COPENHAGEN – The location of cerebral microbleeds appears to be strongly associated with dementia subtypes, perhaps reflecting the disorders’ underlying pathologies.

"This regional association with dementia subtypes is consistent with the hypothesis that lobar cerebral microbleeds reflect cerebral amyloid angiopathy, which is consistent with Alzheimer’s disease, while those in deep areas reflect hypertensive arteriopathy, which is important in vascular dementia," Lenore Launer, Ph.D., said at the Alzheimer’s Association International Conference 2014.

Dr. Launer, chief of the neuroepidemiology section in the laboratory of epidemiology and population science at the National Institute on Aging, and her colleagues examined the relationship between incident microbleeds and dementia in the AGES (Age, Gene/Environment Susceptibility) Reykjavik Study.

The population-based study is a project of the Icelandic Heart Association. It was established in 1967 and has followed more than 9,000 people, all of whom were born between 1907 and 1935. In 2000, the group partnered with the National Institute on Aging to further study diseases of old age, with an emphasis on imaging.

Since then, participants have undergone extensive phenotyping and repeat brain imaging to look specifically at cerebral microbleeds, infarcts, white-matter hyperintensities, and whole-brain volume.

Dr. Launer’s study comprised 2,482 people who were without stroke or dementia at baseline and who had complete brain MRI data during two 5-year periods: 2002-2006 and 2007-2011.

At baseline, patients’ mean age was 75 years. About 25% were carriers of the apolipoprotein E epsilon 4 allele. Hypertension was common (77% of patients). Almost a third of patients (29%) had brain infarct–like lesions, 11% had white-matter hyperintensities, and 16% had cerebral microbleeds.

Over the study period, 458 (18%) of the cohort’s patients developed new microbleeds, with 30% of those developing multiple bleeds. Of those new microbleeds, 64% were strictly lobar, with 1-15 bleeds per person. The remainder were deep lesions, numbering 1-19 per person.

There were 111 new dementia cases; of those, 83 were diagnosed as Alzheimer’s and 17 as vascular dementia. The rest were designated as "other dementia."

Two multivariate regression analyses examined the relationship between microbleed location and dementia subtype. Both controlled for a number of clinical and demographic factors. The first analysis included age, gender, and baseline cerebral microbleeds. The second analysis included all of those factors, plus education, depression, baseline vascular risk factors (hypertension, smoking, diabetes, body mass index, and total cholesterol), and baseline MRI markers (infarcts, total brain volume, and hyperintense lesions).

In the fully adjusted model, microbleed location showed a significant relationship with dementia subtypes. Lobar microbleeds were associated with a doubling in the risk of Alzheimer’s disease, while deep bleeds increased the risk of vascular dementia sixfold.

"It’s difficult to disentangle the temporal relationship here," Dr. Launer said. "But incident cerebral microbleeds may indicate more severe small-vessel disease, and be the thing that pushes a person off the cliff into the clinical presentation of dementia."

The Icelandic Heart Association and the National Institute on Aging sponsored the study. As a government employee, Dr. Launer has no financial disclosures.

[email protected]

On Twitter @alz_gal

COPENHAGEN – The location of cerebral microbleeds appears to be strongly associated with dementia subtypes, perhaps reflecting the disorders’ underlying pathologies.

"This regional association with dementia subtypes is consistent with the hypothesis that lobar cerebral microbleeds reflect cerebral amyloid angiopathy, which is consistent with Alzheimer’s disease, while those in deep areas reflect hypertensive arteriopathy, which is important in vascular dementia," Lenore Launer, Ph.D., said at the Alzheimer’s Association International Conference 2014.

Dr. Launer, chief of the neuroepidemiology section in the laboratory of epidemiology and population science at the National Institute on Aging, and her colleagues examined the relationship between incident microbleeds and dementia in the AGES (Age, Gene/Environment Susceptibility) Reykjavik Study.

The population-based study is a project of the Icelandic Heart Association. It was established in 1967 and has followed more than 9,000 people, all of whom were born between 1907 and 1935. In 2000, the group partnered with the National Institute on Aging to further study diseases of old age, with an emphasis on imaging.

Since then, participants have undergone extensive phenotyping and repeat brain imaging to look specifically at cerebral microbleeds, infarcts, white-matter hyperintensities, and whole-brain volume.

Dr. Launer’s study comprised 2,482 people who were without stroke or dementia at baseline and who had complete brain MRI data during two 5-year periods: 2002-2006 and 2007-2011.

At baseline, patients’ mean age was 75 years. About 25% were carriers of the apolipoprotein E epsilon 4 allele. Hypertension was common (77% of patients). Almost a third of patients (29%) had brain infarct–like lesions, 11% had white-matter hyperintensities, and 16% had cerebral microbleeds.

Over the study period, 458 (18%) of the cohort’s patients developed new microbleeds, with 30% of those developing multiple bleeds. Of those new microbleeds, 64% were strictly lobar, with 1-15 bleeds per person. The remainder were deep lesions, numbering 1-19 per person.

There were 111 new dementia cases; of those, 83 were diagnosed as Alzheimer’s and 17 as vascular dementia. The rest were designated as "other dementia."

Two multivariate regression analyses examined the relationship between microbleed location and dementia subtype. Both controlled for a number of clinical and demographic factors. The first analysis included age, gender, and baseline cerebral microbleeds. The second analysis included all of those factors, plus education, depression, baseline vascular risk factors (hypertension, smoking, diabetes, body mass index, and total cholesterol), and baseline MRI markers (infarcts, total brain volume, and hyperintense lesions).

In the fully adjusted model, microbleed location showed a significant relationship with dementia subtypes. Lobar microbleeds were associated with a doubling in the risk of Alzheimer’s disease, while deep bleeds increased the risk of vascular dementia sixfold.

"It’s difficult to disentangle the temporal relationship here," Dr. Launer said. "But incident cerebral microbleeds may indicate more severe small-vessel disease, and be the thing that pushes a person off the cliff into the clinical presentation of dementia."

The Icelandic Heart Association and the National Institute on Aging sponsored the study. As a government employee, Dr. Launer has no financial disclosures.

[email protected]

On Twitter @alz_gal

COPENHAGEN – The location of cerebral microbleeds appears to be strongly associated with dementia subtypes, perhaps reflecting the disorders’ underlying pathologies.

"This regional association with dementia subtypes is consistent with the hypothesis that lobar cerebral microbleeds reflect cerebral amyloid angiopathy, which is consistent with Alzheimer’s disease, while those in deep areas reflect hypertensive arteriopathy, which is important in vascular dementia," Lenore Launer, Ph.D., said at the Alzheimer’s Association International Conference 2014.

Dr. Launer, chief of the neuroepidemiology section in the laboratory of epidemiology and population science at the National Institute on Aging, and her colleagues examined the relationship between incident microbleeds and dementia in the AGES (Age, Gene/Environment Susceptibility) Reykjavik Study.

The population-based study is a project of the Icelandic Heart Association. It was established in 1967 and has followed more than 9,000 people, all of whom were born between 1907 and 1935. In 2000, the group partnered with the National Institute on Aging to further study diseases of old age, with an emphasis on imaging.

Since then, participants have undergone extensive phenotyping and repeat brain imaging to look specifically at cerebral microbleeds, infarcts, white-matter hyperintensities, and whole-brain volume.

Dr. Launer’s study comprised 2,482 people who were without stroke or dementia at baseline and who had complete brain MRI data during two 5-year periods: 2002-2006 and 2007-2011.

At baseline, patients’ mean age was 75 years. About 25% were carriers of the apolipoprotein E epsilon 4 allele. Hypertension was common (77% of patients). Almost a third of patients (29%) had brain infarct–like lesions, 11% had white-matter hyperintensities, and 16% had cerebral microbleeds.

Over the study period, 458 (18%) of the cohort’s patients developed new microbleeds, with 30% of those developing multiple bleeds. Of those new microbleeds, 64% were strictly lobar, with 1-15 bleeds per person. The remainder were deep lesions, numbering 1-19 per person.

There were 111 new dementia cases; of those, 83 were diagnosed as Alzheimer’s and 17 as vascular dementia. The rest were designated as "other dementia."

Two multivariate regression analyses examined the relationship between microbleed location and dementia subtype. Both controlled for a number of clinical and demographic factors. The first analysis included age, gender, and baseline cerebral microbleeds. The second analysis included all of those factors, plus education, depression, baseline vascular risk factors (hypertension, smoking, diabetes, body mass index, and total cholesterol), and baseline MRI markers (infarcts, total brain volume, and hyperintense lesions).

In the fully adjusted model, microbleed location showed a significant relationship with dementia subtypes. Lobar microbleeds were associated with a doubling in the risk of Alzheimer’s disease, while deep bleeds increased the risk of vascular dementia sixfold.

"It’s difficult to disentangle the temporal relationship here," Dr. Launer said. "But incident cerebral microbleeds may indicate more severe small-vessel disease, and be the thing that pushes a person off the cliff into the clinical presentation of dementia."

The Icelandic Heart Association and the National Institute on Aging sponsored the study. As a government employee, Dr. Launer has no financial disclosures.

[email protected]

On Twitter @alz_gal

Adults who consumed high levels of omega-3 polyunsaturated fatty acids showed a markedly reduced risk of developing amyotrophic lateral sclerosis in a pooled analysis of five large prospective cohort studies that assessed diet.

Diet-derived omega-3 polyunsaturated fatty acids (PUFAs) are known to have neuroprotective effects, and those present in neural plasma membranes can modulate oxidative stress, excitotoxicity, and inflammation. But no prospective studies have explored a possible relationship between omega-3 PUFA intake and amyotrophic lateral sclerosis (ALS) risk, according to Kathryn C. Fitzgerald of the department of nutrition, Harvard School of Public Health, Boston, and her associates.

© Suprijono Suharjoto - Fotolia.com

In a study published July 14 in JAMA Neurology, Ms. Fitzgerald and her colleagues pooled data from the Health Professionals Follow-up Study, the Nurses’ Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health-AARP Diet and Health Study. A total of 995 ALS patients were identified among 1,002,082 participants in these studies. The five studies included detailed dietary information and tracked the occurrence of ALS in the study participants through the National Death Index.

Omega-3 PUFA intake in the highest quintile of consumption at a median of 2.11 g/day was associated with a 34% reduced risk of developing ALS, compared with the lowest quintile of consumption at a median of 0.94 g/day. This finding was consistent across all five studies. This means that adding 0.5% of energy from omega-3 PUFAs and maintaining a constant intake of omega-6 fatty acids while reducing the intake of other types of fat would reduce ALS risk by 34%. Consumption of alpha-linolenic acid, another PUFA, also was associated with significantly reduced risk of developing ALS. In contrast, consumption of omega-6 PUFAs, consumption of linolenic acid, total energy intake, and percentage of energy from other types of fat showed no association with ALS risk, the investigators said (JAMA Neurol. 2014 July 14 [doi:10.1001/jamaneurol.2014.1214]).

Foods that are rich in omega-3 PUFAs include fatty fish (salmon, sardines, tuna, herring) and fish oils; vegetable oils (corn, safflower, canola, soy, and flaxseed oils); and nuts and seeds (walnuts, chia seeds, butternuts, and sunflower seeds). Further studies are needed to confirm this protective effect in ALS and to determine whether patients who already have the disease would benefit from the addition of omega-3 PUFAs to their diets, Ms. Fitzgerald and her associates added.

The findings from Ms. Fitzgerald and her associates are persuasive and consistent with earlier suggestions that PUFAs may play a role in other neurodegenerative conditions, Dr. Michael Swash said in a related editorial (JAMA Neurol. 2014 July 14 [doi:10.1001/jamaneurol.2014.1894]).

"Ideas on long-term risk-susceptibility factors are very much welcomed in trying to unravel the mystery that is ALS. Now, in addition to genetic factors, there are the following five risk factors to work on: male sex, smoking status, BMI, physical exercise, and dietary intake of PUFAs," said Dr. Swash of the Royal London Hospital, Queen Mary University of London, and the Institute of Neuroscience at the University of Lisbon.

This study was supported by the National Institute of Neurological Diseases and Stroke, the National Cancer Institute, and the ALS Therapy Alliance Foundation. The study authors and Dr. Swash had no financial disclosures.

Adults who consumed high levels of omega-3 polyunsaturated fatty acids showed a markedly reduced risk of developing amyotrophic lateral sclerosis in a pooled analysis of five large prospective cohort studies that assessed diet.

Diet-derived omega-3 polyunsaturated fatty acids (PUFAs) are known to have neuroprotective effects, and those present in neural plasma membranes can modulate oxidative stress, excitotoxicity, and inflammation. But no prospective studies have explored a possible relationship between omega-3 PUFA intake and amyotrophic lateral sclerosis (ALS) risk, according to Kathryn C. Fitzgerald of the department of nutrition, Harvard School of Public Health, Boston, and her associates.

© Suprijono Suharjoto - Fotolia.com

In a study published July 14 in JAMA Neurology, Ms. Fitzgerald and her colleagues pooled data from the Health Professionals Follow-up Study, the Nurses’ Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health-AARP Diet and Health Study. A total of 995 ALS patients were identified among 1,002,082 participants in these studies. The five studies included detailed dietary information and tracked the occurrence of ALS in the study participants through the National Death Index.

Omega-3 PUFA intake in the highest quintile of consumption at a median of 2.11 g/day was associated with a 34% reduced risk of developing ALS, compared with the lowest quintile of consumption at a median of 0.94 g/day. This finding was consistent across all five studies. This means that adding 0.5% of energy from omega-3 PUFAs and maintaining a constant intake of omega-6 fatty acids while reducing the intake of other types of fat would reduce ALS risk by 34%. Consumption of alpha-linolenic acid, another PUFA, also was associated with significantly reduced risk of developing ALS. In contrast, consumption of omega-6 PUFAs, consumption of linolenic acid, total energy intake, and percentage of energy from other types of fat showed no association with ALS risk, the investigators said (JAMA Neurol. 2014 July 14 [doi:10.1001/jamaneurol.2014.1214]).

Foods that are rich in omega-3 PUFAs include fatty fish (salmon, sardines, tuna, herring) and fish oils; vegetable oils (corn, safflower, canola, soy, and flaxseed oils); and nuts and seeds (walnuts, chia seeds, butternuts, and sunflower seeds). Further studies are needed to confirm this protective effect in ALS and to determine whether patients who already have the disease would benefit from the addition of omega-3 PUFAs to their diets, Ms. Fitzgerald and her associates added.

The findings from Ms. Fitzgerald and her associates are persuasive and consistent with earlier suggestions that PUFAs may play a role in other neurodegenerative conditions, Dr. Michael Swash said in a related editorial (JAMA Neurol. 2014 July 14 [doi:10.1001/jamaneurol.2014.1894]).

"Ideas on long-term risk-susceptibility factors are very much welcomed in trying to unravel the mystery that is ALS. Now, in addition to genetic factors, there are the following five risk factors to work on: male sex, smoking status, BMI, physical exercise, and dietary intake of PUFAs," said Dr. Swash of the Royal London Hospital, Queen Mary University of London, and the Institute of Neuroscience at the University of Lisbon.

This study was supported by the National Institute of Neurological Diseases and Stroke, the National Cancer Institute, and the ALS Therapy Alliance Foundation. The study authors and Dr. Swash had no financial disclosures.

Adults who consumed high levels of omega-3 polyunsaturated fatty acids showed a markedly reduced risk of developing amyotrophic lateral sclerosis in a pooled analysis of five large prospective cohort studies that assessed diet.

Diet-derived omega-3 polyunsaturated fatty acids (PUFAs) are known to have neuroprotective effects, and those present in neural plasma membranes can modulate oxidative stress, excitotoxicity, and inflammation. But no prospective studies have explored a possible relationship between omega-3 PUFA intake and amyotrophic lateral sclerosis (ALS) risk, according to Kathryn C. Fitzgerald of the department of nutrition, Harvard School of Public Health, Boston, and her associates.

© Suprijono Suharjoto - Fotolia.com

In a study published July 14 in JAMA Neurology, Ms. Fitzgerald and her colleagues pooled data from the Health Professionals Follow-up Study, the Nurses’ Health Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health-AARP Diet and Health Study. A total of 995 ALS patients were identified among 1,002,082 participants in these studies. The five studies included detailed dietary information and tracked the occurrence of ALS in the study participants through the National Death Index.

Omega-3 PUFA intake in the highest quintile of consumption at a median of 2.11 g/day was associated with a 34% reduced risk of developing ALS, compared with the lowest quintile of consumption at a median of 0.94 g/day. This finding was consistent across all five studies. This means that adding 0.5% of energy from omega-3 PUFAs and maintaining a constant intake of omega-6 fatty acids while reducing the intake of other types of fat would reduce ALS risk by 34%. Consumption of alpha-linolenic acid, another PUFA, also was associated with significantly reduced risk of developing ALS. In contrast, consumption of omega-6 PUFAs, consumption of linolenic acid, total energy intake, and percentage of energy from other types of fat showed no association with ALS risk, the investigators said (JAMA Neurol. 2014 July 14 [doi:10.1001/jamaneurol.2014.1214]).

Foods that are rich in omega-3 PUFAs include fatty fish (salmon, sardines, tuna, herring) and fish oils; vegetable oils (corn, safflower, canola, soy, and flaxseed oils); and nuts and seeds (walnuts, chia seeds, butternuts, and sunflower seeds). Further studies are needed to confirm this protective effect in ALS and to determine whether patients who already have the disease would benefit from the addition of omega-3 PUFAs to their diets, Ms. Fitzgerald and her associates added.

The findings from Ms. Fitzgerald and her associates are persuasive and consistent with earlier suggestions that PUFAs may play a role in other neurodegenerative conditions, Dr. Michael Swash said in a related editorial (JAMA Neurol. 2014 July 14 [doi:10.1001/jamaneurol.2014.1894]).

"Ideas on long-term risk-susceptibility factors are very much welcomed in trying to unravel the mystery that is ALS. Now, in addition to genetic factors, there are the following five risk factors to work on: male sex, smoking status, BMI, physical exercise, and dietary intake of PUFAs," said Dr. Swash of the Royal London Hospital, Queen Mary University of London, and the Institute of Neuroscience at the University of Lisbon.

This study was supported by the National Institute of Neurological Diseases and Stroke, the National Cancer Institute, and the ALS Therapy Alliance Foundation. The study authors and Dr. Swash had no financial disclosures.

 

 

Patient receiving chemotherapy

Credit: Rhoda Baer

 

Differences in treatment access and quality may explain why survival rates vary widely for European patients with hematologic malignancies, researchers have reported in The Lancet Oncology.

“The good news is that 5-year survival for most cancers of the blood has increased over the past 11 years, most likely reflecting the approval of new targeted drugs in the early 2000s . . . ,” said Milena Sant, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy.

“But there continue to be persistent differences between regions. For example, the uptake and use of new technologies and effective treatments has been far slower in eastern Europe than other regions. This might have contributed to the large differences in the management and outcomes of patients.”

Dr Sant and her colleagues uncovered these differences by analyzing data from 30 cancer registries covering all patients diagnosed in 20 European countries.*

The researchers compared changes in 5-year survival for 560,444 adults (aged 15 years and older) who were diagnosed with 11 lymphoid and myeloid cancers between 1997 and 2008, and followed up to the end of 2008.

Some cancers have shown particularly large increases in survival between 1997-1999 and 2006-2008, such as follicular lymphoma (59% to 74%), diffuse large B-cell lymphoma (42% to 55%), chronic myeloid leukemia (32% to 54%), and acute promyelocytic leukemia (50% to 62%).

The greatest improvements in survival have been in northern, central, and eastern Europe, even though adults in eastern Europe (where survival in 1997 was the lowest) continue to have lower survival for most hematologic malignancies than elsewhere.

Survival gains have been lower in southern Europe and the UK. For example, improvements in 5-year chronic myeloid leukemia survival in northern Europe (29% to 60%) and central Europe (34% to 65%) have been persistently higher than in the UK (35% to 56%) and southern Europe (37% to 55%).

Overall, the risk of death within 5 years from diagnosis fell significantly for all malignancies except myelodysplastic syndromes. But not all regions have seen such improvements.

For example, compared with the UK, the excess risk of death was significantly higher in eastern Europe than in other regions for most of the cancers investigated, but significantly lower in northern Europe.

The researchers said the most likely reasons for continuing geographical differences in survival are inequalities in the provision of care and in the availability and use of new treatments.

“We know that rituximab, imatinib, thalidomide, and bortezomib were first made available for general use in Europe in 1997, 2001, 1998, and 2003, respectively,” the researchers wrote.

“The years following general release of these drugs coincided with large increases in survival for chronic myeloid leukemia, diffuse large B-cell lymphoma, and follicular lymphoma, with a smaller but still significant survival increase for multiple myeloma plasmacytoma.”

However, they pointed out that the uptake and use of these drugs has not been uniform across Europe. For example, market uptake of rituximab, imatinib, and bortezomib was lower in eastern Europe than elsewhere and might explain the consistently lower survival in this region.

Writing in a linked comment article, Alastair Munro, MD, of the University of Dundee Medical School in Scotland, questioned whether improvements in survival can be attributed to drugs alone.

He said that better understanding of the conclusions from this study (called EUROCARE-5) requires additional information about changes affecting survival according to disease categories, the distribution of histological subtypes and their relation with the age distribution of the population, the distribution of stages at diagnosis, and the timing of active intervention for indolent tumors.

*The areas included in the study were northern Europe (Denmark, Iceland, and Norway), the UK (England, Northern Ireland, Scotland, and Wales), central Europe (Austria, France, Germany, Switzerland, and The Netherlands), eastern Europe (Bulgaria, Estonia, Lithuania, Poland, and Slovakia), and southern Europe (Italy, Malta, and Slovenia).

 

 

Patient receiving chemotherapy

Credit: Rhoda Baer

 

Differences in treatment access and quality may explain why survival rates vary widely for European patients with hematologic malignancies, researchers have reported in The Lancet Oncology.

“The good news is that 5-year survival for most cancers of the blood has increased over the past 11 years, most likely reflecting the approval of new targeted drugs in the early 2000s . . . ,” said Milena Sant, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy.

“But there continue to be persistent differences between regions. For example, the uptake and use of new technologies and effective treatments has been far slower in eastern Europe than other regions. This might have contributed to the large differences in the management and outcomes of patients.”

Dr Sant and her colleagues uncovered these differences by analyzing data from 30 cancer registries covering all patients diagnosed in 20 European countries.*

The researchers compared changes in 5-year survival for 560,444 adults (aged 15 years and older) who were diagnosed with 11 lymphoid and myeloid cancers between 1997 and 2008, and followed up to the end of 2008.

Some cancers have shown particularly large increases in survival between 1997-1999 and 2006-2008, such as follicular lymphoma (59% to 74%), diffuse large B-cell lymphoma (42% to 55%), chronic myeloid leukemia (32% to 54%), and acute promyelocytic leukemia (50% to 62%).

The greatest improvements in survival have been in northern, central, and eastern Europe, even though adults in eastern Europe (where survival in 1997 was the lowest) continue to have lower survival for most hematologic malignancies than elsewhere.

Survival gains have been lower in southern Europe and the UK. For example, improvements in 5-year chronic myeloid leukemia survival in northern Europe (29% to 60%) and central Europe (34% to 65%) have been persistently higher than in the UK (35% to 56%) and southern Europe (37% to 55%).

Overall, the risk of death within 5 years from diagnosis fell significantly for all malignancies except myelodysplastic syndromes. But not all regions have seen such improvements.

For example, compared with the UK, the excess risk of death was significantly higher in eastern Europe than in other regions for most of the cancers investigated, but significantly lower in northern Europe.

The researchers said the most likely reasons for continuing geographical differences in survival are inequalities in the provision of care and in the availability and use of new treatments.

“We know that rituximab, imatinib, thalidomide, and bortezomib were first made available for general use in Europe in 1997, 2001, 1998, and 2003, respectively,” the researchers wrote.

“The years following general release of these drugs coincided with large increases in survival for chronic myeloid leukemia, diffuse large B-cell lymphoma, and follicular lymphoma, with a smaller but still significant survival increase for multiple myeloma plasmacytoma.”

However, they pointed out that the uptake and use of these drugs has not been uniform across Europe. For example, market uptake of rituximab, imatinib, and bortezomib was lower in eastern Europe than elsewhere and might explain the consistently lower survival in this region.

Writing in a linked comment article, Alastair Munro, MD, of the University of Dundee Medical School in Scotland, questioned whether improvements in survival can be attributed to drugs alone.

He said that better understanding of the conclusions from this study (called EUROCARE-5) requires additional information about changes affecting survival according to disease categories, the distribution of histological subtypes and their relation with the age distribution of the population, the distribution of stages at diagnosis, and the timing of active intervention for indolent tumors.

*The areas included in the study were northern Europe (Denmark, Iceland, and Norway), the UK (England, Northern Ireland, Scotland, and Wales), central Europe (Austria, France, Germany, Switzerland, and The Netherlands), eastern Europe (Bulgaria, Estonia, Lithuania, Poland, and Slovakia), and southern Europe (Italy, Malta, and Slovenia).

 

 

Patient receiving chemotherapy

Credit: Rhoda Baer

 

Differences in treatment access and quality may explain why survival rates vary widely for European patients with hematologic malignancies, researchers have reported in The Lancet Oncology.

“The good news is that 5-year survival for most cancers of the blood has increased over the past 11 years, most likely reflecting the approval of new targeted drugs in the early 2000s . . . ,” said Milena Sant, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy.

“But there continue to be persistent differences between regions. For example, the uptake and use of new technologies and effective treatments has been far slower in eastern Europe than other regions. This might have contributed to the large differences in the management and outcomes of patients.”

Dr Sant and her colleagues uncovered these differences by analyzing data from 30 cancer registries covering all patients diagnosed in 20 European countries.*

The researchers compared changes in 5-year survival for 560,444 adults (aged 15 years and older) who were diagnosed with 11 lymphoid and myeloid cancers between 1997 and 2008, and followed up to the end of 2008.

Some cancers have shown particularly large increases in survival between 1997-1999 and 2006-2008, such as follicular lymphoma (59% to 74%), diffuse large B-cell lymphoma (42% to 55%), chronic myeloid leukemia (32% to 54%), and acute promyelocytic leukemia (50% to 62%).

The greatest improvements in survival have been in northern, central, and eastern Europe, even though adults in eastern Europe (where survival in 1997 was the lowest) continue to have lower survival for most hematologic malignancies than elsewhere.

Survival gains have been lower in southern Europe and the UK. For example, improvements in 5-year chronic myeloid leukemia survival in northern Europe (29% to 60%) and central Europe (34% to 65%) have been persistently higher than in the UK (35% to 56%) and southern Europe (37% to 55%).

Overall, the risk of death within 5 years from diagnosis fell significantly for all malignancies except myelodysplastic syndromes. But not all regions have seen such improvements.

For example, compared with the UK, the excess risk of death was significantly higher in eastern Europe than in other regions for most of the cancers investigated, but significantly lower in northern Europe.

The researchers said the most likely reasons for continuing geographical differences in survival are inequalities in the provision of care and in the availability and use of new treatments.

“We know that rituximab, imatinib, thalidomide, and bortezomib were first made available for general use in Europe in 1997, 2001, 1998, and 2003, respectively,” the researchers wrote.

“The years following general release of these drugs coincided with large increases in survival for chronic myeloid leukemia, diffuse large B-cell lymphoma, and follicular lymphoma, with a smaller but still significant survival increase for multiple myeloma plasmacytoma.”

However, they pointed out that the uptake and use of these drugs has not been uniform across Europe. For example, market uptake of rituximab, imatinib, and bortezomib was lower in eastern Europe than elsewhere and might explain the consistently lower survival in this region.

Writing in a linked comment article, Alastair Munro, MD, of the University of Dundee Medical School in Scotland, questioned whether improvements in survival can be attributed to drugs alone.

He said that better understanding of the conclusions from this study (called EUROCARE-5) requires additional information about changes affecting survival according to disease categories, the distribution of histological subtypes and their relation with the age distribution of the population, the distribution of stages at diagnosis, and the timing of active intervention for indolent tumors.

*The areas included in the study were northern Europe (Denmark, Iceland, and Norway), the UK (England, Northern Ireland, Scotland, and Wales), central Europe (Austria, France, Germany, Switzerland, and The Netherlands), eastern Europe (Bulgaria, Estonia, Lithuania, Poland, and Slovakia), and southern Europe (Italy, Malta, and Slovenia).

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) has placed a hold on patient enrollment and dosing of drugs under investigation in the phase 3 REGULATE-PCI trial.

The trial is a comparison of the reversible thrombin inhibitor bivalirudin and the Revolixys Kit—a 2-component system consisting of pegnivacogin, an anticoagulant aptamer targeting coagulation Factor IXa, and its complementary oligonucleotide active control agent, anivamersen—in patients undergoing percutaneous coronary intervention (PCI).

The company sponsoring the REGULATE-PCI trial, Regado Biosciences, had voluntarily halted enrollment prior to the FDA’s announcement. The FDA’s clinical hold formalizes its involvement in any decision to re-initiate enrollment and dosing in the trial in the future.

Regado stopped enrollment after its Data Safety Monitoring Board (DSMB) started an unplanned review of the study data. The board has said the review is focusing on serious adverse events and allergic reactions.

“[W]e remain blinded to REGULATE-PCI study data and are awaiting the outcome of the full safety and efficacy analysis, including an analysis of benefit/risk ratio, being performed by our DSMB,” said David J Mazzo, PhD, CEO of Regado.

“Any recommendation to re-initiate patient enrollment in REGULATE-PCI will be based on the DSMB’s conclusions and would always be implemented in agreement with FDA.”

The REGULATE-PCI trial is a comparison of the Revolixys Kit (formerly known as REG-1) with bivalirudin (Angiomax) in patients undergoing PCI. The goal is to enroll 13,200 patients, and 3234 have been enrolled to date.

Eligible patients are those receiving PCI electively or for the treatment of unstable angina or non-ST elevated myocardial infarction.

Patients randomized to the Revolixys arm receive pegnivacogin at a dose of 1 mg/kg along with an 80% reversal dose of anivamersen. The timing of the remaining 20% is at the discretion of the treating physician.

The trial is powered to show superiority in efficacy and noninferiority in safety of the Revolixys Kit compared to bivalirudin. The study’s primary endpoint is a composite of death, nonfatal myocardial infarction, nonfatal stroke, and urgent target lesion revascularization through day 3 post-PCI.

For more details, visit clinicaltrials.gov.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) has placed a hold on patient enrollment and dosing of drugs under investigation in the phase 3 REGULATE-PCI trial.

The trial is a comparison of the reversible thrombin inhibitor bivalirudin and the Revolixys Kit—a 2-component system consisting of pegnivacogin, an anticoagulant aptamer targeting coagulation Factor IXa, and its complementary oligonucleotide active control agent, anivamersen—in patients undergoing percutaneous coronary intervention (PCI).

The company sponsoring the REGULATE-PCI trial, Regado Biosciences, had voluntarily halted enrollment prior to the FDA’s announcement. The FDA’s clinical hold formalizes its involvement in any decision to re-initiate enrollment and dosing in the trial in the future.

Regado stopped enrollment after its Data Safety Monitoring Board (DSMB) started an unplanned review of the study data. The board has said the review is focusing on serious adverse events and allergic reactions.

“[W]e remain blinded to REGULATE-PCI study data and are awaiting the outcome of the full safety and efficacy analysis, including an analysis of benefit/risk ratio, being performed by our DSMB,” said David J Mazzo, PhD, CEO of Regado.

“Any recommendation to re-initiate patient enrollment in REGULATE-PCI will be based on the DSMB’s conclusions and would always be implemented in agreement with FDA.”

The REGULATE-PCI trial is a comparison of the Revolixys Kit (formerly known as REG-1) with bivalirudin (Angiomax) in patients undergoing PCI. The goal is to enroll 13,200 patients, and 3234 have been enrolled to date.

Eligible patients are those receiving PCI electively or for the treatment of unstable angina or non-ST elevated myocardial infarction.

Patients randomized to the Revolixys arm receive pegnivacogin at a dose of 1 mg/kg along with an 80% reversal dose of anivamersen. The timing of the remaining 20% is at the discretion of the treating physician.

The trial is powered to show superiority in efficacy and noninferiority in safety of the Revolixys Kit compared to bivalirudin. The study’s primary endpoint is a composite of death, nonfatal myocardial infarction, nonfatal stroke, and urgent target lesion revascularization through day 3 post-PCI.

For more details, visit clinicaltrials.gov.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) has placed a hold on patient enrollment and dosing of drugs under investigation in the phase 3 REGULATE-PCI trial.

The trial is a comparison of the reversible thrombin inhibitor bivalirudin and the Revolixys Kit—a 2-component system consisting of pegnivacogin, an anticoagulant aptamer targeting coagulation Factor IXa, and its complementary oligonucleotide active control agent, anivamersen—in patients undergoing percutaneous coronary intervention (PCI).

The company sponsoring the REGULATE-PCI trial, Regado Biosciences, had voluntarily halted enrollment prior to the FDA’s announcement. The FDA’s clinical hold formalizes its involvement in any decision to re-initiate enrollment and dosing in the trial in the future.

Regado stopped enrollment after its Data Safety Monitoring Board (DSMB) started an unplanned review of the study data. The board has said the review is focusing on serious adverse events and allergic reactions.

“[W]e remain blinded to REGULATE-PCI study data and are awaiting the outcome of the full safety and efficacy analysis, including an analysis of benefit/risk ratio, being performed by our DSMB,” said David J Mazzo, PhD, CEO of Regado.

“Any recommendation to re-initiate patient enrollment in REGULATE-PCI will be based on the DSMB’s conclusions and would always be implemented in agreement with FDA.”

The REGULATE-PCI trial is a comparison of the Revolixys Kit (formerly known as REG-1) with bivalirudin (Angiomax) in patients undergoing PCI. The goal is to enroll 13,200 patients, and 3234 have been enrolled to date.

Eligible patients are those receiving PCI electively or for the treatment of unstable angina or non-ST elevated myocardial infarction.

Patients randomized to the Revolixys arm receive pegnivacogin at a dose of 1 mg/kg along with an 80% reversal dose of anivamersen. The timing of the remaining 20% is at the discretion of the treating physician.

The trial is powered to show superiority in efficacy and noninferiority in safety of the Revolixys Kit compared to bivalirudin. The study’s primary endpoint is a composite of death, nonfatal myocardial infarction, nonfatal stroke, and urgent target lesion revascularization through day 3 post-PCI.

For more details, visit clinicaltrials.gov.

Berries are rich in antioxidants

Two researchers have offered an explanation as to why antioxidants are not effective in fighting cancers and suggested a way to change that.

The duo proposed that antioxidants from supplements or dietary sources are proving ineffective because they are not acting where reactive oxygen species (ROS) are produced.

So therapies that directly inhibit the production of mitochondrial- and NADPH oxidase-derived ROS, or that scavenge ROS at these sites, may be more effective.

David Tuveson, MD, PhD, of the Cold Spring Harbor Laboratory in New York, and Navdeep S. Chandel, PhD, of the Feinberg School of Medicine at Northwestern University in Chicago, detailed these theories in a report published in The New England Journal of Medicine.

The pair’s insights are based on recent advances in understanding the cell system that establishes a natural balance between oxidizing and antioxidizing compounds.

Oxidants like hydrogen peroxide are manufactured within cells and are essential in small quantities. But oxidants are toxic in large amounts, and cells naturally generate their own antioxidants to neutralize oxidants.

It has seemed logical, therefore, to boost a person’s intake of antioxidants to counter the effects of hydrogen peroxide and other similarly toxic ROS. All the more because cancer cells are known to generate higher levels of ROS to help feed their abnormal growth.

However, Drs Tuveson and Chandel proposed that taking antioxidant pills or eating foods rich in antioxidants may be failing to show a beneficial effect against cancer because antioxidants do not act where tumor-promoting ROS are produced—at mitochondria.

Rather, supplements and dietary antioxidants tend to accumulate at scattered distant sites in the cell, “leaving tumor-promoting ROS relatively unperturbed.”

Therefore, the authors suggested therapies that directly inhibit the production of mitochondrial- and NADPH oxidase-derived ROS, or that scavenge ROS at these sites, will be more effective than dietary antioxidants.

An alternative approach

Drs Tuveson and Chandel also proposed an alternative approach: disabling antioxidants in cancer cells. They noted that quantities of both ROS and natural antioxidants are higher in cancer cells. The higher levels of antioxidants are a natural defense by cancer cells to keep their higher levels of oxidants in check so that growth can continue.

In fact, therapies that raise the levels of oxidants in cells can be beneficial, whereas those that act as antioxidants may further stimulate the cancer cells.

So the authors suggested that genetic or pharmacologic inhibition of antioxidant proteins—a concept tested successfully in rodent models of lung and pancreatic cancers—may be a useful therapeutic approach in humans.

The key challenge is to identify antioxidant proteins and pathways in cells that are used only by cancer cells and not by healthy cells. Impeding antioxidant production in healthy cells will upset the delicate redox balance upon which normal cellular function depends.

So it seems research is needed to profile antioxidant pathways in tumor and adjacent normal cells, to identify possible therapeutic targets.

Berries are rich in antioxidants

Two researchers have offered an explanation as to why antioxidants are not effective in fighting cancers and suggested a way to change that.

The duo proposed that antioxidants from supplements or dietary sources are proving ineffective because they are not acting where reactive oxygen species (ROS) are produced.

So therapies that directly inhibit the production of mitochondrial- and NADPH oxidase-derived ROS, or that scavenge ROS at these sites, may be more effective.

David Tuveson, MD, PhD, of the Cold Spring Harbor Laboratory in New York, and Navdeep S. Chandel, PhD, of the Feinberg School of Medicine at Northwestern University in Chicago, detailed these theories in a report published in The New England Journal of Medicine.

The pair’s insights are based on recent advances in understanding the cell system that establishes a natural balance between oxidizing and antioxidizing compounds.

Oxidants like hydrogen peroxide are manufactured within cells and are essential in small quantities. But oxidants are toxic in large amounts, and cells naturally generate their own antioxidants to neutralize oxidants.

It has seemed logical, therefore, to boost a person’s intake of antioxidants to counter the effects of hydrogen peroxide and other similarly toxic ROS. All the more because cancer cells are known to generate higher levels of ROS to help feed their abnormal growth.

However, Drs Tuveson and Chandel proposed that taking antioxidant pills or eating foods rich in antioxidants may be failing to show a beneficial effect against cancer because antioxidants do not act where tumor-promoting ROS are produced—at mitochondria.

Rather, supplements and dietary antioxidants tend to accumulate at scattered distant sites in the cell, “leaving tumor-promoting ROS relatively unperturbed.”

Therefore, the authors suggested therapies that directly inhibit the production of mitochondrial- and NADPH oxidase-derived ROS, or that scavenge ROS at these sites, will be more effective than dietary antioxidants.

An alternative approach

Drs Tuveson and Chandel also proposed an alternative approach: disabling antioxidants in cancer cells. They noted that quantities of both ROS and natural antioxidants are higher in cancer cells. The higher levels of antioxidants are a natural defense by cancer cells to keep their higher levels of oxidants in check so that growth can continue.

In fact, therapies that raise the levels of oxidants in cells can be beneficial, whereas those that act as antioxidants may further stimulate the cancer cells.

So the authors suggested that genetic or pharmacologic inhibition of antioxidant proteins—a concept tested successfully in rodent models of lung and pancreatic cancers—may be a useful therapeutic approach in humans.

The key challenge is to identify antioxidant proteins and pathways in cells that are used only by cancer cells and not by healthy cells. Impeding antioxidant production in healthy cells will upset the delicate redox balance upon which normal cellular function depends.

So it seems research is needed to profile antioxidant pathways in tumor and adjacent normal cells, to identify possible therapeutic targets.

Berries are rich in antioxidants

Two researchers have offered an explanation as to why antioxidants are not effective in fighting cancers and suggested a way to change that.

The duo proposed that antioxidants from supplements or dietary sources are proving ineffective because they are not acting where reactive oxygen species (ROS) are produced.

So therapies that directly inhibit the production of mitochondrial- and NADPH oxidase-derived ROS, or that scavenge ROS at these sites, may be more effective.

David Tuveson, MD, PhD, of the Cold Spring Harbor Laboratory in New York, and Navdeep S. Chandel, PhD, of the Feinberg School of Medicine at Northwestern University in Chicago, detailed these theories in a report published in The New England Journal of Medicine.

The pair’s insights are based on recent advances in understanding the cell system that establishes a natural balance between oxidizing and antioxidizing compounds.

Oxidants like hydrogen peroxide are manufactured within cells and are essential in small quantities. But oxidants are toxic in large amounts, and cells naturally generate their own antioxidants to neutralize oxidants.

It has seemed logical, therefore, to boost a person’s intake of antioxidants to counter the effects of hydrogen peroxide and other similarly toxic ROS. All the more because cancer cells are known to generate higher levels of ROS to help feed their abnormal growth.

However, Drs Tuveson and Chandel proposed that taking antioxidant pills or eating foods rich in antioxidants may be failing to show a beneficial effect against cancer because antioxidants do not act where tumor-promoting ROS are produced—at mitochondria.

Rather, supplements and dietary antioxidants tend to accumulate at scattered distant sites in the cell, “leaving tumor-promoting ROS relatively unperturbed.”

Therefore, the authors suggested therapies that directly inhibit the production of mitochondrial- and NADPH oxidase-derived ROS, or that scavenge ROS at these sites, will be more effective than dietary antioxidants.

An alternative approach

Drs Tuveson and Chandel also proposed an alternative approach: disabling antioxidants in cancer cells. They noted that quantities of both ROS and natural antioxidants are higher in cancer cells. The higher levels of antioxidants are a natural defense by cancer cells to keep their higher levels of oxidants in check so that growth can continue.

In fact, therapies that raise the levels of oxidants in cells can be beneficial, whereas those that act as antioxidants may further stimulate the cancer cells.

So the authors suggested that genetic or pharmacologic inhibition of antioxidant proteins—a concept tested successfully in rodent models of lung and pancreatic cancers—may be a useful therapeutic approach in humans.

The key challenge is to identify antioxidant proteins and pathways in cells that are used only by cancer cells and not by healthy cells. Impeding antioxidant production in healthy cells will upset the delicate redox balance upon which normal cellular function depends.

So it seems research is needed to profile antioxidant pathways in tumor and adjacent normal cells, to identify possible therapeutic targets.

Recalled product

Image courtesy of Hospira

Hospira, Inc., has announced a US-wide, user-level recall of one lot of Lactated Ringers and 5% Dextrose Injection, USP, 1000 mL, Flexible Container (NDC 0409-7929-09, Lot 35-118-JT).

The company confirmed a report of particulate within the solution of the primary container. It was a filamentous-like structured particulate indicative of mold.

An analysis of the primary container and overwrap revealed a puncture that had caused the container to leak.

Intravenous administration of a non-sterile product can result in infections that may be life-threatening and could result in prolonged hospitalization or organ failure.

However, Hospira has not received reports of any adverse events associated with this issue for this lot and has not identified any quality issues with retention samples for this lot.

Lactated Ringers and 5% Dextrose Injection is indicated for parenteral replacement of extracellular losses of fluid and electrolytes, with or without minimal carbohydrate calories, as required by the clinical condition of the patient.

The product is packaged in 1000mL flexible containers, 1 container per overwrap, and 12 overwrapped containers in each case. The lot number is located in the upper left hand side of the primary container.

This lot (35-118-JT) was distributed nationwide—from December 2013 through February 2014—to hospitals, clinics, wholesalers, and distributors.

Anyone with an existing inventory should stop use and distribution, quarantine the product immediately, and call Stericycle at 1-888-912-8457 (8am to 5pm EST, Monday through Friday) to arrange for the return of the product.

For medical inquiries, contact Hospira Medical Communications at 1-800-615-0187 (available 24 hours a day, 7 days per week) or [email protected].

To report adverse events or product complaints, contact Hospira Global

Complaint Management at 1-800-441-4100 (8am to 5pm CT, Monday through Friday) or

[email protected].

Adverse events or quality problems can also be reported to the Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

Recalled product

Image courtesy of Hospira

Hospira, Inc., has announced a US-wide, user-level recall of one lot of Lactated Ringers and 5% Dextrose Injection, USP, 1000 mL, Flexible Container (NDC 0409-7929-09, Lot 35-118-JT).

The company confirmed a report of particulate within the solution of the primary container. It was a filamentous-like structured particulate indicative of mold.

An analysis of the primary container and overwrap revealed a puncture that had caused the container to leak.

Intravenous administration of a non-sterile product can result in infections that may be life-threatening and could result in prolonged hospitalization or organ failure.

However, Hospira has not received reports of any adverse events associated with this issue for this lot and has not identified any quality issues with retention samples for this lot.

Lactated Ringers and 5% Dextrose Injection is indicated for parenteral replacement of extracellular losses of fluid and electrolytes, with or without minimal carbohydrate calories, as required by the clinical condition of the patient.

The product is packaged in 1000mL flexible containers, 1 container per overwrap, and 12 overwrapped containers in each case. The lot number is located in the upper left hand side of the primary container.

This lot (35-118-JT) was distributed nationwide—from December 2013 through February 2014—to hospitals, clinics, wholesalers, and distributors.

Anyone with an existing inventory should stop use and distribution, quarantine the product immediately, and call Stericycle at 1-888-912-8457 (8am to 5pm EST, Monday through Friday) to arrange for the return of the product.

For medical inquiries, contact Hospira Medical Communications at 1-800-615-0187 (available 24 hours a day, 7 days per week) or [email protected].

To report adverse events or product complaints, contact Hospira Global

Complaint Management at 1-800-441-4100 (8am to 5pm CT, Monday through Friday) or

[email protected].

Adverse events or quality problems can also be reported to the Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

Recalled product

Image courtesy of Hospira

Hospira, Inc., has announced a US-wide, user-level recall of one lot of Lactated Ringers and 5% Dextrose Injection, USP, 1000 mL, Flexible Container (NDC 0409-7929-09, Lot 35-118-JT).

The company confirmed a report of particulate within the solution of the primary container. It was a filamentous-like structured particulate indicative of mold.

An analysis of the primary container and overwrap revealed a puncture that had caused the container to leak.

Intravenous administration of a non-sterile product can result in infections that may be life-threatening and could result in prolonged hospitalization or organ failure.

However, Hospira has not received reports of any adverse events associated with this issue for this lot and has not identified any quality issues with retention samples for this lot.

Lactated Ringers and 5% Dextrose Injection is indicated for parenteral replacement of extracellular losses of fluid and electrolytes, with or without minimal carbohydrate calories, as required by the clinical condition of the patient.

The product is packaged in 1000mL flexible containers, 1 container per overwrap, and 12 overwrapped containers in each case. The lot number is located in the upper left hand side of the primary container.

This lot (35-118-JT) was distributed nationwide—from December 2013 through February 2014—to hospitals, clinics, wholesalers, and distributors.

Anyone with an existing inventory should stop use and distribution, quarantine the product immediately, and call Stericycle at 1-888-912-8457 (8am to 5pm EST, Monday through Friday) to arrange for the return of the product.

For medical inquiries, contact Hospira Medical Communications at 1-800-615-0187 (available 24 hours a day, 7 days per week) or [email protected].

To report adverse events or product complaints, contact Hospira Global

Complaint Management at 1-800-441-4100 (8am to 5pm CT, Monday through Friday) or

[email protected].

Adverse events or quality problems can also be reported to the Food and Drug Administration’s MedWatch Adverse Event Reporting Program.

SILVER SPRING, MD. – Without power morcellation, the number of hysterectomies performed using an open approach would dramatically increase – and the combined mortality from laparoscopic hysterectomy and potential dissemination of leiomyosarcoma would be less than that of open hysterectomy, according to testimony given July 11 at a Food and Drug Administration expert panel meeting.

Dr. Jubilee Brown, director of gynecologic oncology at the Woman's Hospital of Texas, University of Texas M.D. Anderson Cancer Center, Houston, testified at the meeting on behalf of the AAGL, an association that promotes minimally invasive gynecologic surgery. She presented results of a decision analysis suggesting that if all U.S. cases were converted to open hysterectomy from laparoscopic hysterectomy (LH) with morcellation of fibroids, 17 more women each year would die from the open procedure than from the combination LH and morcellation.

"Improve – but do not abandon – power morcellation," Dr. Brown told the FDA Obstetrics and Gynecology Devices Advisory Committee. She discussed her testimony during this video interview.

Dr. Brown said she had no relevant financial conflicts of interest.

[email protected]

SILVER SPRING, MD. – Without power morcellation, the number of hysterectomies performed using an open approach would dramatically increase – and the combined mortality from laparoscopic hysterectomy and potential dissemination of leiomyosarcoma would be less than that of open hysterectomy, according to testimony given July 11 at a Food and Drug Administration expert panel meeting.

Dr. Jubilee Brown, director of gynecologic oncology at the Woman's Hospital of Texas, University of Texas M.D. Anderson Cancer Center, Houston, testified at the meeting on behalf of the AAGL, an association that promotes minimally invasive gynecologic surgery. She presented results of a decision analysis suggesting that if all U.S. cases were converted to open hysterectomy from laparoscopic hysterectomy (LH) with morcellation of fibroids, 17 more women each year would die from the open procedure than from the combination LH and morcellation.

"Improve – but do not abandon – power morcellation," Dr. Brown told the FDA Obstetrics and Gynecology Devices Advisory Committee. She discussed her testimony during this video interview.

Dr. Brown said she had no relevant financial conflicts of interest.

[email protected]

SILVER SPRING, MD. – Without power morcellation, the number of hysterectomies performed using an open approach would dramatically increase – and the combined mortality from laparoscopic hysterectomy and potential dissemination of leiomyosarcoma would be less than that of open hysterectomy, according to testimony given July 11 at a Food and Drug Administration expert panel meeting.

Dr. Jubilee Brown, director of gynecologic oncology at the Woman's Hospital of Texas, University of Texas M.D. Anderson Cancer Center, Houston, testified at the meeting on behalf of the AAGL, an association that promotes minimally invasive gynecologic surgery. She presented results of a decision analysis suggesting that if all U.S. cases were converted to open hysterectomy from laparoscopic hysterectomy (LH) with morcellation of fibroids, 17 more women each year would die from the open procedure than from the combination LH and morcellation.

"Improve – but do not abandon – power morcellation," Dr. Brown told the FDA Obstetrics and Gynecology Devices Advisory Committee. She discussed her testimony during this video interview.

Dr. Brown said she had no relevant financial conflicts of interest.

[email protected]

The RIVUR [Randomized Intervention for Children With Vesicoureteral Reflux] trial investigators set out to reevaluate the role of antimicrobial prophylaxis for the prevention of recurrences in children with vesicoureteral reflux. As recent randomized trials have produced conflicting results, the goal of the RIVUR investigators was to determine whether antimicrobial prophylaxis could prevent febrile or symptomatic urinary tract infection and whether prevention would reduce the likelihood of subsequent renal scarring. The results, recently published in the New England Journal of Medicine (2014;370:2367-76), demonstrated that nearly 18% of children, 2 months to 6 years of age, have a febrile or symptomatic recurrence within the first year after the initial or presenting episode. The recurrence rate for febrile or symptomatic episodes was reduced by approximately 50% in the treatment group (trimethoprim-sulfamethoxazole) to nearly 8%.

In addition, the proportion of children considered treatment failures (defined as a combination of febrile or symptomatic UTIs or development of new renal scarring) occurred twice as often in the placebo group as in the treatment group. However, despite the reduction in febrile or symptomatic episodes in the treatment group, approximately 8% of children in both treatment and placebo groups developed new renal scarring, as defined by a decreased uptake of tracer or cortical thinning.

The study confirmed that children with higher grades of reflux (III or IV at baseline) were more likely to have febrile or symptomatic recurrences, that children with bladder and bowel dysfunction (based on a modified Dysfunctional Voiding Symptom Score) also were more likely to have febrile or symptomatic recurrences, and that recurrences in children on prophylaxis were more likely to be resistant to trimethoprim-sulfamethoxazole than were those in children on placebo.

Implications for prevention of UTI

The American Academy of Pediatrics guidelines for the management of UTI in children were updated in 2011 (Pediatrics 2011;128:595-610). The authors contacted the six researchers who had conducted the most recent randomized controlled trials and completed a formal meta-analysis that did not detect a statistically significant benefit of prophylaxis for stopping the recurrence of febrile UTI/pyelonephritis in infants without reflux or those with grades I, II, III, or IV. The 2011 recommendations reflected the findings of an AAP subcommittee that antimicrobial prophylaxis was not effective, as had been presumed in a 1999 report (Pediatrics 1999;103:843-52).

The AAP subcommittee on urinary tract infection of the Steering Committee on Quality Improvement and Management – authors of the 2011 revised guidelines – have recently reviewed the RIVUR study data (AAP News, July 1 2014) and concluded that antimicrobial prophylaxis did not alter the development of new renal scarring/damage, that the benefits of daily antimicrobial prophylaxis were modest, and that the increased likelihood of resistance to trimethoprim-sulfamethoxazole at recurrences was significant. The subcommittee reaffirmed the 2011 guidance concerning a "less aggressive" approach: Renal and bladder ultrasound are adequate for assessment of risk for renal scarring at first episodes, and watchful waiting without performing voiding cystourethrography (VCUG) or initiating prophylaxis is appropriate. VCUG is indicated after a first episode if renal and bladder ultrasonography reveals hydronephrosis, scarring, or other findings that would suggest either high-grade vesicoureteral reflux (VUR) or obstructive uropathy and in other atypical or complex clinical circumstances. As well, VCUG also should be performed if there is a recurrence of a febrile UTI (Pediatrics 2011;128:595-610).

The current subcommittee opined that prompt diagnosis and effective treatment of a febrile UTI recurrence may be of greater importance, regardless of whether VUR is present or the child is receiving antimicrobial prophylaxis.

My take

For me, the RIVUR data provide further insights into both the risk of any recurrence (approximately 18% by 12 months, approximately 25% by 24 months) and the risk for multiple recurrences (approximately 10%). The data identify those at highest risk for recurrences (patients with bladder and bowel dysfunction or higher grades of reflux) and provide evidence that trimethoprim-sulfamethoxazole prophylaxis is highly effective in such groups. No serious side effects were observed during the RIVUR trial; however, Stevens-Johnson syndrome is documented to occur rarely after administration of trimethoprim-sulfamethoxazole, and the potential for this life-threatening event should be part of the decision process. I believe the value of the new data is that they provide confidence that antimicrobial prophylaxis can be effective for the prevention of febrile/symptomatic UTI, and that in select children at great risk for recurrences and subsequent renal damage, antimicrobial prophylaxis can be part of our toolbox.

Dr. Pelton is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. He said that he had no relevant financial disclosures.

The RIVUR [Randomized Intervention for Children With Vesicoureteral Reflux] trial investigators set out to reevaluate the role of antimicrobial prophylaxis for the prevention of recurrences in children with vesicoureteral reflux. As recent randomized trials have produced conflicting results, the goal of the RIVUR investigators was to determine whether antimicrobial prophylaxis could prevent febrile or symptomatic urinary tract infection and whether prevention would reduce the likelihood of subsequent renal scarring. The results, recently published in the New England Journal of Medicine (2014;370:2367-76), demonstrated that nearly 18% of children, 2 months to 6 years of age, have a febrile or symptomatic recurrence within the first year after the initial or presenting episode. The recurrence rate for febrile or symptomatic episodes was reduced by approximately 50% in the treatment group (trimethoprim-sulfamethoxazole) to nearly 8%.

In addition, the proportion of children considered treatment failures (defined as a combination of febrile or symptomatic UTIs or development of new renal scarring) occurred twice as often in the placebo group as in the treatment group. However, despite the reduction in febrile or symptomatic episodes in the treatment group, approximately 8% of children in both treatment and placebo groups developed new renal scarring, as defined by a decreased uptake of tracer or cortical thinning.

The study confirmed that children with higher grades of reflux (III or IV at baseline) were more likely to have febrile or symptomatic recurrences, that children with bladder and bowel dysfunction (based on a modified Dysfunctional Voiding Symptom Score) also were more likely to have febrile or symptomatic recurrences, and that recurrences in children on prophylaxis were more likely to be resistant to trimethoprim-sulfamethoxazole than were those in children on placebo.

Implications for prevention of UTI

The American Academy of Pediatrics guidelines for the management of UTI in children were updated in 2011 (Pediatrics 2011;128:595-610). The authors contacted the six researchers who had conducted the most recent randomized controlled trials and completed a formal meta-analysis that did not detect a statistically significant benefit of prophylaxis for stopping the recurrence of febrile UTI/pyelonephritis in infants without reflux or those with grades I, II, III, or IV. The 2011 recommendations reflected the findings of an AAP subcommittee that antimicrobial prophylaxis was not effective, as had been presumed in a 1999 report (Pediatrics 1999;103:843-52).

The AAP subcommittee on urinary tract infection of the Steering Committee on Quality Improvement and Management – authors of the 2011 revised guidelines – have recently reviewed the RIVUR study data (AAP News, July 1 2014) and concluded that antimicrobial prophylaxis did not alter the development of new renal scarring/damage, that the benefits of daily antimicrobial prophylaxis were modest, and that the increased likelihood of resistance to trimethoprim-sulfamethoxazole at recurrences was significant. The subcommittee reaffirmed the 2011 guidance concerning a "less aggressive" approach: Renal and bladder ultrasound are adequate for assessment of risk for renal scarring at first episodes, and watchful waiting without performing voiding cystourethrography (VCUG) or initiating prophylaxis is appropriate. VCUG is indicated after a first episode if renal and bladder ultrasonography reveals hydronephrosis, scarring, or other findings that would suggest either high-grade vesicoureteral reflux (VUR) or obstructive uropathy and in other atypical or complex clinical circumstances. As well, VCUG also should be performed if there is a recurrence of a febrile UTI (Pediatrics 2011;128:595-610).

The current subcommittee opined that prompt diagnosis and effective treatment of a febrile UTI recurrence may be of greater importance, regardless of whether VUR is present or the child is receiving antimicrobial prophylaxis.

My take

For me, the RIVUR data provide further insights into both the risk of any recurrence (approximately 18% by 12 months, approximately 25% by 24 months) and the risk for multiple recurrences (approximately 10%). The data identify those at highest risk for recurrences (patients with bladder and bowel dysfunction or higher grades of reflux) and provide evidence that trimethoprim-sulfamethoxazole prophylaxis is highly effective in such groups. No serious side effects were observed during the RIVUR trial; however, Stevens-Johnson syndrome is documented to occur rarely after administration of trimethoprim-sulfamethoxazole, and the potential for this life-threatening event should be part of the decision process. I believe the value of the new data is that they provide confidence that antimicrobial prophylaxis can be effective for the prevention of febrile/symptomatic UTI, and that in select children at great risk for recurrences and subsequent renal damage, antimicrobial prophylaxis can be part of our toolbox.

Dr. Pelton is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. He said that he had no relevant financial disclosures.

The RIVUR [Randomized Intervention for Children With Vesicoureteral Reflux] trial investigators set out to reevaluate the role of antimicrobial prophylaxis for the prevention of recurrences in children with vesicoureteral reflux. As recent randomized trials have produced conflicting results, the goal of the RIVUR investigators was to determine whether antimicrobial prophylaxis could prevent febrile or symptomatic urinary tract infection and whether prevention would reduce the likelihood of subsequent renal scarring. The results, recently published in the New England Journal of Medicine (2014;370:2367-76), demonstrated that nearly 18% of children, 2 months to 6 years of age, have a febrile or symptomatic recurrence within the first year after the initial or presenting episode. The recurrence rate for febrile or symptomatic episodes was reduced by approximately 50% in the treatment group (trimethoprim-sulfamethoxazole) to nearly 8%.

In addition, the proportion of children considered treatment failures (defined as a combination of febrile or symptomatic UTIs or development of new renal scarring) occurred twice as often in the placebo group as in the treatment group. However, despite the reduction in febrile or symptomatic episodes in the treatment group, approximately 8% of children in both treatment and placebo groups developed new renal scarring, as defined by a decreased uptake of tracer or cortical thinning.

The study confirmed that children with higher grades of reflux (III or IV at baseline) were more likely to have febrile or symptomatic recurrences, that children with bladder and bowel dysfunction (based on a modified Dysfunctional Voiding Symptom Score) also were more likely to have febrile or symptomatic recurrences, and that recurrences in children on prophylaxis were more likely to be resistant to trimethoprim-sulfamethoxazole than were those in children on placebo.

Implications for prevention of UTI

The American Academy of Pediatrics guidelines for the management of UTI in children were updated in 2011 (Pediatrics 2011;128:595-610). The authors contacted the six researchers who had conducted the most recent randomized controlled trials and completed a formal meta-analysis that did not detect a statistically significant benefit of prophylaxis for stopping the recurrence of febrile UTI/pyelonephritis in infants without reflux or those with grades I, II, III, or IV. The 2011 recommendations reflected the findings of an AAP subcommittee that antimicrobial prophylaxis was not effective, as had been presumed in a 1999 report (Pediatrics 1999;103:843-52).

The AAP subcommittee on urinary tract infection of the Steering Committee on Quality Improvement and Management – authors of the 2011 revised guidelines – have recently reviewed the RIVUR study data (AAP News, July 1 2014) and concluded that antimicrobial prophylaxis did not alter the development of new renal scarring/damage, that the benefits of daily antimicrobial prophylaxis were modest, and that the increased likelihood of resistance to trimethoprim-sulfamethoxazole at recurrences was significant. The subcommittee reaffirmed the 2011 guidance concerning a "less aggressive" approach: Renal and bladder ultrasound are adequate for assessment of risk for renal scarring at first episodes, and watchful waiting without performing voiding cystourethrography (VCUG) or initiating prophylaxis is appropriate. VCUG is indicated after a first episode if renal and bladder ultrasonography reveals hydronephrosis, scarring, or other findings that would suggest either high-grade vesicoureteral reflux (VUR) or obstructive uropathy and in other atypical or complex clinical circumstances. As well, VCUG also should be performed if there is a recurrence of a febrile UTI (Pediatrics 2011;128:595-610).

The current subcommittee opined that prompt diagnosis and effective treatment of a febrile UTI recurrence may be of greater importance, regardless of whether VUR is present or the child is receiving antimicrobial prophylaxis.

My take

For me, the RIVUR data provide further insights into both the risk of any recurrence (approximately 18% by 12 months, approximately 25% by 24 months) and the risk for multiple recurrences (approximately 10%). The data identify those at highest risk for recurrences (patients with bladder and bowel dysfunction or higher grades of reflux) and provide evidence that trimethoprim-sulfamethoxazole prophylaxis is highly effective in such groups. No serious side effects were observed during the RIVUR trial; however, Stevens-Johnson syndrome is documented to occur rarely after administration of trimethoprim-sulfamethoxazole, and the potential for this life-threatening event should be part of the decision process. I believe the value of the new data is that they provide confidence that antimicrobial prophylaxis can be effective for the prevention of febrile/symptomatic UTI, and that in select children at great risk for recurrences and subsequent renal damage, antimicrobial prophylaxis can be part of our toolbox.

Dr. Pelton is chief of pediatric infectious disease and coordinator of the maternal-child HIV program at Boston Medical Center. He said that he had no relevant financial disclosures.

SILVER SPRING, MD. – Power morcellation devices should be never used for gynecologic procedures, Dr. Hooman Noorchashm testified to a Food and Drug Administration expert panel on July ll.

He called out members of the FDA Obstetrics and Gynecology Devices Panel Advisory Committee by name, seeking to shame them into action to disallow power morcellation for suspected uterine fibroids.

"Is this a safe and logical device?" said Dr. Noorchashm, a cardiothoracic surgeon at Brigham and Women’s Hospital in Boston. "The only classification for this device is banned – unsafe, illogical, incorrect, and deadly."

Dr. Noorchashm’s wife, Dr. Amy Reed, had a hysterectomy with morcellation for suspected fibroids. Biopsy later confirmed sarcoma was present. Use of power morcellation caused tumor cells to spread, upstaging her sarcoma to stage IV.

[email protected]

On Twitter @denisefulton

SILVER SPRING, MD. – Power morcellation devices should be never used for gynecologic procedures, Dr. Hooman Noorchashm testified to a Food and Drug Administration expert panel on July ll.

He called out members of the FDA Obstetrics and Gynecology Devices Panel Advisory Committee by name, seeking to shame them into action to disallow power morcellation for suspected uterine fibroids.

"Is this a safe and logical device?" said Dr. Noorchashm, a cardiothoracic surgeon at Brigham and Women’s Hospital in Boston. "The only classification for this device is banned – unsafe, illogical, incorrect, and deadly."

Dr. Noorchashm’s wife, Dr. Amy Reed, had a hysterectomy with morcellation for suspected fibroids. Biopsy later confirmed sarcoma was present. Use of power morcellation caused tumor cells to spread, upstaging her sarcoma to stage IV.

[email protected]

On Twitter @denisefulton

SILVER SPRING, MD. – Power morcellation devices should be never used for gynecologic procedures, Dr. Hooman Noorchashm testified to a Food and Drug Administration expert panel on July ll.

He called out members of the FDA Obstetrics and Gynecology Devices Panel Advisory Committee by name, seeking to shame them into action to disallow power morcellation for suspected uterine fibroids.

"Is this a safe and logical device?" said Dr. Noorchashm, a cardiothoracic surgeon at Brigham and Women’s Hospital in Boston. "The only classification for this device is banned – unsafe, illogical, incorrect, and deadly."

Dr. Noorchashm’s wife, Dr. Amy Reed, had a hysterectomy with morcellation for suspected fibroids. Biopsy later confirmed sarcoma was present. Use of power morcellation caused tumor cells to spread, upstaging her sarcoma to stage IV.

[email protected]

On Twitter @denisefulton

The left panel shows

misshapen nuclear envelopes

(red) from iPSCs (DNA in blue).

The right panel shows

gene-edited iPSCs.

Credit: Salk Institute

Results of new research may ease previous concerns that gene-editing techniques could add unwanted mutations to stem cells.

Researchers compared gene editing techniques in lines of induced pluripotent stem cells (iPSCs) derived from a patient with sickle cell disease (SCD).

And they found that neither viral nor nuclease-based gene-editing methods increased the frequency of mutations in the iPSCs.

The team reported these results in Cell Stem Cell.

“The ability to precisely modify the DNA of stem cells has greatly accelerated research on human diseases and cell therapy,” said senior study author Juan Carlos Izpisua Belmonte, PhD, of the Salk Institute for Biological Studies in La Jolla, California.

“To successfully translate this technology into the clinic, we first need to scrutinize the safety of these modified stem cells, such as their genome stability and mutational load.”

Previously, Dr Belmonte’s lab pioneered the use of modified viruses, called helper-dependent adenoviral vectors (HDAdVs), to correct the genetic mutation that causes SCD.

He and his colleagues used HDAdVs to replace the mutated gene in a line of iPSCs with a mutant-free version, creating stem cells that could, theoretically, be infused into patients’ bone marrow and help create healthy blood cells.

Before such technologies are applied to humans, though, Dr Belmonte and his colleagues wanted to know whether there were risks related to editing the genes in iPSCs.

“As cells are being reprogrammed into stem cells, they tend to accumulate many mutations,” said Mo Li, PhD, a postdoctoral fellow in Dr Belmonte’s lab.

“So people naturally worry that any process you perform with these cells in vitro—including gene editing—might generate even more mutations.”

To find out whether this was the case, the researchers conducted tests in a line of SCD-derived iPSCs.

They edited the genes of some cells using 1 of 2 HDAdV designs. And they edited others using 1 of 2 transcription activator-like effector nuclease (TALEN) proteins.

They kept the rest of the SCD iPSCs in culture without editing them. Then, the team sequenced the entire genome of each cell from the 4 edits and control experiment.

While all of the cells gained a low level of random gene mutations during the experiments, the cells that had undergone gene-editing—whether through HDAdV- or TALEN-based approaches—had no more mutations than the cells kept in culture.

“We were pleasantly surprised by the results,” said Keiichiro Suzuki, PhD, a postdoctoral fellow in Dr Belmonte’s lab.

“People have found thousands of mutations introduced during iPSC reprogramming. We found less than a hundred single nucleotide variants in all cases.”

The researchers noted that this finding doesn’t necessarily mean there are no inherent risks to using stem cells with edited genes. However, it does suggest the editing process doesn’t make iPSCs any less safe.

“We concluded that the risk of mutation isn’t inherently connected to gene editing,” Dr Li said. “These cells present the same risks as using any other cells manipulated for cell or gene therapy.”

The Belmonte group is now planning more studies to address whether gene-repair in other cell types, using other approaches, or targeting other genes could be more or less likely to cause unwanted mutations.

For now, they hope their findings encourage those in the field to keep pursuing gene-editing techniques as a potential way to treat genetic diseases in the future.

The left panel shows

misshapen nuclear envelopes

(red) from iPSCs (DNA in blue).

The right panel shows

gene-edited iPSCs.

Credit: Salk Institute

Results of new research may ease previous concerns that gene-editing techniques could add unwanted mutations to stem cells.

Researchers compared gene editing techniques in lines of induced pluripotent stem cells (iPSCs) derived from a patient with sickle cell disease (SCD).

And they found that neither viral nor nuclease-based gene-editing methods increased the frequency of mutations in the iPSCs.

The team reported these results in Cell Stem Cell.

“The ability to precisely modify the DNA of stem cells has greatly accelerated research on human diseases and cell therapy,” said senior study author Juan Carlos Izpisua Belmonte, PhD, of the Salk Institute for Biological Studies in La Jolla, California.

“To successfully translate this technology into the clinic, we first need to scrutinize the safety of these modified stem cells, such as their genome stability and mutational load.”

Previously, Dr Belmonte’s lab pioneered the use of modified viruses, called helper-dependent adenoviral vectors (HDAdVs), to correct the genetic mutation that causes SCD.

He and his colleagues used HDAdVs to replace the mutated gene in a line of iPSCs with a mutant-free version, creating stem cells that could, theoretically, be infused into patients’ bone marrow and help create healthy blood cells.

Before such technologies are applied to humans, though, Dr Belmonte and his colleagues wanted to know whether there were risks related to editing the genes in iPSCs.

“As cells are being reprogrammed into stem cells, they tend to accumulate many mutations,” said Mo Li, PhD, a postdoctoral fellow in Dr Belmonte’s lab.

“So people naturally worry that any process you perform with these cells in vitro—including gene editing—might generate even more mutations.”

To find out whether this was the case, the researchers conducted tests in a line of SCD-derived iPSCs.

They edited the genes of some cells using 1 of 2 HDAdV designs. And they edited others using 1 of 2 transcription activator-like effector nuclease (TALEN) proteins.

They kept the rest of the SCD iPSCs in culture without editing them. Then, the team sequenced the entire genome of each cell from the 4 edits and control experiment.

While all of the cells gained a low level of random gene mutations during the experiments, the cells that had undergone gene-editing—whether through HDAdV- or TALEN-based approaches—had no more mutations than the cells kept in culture.

“We were pleasantly surprised by the results,” said Keiichiro Suzuki, PhD, a postdoctoral fellow in Dr Belmonte’s lab.

“People have found thousands of mutations introduced during iPSC reprogramming. We found less than a hundred single nucleotide variants in all cases.”

The researchers noted that this finding doesn’t necessarily mean there are no inherent risks to using stem cells with edited genes. However, it does suggest the editing process doesn’t make iPSCs any less safe.

“We concluded that the risk of mutation isn’t inherently connected to gene editing,” Dr Li said. “These cells present the same risks as using any other cells manipulated for cell or gene therapy.”

The Belmonte group is now planning more studies to address whether gene-repair in other cell types, using other approaches, or targeting other genes could be more or less likely to cause unwanted mutations.

For now, they hope their findings encourage those in the field to keep pursuing gene-editing techniques as a potential way to treat genetic diseases in the future.

The left panel shows

misshapen nuclear envelopes

(red) from iPSCs (DNA in blue).

The right panel shows

gene-edited iPSCs.

Credit: Salk Institute

Results of new research may ease previous concerns that gene-editing techniques could add unwanted mutations to stem cells.

Researchers compared gene editing techniques in lines of induced pluripotent stem cells (iPSCs) derived from a patient with sickle cell disease (SCD).

And they found that neither viral nor nuclease-based gene-editing methods increased the frequency of mutations in the iPSCs.

The team reported these results in Cell Stem Cell.

“The ability to precisely modify the DNA of stem cells has greatly accelerated research on human diseases and cell therapy,” said senior study author Juan Carlos Izpisua Belmonte, PhD, of the Salk Institute for Biological Studies in La Jolla, California.

“To successfully translate this technology into the clinic, we first need to scrutinize the safety of these modified stem cells, such as their genome stability and mutational load.”

Previously, Dr Belmonte’s lab pioneered the use of modified viruses, called helper-dependent adenoviral vectors (HDAdVs), to correct the genetic mutation that causes SCD.

He and his colleagues used HDAdVs to replace the mutated gene in a line of iPSCs with a mutant-free version, creating stem cells that could, theoretically, be infused into patients’ bone marrow and help create healthy blood cells.

Before such technologies are applied to humans, though, Dr Belmonte and his colleagues wanted to know whether there were risks related to editing the genes in iPSCs.

“As cells are being reprogrammed into stem cells, they tend to accumulate many mutations,” said Mo Li, PhD, a postdoctoral fellow in Dr Belmonte’s lab.

“So people naturally worry that any process you perform with these cells in vitro—including gene editing—might generate even more mutations.”

To find out whether this was the case, the researchers conducted tests in a line of SCD-derived iPSCs.

They edited the genes of some cells using 1 of 2 HDAdV designs. And they edited others using 1 of 2 transcription activator-like effector nuclease (TALEN) proteins.

They kept the rest of the SCD iPSCs in culture without editing them. Then, the team sequenced the entire genome of each cell from the 4 edits and control experiment.

While all of the cells gained a low level of random gene mutations during the experiments, the cells that had undergone gene-editing—whether through HDAdV- or TALEN-based approaches—had no more mutations than the cells kept in culture.

“We were pleasantly surprised by the results,” said Keiichiro Suzuki, PhD, a postdoctoral fellow in Dr Belmonte’s lab.

“People have found thousands of mutations introduced during iPSC reprogramming. We found less than a hundred single nucleotide variants in all cases.”

The researchers noted that this finding doesn’t necessarily mean there are no inherent risks to using stem cells with edited genes. However, it does suggest the editing process doesn’t make iPSCs any less safe.

“We concluded that the risk of mutation isn’t inherently connected to gene editing,” Dr Li said. “These cells present the same risks as using any other cells manipulated for cell or gene therapy.”

The Belmonte group is now planning more studies to address whether gene-repair in other cell types, using other approaches, or targeting other genes could be more or less likely to cause unwanted mutations.

For now, they hope their findings encourage those in the field to keep pursuing gene-editing techniques as a potential way to treat genetic diseases in the future.