this point, she’d already developed cardiomyopathy, and she would later develop atrial fibrillation and heart failure. Earlier this year, Gilead was kind enough to give her its new drug sofosbuvir for free, but given her comorbidities, she could not tolerate it.
Recently, she was discharged after a protracted admission for heart failure. At that point, her hematologist, cardiologist, and hepatologist held a family meeting with her parents and siblings and pointed out the futility of her situation. Her family brought her home. They did what Filipino families in desperation do. They prayed and reached out to a “faith healer” – someone who uses poultices made from taro leaves, mutters incantations, and provides homemade remedies for any ailment. From a patient’s perspective, they provide hope where no one else will; from an outsider’s perspective, they are simply preying on the vulnerable.
Despite her family’s efforts, my cousin died about a month after coming home. She was only 27 years old. She woke up one morning feeling short of breath, weighed down by anasarca. She was brought to the hospital. Surrounded by her family, she asked her brother why he was crying. She asked her family not to bother calling her boyfriend; she’d talk to him when he came around. Then she fell asleep for the last time.
She did not know that she was dying. Her family had chosen to keep this from her.
When I learned about the circumstances of her passing I was angry and indignant at first. Why wouldn’t they tell her? What about patient self-determination and letting her be the judge of whether she wanted to be taken back to the hospital? Why would they deprive her of the opportunity to say goodbye? How is it that this sort of paternalistic, “I know what’s best for you” attitude still exists?
But I tried to put myself in her shoes, and it didn’t take long for me to question my certitude.
We romanticize the last moments of our lives. We imagine it to be filled with equanimity, a dignified acceptance of the inevitable. But that cannot always be the case. I can just as easily imagine myself to be angry, bitter, and, worst of all, fearful. Overwhelmed with sadness that it makes my last moments joyless rather than joyful.
Dying is intensely personal. Billions of people have led lives and reached endings unique to them. We may make noise about patient self-determination, but really, what is that if not just another manifestation of our arrogance that we know best? Is not insisting on patient self-determination just the other side of the same protect-the-patient-by-withholding-information coin?
I was humbled by my own ambivalence toward how her family handled her death, and a bit ashamed that I would be so quick to judge them. They did what they thought was best; who am I to question that? I may understand the science of life and death, but I cannot claim to understand living and dying.
Dr. Chan practices rheumatology in Pawtucket, R.I.
I had a young cousin with thalassemia major. She had the textbook chipmunk facies, but you otherwise would not have known she was ill. Despite requiring blood transfusions every 3 weeks, she led a fairly normal life, graduating from college and holding down a good job.
In 2012, we found out that she had hepatitis C. She received treatment, but it did not succeed. By this point, she’d already developed cardiomyopathy, and she would later develop atrial fibrillation and heart failure. Earlier this year, Gilead was kind enough to give her its new drug sofosbuvir for free, but given her comorbidities, she could not tolerate it.
Recently, she was discharged after a protracted admission for heart failure. At that point, her hematologist, cardiologist, and hepatologist held a family meeting with her parents and siblings and pointed out the futility of her situation. Her family brought her home. They did what Filipino families in desperation do. They prayed and reached out to a “faith healer” – someone who uses poultices made from taro leaves, mutters incantations, and provides homemade remedies for any ailment. From a patient’s perspective, they provide hope where no one else will; from an outsider’s perspective, they are simply preying on the vulnerable.
Despite her family’s efforts, my cousin died about a month after coming home. She was only 27 years old. She woke up one morning feeling short of breath, weighed down by anasarca. She was brought to the hospital. Surrounded by her family, she asked her brother why he was crying. She asked her family not to bother calling her boyfriend; she’d talk to him when he came around. Then she fell asleep for the last time.
She did not know that she was dying. Her family had chosen to keep this from her.
When I learned about the circumstances of her passing I was angry and indignant at first. Why wouldn’t they tell her? What about patient self-determination and letting her be the judge of whether she wanted to be taken back to the hospital? Why would they deprive her of the opportunity to say goodbye? How is it that this sort of paternalistic, “I know what’s best for you” attitude still exists?
But I tried to put myself in her shoes, and it didn’t take long for me to question my certitude.
We romanticize the last moments of our lives. We imagine it to be filled with equanimity, a dignified acceptance of the inevitable. But that cannot always be the case. I can just as easily imagine myself to be angry, bitter, and, worst of all, fearful. Overwhelmed with sadness that it makes my last moments joyless rather than joyful.
Dying is intensely personal. Billions of people have led lives and reached endings unique to them. We may make noise about patient self-determination, but really, what is that if not just another manifestation of our arrogance that we know best? Is not insisting on patient self-determination just the other side of the same protect-the-patient-by-withholding-information coin?
I was humbled by my own ambivalence toward how her family handled her death, and a bit ashamed that I would be so quick to judge them. They did what they thought was best; who am I to question that? I may understand the science of life and death, but I cannot claim to understand living and dying.
Dr. Chan practices rheumatology in Pawtucket, R.I.
Efficacy, not tolerability, of bowel prep is primary
The efficacy, not the tolerability, of bowel cleansing is the primary concern in patients undergoing colonoscopy, because of the substantial adverse consequences of inadequate bowel preparation, according to a consensus report published simultaneously in Gastroenterology, the American Journal of Gastroenterology, and Gastrointestinal Endoscopy.
As many as 20%-25% of all colonoscopies reportedly have inadequate bowel cleansing, which is associated with lower rates of lesion detection, longer procedure times, and increased electrocautery risks, in addition to the excess costs and risks of repeat procedures. “Efficacy should be a higher priority than tolerability, [so] the choice of a bowel-cleansing regimen should be based on cleansing efficacy first and patient tolerability second,” said Dr. David A. Johnson of Eastern Veterans Administration Medical School, Norfolk (Va.) and his associates on the U.S. Multi-Society Task Force on Colorectal Cancer.
The USMSTF comprised representatives from the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy, who compiled recommendations and wrote this report based on a systematic review and meta-analysis of the literature concerning bowel preparation from 1980 to the present.
When selecting a bowel-cleansing regimen for patients, physicians should consider the patient’s medical history, medications, and, if applicable, the adequacy of bowel preparation for previous colonoscopies. High-quality evidence shows that a split-dose regimen of 4 liters of polyethylene glycol–electrolyte lavage solution (PEG-ELS) provides superior bowel cleansing to other doses and solutions. The second dose ideally should begin 4-6 hours and conclude at least 2 hours before the procedure time. However, same-day regimens are acceptable, especially for patients scheduled for an afternoon colonoscopy.
Using a split-dose regimen allows some flexibility with the diet on the day before the procedure. Instead of ingesting only clear liquids, patients can consume either a full liquid or a low-residue diet for part or all of the day preceding colonoscopy, which improves their tolerance of the bowel preparation.
Over-the-counter, nonapproved (by the FDA) bowel-cleansing agents have widely varying efficacy, ranging from adequate to excellent. They generally are safe, but “caution is required when using these agents in certain populations” such as patients with chronic kidney disease. The routine use of adjunctive agents intended to enhance purgation or visualization of the mucosa is not recommended, Dr. Johnson and his associates said (Gastroenterology 2014;147:903-24).
At present, the evidence is insufficient to allow recommendation of specific bowel-preparation regimens for special patient populations such as the elderly, children and adolescents, people with inflammatory bowel disease, patients who have undergone bariatric surgery, and people with spinal cord injury. However, sodium phosphate preparations should be avoided in the elderly, children, and people with IBD. Additional bowel purgatives can be considered for patients at risk for inadequate preparation, such as those with a history of constipation, those using opioids or other constipating medications, those who have undergone previous colon resection, and those with spinal cord injury.
The report also includes recommendations concerning patient education, the risk factors for inadequate bowel preparation, assessing the adequacy of bowel preparation before and during the procedure, and salvage options for cases in which preparation is inadequate. It is available at http://dx.doi.org/10.1053/j.gastro.2014.07.002.
The efficacy, not the tolerability, of bowel cleansing is the primary concern in patients undergoing colonoscopy, because of the substantial adverse consequences of inadequate bowel preparation, according to a consensus report published simultaneously in Gastroenterology, the American Journal of Gastroenterology, and Gastrointestinal Endoscopy.
As many as 20%-25% of all colonoscopies reportedly have inadequate bowel cleansing, which is associated with lower rates of lesion detection, longer procedure times, and increased electrocautery risks, in addition to the excess costs and risks of repeat procedures. “Efficacy should be a higher priority than tolerability, [so] the choice of a bowel-cleansing regimen should be based on cleansing efficacy first and patient tolerability second,” said Dr. David A. Johnson of Eastern Veterans Administration Medical School, Norfolk (Va.) and his associates on the U.S. Multi-Society Task Force on Colorectal Cancer.
The USMSTF comprised representatives from the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy, who compiled recommendations and wrote this report based on a systematic review and meta-analysis of the literature concerning bowel preparation from 1980 to the present.
When selecting a bowel-cleansing regimen for patients, physicians should consider the patient’s medical history, medications, and, if applicable, the adequacy of bowel preparation for previous colonoscopies. High-quality evidence shows that a split-dose regimen of 4 liters of polyethylene glycol–electrolyte lavage solution (PEG-ELS) provides superior bowel cleansing to other doses and solutions. The second dose ideally should begin 4-6 hours and conclude at least 2 hours before the procedure time. However, same-day regimens are acceptable, especially for patients scheduled for an afternoon colonoscopy.
Using a split-dose regimen allows some flexibility with the diet on the day before the procedure. Instead of ingesting only clear liquids, patients can consume either a full liquid or a low-residue diet for part or all of the day preceding colonoscopy, which improves their tolerance of the bowel preparation.
Over-the-counter, nonapproved (by the FDA) bowel-cleansing agents have widely varying efficacy, ranging from adequate to excellent. They generally are safe, but “caution is required when using these agents in certain populations” such as patients with chronic kidney disease. The routine use of adjunctive agents intended to enhance purgation or visualization of the mucosa is not recommended, Dr. Johnson and his associates said (Gastroenterology 2014;147:903-24).
At present, the evidence is insufficient to allow recommendation of specific bowel-preparation regimens for special patient populations such as the elderly, children and adolescents, people with inflammatory bowel disease, patients who have undergone bariatric surgery, and people with spinal cord injury. However, sodium phosphate preparations should be avoided in the elderly, children, and people with IBD. Additional bowel purgatives can be considered for patients at risk for inadequate preparation, such as those with a history of constipation, those using opioids or other constipating medications, those who have undergone previous colon resection, and those with spinal cord injury.
The report also includes recommendations concerning patient education, the risk factors for inadequate bowel preparation, assessing the adequacy of bowel preparation before and during the procedure, and salvage options for cases in which preparation is inadequate. It is available at http://dx.doi.org/10.1053/j.gastro.2014.07.002.
The efficacy, not the tolerability, of bowel cleansing is the primary concern in patients undergoing colonoscopy, because of the substantial adverse consequences of inadequate bowel preparation, according to a consensus report published simultaneously in Gastroenterology, the American Journal of Gastroenterology, and Gastrointestinal Endoscopy.
As many as 20%-25% of all colonoscopies reportedly have inadequate bowel cleansing, which is associated with lower rates of lesion detection, longer procedure times, and increased electrocautery risks, in addition to the excess costs and risks of repeat procedures. “Efficacy should be a higher priority than tolerability, [so] the choice of a bowel-cleansing regimen should be based on cleansing efficacy first and patient tolerability second,” said Dr. David A. Johnson of Eastern Veterans Administration Medical School, Norfolk (Va.) and his associates on the U.S. Multi-Society Task Force on Colorectal Cancer.
The USMSTF comprised representatives from the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy, who compiled recommendations and wrote this report based on a systematic review and meta-analysis of the literature concerning bowel preparation from 1980 to the present.
When selecting a bowel-cleansing regimen for patients, physicians should consider the patient’s medical history, medications, and, if applicable, the adequacy of bowel preparation for previous colonoscopies. High-quality evidence shows that a split-dose regimen of 4 liters of polyethylene glycol–electrolyte lavage solution (PEG-ELS) provides superior bowel cleansing to other doses and solutions. The second dose ideally should begin 4-6 hours and conclude at least 2 hours before the procedure time. However, same-day regimens are acceptable, especially for patients scheduled for an afternoon colonoscopy.
Using a split-dose regimen allows some flexibility with the diet on the day before the procedure. Instead of ingesting only clear liquids, patients can consume either a full liquid or a low-residue diet for part or all of the day preceding colonoscopy, which improves their tolerance of the bowel preparation.
Over-the-counter, nonapproved (by the FDA) bowel-cleansing agents have widely varying efficacy, ranging from adequate to excellent. They generally are safe, but “caution is required when using these agents in certain populations” such as patients with chronic kidney disease. The routine use of adjunctive agents intended to enhance purgation or visualization of the mucosa is not recommended, Dr. Johnson and his associates said (Gastroenterology 2014;147:903-24).
At present, the evidence is insufficient to allow recommendation of specific bowel-preparation regimens for special patient populations such as the elderly, children and adolescents, people with inflammatory bowel disease, patients who have undergone bariatric surgery, and people with spinal cord injury. However, sodium phosphate preparations should be avoided in the elderly, children, and people with IBD. Additional bowel purgatives can be considered for patients at risk for inadequate preparation, such as those with a history of constipation, those using opioids or other constipating medications, those who have undergone previous colon resection, and those with spinal cord injury.
The report also includes recommendations concerning patient education, the risk factors for inadequate bowel preparation, assessing the adequacy of bowel preparation before and during the procedure, and salvage options for cases in which preparation is inadequate. It is available at http://dx.doi.org/10.1053/j.gastro.2014.07.002.
FROM GASTROENTEROLOGY
Key clinical point: Efficacy, not tolerability, of bowel preparation is the primary concern before colonoscopy.
Major finding: Up to 20%-25% of all colonoscopies have inadequate bowel preparation, which lowers detection rates, lengthens procedure time, raises electrocautery risks, and raises overall costs and risks by requiring repeat procedures.
Data source: A consensus statement based on a systematic review and meta-analysis of the literature concerning bowel preparation for colonoscopy.
Disclosures: This report was supported by the American College of Gastroenterology, the American Gastroenterological Association, and the American Society for Gastrointestinal Endoscopy, with further support provided by the U.S. Veterans Health Administration. Dr. Johnson reported serving as a consultant and clinical investigator for Epigenomics, Given Imaging, and Exact Sciences; his associates reported numerous ties to industry sources.
Point/Counterpoint: Is TEVAR required for all Type B aortic dissections?
Yes, TEVAR is clearly indicated.
Aortic dissection is a devastating condition afflicting an estimated two to eight per 100,000 people annually and comprises a large portion of the clinical entity known as the acute aortic syndromes. Patients presenting with an uncomplicated type B acute aortic dissection (TBAD) generally have low in-hospital mortality rates (2.4%-9%) when managed appropriately with anti-impulse therapy. However, survival continues to decrease with follow-up, with survival ranging between 80% and more than 95% at 1 year, progressing to approximately 75% at 3-4 years, and 48%-65% at 10 years. In late follow-up, the development of a new dissection with complications is estimated to occur in 20%-50% of patients. Complicated aortic dissections affect between 22% and 47%, and when present, mortality reaches more than 50% within the first week. TEVAR in these patients has been shown to be clearly indicated in a variety of studies with marked improvements in early mortality and late survival. Thus, one can see that aortic dissection is a disease that needs to be managed lifelong, and is associated with a high risk of mortality for the next 10 years after the initial presentation.1,2,3
The long-term effects of a patent false lumen have been well documented. Several studies following patients with chronic TBAD have documented progressive enlargement in aortic diameter with a patent false lumen. The mean increase in maximum aortic diameter ranges from 3.8 to 7.1 mm annually with any flow in the false lumen (FL) versus 1-2 mm per year with a thrombosed FL. Patients with a patent FL had 7.5 times increased risk of a dissection-related death or need for surgery as compared to patients with thrombosis of the FL. Dissection-related death or need for surgery occurred at a significantly earlier follow-up period in the patients with a patent FL.1,2,3
The aortic diameter may also influence the patency of the FL at presentation. In a review of 110 patients presenting with acute uncomplicated TBAD, 44% were identified to have a patent FL on initial imaging. Thirty-one percent of these patients had a maximum aortic diameter of 45 mm or more versus 14% of patients with a thrombosed FL (P = .053). Incidentally, patients with FL patency were on average 4 years younger than their thrombosed counterparts (62 vs. 66 years, P = .009).
Moreover, it appears that the long-term risks associated with a patent FL are further augmented by aortic dilatation at presentation. When combining both risk factors (FL patency and aortic diameter of 40 mm or more), only 22% of patients are dissection-related event–free at 5-year follow-up.Onitsuka et al.4 substantiated this finding on multivariate analysis. Interestingly, 10 of the 76 patients included in that study met both conditions, and seven of those patients (70%) experienced a dissection-related death or surgical conversion. Certainly patients meeting both criteria merit close follow-up for the development of aortic enlargement or symptoms of impending rupture.
The natural history of TBAD lends itself to at least some thrombus formation within the FL and is a common finding as the dissection becomes chronic. But in fact, partial thrombosis of the FL is associated with higher mortality in patients discharged from the hospital with stable TBAD at 1- and 3-year follow-up (15.4% and 31.6%, respectively). Matched patients with a patent FL had a 5.4% and 13.7% rate of mortality at 1 and 3 years, and patients with complete FL thrombosis were found to have mortality rates of 0% and 22.6% at the same follow-up.
Aortic remodeling after TEVAR
Placement of a thoracic endograft under these acute circumstances can often significantly alter the preoperative morphology of the true and false lumen. Schoder and colleagues5 followed changes in the TL and FL diameter in 20 patients after TEVAR for acute complicated dissection. Ninety percent of patients were found to have complete FL thrombosis of the thoracic aorta at 1 year, with a mean decrease in FL diameter of 11.6 mm. Two patients with a patent FL showed a mean increase in the maximal aortic diameter of 4.5 mm. In a similar study, Conrad et al.6 documented aortic remodeling of 21 patients in the year following TEVAR, 88% of whom had thrombosis of the FL. Most often the mobile septum is easily displaced by the radial force of the stent graft, with minimal limitation of expansion to the design diameter. Thus, endograft selection should be directed by the diameter of the normal unaffected aorta with minimal oversizing commonly limited to 5%-10%. Balloon profiling is not typically necessary.
The INSTEAD trial7 evaluated the management of uncomplicated type B aortic dissection and compared optimum medical therapy (OMT) to OMT with TEVAR. A total of 140 subjects were enrolled at seven European sites with 68 patients enrolled in OMT and 72 in OMT with TEVAR. In patients treated with TEVAR there was 90.6% complete FL thrombosis with a maximum true lumen diameter of 32.6 mm as compared to 22% and 18.7 mm in those treated with medical therapy alone. Furthermore, there was a 12.4% absolute risk reduction in aortic specific mortality and a 19.1% absolute risk reduction in disease progression in patients treated with TEVAR.
It is clear that patients that present with complicated type B aortic dissections mandate intervention with TEVAR and potentially other interventions to alleviate the complications at presentation. INSTEAD demonstrates that elective TEVAR results in favorable aortic remodeling and long-term survival, reinterventions were low, and it prevents late expansion and malperfusion. TEVAR was also associated with improved 5-year aortic-specific survival. TEVAR appears to be beneficial in those patients who present initially with a false lumen diameter of greater than 22 mm and an aortic diameter of greater than 40 mm with a patent false lumen.
References
1. Circ. Cardiovasc. Interv. 2013;4:407-16.
2. J. Vasc. Surg. 2012;55:641-51.
3. J. Vasc. Surg. 2011;54:985-92
4. Ann. Thorac. Surg. 2004;78:1268-73.
5. Ann. Thorac. Surg. 2007;83:1059-66.
6. J. Vasc. Surg. 2009;50:510-17.
7. Circulation 2009;120:2519-28.
Dr. Arko is with the Aortic Institute, Sanger Heart & Vascular Institute, Charlotte, N.C. He reported no relevant conflicts.
No, evidence supports careful choice of patients.
While the role of TEVAR has been proven to treat complications of acute type B dissections,1 its value as a prophylactic treatment in uncomplicated cases remains controversial. Optimal medical treatment (OMT) with strict blood pressure (SBP less than 120 mm Hg) and heart rate control is associated with a low morbidity and mortality, despite the risk of progressive aortic dilation. On the other hand TEVAR can result in early death and significant neurologic complications; other devastating complications of TEVAR include retrograde aortic dissection and access vessel rupture with a high associated mortality.
A meta-analysis of the published literature reported a high technical success of TEVAR for uncomplicated type B dissection and a relatively high conversion rate (20%) for patient treated with OMT, however the results did not identify an advantage for TEVAR with respect to 30-day and 2-year mortality.2
An expert panel review of the world literature also did not find significant data to support use of TEVAR for uncomplicated type B dissection.3 In the only randomized prospective trial to examine the role of TEVAR for uncomplicated type B dissection, the INSTEAD trial randomized 140 patients to OMT vs. OMT and TEVAR.4 The study results also did not support the use of TEVAR for the treatment of uncomplicated type B dissection, there was no survival advantage at 2 years, while TEVAR was associated with a 11.1% overall mortality and 4.3% neurologic complication rate, compared with 4.4% and 1.4% in the OMT group. The initial study did however report improved aortic remodeling at 2 years with TEVAR. The results of INSTEAD have been challenged because critical analysis of the INSTEAD trial has determined that the results were underpowered and that there was a 21% crossover in the OMT group and four patients received TEVAR that should have been excluded.5
Subsequent long-term analysis of the INSTEAD XL data do demonstrate a significant survival benefit and freedom from aortic adverse events in the TEVAR group after the initial 2-year analysis.6 At the 5-year follow up only 27 patients remained without a TEVAR. Fortunately there were no adverse events in the patients that crossed over to TEVAR from the OMT group demonstrating the safety of delayed TEVAR in this group. The high rate of aortic associated adverse events may favor early TEVAR. The INSTEAD XL study did identify a large primary tear (more than 10 mm) and an initial aortic diameter of 40 mm as risk factors to crossover suggesting a more aggressive approach in this subset of patients.
So while the INSTEAD XL trial now supports the use of TEVAR for uncomplicated type B dissections this was a relatively small trial that was underpowered in its initial analysis. Expert review of the world literature still supports medical management in the initial phase of treatment. Obviously in cases of failure of medical management TEVAR provides an effective treatment to restore the true lumen and visceral perfusion with possible sustained remodeling of the false lumen.
Given the not insignificant morbidity associated with TEVAR placement, routine treatment of all acute, uncomplicated type B dissections cannot be supported with the current evidence. However, a strategy of selective treatment based on size of the entry tear, extent of dissection, false lumen diameter and extent of thrombosis, effectiveness of antihypertension medications, ability to comply with medical therapy, and surveillance may be implemented. Furthermore treatment at centers of excellence with extensive TEVAR experience based on established protocols favor improved patient outcomes.
References
1. N. Engl. J. Med. 199;340:1546-52
2. Vasc. Endovascular. Surg. 2013 Oct 12;47(7):497-501. Epub 2013 Jul 12.
3. J. Am. Coll. Cardiol. 2013;61(16):1661-78.
4. Circulation 2009;120:2519-28.
5. Circulation 2009;120:2513-14.
6. Circ. Cardiovasc. Interv. 2013;6:407-16.
Dr. Shames is professor of surgery and radiology and program director of vascular surgery at the University of South Florida, Tampa. He reported no relevant conflicts.
Yes, TEVAR is clearly indicated.
Aortic dissection is a devastating condition afflicting an estimated two to eight per 100,000 people annually and comprises a large portion of the clinical entity known as the acute aortic syndromes. Patients presenting with an uncomplicated type B acute aortic dissection (TBAD) generally have low in-hospital mortality rates (2.4%-9%) when managed appropriately with anti-impulse therapy. However, survival continues to decrease with follow-up, with survival ranging between 80% and more than 95% at 1 year, progressing to approximately 75% at 3-4 years, and 48%-65% at 10 years. In late follow-up, the development of a new dissection with complications is estimated to occur in 20%-50% of patients. Complicated aortic dissections affect between 22% and 47%, and when present, mortality reaches more than 50% within the first week. TEVAR in these patients has been shown to be clearly indicated in a variety of studies with marked improvements in early mortality and late survival. Thus, one can see that aortic dissection is a disease that needs to be managed lifelong, and is associated with a high risk of mortality for the next 10 years after the initial presentation.1,2,3
The long-term effects of a patent false lumen have been well documented. Several studies following patients with chronic TBAD have documented progressive enlargement in aortic diameter with a patent false lumen. The mean increase in maximum aortic diameter ranges from 3.8 to 7.1 mm annually with any flow in the false lumen (FL) versus 1-2 mm per year with a thrombosed FL. Patients with a patent FL had 7.5 times increased risk of a dissection-related death or need for surgery as compared to patients with thrombosis of the FL. Dissection-related death or need for surgery occurred at a significantly earlier follow-up period in the patients with a patent FL.1,2,3
The aortic diameter may also influence the patency of the FL at presentation. In a review of 110 patients presenting with acute uncomplicated TBAD, 44% were identified to have a patent FL on initial imaging. Thirty-one percent of these patients had a maximum aortic diameter of 45 mm or more versus 14% of patients with a thrombosed FL (P = .053). Incidentally, patients with FL patency were on average 4 years younger than their thrombosed counterparts (62 vs. 66 years, P = .009).
Moreover, it appears that the long-term risks associated with a patent FL are further augmented by aortic dilatation at presentation. When combining both risk factors (FL patency and aortic diameter of 40 mm or more), only 22% of patients are dissection-related event–free at 5-year follow-up.Onitsuka et al.4 substantiated this finding on multivariate analysis. Interestingly, 10 of the 76 patients included in that study met both conditions, and seven of those patients (70%) experienced a dissection-related death or surgical conversion. Certainly patients meeting both criteria merit close follow-up for the development of aortic enlargement or symptoms of impending rupture.
The natural history of TBAD lends itself to at least some thrombus formation within the FL and is a common finding as the dissection becomes chronic. But in fact, partial thrombosis of the FL is associated with higher mortality in patients discharged from the hospital with stable TBAD at 1- and 3-year follow-up (15.4% and 31.6%, respectively). Matched patients with a patent FL had a 5.4% and 13.7% rate of mortality at 1 and 3 years, and patients with complete FL thrombosis were found to have mortality rates of 0% and 22.6% at the same follow-up.
Aortic remodeling after TEVAR
Placement of a thoracic endograft under these acute circumstances can often significantly alter the preoperative morphology of the true and false lumen. Schoder and colleagues5 followed changes in the TL and FL diameter in 20 patients after TEVAR for acute complicated dissection. Ninety percent of patients were found to have complete FL thrombosis of the thoracic aorta at 1 year, with a mean decrease in FL diameter of 11.6 mm. Two patients with a patent FL showed a mean increase in the maximal aortic diameter of 4.5 mm. In a similar study, Conrad et al.6 documented aortic remodeling of 21 patients in the year following TEVAR, 88% of whom had thrombosis of the FL. Most often the mobile septum is easily displaced by the radial force of the stent graft, with minimal limitation of expansion to the design diameter. Thus, endograft selection should be directed by the diameter of the normal unaffected aorta with minimal oversizing commonly limited to 5%-10%. Balloon profiling is not typically necessary.
The INSTEAD trial7 evaluated the management of uncomplicated type B aortic dissection and compared optimum medical therapy (OMT) to OMT with TEVAR. A total of 140 subjects were enrolled at seven European sites with 68 patients enrolled in OMT and 72 in OMT with TEVAR. In patients treated with TEVAR there was 90.6% complete FL thrombosis with a maximum true lumen diameter of 32.6 mm as compared to 22% and 18.7 mm in those treated with medical therapy alone. Furthermore, there was a 12.4% absolute risk reduction in aortic specific mortality and a 19.1% absolute risk reduction in disease progression in patients treated with TEVAR.
It is clear that patients that present with complicated type B aortic dissections mandate intervention with TEVAR and potentially other interventions to alleviate the complications at presentation. INSTEAD demonstrates that elective TEVAR results in favorable aortic remodeling and long-term survival, reinterventions were low, and it prevents late expansion and malperfusion. TEVAR was also associated with improved 5-year aortic-specific survival. TEVAR appears to be beneficial in those patients who present initially with a false lumen diameter of greater than 22 mm and an aortic diameter of greater than 40 mm with a patent false lumen.
References
1. Circ. Cardiovasc. Interv. 2013;4:407-16.
2. J. Vasc. Surg. 2012;55:641-51.
3. J. Vasc. Surg. 2011;54:985-92
4. Ann. Thorac. Surg. 2004;78:1268-73.
5. Ann. Thorac. Surg. 2007;83:1059-66.
6. J. Vasc. Surg. 2009;50:510-17.
7. Circulation 2009;120:2519-28.
Dr. Arko is with the Aortic Institute, Sanger Heart & Vascular Institute, Charlotte, N.C. He reported no relevant conflicts.
No, evidence supports careful choice of patients.
While the role of TEVAR has been proven to treat complications of acute type B dissections,1 its value as a prophylactic treatment in uncomplicated cases remains controversial. Optimal medical treatment (OMT) with strict blood pressure (SBP less than 120 mm Hg) and heart rate control is associated with a low morbidity and mortality, despite the risk of progressive aortic dilation. On the other hand TEVAR can result in early death and significant neurologic complications; other devastating complications of TEVAR include retrograde aortic dissection and access vessel rupture with a high associated mortality.
A meta-analysis of the published literature reported a high technical success of TEVAR for uncomplicated type B dissection and a relatively high conversion rate (20%) for patient treated with OMT, however the results did not identify an advantage for TEVAR with respect to 30-day and 2-year mortality.2
An expert panel review of the world literature also did not find significant data to support use of TEVAR for uncomplicated type B dissection.3 In the only randomized prospective trial to examine the role of TEVAR for uncomplicated type B dissection, the INSTEAD trial randomized 140 patients to OMT vs. OMT and TEVAR.4 The study results also did not support the use of TEVAR for the treatment of uncomplicated type B dissection, there was no survival advantage at 2 years, while TEVAR was associated with a 11.1% overall mortality and 4.3% neurologic complication rate, compared with 4.4% and 1.4% in the OMT group. The initial study did however report improved aortic remodeling at 2 years with TEVAR. The results of INSTEAD have been challenged because critical analysis of the INSTEAD trial has determined that the results were underpowered and that there was a 21% crossover in the OMT group and four patients received TEVAR that should have been excluded.5
Subsequent long-term analysis of the INSTEAD XL data do demonstrate a significant survival benefit and freedom from aortic adverse events in the TEVAR group after the initial 2-year analysis.6 At the 5-year follow up only 27 patients remained without a TEVAR. Fortunately there were no adverse events in the patients that crossed over to TEVAR from the OMT group demonstrating the safety of delayed TEVAR in this group. The high rate of aortic associated adverse events may favor early TEVAR. The INSTEAD XL study did identify a large primary tear (more than 10 mm) and an initial aortic diameter of 40 mm as risk factors to crossover suggesting a more aggressive approach in this subset of patients.
So while the INSTEAD XL trial now supports the use of TEVAR for uncomplicated type B dissections this was a relatively small trial that was underpowered in its initial analysis. Expert review of the world literature still supports medical management in the initial phase of treatment. Obviously in cases of failure of medical management TEVAR provides an effective treatment to restore the true lumen and visceral perfusion with possible sustained remodeling of the false lumen.
Given the not insignificant morbidity associated with TEVAR placement, routine treatment of all acute, uncomplicated type B dissections cannot be supported with the current evidence. However, a strategy of selective treatment based on size of the entry tear, extent of dissection, false lumen diameter and extent of thrombosis, effectiveness of antihypertension medications, ability to comply with medical therapy, and surveillance may be implemented. Furthermore treatment at centers of excellence with extensive TEVAR experience based on established protocols favor improved patient outcomes.
References
1. N. Engl. J. Med. 199;340:1546-52
2. Vasc. Endovascular. Surg. 2013 Oct 12;47(7):497-501. Epub 2013 Jul 12.
3. J. Am. Coll. Cardiol. 2013;61(16):1661-78.
4. Circulation 2009;120:2519-28.
5. Circulation 2009;120:2513-14.
6. Circ. Cardiovasc. Interv. 2013;6:407-16.
Dr. Shames is professor of surgery and radiology and program director of vascular surgery at the University of South Florida, Tampa. He reported no relevant conflicts.
Yes, TEVAR is clearly indicated.
Aortic dissection is a devastating condition afflicting an estimated two to eight per 100,000 people annually and comprises a large portion of the clinical entity known as the acute aortic syndromes. Patients presenting with an uncomplicated type B acute aortic dissection (TBAD) generally have low in-hospital mortality rates (2.4%-9%) when managed appropriately with anti-impulse therapy. However, survival continues to decrease with follow-up, with survival ranging between 80% and more than 95% at 1 year, progressing to approximately 75% at 3-4 years, and 48%-65% at 10 years. In late follow-up, the development of a new dissection with complications is estimated to occur in 20%-50% of patients. Complicated aortic dissections affect between 22% and 47%, and when present, mortality reaches more than 50% within the first week. TEVAR in these patients has been shown to be clearly indicated in a variety of studies with marked improvements in early mortality and late survival. Thus, one can see that aortic dissection is a disease that needs to be managed lifelong, and is associated with a high risk of mortality for the next 10 years after the initial presentation.1,2,3
The long-term effects of a patent false lumen have been well documented. Several studies following patients with chronic TBAD have documented progressive enlargement in aortic diameter with a patent false lumen. The mean increase in maximum aortic diameter ranges from 3.8 to 7.1 mm annually with any flow in the false lumen (FL) versus 1-2 mm per year with a thrombosed FL. Patients with a patent FL had 7.5 times increased risk of a dissection-related death or need for surgery as compared to patients with thrombosis of the FL. Dissection-related death or need for surgery occurred at a significantly earlier follow-up period in the patients with a patent FL.1,2,3
The aortic diameter may also influence the patency of the FL at presentation. In a review of 110 patients presenting with acute uncomplicated TBAD, 44% were identified to have a patent FL on initial imaging. Thirty-one percent of these patients had a maximum aortic diameter of 45 mm or more versus 14% of patients with a thrombosed FL (P = .053). Incidentally, patients with FL patency were on average 4 years younger than their thrombosed counterparts (62 vs. 66 years, P = .009).
Moreover, it appears that the long-term risks associated with a patent FL are further augmented by aortic dilatation at presentation. When combining both risk factors (FL patency and aortic diameter of 40 mm or more), only 22% of patients are dissection-related event–free at 5-year follow-up.Onitsuka et al.4 substantiated this finding on multivariate analysis. Interestingly, 10 of the 76 patients included in that study met both conditions, and seven of those patients (70%) experienced a dissection-related death or surgical conversion. Certainly patients meeting both criteria merit close follow-up for the development of aortic enlargement or symptoms of impending rupture.
The natural history of TBAD lends itself to at least some thrombus formation within the FL and is a common finding as the dissection becomes chronic. But in fact, partial thrombosis of the FL is associated with higher mortality in patients discharged from the hospital with stable TBAD at 1- and 3-year follow-up (15.4% and 31.6%, respectively). Matched patients with a patent FL had a 5.4% and 13.7% rate of mortality at 1 and 3 years, and patients with complete FL thrombosis were found to have mortality rates of 0% and 22.6% at the same follow-up.
Aortic remodeling after TEVAR
Placement of a thoracic endograft under these acute circumstances can often significantly alter the preoperative morphology of the true and false lumen. Schoder and colleagues5 followed changes in the TL and FL diameter in 20 patients after TEVAR for acute complicated dissection. Ninety percent of patients were found to have complete FL thrombosis of the thoracic aorta at 1 year, with a mean decrease in FL diameter of 11.6 mm. Two patients with a patent FL showed a mean increase in the maximal aortic diameter of 4.5 mm. In a similar study, Conrad et al.6 documented aortic remodeling of 21 patients in the year following TEVAR, 88% of whom had thrombosis of the FL. Most often the mobile septum is easily displaced by the radial force of the stent graft, with minimal limitation of expansion to the design diameter. Thus, endograft selection should be directed by the diameter of the normal unaffected aorta with minimal oversizing commonly limited to 5%-10%. Balloon profiling is not typically necessary.
The INSTEAD trial7 evaluated the management of uncomplicated type B aortic dissection and compared optimum medical therapy (OMT) to OMT with TEVAR. A total of 140 subjects were enrolled at seven European sites with 68 patients enrolled in OMT and 72 in OMT with TEVAR. In patients treated with TEVAR there was 90.6% complete FL thrombosis with a maximum true lumen diameter of 32.6 mm as compared to 22% and 18.7 mm in those treated with medical therapy alone. Furthermore, there was a 12.4% absolute risk reduction in aortic specific mortality and a 19.1% absolute risk reduction in disease progression in patients treated with TEVAR.
It is clear that patients that present with complicated type B aortic dissections mandate intervention with TEVAR and potentially other interventions to alleviate the complications at presentation. INSTEAD demonstrates that elective TEVAR results in favorable aortic remodeling and long-term survival, reinterventions were low, and it prevents late expansion and malperfusion. TEVAR was also associated with improved 5-year aortic-specific survival. TEVAR appears to be beneficial in those patients who present initially with a false lumen diameter of greater than 22 mm and an aortic diameter of greater than 40 mm with a patent false lumen.
References
1. Circ. Cardiovasc. Interv. 2013;4:407-16.
2. J. Vasc. Surg. 2012;55:641-51.
3. J. Vasc. Surg. 2011;54:985-92
4. Ann. Thorac. Surg. 2004;78:1268-73.
5. Ann. Thorac. Surg. 2007;83:1059-66.
6. J. Vasc. Surg. 2009;50:510-17.
7. Circulation 2009;120:2519-28.
Dr. Arko is with the Aortic Institute, Sanger Heart & Vascular Institute, Charlotte, N.C. He reported no relevant conflicts.
No, evidence supports careful choice of patients.
While the role of TEVAR has been proven to treat complications of acute type B dissections,1 its value as a prophylactic treatment in uncomplicated cases remains controversial. Optimal medical treatment (OMT) with strict blood pressure (SBP less than 120 mm Hg) and heart rate control is associated with a low morbidity and mortality, despite the risk of progressive aortic dilation. On the other hand TEVAR can result in early death and significant neurologic complications; other devastating complications of TEVAR include retrograde aortic dissection and access vessel rupture with a high associated mortality.
A meta-analysis of the published literature reported a high technical success of TEVAR for uncomplicated type B dissection and a relatively high conversion rate (20%) for patient treated with OMT, however the results did not identify an advantage for TEVAR with respect to 30-day and 2-year mortality.2
An expert panel review of the world literature also did not find significant data to support use of TEVAR for uncomplicated type B dissection.3 In the only randomized prospective trial to examine the role of TEVAR for uncomplicated type B dissection, the INSTEAD trial randomized 140 patients to OMT vs. OMT and TEVAR.4 The study results also did not support the use of TEVAR for the treatment of uncomplicated type B dissection, there was no survival advantage at 2 years, while TEVAR was associated with a 11.1% overall mortality and 4.3% neurologic complication rate, compared with 4.4% and 1.4% in the OMT group. The initial study did however report improved aortic remodeling at 2 years with TEVAR. The results of INSTEAD have been challenged because critical analysis of the INSTEAD trial has determined that the results were underpowered and that there was a 21% crossover in the OMT group and four patients received TEVAR that should have been excluded.5
Subsequent long-term analysis of the INSTEAD XL data do demonstrate a significant survival benefit and freedom from aortic adverse events in the TEVAR group after the initial 2-year analysis.6 At the 5-year follow up only 27 patients remained without a TEVAR. Fortunately there were no adverse events in the patients that crossed over to TEVAR from the OMT group demonstrating the safety of delayed TEVAR in this group. The high rate of aortic associated adverse events may favor early TEVAR. The INSTEAD XL study did identify a large primary tear (more than 10 mm) and an initial aortic diameter of 40 mm as risk factors to crossover suggesting a more aggressive approach in this subset of patients.
So while the INSTEAD XL trial now supports the use of TEVAR for uncomplicated type B dissections this was a relatively small trial that was underpowered in its initial analysis. Expert review of the world literature still supports medical management in the initial phase of treatment. Obviously in cases of failure of medical management TEVAR provides an effective treatment to restore the true lumen and visceral perfusion with possible sustained remodeling of the false lumen.
Given the not insignificant morbidity associated with TEVAR placement, routine treatment of all acute, uncomplicated type B dissections cannot be supported with the current evidence. However, a strategy of selective treatment based on size of the entry tear, extent of dissection, false lumen diameter and extent of thrombosis, effectiveness of antihypertension medications, ability to comply with medical therapy, and surveillance may be implemented. Furthermore treatment at centers of excellence with extensive TEVAR experience based on established protocols favor improved patient outcomes.
References
1. N. Engl. J. Med. 199;340:1546-52
2. Vasc. Endovascular. Surg. 2013 Oct 12;47(7):497-501. Epub 2013 Jul 12.
3. J. Am. Coll. Cardiol. 2013;61(16):1661-78.
4. Circulation 2009;120:2519-28.
5. Circulation 2009;120:2513-14.
6. Circ. Cardiovasc. Interv. 2013;6:407-16.
Dr. Shames is professor of surgery and radiology and program director of vascular surgery at the University of South Florida, Tampa. He reported no relevant conflicts.
Shorter regimen can prevent GVHD
Credit: Chad McNeeley
Combining a couple of “promising” treatment approaches can prevent graft-vs-host disease (GVHD) as well as conventional therapy, researchers have reported in the Journal of Clinical Oncology.
They combined a 4-day myeloablative conditioning regimen of busulfan and fludarabine with 2 days of high-dose cyclophosphamide after transplant.
Typically, patients receive 6 months of immunosuppressive therapy to reduce their risk of GVHD.
The conditioning regimen and post-transplant cyclophosphamide have been tested separately in other studies and have good track records in controlling cancer and preventing severe GVHD.
Those successes led Leo Luznik, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues to combine the 2 therapies.
The team tested the combination in 92 patients with high-risk hematologic malignancies. Diagnoses included acute and chronic leukemias, multiple myeloma, non-Hodgkin lymphoma, and myelodysplastic syndromes. Patients had a median age of 49 (range, 21-65).
All patients received 40 mg/m2/day of intravenous (IV) fludarabine immediately before busulfan on all 4 days of conditioning. The busulfan dose of 130 mg/m2 IV daily was adjusted based on pharmacokinetics.
One or 2 days of rest were allowed before patients received a T-cell-replete bone marrow allograft. Forty-five patients had a matched, related donor, and 47 had a matched, unrelated donor.
Patients received 50 mg/kg/day of IV cyclophosphamide for 2 days, with the first dose starting 62 to 72 hours after the start of allograft infusion.
At 100 days after transplant, 51% of patients had developed grade 2-4 acute GVHD, and 15% had grade 3-4 acute GVHD. Fourteen percent of patients developed chronic GVHD.
The 2-year overall survival rate was 67%, and 2-year event-free survival was 62%.
Dr Luznik said he was encouraged by the low rate of chronic GVHD with the regimen. And he noted that percentages of acute GVHD are similar to those seen with the standard 6-month regimen of immunosuppressive drugs.
Reducing the post-transplant treatment to 2 days with cyclophosphamide, he said, “also allows for the earlier integration of other treatments.”
For example, immunotherapies used to eradicate any remaining cancer could be started much sooner with this regimen, said study author Christopher Kanakry, MD, of the Sidney Kimmel Cancer Center at Johns Hopkins.
“If you give patients immune cells to eradicate any remaining cancer cells that might be present,” he said, “those immune cells would not be prevented from doing their job by ongoing immune suppression drugs that are being used in patients treated with conventional transplant approaches.”
Dr Luznik said the researchers’ next step will be a phase 3 trial comparing this regimen to another experimental approach to prevent GVHD or to the more traditional 6-month immunosuppressive therapy.
Funding for this study was provided by Otsuka Pharmaceutical Co., Ltd. and the National Institutes of Health.
Credit: Chad McNeeley
Combining a couple of “promising” treatment approaches can prevent graft-vs-host disease (GVHD) as well as conventional therapy, researchers have reported in the Journal of Clinical Oncology.
They combined a 4-day myeloablative conditioning regimen of busulfan and fludarabine with 2 days of high-dose cyclophosphamide after transplant.
Typically, patients receive 6 months of immunosuppressive therapy to reduce their risk of GVHD.
The conditioning regimen and post-transplant cyclophosphamide have been tested separately in other studies and have good track records in controlling cancer and preventing severe GVHD.
Those successes led Leo Luznik, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues to combine the 2 therapies.
The team tested the combination in 92 patients with high-risk hematologic malignancies. Diagnoses included acute and chronic leukemias, multiple myeloma, non-Hodgkin lymphoma, and myelodysplastic syndromes. Patients had a median age of 49 (range, 21-65).
All patients received 40 mg/m2/day of intravenous (IV) fludarabine immediately before busulfan on all 4 days of conditioning. The busulfan dose of 130 mg/m2 IV daily was adjusted based on pharmacokinetics.
One or 2 days of rest were allowed before patients received a T-cell-replete bone marrow allograft. Forty-five patients had a matched, related donor, and 47 had a matched, unrelated donor.
Patients received 50 mg/kg/day of IV cyclophosphamide for 2 days, with the first dose starting 62 to 72 hours after the start of allograft infusion.
At 100 days after transplant, 51% of patients had developed grade 2-4 acute GVHD, and 15% had grade 3-4 acute GVHD. Fourteen percent of patients developed chronic GVHD.
The 2-year overall survival rate was 67%, and 2-year event-free survival was 62%.
Dr Luznik said he was encouraged by the low rate of chronic GVHD with the regimen. And he noted that percentages of acute GVHD are similar to those seen with the standard 6-month regimen of immunosuppressive drugs.
Reducing the post-transplant treatment to 2 days with cyclophosphamide, he said, “also allows for the earlier integration of other treatments.”
For example, immunotherapies used to eradicate any remaining cancer could be started much sooner with this regimen, said study author Christopher Kanakry, MD, of the Sidney Kimmel Cancer Center at Johns Hopkins.
“If you give patients immune cells to eradicate any remaining cancer cells that might be present,” he said, “those immune cells would not be prevented from doing their job by ongoing immune suppression drugs that are being used in patients treated with conventional transplant approaches.”
Dr Luznik said the researchers’ next step will be a phase 3 trial comparing this regimen to another experimental approach to prevent GVHD or to the more traditional 6-month immunosuppressive therapy.
Funding for this study was provided by Otsuka Pharmaceutical Co., Ltd. and the National Institutes of Health.
Credit: Chad McNeeley
Combining a couple of “promising” treatment approaches can prevent graft-vs-host disease (GVHD) as well as conventional therapy, researchers have reported in the Journal of Clinical Oncology.
They combined a 4-day myeloablative conditioning regimen of busulfan and fludarabine with 2 days of high-dose cyclophosphamide after transplant.
Typically, patients receive 6 months of immunosuppressive therapy to reduce their risk of GVHD.
The conditioning regimen and post-transplant cyclophosphamide have been tested separately in other studies and have good track records in controlling cancer and preventing severe GVHD.
Those successes led Leo Luznik, MD, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues to combine the 2 therapies.
The team tested the combination in 92 patients with high-risk hematologic malignancies. Diagnoses included acute and chronic leukemias, multiple myeloma, non-Hodgkin lymphoma, and myelodysplastic syndromes. Patients had a median age of 49 (range, 21-65).
All patients received 40 mg/m2/day of intravenous (IV) fludarabine immediately before busulfan on all 4 days of conditioning. The busulfan dose of 130 mg/m2 IV daily was adjusted based on pharmacokinetics.
One or 2 days of rest were allowed before patients received a T-cell-replete bone marrow allograft. Forty-five patients had a matched, related donor, and 47 had a matched, unrelated donor.
Patients received 50 mg/kg/day of IV cyclophosphamide for 2 days, with the first dose starting 62 to 72 hours after the start of allograft infusion.
At 100 days after transplant, 51% of patients had developed grade 2-4 acute GVHD, and 15% had grade 3-4 acute GVHD. Fourteen percent of patients developed chronic GVHD.
The 2-year overall survival rate was 67%, and 2-year event-free survival was 62%.
Dr Luznik said he was encouraged by the low rate of chronic GVHD with the regimen. And he noted that percentages of acute GVHD are similar to those seen with the standard 6-month regimen of immunosuppressive drugs.
Reducing the post-transplant treatment to 2 days with cyclophosphamide, he said, “also allows for the earlier integration of other treatments.”
For example, immunotherapies used to eradicate any remaining cancer could be started much sooner with this regimen, said study author Christopher Kanakry, MD, of the Sidney Kimmel Cancer Center at Johns Hopkins.
“If you give patients immune cells to eradicate any remaining cancer cells that might be present,” he said, “those immune cells would not be prevented from doing their job by ongoing immune suppression drugs that are being used in patients treated with conventional transplant approaches.”
Dr Luznik said the researchers’ next step will be a phase 3 trial comparing this regimen to another experimental approach to prevent GVHD or to the more traditional 6-month immunosuppressive therapy.
Funding for this study was provided by Otsuka Pharmaceutical Co., Ltd. and the National Institutes of Health.
A safer gene therapy for SCID-X1?
Credit: Chad McNeeley
A new gene therapy appears safe and effective for boys with X-linked severe combined immunodeficiency syndrome (SCID-X1).
Early data from a small trial suggest the treatment may not pose a risk of leukemia, which was seen in previous trials of gene therapy in SCID-X1 patients.
The new therapy is a self-inactivating γ-retrovirus designed to deliver its payload while minimizing the chance of inadvertently activating
oncogenes that could lead to leukemia.
Researchers described results with this therapy in The New England Journal of Medicine.
The team enrolled 9 boys with SCID-X1. They received bone marrow-derived CD34+ cells transduced with the self-inactivating γ-chain vector, without preparative conditioning.
Eight boys are still alive after 12.1 to 38.7 months of follow-up, with no SCID-X1-associated infections. One child died of an overwhelming infection that was present at the time gene therapy began.
Gene therapy alone generated functioning immune systems in 7 of the patients.
Genetic studies of the boys’ new T cells revealed that the viral vector did not lead to an expansion of cells with vector insertions near known oncogenes, raising cautious hopes about the vector’s long-term safety.
The researchers said they will continue to monitor the patients for any signs of treatment-related leukemia for 15 years.
In prior European trials, which were the first to demonstrate gene therapy’s potential to successfully cure a disease, leukemia appeared 2 to 5 years after treatment. This outcome was one of several events that, together, slowed clinical progress in gene therapy for many years.
“Our goal was to take the molecular data from the prior trial and use it to produce a vector that would remain effective and, at the same time, reduce the risk of leukemia,” said David A. Williams, MD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts.
“The efficacy data from our study is clear: The vector does work to correct the disease. And by a surrogate endpoint, we have improved the treatment’s safety, although it’s too early to say that we’ve completely eliminated the long-term risk of leukemia.”
After a single round of treatment, 6 of 7 boys for whom the gene therapy was successful had achieved the trial’s primary efficacy endpoints—a T-cell count greater than 300 cells per microliter of blood and T-cell proliferation in response to stimulation with phytohemagglutinin.
The seventh boy received a second round of gene therapy and remains healthy despite having relatively low T-cell counts. The eighth surviving patient was successfully treated with a conventional hematopoietic stem cell transplant after gene therapy failed to stimulate T-cell production.
Credit: Chad McNeeley
A new gene therapy appears safe and effective for boys with X-linked severe combined immunodeficiency syndrome (SCID-X1).
Early data from a small trial suggest the treatment may not pose a risk of leukemia, which was seen in previous trials of gene therapy in SCID-X1 patients.
The new therapy is a self-inactivating γ-retrovirus designed to deliver its payload while minimizing the chance of inadvertently activating
oncogenes that could lead to leukemia.
Researchers described results with this therapy in The New England Journal of Medicine.
The team enrolled 9 boys with SCID-X1. They received bone marrow-derived CD34+ cells transduced with the self-inactivating γ-chain vector, without preparative conditioning.
Eight boys are still alive after 12.1 to 38.7 months of follow-up, with no SCID-X1-associated infections. One child died of an overwhelming infection that was present at the time gene therapy began.
Gene therapy alone generated functioning immune systems in 7 of the patients.
Genetic studies of the boys’ new T cells revealed that the viral vector did not lead to an expansion of cells with vector insertions near known oncogenes, raising cautious hopes about the vector’s long-term safety.
The researchers said they will continue to monitor the patients for any signs of treatment-related leukemia for 15 years.
In prior European trials, which were the first to demonstrate gene therapy’s potential to successfully cure a disease, leukemia appeared 2 to 5 years after treatment. This outcome was one of several events that, together, slowed clinical progress in gene therapy for many years.
“Our goal was to take the molecular data from the prior trial and use it to produce a vector that would remain effective and, at the same time, reduce the risk of leukemia,” said David A. Williams, MD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts.
“The efficacy data from our study is clear: The vector does work to correct the disease. And by a surrogate endpoint, we have improved the treatment’s safety, although it’s too early to say that we’ve completely eliminated the long-term risk of leukemia.”
After a single round of treatment, 6 of 7 boys for whom the gene therapy was successful had achieved the trial’s primary efficacy endpoints—a T-cell count greater than 300 cells per microliter of blood and T-cell proliferation in response to stimulation with phytohemagglutinin.
The seventh boy received a second round of gene therapy and remains healthy despite having relatively low T-cell counts. The eighth surviving patient was successfully treated with a conventional hematopoietic stem cell transplant after gene therapy failed to stimulate T-cell production.
Credit: Chad McNeeley
A new gene therapy appears safe and effective for boys with X-linked severe combined immunodeficiency syndrome (SCID-X1).
Early data from a small trial suggest the treatment may not pose a risk of leukemia, which was seen in previous trials of gene therapy in SCID-X1 patients.
The new therapy is a self-inactivating γ-retrovirus designed to deliver its payload while minimizing the chance of inadvertently activating
oncogenes that could lead to leukemia.
Researchers described results with this therapy in The New England Journal of Medicine.
The team enrolled 9 boys with SCID-X1. They received bone marrow-derived CD34+ cells transduced with the self-inactivating γ-chain vector, without preparative conditioning.
Eight boys are still alive after 12.1 to 38.7 months of follow-up, with no SCID-X1-associated infections. One child died of an overwhelming infection that was present at the time gene therapy began.
Gene therapy alone generated functioning immune systems in 7 of the patients.
Genetic studies of the boys’ new T cells revealed that the viral vector did not lead to an expansion of cells with vector insertions near known oncogenes, raising cautious hopes about the vector’s long-term safety.
The researchers said they will continue to monitor the patients for any signs of treatment-related leukemia for 15 years.
In prior European trials, which were the first to demonstrate gene therapy’s potential to successfully cure a disease, leukemia appeared 2 to 5 years after treatment. This outcome was one of several events that, together, slowed clinical progress in gene therapy for many years.
“Our goal was to take the molecular data from the prior trial and use it to produce a vector that would remain effective and, at the same time, reduce the risk of leukemia,” said David A. Williams, MD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts.
“The efficacy data from our study is clear: The vector does work to correct the disease. And by a surrogate endpoint, we have improved the treatment’s safety, although it’s too early to say that we’ve completely eliminated the long-term risk of leukemia.”
After a single round of treatment, 6 of 7 boys for whom the gene therapy was successful had achieved the trial’s primary efficacy endpoints—a T-cell count greater than 300 cells per microliter of blood and T-cell proliferation in response to stimulation with phytohemagglutinin.
The seventh boy received a second round of gene therapy and remains healthy despite having relatively low T-cell counts. The eighth surviving patient was successfully treated with a conventional hematopoietic stem cell transplant after gene therapy failed to stimulate T-cell production.
Microscopy advances net Nobel Prize
Credit: Max Planck Institute
for Biophysical Chemistry
Three scientists have received the 2014 Nobel Prize in Chemistry for aiding the development of super-resolved fluorescence microscopy.
For a long time, optical microscopy was held back by a presumed limitation: that it would never obtain a better resolution than half the wavelength
of light.
Working separately, this year’s Nobel Laureates in Chemistry circumvented this limitation and brought optical microscopy into the nanodimension.
Now, scientists can monitor the interplay between individual molecules inside cells, watch disease-related proteins aggregate, and track cell division at the nanolevel.
For enabling these advances, Eric Betzig, PhD, of the Howard Hughes Medical Institute in Ashburn, Virginia; Stefan W. Hell, PhD, of the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany; and William E. Moerner, PhD, of Stanford University in California, received the prize. The prize amount was SEK 8 million, to be shared equally among the Laureates.
The work in brief
In 1873, the microscopist Ernst Abbe stipulated a physical limit for the maximum resolution of traditional optical microscopy—0.2 micrometers. Drs Moerner, Hell, and Betzig were able to bypass this limit.
Dr Hell developed stimulated emission depletion (STED) microscopy. This method employs 2 laser beams. One stimulates fluorescent molecules to glow, and another cancels out all fluorescence except for that in a nanometer-sized volume.
Scanning over the sample, nanometer for nanometer, yields an image with a resolution better than Abbe’s stipulated limit.
Drs Betzig and Moerner laid the foundation for another method, single-molecule microscopy. This method relies upon the possibility to turn the fluorescence of individual molecules on and off.
Scientists image the same area multiple times, letting just a few interspersed molecules glow each time. Superimposing these images yields a dense super-image resolved at the nanolevel. In 2006, Dr Betzig used this method for the first time.
For more details on the Nobel Laureates and their work, visit Nobelprize.org.
Credit: Max Planck Institute
for Biophysical Chemistry
Three scientists have received the 2014 Nobel Prize in Chemistry for aiding the development of super-resolved fluorescence microscopy.
For a long time, optical microscopy was held back by a presumed limitation: that it would never obtain a better resolution than half the wavelength
of light.
Working separately, this year’s Nobel Laureates in Chemistry circumvented this limitation and brought optical microscopy into the nanodimension.
Now, scientists can monitor the interplay between individual molecules inside cells, watch disease-related proteins aggregate, and track cell division at the nanolevel.
For enabling these advances, Eric Betzig, PhD, of the Howard Hughes Medical Institute in Ashburn, Virginia; Stefan W. Hell, PhD, of the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany; and William E. Moerner, PhD, of Stanford University in California, received the prize. The prize amount was SEK 8 million, to be shared equally among the Laureates.
The work in brief
In 1873, the microscopist Ernst Abbe stipulated a physical limit for the maximum resolution of traditional optical microscopy—0.2 micrometers. Drs Moerner, Hell, and Betzig were able to bypass this limit.
Dr Hell developed stimulated emission depletion (STED) microscopy. This method employs 2 laser beams. One stimulates fluorescent molecules to glow, and another cancels out all fluorescence except for that in a nanometer-sized volume.
Scanning over the sample, nanometer for nanometer, yields an image with a resolution better than Abbe’s stipulated limit.
Drs Betzig and Moerner laid the foundation for another method, single-molecule microscopy. This method relies upon the possibility to turn the fluorescence of individual molecules on and off.
Scientists image the same area multiple times, letting just a few interspersed molecules glow each time. Superimposing these images yields a dense super-image resolved at the nanolevel. In 2006, Dr Betzig used this method for the first time.
For more details on the Nobel Laureates and their work, visit Nobelprize.org.
Credit: Max Planck Institute
for Biophysical Chemistry
Three scientists have received the 2014 Nobel Prize in Chemistry for aiding the development of super-resolved fluorescence microscopy.
For a long time, optical microscopy was held back by a presumed limitation: that it would never obtain a better resolution than half the wavelength
of light.
Working separately, this year’s Nobel Laureates in Chemistry circumvented this limitation and brought optical microscopy into the nanodimension.
Now, scientists can monitor the interplay between individual molecules inside cells, watch disease-related proteins aggregate, and track cell division at the nanolevel.
For enabling these advances, Eric Betzig, PhD, of the Howard Hughes Medical Institute in Ashburn, Virginia; Stefan W. Hell, PhD, of the Max Planck Institute for Biophysical Chemistry in Göttingen, Germany; and William E. Moerner, PhD, of Stanford University in California, received the prize. The prize amount was SEK 8 million, to be shared equally among the Laureates.
The work in brief
In 1873, the microscopist Ernst Abbe stipulated a physical limit for the maximum resolution of traditional optical microscopy—0.2 micrometers. Drs Moerner, Hell, and Betzig were able to bypass this limit.
Dr Hell developed stimulated emission depletion (STED) microscopy. This method employs 2 laser beams. One stimulates fluorescent molecules to glow, and another cancels out all fluorescence except for that in a nanometer-sized volume.
Scanning over the sample, nanometer for nanometer, yields an image with a resolution better than Abbe’s stipulated limit.
Drs Betzig and Moerner laid the foundation for another method, single-molecule microscopy. This method relies upon the possibility to turn the fluorescence of individual molecules on and off.
Scientists image the same area multiple times, letting just a few interspersed molecules glow each time. Superimposing these images yields a dense super-image resolved at the nanolevel. In 2006, Dr Betzig used this method for the first time.
For more details on the Nobel Laureates and their work, visit Nobelprize.org.
Price increases drive spending on cancer drugs
Credit: Steven Harbour
The recent surge in spending on oral anticancer drugs in the US exceeds the increase in use of these drugs, new research shows.
Average quarterly national spending on oral oncologics increased 37% during the period studied, from $940 million in the first quarter of 2006 to $1.4 billion in the third quarter of 2011.
But the average quarterly use of these drugs in the same time period increased by only 10%.
This suggests price increases are a significant driver of spending trends.
Rena M. Conti, PhD, of the University of Chicago in Illinois, and her colleagues examined recent trends in spending and use of oral oncologics and disclosed their findings in Health Affairs.
Of the 47 drugs analyzed, most were targeted agents (30%), hormonal agents (26%), and alkylating agents (19%).
The researchers observed a significant increase in national spending on oral oncologics from 2006 to 2011—an estimated average quarterly increase of $20 million.
This was driven by brand-name, patent-protected drugs, but the use of these drugs climbed a comparatively small amount. Average quarterly spending of patent-protected drugs increased 61%, and average quarterly use increased 30% between 2006 and the period from September 2010 to September 2011.
“This is an exciting time, an era of breakthrough cancer drugs,” Dr Conti said. “Some of these medications have extended the lives of many people with certain types of cancer. However, spending on these brand-name oral oncologics is outstripping national spending on all pharmaceuticals and all medical care spending generally.”
The researchers also discovered that when oncologics lose patent protection, spending takes a nosedive. The use of newly off-patent drugs increased by 16%, but average quarterly spending on those drugs fell by 65%.
Another finding was that US spending on targeted anticancer agents increased from 35% of all oral cancer drugs in 2006 to nearly 60% in 2011.
Meanwhile, spending on hormonal agents decreased from 42% of total spending to 19%, spending on antimetabolites increased from 11% to 12%, and spending on alkylating agents decreased from 10% to 8%.
Credit: Steven Harbour
The recent surge in spending on oral anticancer drugs in the US exceeds the increase in use of these drugs, new research shows.
Average quarterly national spending on oral oncologics increased 37% during the period studied, from $940 million in the first quarter of 2006 to $1.4 billion in the third quarter of 2011.
But the average quarterly use of these drugs in the same time period increased by only 10%.
This suggests price increases are a significant driver of spending trends.
Rena M. Conti, PhD, of the University of Chicago in Illinois, and her colleagues examined recent trends in spending and use of oral oncologics and disclosed their findings in Health Affairs.
Of the 47 drugs analyzed, most were targeted agents (30%), hormonal agents (26%), and alkylating agents (19%).
The researchers observed a significant increase in national spending on oral oncologics from 2006 to 2011—an estimated average quarterly increase of $20 million.
This was driven by brand-name, patent-protected drugs, but the use of these drugs climbed a comparatively small amount. Average quarterly spending of patent-protected drugs increased 61%, and average quarterly use increased 30% between 2006 and the period from September 2010 to September 2011.
“This is an exciting time, an era of breakthrough cancer drugs,” Dr Conti said. “Some of these medications have extended the lives of many people with certain types of cancer. However, spending on these brand-name oral oncologics is outstripping national spending on all pharmaceuticals and all medical care spending generally.”
The researchers also discovered that when oncologics lose patent protection, spending takes a nosedive. The use of newly off-patent drugs increased by 16%, but average quarterly spending on those drugs fell by 65%.
Another finding was that US spending on targeted anticancer agents increased from 35% of all oral cancer drugs in 2006 to nearly 60% in 2011.
Meanwhile, spending on hormonal agents decreased from 42% of total spending to 19%, spending on antimetabolites increased from 11% to 12%, and spending on alkylating agents decreased from 10% to 8%.
Credit: Steven Harbour
The recent surge in spending on oral anticancer drugs in the US exceeds the increase in use of these drugs, new research shows.
Average quarterly national spending on oral oncologics increased 37% during the period studied, from $940 million in the first quarter of 2006 to $1.4 billion in the third quarter of 2011.
But the average quarterly use of these drugs in the same time period increased by only 10%.
This suggests price increases are a significant driver of spending trends.
Rena M. Conti, PhD, of the University of Chicago in Illinois, and her colleagues examined recent trends in spending and use of oral oncologics and disclosed their findings in Health Affairs.
Of the 47 drugs analyzed, most were targeted agents (30%), hormonal agents (26%), and alkylating agents (19%).
The researchers observed a significant increase in national spending on oral oncologics from 2006 to 2011—an estimated average quarterly increase of $20 million.
This was driven by brand-name, patent-protected drugs, but the use of these drugs climbed a comparatively small amount. Average quarterly spending of patent-protected drugs increased 61%, and average quarterly use increased 30% between 2006 and the period from September 2010 to September 2011.
“This is an exciting time, an era of breakthrough cancer drugs,” Dr Conti said. “Some of these medications have extended the lives of many people with certain types of cancer. However, spending on these brand-name oral oncologics is outstripping national spending on all pharmaceuticals and all medical care spending generally.”
The researchers also discovered that when oncologics lose patent protection, spending takes a nosedive. The use of newly off-patent drugs increased by 16%, but average quarterly spending on those drugs fell by 65%.
Another finding was that US spending on targeted anticancer agents increased from 35% of all oral cancer drugs in 2006 to nearly 60% in 2011.
Meanwhile, spending on hormonal agents decreased from 42% of total spending to 19%, spending on antimetabolites increased from 11% to 12%, and spending on alkylating agents decreased from 10% to 8%.