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Understanding a rare hemoglobin mutation
Smoking can prevent anemia in individuals with a rare hemoglobin mutation, according to research published in the Journal of Biological Chemistry.
The so-called Kirklareli mutation was found to be the cause of mild anemia in a young woman in Germany.
But a smoking habit protected the young woman’s father, who also carried the mutation, from developing anemia.
The Kirklareli mutation is one of more than 1000 discovered so far in adult human hemoglobin.
Most of these mutations appear to have no effect on people, but when medical problems occur, the disease is called a hemoglobinopathy and often named after the city or hospital where it was discovered. In this case, the family was living in Mannheim, Germany, but the father was born in the Turkish city of Kirklareli.
The Kirklareli mutation did not affect the iron content of the father’s blood, but it did appear to be the root cause of the young woman’s chronic anemia, according to researchers.
Further investigation revealed that absorbing carbon monoxide from cigarette smoke is therapeutic for individuals with this rare genetic disorder.
The Kirklareli mutation is in the alpha subunit of human hemoglobin (H58L) and causes it to rapidly auto-oxidize, which causes the protein to fall apart, lose heme, and precipitate. As a result, the protein loses its ability to carry oxygen. Eventually, red cells become deformed and are destroyed.
This mutation also gives the protein an 80,000-fold higher affinity for carbon monoxide than for oxygen. Carbon monoxide from a cigarette will be selectively taken up by the mutant hemoglobin and prevent it from oxidizing and denaturing.
This high affinity for carbon monoxide explained why the father showed no signs of anemia, the researchers said.
“He may never be an athlete because his blood can’t carry as much oxygen, but smoking has prevented him from being anemic,” said study author John Olson, PhD, of Rice University in Houston, Texas.
“And there’s a side benefit. People with this trait are more resistant to carbon monoxide poisoning.”
Dr Olson said he doesn’t know how or if doctors treated the young woman, but he suspects her iron-deficiency anemia was more an annoyance than a threat to her life and would not recommend she start smoking to relieve it.
“She shouldn’t smoke,” Dr Olson said. “But she could take antioxidants, such as a lot of vitamin C, which would help prevent oxidation of her mutant hemoglobin. Her anemia is not that severe. At the same time, she shouldn’t worry too much about secondhand smoke, which might have a positive effect.”
After ruling out common causes of anemia—such as blood loss, gastritis, or congenital defects—the woman’s doctors were curious enough about her ailment to call upon Emmanuel Bissé, MD, PhD, a researcher at Universitätsklinikum Freiburg in Freiburg, Germany, who discovered the Kirklareli mutation after sequencing the woman’s DNA.
Dr Bissé, in turn, recruited Dr Olson and his team to help determine why the histidine-to-leucine change caused anemia in the daughter but not the father.
Coincidentally, Ivan Birukou, a graduate student in Dr Olson’s lab, had already generated the Kirklareli mutation in human hemoglobin to study how the protein rapidly and selectively binds oxygen.
“Emmanuel wrote to me and said, ‘I know you’ve been making all these mutants in hemoglobin, and you’ve probably done the H58L mutation in [alpha] chains. Does this phenotype make sense?’” Dr Olson recalled.
“I said, ‘We can do a really neat study here, because we’ve already made the mutant hemoglobin in a recombinant system.’ We actually had a crystal structure [matching Kirklareli] that Ivan and [staff scientist] Jayashree Soman never published but had deposited in the Protein Data Bank. We had made this mutation to try to understand what the distal histidine was doing in alpha subunits.”
The researchers found in a 2010 study that replacing the histidine, which forms a strong hydrogen bond to oxygen, with leucine caused a dramatic decrease in oxygen affinity and an increase in carbon monoxide binding.
Dr Olson and Birukou realized back then that histidine played a key role in discriminating between oxygen and carbon monoxide in hemoglobin.
“When Emmanuel wrote to me about his discovery, I already ‘knew’ what was happening with respect to carbon monoxide binding,” Dr Olson said.
He said the normal hydrogen bond causes bound oxygen to stick more tightly to hemoglobin in the same way hydrogen bonds cause spilled soda to feel sticky.
“When you touch it, the sugar oxygens and hydrogens make hydrogen bonds with the polysaccharides on your finger,” Dr Olson said. “That stickiness helps hold onto oxygen. But leucine is more like an oil, like butane or hexane, and oxygen does not stick well inside hemoglobin. In contrast, bound carbon monoxide is more like methane or ethane and can’t form hydrogen bonds.”
Andres Benitez Cardenas, PhD, a researcher in Dr Olson’s lab, did the experiment in which he put carbon monoxide on the mutant alpha subunit of hemoglobin Kirklareli. The bound carbon monoxide slowed down oxidation of the protein and prevented loss of heme and precipitation.
“In effect, Andres did the ‘smoking experiment’ to show why the father’s hemoglobin didn’t denature and cause anemia,” Dr Olson said.
He noted that the effect caused by Kirklareli, though unusual, is not unique. Patients with hemoglobin Zurich also have an abnormal form of hemoglobin that more readily binds to carbon monoxide. 
Smoking can prevent anemia in individuals with a rare hemoglobin mutation, according to research published in the Journal of Biological Chemistry.
The so-called Kirklareli mutation was found to be the cause of mild anemia in a young woman in Germany.
But a smoking habit protected the young woman’s father, who also carried the mutation, from developing anemia.
The Kirklareli mutation is one of more than 1000 discovered so far in adult human hemoglobin.
Most of these mutations appear to have no effect on people, but when medical problems occur, the disease is called a hemoglobinopathy and often named after the city or hospital where it was discovered. In this case, the family was living in Mannheim, Germany, but the father was born in the Turkish city of Kirklareli.
The Kirklareli mutation did not affect the iron content of the father’s blood, but it did appear to be the root cause of the young woman’s chronic anemia, according to researchers.
Further investigation revealed that absorbing carbon monoxide from cigarette smoke is therapeutic for individuals with this rare genetic disorder.
The Kirklareli mutation is in the alpha subunit of human hemoglobin (H58L) and causes it to rapidly auto-oxidize, which causes the protein to fall apart, lose heme, and precipitate. As a result, the protein loses its ability to carry oxygen. Eventually, red cells become deformed and are destroyed.
This mutation also gives the protein an 80,000-fold higher affinity for carbon monoxide than for oxygen. Carbon monoxide from a cigarette will be selectively taken up by the mutant hemoglobin and prevent it from oxidizing and denaturing.
This high affinity for carbon monoxide explained why the father showed no signs of anemia, the researchers said.
“He may never be an athlete because his blood can’t carry as much oxygen, but smoking has prevented him from being anemic,” said study author John Olson, PhD, of Rice University in Houston, Texas.
“And there’s a side benefit. People with this trait are more resistant to carbon monoxide poisoning.”
Dr Olson said he doesn’t know how or if doctors treated the young woman, but he suspects her iron-deficiency anemia was more an annoyance than a threat to her life and would not recommend she start smoking to relieve it.
“She shouldn’t smoke,” Dr Olson said. “But she could take antioxidants, such as a lot of vitamin C, which would help prevent oxidation of her mutant hemoglobin. Her anemia is not that severe. At the same time, she shouldn’t worry too much about secondhand smoke, which might have a positive effect.”
After ruling out common causes of anemia—such as blood loss, gastritis, or congenital defects—the woman’s doctors were curious enough about her ailment to call upon Emmanuel Bissé, MD, PhD, a researcher at Universitätsklinikum Freiburg in Freiburg, Germany, who discovered the Kirklareli mutation after sequencing the woman’s DNA.
Dr Bissé, in turn, recruited Dr Olson and his team to help determine why the histidine-to-leucine change caused anemia in the daughter but not the father.
Coincidentally, Ivan Birukou, a graduate student in Dr Olson’s lab, had already generated the Kirklareli mutation in human hemoglobin to study how the protein rapidly and selectively binds oxygen.
“Emmanuel wrote to me and said, ‘I know you’ve been making all these mutants in hemoglobin, and you’ve probably done the H58L mutation in [alpha] chains. Does this phenotype make sense?’” Dr Olson recalled.
“I said, ‘We can do a really neat study here, because we’ve already made the mutant hemoglobin in a recombinant system.’ We actually had a crystal structure [matching Kirklareli] that Ivan and [staff scientist] Jayashree Soman never published but had deposited in the Protein Data Bank. We had made this mutation to try to understand what the distal histidine was doing in alpha subunits.”
The researchers found in a 2010 study that replacing the histidine, which forms a strong hydrogen bond to oxygen, with leucine caused a dramatic decrease in oxygen affinity and an increase in carbon monoxide binding.
Dr Olson and Birukou realized back then that histidine played a key role in discriminating between oxygen and carbon monoxide in hemoglobin.
“When Emmanuel wrote to me about his discovery, I already ‘knew’ what was happening with respect to carbon monoxide binding,” Dr Olson said.
He said the normal hydrogen bond causes bound oxygen to stick more tightly to hemoglobin in the same way hydrogen bonds cause spilled soda to feel sticky.
“When you touch it, the sugar oxygens and hydrogens make hydrogen bonds with the polysaccharides on your finger,” Dr Olson said. “That stickiness helps hold onto oxygen. But leucine is more like an oil, like butane or hexane, and oxygen does not stick well inside hemoglobin. In contrast, bound carbon monoxide is more like methane or ethane and can’t form hydrogen bonds.”
Andres Benitez Cardenas, PhD, a researcher in Dr Olson’s lab, did the experiment in which he put carbon monoxide on the mutant alpha subunit of hemoglobin Kirklareli. The bound carbon monoxide slowed down oxidation of the protein and prevented loss of heme and precipitation.
“In effect, Andres did the ‘smoking experiment’ to show why the father’s hemoglobin didn’t denature and cause anemia,” Dr Olson said.
He noted that the effect caused by Kirklareli, though unusual, is not unique. Patients with hemoglobin Zurich also have an abnormal form of hemoglobin that more readily binds to carbon monoxide.
Smoking can prevent anemia in individuals with a rare hemoglobin mutation, according to research published in the Journal of Biological Chemistry.
The so-called Kirklareli mutation was found to be the cause of mild anemia in a young woman in Germany.
But a smoking habit protected the young woman’s father, who also carried the mutation, from developing anemia.
The Kirklareli mutation is one of more than 1000 discovered so far in adult human hemoglobin.
Most of these mutations appear to have no effect on people, but when medical problems occur, the disease is called a hemoglobinopathy and often named after the city or hospital where it was discovered. In this case, the family was living in Mannheim, Germany, but the father was born in the Turkish city of Kirklareli.
The Kirklareli mutation did not affect the iron content of the father’s blood, but it did appear to be the root cause of the young woman’s chronic anemia, according to researchers.
Further investigation revealed that absorbing carbon monoxide from cigarette smoke is therapeutic for individuals with this rare genetic disorder.
The Kirklareli mutation is in the alpha subunit of human hemoglobin (H58L) and causes it to rapidly auto-oxidize, which causes the protein to fall apart, lose heme, and precipitate. As a result, the protein loses its ability to carry oxygen. Eventually, red cells become deformed and are destroyed.
This mutation also gives the protein an 80,000-fold higher affinity for carbon monoxide than for oxygen. Carbon monoxide from a cigarette will be selectively taken up by the mutant hemoglobin and prevent it from oxidizing and denaturing.
This high affinity for carbon monoxide explained why the father showed no signs of anemia, the researchers said.
“He may never be an athlete because his blood can’t carry as much oxygen, but smoking has prevented him from being anemic,” said study author John Olson, PhD, of Rice University in Houston, Texas.
“And there’s a side benefit. People with this trait are more resistant to carbon monoxide poisoning.”
Dr Olson said he doesn’t know how or if doctors treated the young woman, but he suspects her iron-deficiency anemia was more an annoyance than a threat to her life and would not recommend she start smoking to relieve it.
“She shouldn’t smoke,” Dr Olson said. “But she could take antioxidants, such as a lot of vitamin C, which would help prevent oxidation of her mutant hemoglobin. Her anemia is not that severe. At the same time, she shouldn’t worry too much about secondhand smoke, which might have a positive effect.”
After ruling out common causes of anemia—such as blood loss, gastritis, or congenital defects—the woman’s doctors were curious enough about her ailment to call upon Emmanuel Bissé, MD, PhD, a researcher at Universitätsklinikum Freiburg in Freiburg, Germany, who discovered the Kirklareli mutation after sequencing the woman’s DNA.
Dr Bissé, in turn, recruited Dr Olson and his team to help determine why the histidine-to-leucine change caused anemia in the daughter but not the father.
Coincidentally, Ivan Birukou, a graduate student in Dr Olson’s lab, had already generated the Kirklareli mutation in human hemoglobin to study how the protein rapidly and selectively binds oxygen.
“Emmanuel wrote to me and said, ‘I know you’ve been making all these mutants in hemoglobin, and you’ve probably done the H58L mutation in [alpha] chains. Does this phenotype make sense?’” Dr Olson recalled.
“I said, ‘We can do a really neat study here, because we’ve already made the mutant hemoglobin in a recombinant system.’ We actually had a crystal structure [matching Kirklareli] that Ivan and [staff scientist] Jayashree Soman never published but had deposited in the Protein Data Bank. We had made this mutation to try to understand what the distal histidine was doing in alpha subunits.”
The researchers found in a 2010 study that replacing the histidine, which forms a strong hydrogen bond to oxygen, with leucine caused a dramatic decrease in oxygen affinity and an increase in carbon monoxide binding.
Dr Olson and Birukou realized back then that histidine played a key role in discriminating between oxygen and carbon monoxide in hemoglobin.
“When Emmanuel wrote to me about his discovery, I already ‘knew’ what was happening with respect to carbon monoxide binding,” Dr Olson said.
He said the normal hydrogen bond causes bound oxygen to stick more tightly to hemoglobin in the same way hydrogen bonds cause spilled soda to feel sticky.
“When you touch it, the sugar oxygens and hydrogens make hydrogen bonds with the polysaccharides on your finger,” Dr Olson said. “That stickiness helps hold onto oxygen. But leucine is more like an oil, like butane or hexane, and oxygen does not stick well inside hemoglobin. In contrast, bound carbon monoxide is more like methane or ethane and can’t form hydrogen bonds.”
Andres Benitez Cardenas, PhD, a researcher in Dr Olson’s lab, did the experiment in which he put carbon monoxide on the mutant alpha subunit of hemoglobin Kirklareli. The bound carbon monoxide slowed down oxidation of the protein and prevented loss of heme and precipitation.
“In effect, Andres did the ‘smoking experiment’ to show why the father’s hemoglobin didn’t denature and cause anemia,” Dr Olson said.
He noted that the effect caused by Kirklareli, though unusual, is not unique. Patients with hemoglobin Zurich also have an abnormal form of hemoglobin that more readily binds to carbon monoxide.
Site of care may impact survival for AYAs with ALL, AML
Receiving treatment at specialized cancer centers may improve survival for adolescents and young adults (AYAs) with acute leukemia, according to a study published in Cancer Epidemiology, Biomarkers & Prevention.
The study showed that, when patients were treated at specialized cancer centers, survival rates were similar for younger AYAs and children with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).
However, older AYAs did not appear to reap the same survival benefit from receiving treatment at a specialized cancer center.
And AYAs of all ages had significantly worse survival than children if they were not treated at specialized cancer centers.
AYAs (patients ages 15 to 39) with ALL and AML have significantly worse survival outcomes than children ages 14 and under, according to study author Julie Wolfson, MD, of the University of Alabama at Birmingham.
“A much smaller percentage of AYAs with cancer are treated at specialized cancer centers than children with cancer,” she added. “We wanted to understand whether this difference in the site of cancer care is associated with the difference in survival outcomes.”
Dr Wolfson and her colleagues used data from the Los Angeles County Cancer Surveillance Program to identify patients diagnosed with ALL or AML from ages 1 to 39.
Patients were said to have been treated at a specialized cancer center if, at any age, they were cared for at any of the National Cancer Institute-designated Comprehensive Cancer Centers (CCC) in Los Angeles County or if, at the age of 21 or younger, they were cared for at any of the Children’s Oncology Group (COG) sites not designated a Comprehensive Cancer Center.
Included in the analysis were 978 patients diagnosed with ALL as a child (ages 1 to 14), 402 patients diagnosed with ALL as an AYA (ages 15 to 39), 131 patients diagnosed with AML as a child, and 359 patients diagnosed with AML as an AYA.
Seventy percent of the children with ALL and 30% of the AYAs with ALL were treated at CCC/COG sites. Seventy-four percent of the children with AML and 22% of the AYAs with AML were treated at CCC/COG sites.
Results in ALL
AYAs diagnosed with ALL at ages 15 to 21 and 22 to 29 who were treated at CCC/COG sites had comparable survival to children who were diagnosed with ALL from ages 10 to 14 and treated at CCC/COG sites. The hazard ratios (HRs) were 1.3 for the 15-21 age group (P=0.3) and 1.2 for the 22-29 age group (P=0.8).
The reference group for this analysis was 10- to 14-year-olds treated at CCC/COG sites because the researchers excluded data from children with ALL ages 1 to 9. These patients were excluded because they have significantly better survival than the other groups, potentially as a result of different disease biology.
The researchers also found that treatment at CCC/COG sites did not improve survival for 30- to 39-year-olds with ALL. The HR for them was 3.4 (P<0.001).
Likewise, all AYAs with ALL who were not treated at CCC/COG sites had worse survival than 10- to 14-year-olds treated at CCC/COG sites. The HRs were 1.9 for the 15-21 age group (P=0.005), 2.6 for the 22-29 age group (P<0.001), and 3.0 for the 30-39 age group (P<0.001).
Results in AML
For AML patients, the reference group was 1- to 14-year-olds treated at CCC/COG sites. Compared to these patients, 15- to 21-year-olds not treated at CCC/COG sites had an increased hazard of death (HR=1.7, P=0.02), whereas 15- to 21-year-olds treated at CCC/COG sites did not (HR=1.3; P=0.4).
All 22- to 39-year-olds, regardless of the site of care, had an increased hazard of death compared to the children treated at CCC/COG sites. The HR was 3.4 (P<0.001) for 22- to 39-year-olds treated at CCC/COG sites, and the HR was 3.0 (P<0.001) for 22- to 39-year-olds not treated at CCC/COG sites.
“The fact that the older AYAs did not appear to benefit from treatment at a specialized cancer center suggests to us that the biology of the disease in these patients differs from that in younger individuals,” Dr Wolfson said.
“The most important thing we can do to help these patients is to enroll them on clinical trials so that we can better understand the biology of the disease and its response to therapy.
Receiving treatment at specialized cancer centers may improve survival for adolescents and young adults (AYAs) with acute leukemia, according to a study published in Cancer Epidemiology, Biomarkers & Prevention.
The study showed that, when patients were treated at specialized cancer centers, survival rates were similar for younger AYAs and children with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).
However, older AYAs did not appear to reap the same survival benefit from receiving treatment at a specialized cancer center.
And AYAs of all ages had significantly worse survival than children if they were not treated at specialized cancer centers.
AYAs (patients ages 15 to 39) with ALL and AML have significantly worse survival outcomes than children ages 14 and under, according to study author Julie Wolfson, MD, of the University of Alabama at Birmingham.
“A much smaller percentage of AYAs with cancer are treated at specialized cancer centers than children with cancer,” she added. “We wanted to understand whether this difference in the site of cancer care is associated with the difference in survival outcomes.”
Dr Wolfson and her colleagues used data from the Los Angeles County Cancer Surveillance Program to identify patients diagnosed with ALL or AML from ages 1 to 39.
Patients were said to have been treated at a specialized cancer center if, at any age, they were cared for at any of the National Cancer Institute-designated Comprehensive Cancer Centers (CCC) in Los Angeles County or if, at the age of 21 or younger, they were cared for at any of the Children’s Oncology Group (COG) sites not designated a Comprehensive Cancer Center.
Included in the analysis were 978 patients diagnosed with ALL as a child (ages 1 to 14), 402 patients diagnosed with ALL as an AYA (ages 15 to 39), 131 patients diagnosed with AML as a child, and 359 patients diagnosed with AML as an AYA.
Seventy percent of the children with ALL and 30% of the AYAs with ALL were treated at CCC/COG sites. Seventy-four percent of the children with AML and 22% of the AYAs with AML were treated at CCC/COG sites.
Results in ALL
AYAs diagnosed with ALL at ages 15 to 21 and 22 to 29 who were treated at CCC/COG sites had comparable survival to children who were diagnosed with ALL from ages 10 to 14 and treated at CCC/COG sites. The hazard ratios (HRs) were 1.3 for the 15-21 age group (P=0.3) and 1.2 for the 22-29 age group (P=0.8).
The reference group for this analysis was 10- to 14-year-olds treated at CCC/COG sites because the researchers excluded data from children with ALL ages 1 to 9. These patients were excluded because they have significantly better survival than the other groups, potentially as a result of different disease biology.
The researchers also found that treatment at CCC/COG sites did not improve survival for 30- to 39-year-olds with ALL. The HR for them was 3.4 (P<0.001).
Likewise, all AYAs with ALL who were not treated at CCC/COG sites had worse survival than 10- to 14-year-olds treated at CCC/COG sites. The HRs were 1.9 for the 15-21 age group (P=0.005), 2.6 for the 22-29 age group (P<0.001), and 3.0 for the 30-39 age group (P<0.001).
Results in AML
For AML patients, the reference group was 1- to 14-year-olds treated at CCC/COG sites. Compared to these patients, 15- to 21-year-olds not treated at CCC/COG sites had an increased hazard of death (HR=1.7, P=0.02), whereas 15- to 21-year-olds treated at CCC/COG sites did not (HR=1.3; P=0.4).
All 22- to 39-year-olds, regardless of the site of care, had an increased hazard of death compared to the children treated at CCC/COG sites. The HR was 3.4 (P<0.001) for 22- to 39-year-olds treated at CCC/COG sites, and the HR was 3.0 (P<0.001) for 22- to 39-year-olds not treated at CCC/COG sites.
“The fact that the older AYAs did not appear to benefit from treatment at a specialized cancer center suggests to us that the biology of the disease in these patients differs from that in younger individuals,” Dr Wolfson said.
“The most important thing we can do to help these patients is to enroll them on clinical trials so that we can better understand the biology of the disease and its response to therapy.
Receiving treatment at specialized cancer centers may improve survival for adolescents and young adults (AYAs) with acute leukemia, according to a study published in Cancer Epidemiology, Biomarkers & Prevention.
The study showed that, when patients were treated at specialized cancer centers, survival rates were similar for younger AYAs and children with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).
However, older AYAs did not appear to reap the same survival benefit from receiving treatment at a specialized cancer center.
And AYAs of all ages had significantly worse survival than children if they were not treated at specialized cancer centers.
AYAs (patients ages 15 to 39) with ALL and AML have significantly worse survival outcomes than children ages 14 and under, according to study author Julie Wolfson, MD, of the University of Alabama at Birmingham.
“A much smaller percentage of AYAs with cancer are treated at specialized cancer centers than children with cancer,” she added. “We wanted to understand whether this difference in the site of cancer care is associated with the difference in survival outcomes.”
Dr Wolfson and her colleagues used data from the Los Angeles County Cancer Surveillance Program to identify patients diagnosed with ALL or AML from ages 1 to 39.
Patients were said to have been treated at a specialized cancer center if, at any age, they were cared for at any of the National Cancer Institute-designated Comprehensive Cancer Centers (CCC) in Los Angeles County or if, at the age of 21 or younger, they were cared for at any of the Children’s Oncology Group (COG) sites not designated a Comprehensive Cancer Center.
Included in the analysis were 978 patients diagnosed with ALL as a child (ages 1 to 14), 402 patients diagnosed with ALL as an AYA (ages 15 to 39), 131 patients diagnosed with AML as a child, and 359 patients diagnosed with AML as an AYA.
Seventy percent of the children with ALL and 30% of the AYAs with ALL were treated at CCC/COG sites. Seventy-four percent of the children with AML and 22% of the AYAs with AML were treated at CCC/COG sites.
Results in ALL
AYAs diagnosed with ALL at ages 15 to 21 and 22 to 29 who were treated at CCC/COG sites had comparable survival to children who were diagnosed with ALL from ages 10 to 14 and treated at CCC/COG sites. The hazard ratios (HRs) were 1.3 for the 15-21 age group (P=0.3) and 1.2 for the 22-29 age group (P=0.8).
The reference group for this analysis was 10- to 14-year-olds treated at CCC/COG sites because the researchers excluded data from children with ALL ages 1 to 9. These patients were excluded because they have significantly better survival than the other groups, potentially as a result of different disease biology.
The researchers also found that treatment at CCC/COG sites did not improve survival for 30- to 39-year-olds with ALL. The HR for them was 3.4 (P<0.001).
Likewise, all AYAs with ALL who were not treated at CCC/COG sites had worse survival than 10- to 14-year-olds treated at CCC/COG sites. The HRs were 1.9 for the 15-21 age group (P=0.005), 2.6 for the 22-29 age group (P<0.001), and 3.0 for the 30-39 age group (P<0.001).
Results in AML
For AML patients, the reference group was 1- to 14-year-olds treated at CCC/COG sites. Compared to these patients, 15- to 21-year-olds not treated at CCC/COG sites had an increased hazard of death (HR=1.7, P=0.02), whereas 15- to 21-year-olds treated at CCC/COG sites did not (HR=1.3; P=0.4).
All 22- to 39-year-olds, regardless of the site of care, had an increased hazard of death compared to the children treated at CCC/COG sites. The HR was 3.4 (P<0.001) for 22- to 39-year-olds treated at CCC/COG sites, and the HR was 3.0 (P<0.001) for 22- to 39-year-olds not treated at CCC/COG sites.
“The fact that the older AYAs did not appear to benefit from treatment at a specialized cancer center suggests to us that the biology of the disease in these patients differs from that in younger individuals,” Dr Wolfson said.
“The most important thing we can do to help these patients is to enroll them on clinical trials so that we can better understand the biology of the disease and its response to therapy.
Using mRNA to treat hemophilia B
Researchers have reported the successful treatment of hemophilia B in mice using messenger RNA (mRNA).
In experiments, protein-replacement therapy using mRNA was effective longer than recombinant factor IX (FIX) therapy.
The mRNA therapy also appeared to be safe and produced mild, transient immune responses.
In addition, the researchers noted that the mRNA therapy can be produced more cheaply than recombinant FIX therapy.
They said this research, published in PNAS, is proof-of-concept that mRNA therapy could be used to treat hemophilia B and other genetic diseases.
“We are really excited about this work because, short of correcting a faulty gene, protein-replacement therapy using mRNA is one of the most promising techniques we have at our disposal,” said study author Inder Verma, PhD, of the Salk Institute for Biological Studies in La Jolla, California.
“Now, we have proof that we can successfully treat a disease—with virtually no side effects—at a lower cost than manufacturing the needed protein.”
This work is a collaboration between the Verma lab and Arcturus Therapeutics, a biotech company that developed a system of encapsulating mRNA within lipid nanoparticles.
The researchers created an mRNA blueprint for human FIX nanoparticles and delivered them, via injection, to mice with a faulty FIX gene.
Once in the bloodstream, the nanoparticles traveled to the liver, where their fatty casing helped them ease into cells and deliver to the protein-making machinery the mRNA instructions to assemble FIX.
The hemophilic mice were given 3 injections over a 5-month period, during which their coagulation and immune responses were carefully monitored.
Normal clotting occurred in the mice within 4 hours of receiving the therapy, and the results lasted for up to 6 days.
The mice had a weak immune response to the treatment, which quickly returned to baseline.
“One of the issues with both nanoparticles and mRNA treatment is toxicity, and, in our study, we did not see much evidence of that,” said study author Suvasini Ramaswamy, PhD, of the Salk Institute for Biological Studies.
“We gave the treatment over a long span to give the immune system time to see it and react to it, but the immune response looked more like a mild allergic response and quickly returned to normal, so the technology seems pretty reliable and safe in our mouse model.”
The researchers also gave mice recombinant FIX, directly comparing it to the mRNA therapy. The mRNA therapy proved more effective, maintaining 20% more clotting activity 4 days after injection.
“Conceptually, in vivo mRNA delivery has been around for a long time, but its therapeutic use has been limited by poor stability, immune-reactivity, and problems with reproducible systemic delivery,” said Pad Chivukula, chief scientific officer at Arcturus Therapeutics.
“The results suggest that nanoparticle delivery technology overcomes these challenges and might allow for the development of novel, cost-effective mRNA therapeutics.”
This work was funded by the National Institutes of Health, the Ipsen Foundation, the H.N. and Frances C. Berger Foundation, the Glenn Center for Research on Aging, The Leona M. and Harry B. Helmsley Charitable Trust, and the California Institute for Regenerative Medicine. The lipid nanoparticles were developed by Arcturus Therapeutics.
Researchers have reported the successful treatment of hemophilia B in mice using messenger RNA (mRNA).
In experiments, protein-replacement therapy using mRNA was effective longer than recombinant factor IX (FIX) therapy.
The mRNA therapy also appeared to be safe and produced mild, transient immune responses.
In addition, the researchers noted that the mRNA therapy can be produced more cheaply than recombinant FIX therapy.
They said this research, published in PNAS, is proof-of-concept that mRNA therapy could be used to treat hemophilia B and other genetic diseases.
“We are really excited about this work because, short of correcting a faulty gene, protein-replacement therapy using mRNA is one of the most promising techniques we have at our disposal,” said study author Inder Verma, PhD, of the Salk Institute for Biological Studies in La Jolla, California.
“Now, we have proof that we can successfully treat a disease—with virtually no side effects—at a lower cost than manufacturing the needed protein.”
This work is a collaboration between the Verma lab and Arcturus Therapeutics, a biotech company that developed a system of encapsulating mRNA within lipid nanoparticles.
The researchers created an mRNA blueprint for human FIX nanoparticles and delivered them, via injection, to mice with a faulty FIX gene.
Once in the bloodstream, the nanoparticles traveled to the liver, where their fatty casing helped them ease into cells and deliver to the protein-making machinery the mRNA instructions to assemble FIX.
The hemophilic mice were given 3 injections over a 5-month period, during which their coagulation and immune responses were carefully monitored.
Normal clotting occurred in the mice within 4 hours of receiving the therapy, and the results lasted for up to 6 days.
The mice had a weak immune response to the treatment, which quickly returned to baseline.
“One of the issues with both nanoparticles and mRNA treatment is toxicity, and, in our study, we did not see much evidence of that,” said study author Suvasini Ramaswamy, PhD, of the Salk Institute for Biological Studies.
“We gave the treatment over a long span to give the immune system time to see it and react to it, but the immune response looked more like a mild allergic response and quickly returned to normal, so the technology seems pretty reliable and safe in our mouse model.”
The researchers also gave mice recombinant FIX, directly comparing it to the mRNA therapy. The mRNA therapy proved more effective, maintaining 20% more clotting activity 4 days after injection.
“Conceptually, in vivo mRNA delivery has been around for a long time, but its therapeutic use has been limited by poor stability, immune-reactivity, and problems with reproducible systemic delivery,” said Pad Chivukula, chief scientific officer at Arcturus Therapeutics.
“The results suggest that nanoparticle delivery technology overcomes these challenges and might allow for the development of novel, cost-effective mRNA therapeutics.”
This work was funded by the National Institutes of Health, the Ipsen Foundation, the H.N. and Frances C. Berger Foundation, the Glenn Center for Research on Aging, The Leona M. and Harry B. Helmsley Charitable Trust, and the California Institute for Regenerative Medicine. The lipid nanoparticles were developed by Arcturus Therapeutics.
Researchers have reported the successful treatment of hemophilia B in mice using messenger RNA (mRNA).
In experiments, protein-replacement therapy using mRNA was effective longer than recombinant factor IX (FIX) therapy.
The mRNA therapy also appeared to be safe and produced mild, transient immune responses.
In addition, the researchers noted that the mRNA therapy can be produced more cheaply than recombinant FIX therapy.
They said this research, published in PNAS, is proof-of-concept that mRNA therapy could be used to treat hemophilia B and other genetic diseases.
“We are really excited about this work because, short of correcting a faulty gene, protein-replacement therapy using mRNA is one of the most promising techniques we have at our disposal,” said study author Inder Verma, PhD, of the Salk Institute for Biological Studies in La Jolla, California.
“Now, we have proof that we can successfully treat a disease—with virtually no side effects—at a lower cost than manufacturing the needed protein.”
This work is a collaboration between the Verma lab and Arcturus Therapeutics, a biotech company that developed a system of encapsulating mRNA within lipid nanoparticles.
The researchers created an mRNA blueprint for human FIX nanoparticles and delivered them, via injection, to mice with a faulty FIX gene.
Once in the bloodstream, the nanoparticles traveled to the liver, where their fatty casing helped them ease into cells and deliver to the protein-making machinery the mRNA instructions to assemble FIX.
The hemophilic mice were given 3 injections over a 5-month period, during which their coagulation and immune responses were carefully monitored.
Normal clotting occurred in the mice within 4 hours of receiving the therapy, and the results lasted for up to 6 days.
The mice had a weak immune response to the treatment, which quickly returned to baseline.
“One of the issues with both nanoparticles and mRNA treatment is toxicity, and, in our study, we did not see much evidence of that,” said study author Suvasini Ramaswamy, PhD, of the Salk Institute for Biological Studies.
“We gave the treatment over a long span to give the immune system time to see it and react to it, but the immune response looked more like a mild allergic response and quickly returned to normal, so the technology seems pretty reliable and safe in our mouse model.”
The researchers also gave mice recombinant FIX, directly comparing it to the mRNA therapy. The mRNA therapy proved more effective, maintaining 20% more clotting activity 4 days after injection.
“Conceptually, in vivo mRNA delivery has been around for a long time, but its therapeutic use has been limited by poor stability, immune-reactivity, and problems with reproducible systemic delivery,” said Pad Chivukula, chief scientific officer at Arcturus Therapeutics.
“The results suggest that nanoparticle delivery technology overcomes these challenges and might allow for the development of novel, cost-effective mRNA therapeutics.”
This work was funded by the National Institutes of Health, the Ipsen Foundation, the H.N. and Frances C. Berger Foundation, the Glenn Center for Research on Aging, The Leona M. and Harry B. Helmsley Charitable Trust, and the California Institute for Regenerative Medicine. The lipid nanoparticles were developed by Arcturus Therapeutics.
Vaccine offers some protection during malaria season
In a placebo-controlled trial, an investigational vaccine protected a small but statistically significant proportion of healthy volunteers against naturally acquired malaria infection for the duration of the malaria season in Mali.
The vaccine, known as the PfSPZ Vaccine, contains live but weakened Plasmodium falciparum sporozoites and was developed by scientists at Sanaria Inc.
Results of the phase 1 trial were published in The Lancet Infectious Diseases.
Sanaria was the regulatory sponsor of the trial. The National Institute of Allergy and Infectious Diseases (NIAID) supported the development of the vaccine.
Earlier research suggested the PfSPZ Vaccine was safe and could protect against malaria infection for up to a year in healthy US adults who had not been previously exposed to malaria.
The Mali study was launched in January 2014 to provide additional safety data for the PfSPZ Vaccine and determine if it could protect adults living in a malaria-endemic area against naturally occurring malaria infection.
The study enrolled 109 healthy African men and non-pregnant women ages 18 to 35. Subjects received either 5 doses of the intravenous PfSPZ Vaccine (2.7 × 10⁵) or 5 doses of placebo (saline) over 5 months of the dry season at the study’s clinical site in the Donéguébougou village in rural Mali.
The subjects also received combined artemether and lumefantrine (4 tablets twice per day over 3 days) to eliminate P falciparum before the first and last vaccinations.
Clinical staff monitored the subjects during the 6-month malaria-transmission season for the presence of malaria parasites in the blood. The team collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination.
The investigators said they detected no significant differences in local or systemic adverse events or laboratory abnormalities between the PfSPZ Vaccine group and the placebo group.
The most common solicited systemic adverse events were headache (7% in the vaccine group and 9% in the placebo group), fatigue (2% in the placebo group), fever (2% in the placebo group), and myalgia (2% in each group).
Efficacy
Ninety-three percent of evaluable subjects in the placebo group (37/40) and 66% of evaluable subjects in the PfSPZ Vaccine group (27/41) developed P falciparum malaria infections.
The investigators said the PfSPZ Vaccine demonstrated a 48% protective efficacy by time to first positive malaria blood smear and 29% efficacy by the proportion of participants with at least 1 positive malaria blood smear during a full 20-week malaria transmission season.
By both measures of protective efficacy, there was statistically significant protection in the vaccine group compared to the placebo group.
“This level of sustained efficacy against malaria infection in a region with an intense transmission season has not been seen in previous malaria vaccine studies in Africa,” said Sara Healy, MD, of NIAID in Bethesda, Maryland.
“It is a very encouraging finding that we can, hopefully, build upon.”
The investigators noted that the vaccine-induced antibody response was considerably lower in the Mali study than in the US trial, even though subjects received the same vaccine regimen.
“The poor antibody response to PfSPZ Vaccine among Malians could have been because of the participants’ lifelong exposure to P falciparum,” said Patrick E. Duffy, MD, of NIAID.
Feasibility
The investigators reported that there was no problem administering the PfSPZ Vaccine in a rural, malaria-endemic area—an initial concern about the vaccine’s design.
“Direct venous inoculation is not currently used for any licensed vaccines to prevent an infectious disease,” said Ogobara Doumbo, MD, PhD, of the University of Science, Techniques and Technologies of Bamako in Bamako, Mali.
“In this study, we administered 491 inoculations in a rural setting without a problem, and the dosages were delivered in a matter of seconds. It shows that this approach is feasible from both a logistical and public health standpoint.”
According to the investigators, a malaria vaccine employed in mass vaccination programs to eliminate P falciparum from geographically defined areas would need to prevent malaria infection or transmission in at least 80% of recipients throughout the malaria transmission season.
Clinical trials now underway in Africa, Europe, and the US have been designed to boost the PfSPZ Vaccine’s efficacy by increasing dosage levels and varying the timing and number of doses.
The experimental vaccine is also being examined in demographic groups other than healthy adults, including adolescents, children, and infants.
In a placebo-controlled trial, an investigational vaccine protected a small but statistically significant proportion of healthy volunteers against naturally acquired malaria infection for the duration of the malaria season in Mali.
The vaccine, known as the PfSPZ Vaccine, contains live but weakened Plasmodium falciparum sporozoites and was developed by scientists at Sanaria Inc.
Results of the phase 1 trial were published in The Lancet Infectious Diseases.
Sanaria was the regulatory sponsor of the trial. The National Institute of Allergy and Infectious Diseases (NIAID) supported the development of the vaccine.
Earlier research suggested the PfSPZ Vaccine was safe and could protect against malaria infection for up to a year in healthy US adults who had not been previously exposed to malaria.
The Mali study was launched in January 2014 to provide additional safety data for the PfSPZ Vaccine and determine if it could protect adults living in a malaria-endemic area against naturally occurring malaria infection.
The study enrolled 109 healthy African men and non-pregnant women ages 18 to 35. Subjects received either 5 doses of the intravenous PfSPZ Vaccine (2.7 × 10⁵) or 5 doses of placebo (saline) over 5 months of the dry season at the study’s clinical site in the Donéguébougou village in rural Mali.
The subjects also received combined artemether and lumefantrine (4 tablets twice per day over 3 days) to eliminate P falciparum before the first and last vaccinations.
Clinical staff monitored the subjects during the 6-month malaria-transmission season for the presence of malaria parasites in the blood. The team collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination.
The investigators said they detected no significant differences in local or systemic adverse events or laboratory abnormalities between the PfSPZ Vaccine group and the placebo group.
The most common solicited systemic adverse events were headache (7% in the vaccine group and 9% in the placebo group), fatigue (2% in the placebo group), fever (2% in the placebo group), and myalgia (2% in each group).
Efficacy
Ninety-three percent of evaluable subjects in the placebo group (37/40) and 66% of evaluable subjects in the PfSPZ Vaccine group (27/41) developed P falciparum malaria infections.
The investigators said the PfSPZ Vaccine demonstrated a 48% protective efficacy by time to first positive malaria blood smear and 29% efficacy by the proportion of participants with at least 1 positive malaria blood smear during a full 20-week malaria transmission season.
By both measures of protective efficacy, there was statistically significant protection in the vaccine group compared to the placebo group.
“This level of sustained efficacy against malaria infection in a region with an intense transmission season has not been seen in previous malaria vaccine studies in Africa,” said Sara Healy, MD, of NIAID in Bethesda, Maryland.
“It is a very encouraging finding that we can, hopefully, build upon.”
The investigators noted that the vaccine-induced antibody response was considerably lower in the Mali study than in the US trial, even though subjects received the same vaccine regimen.
“The poor antibody response to PfSPZ Vaccine among Malians could have been because of the participants’ lifelong exposure to P falciparum,” said Patrick E. Duffy, MD, of NIAID.
Feasibility
The investigators reported that there was no problem administering the PfSPZ Vaccine in a rural, malaria-endemic area—an initial concern about the vaccine’s design.
“Direct venous inoculation is not currently used for any licensed vaccines to prevent an infectious disease,” said Ogobara Doumbo, MD, PhD, of the University of Science, Techniques and Technologies of Bamako in Bamako, Mali.
“In this study, we administered 491 inoculations in a rural setting without a problem, and the dosages were delivered in a matter of seconds. It shows that this approach is feasible from both a logistical and public health standpoint.”
According to the investigators, a malaria vaccine employed in mass vaccination programs to eliminate P falciparum from geographically defined areas would need to prevent malaria infection or transmission in at least 80% of recipients throughout the malaria transmission season.
Clinical trials now underway in Africa, Europe, and the US have been designed to boost the PfSPZ Vaccine’s efficacy by increasing dosage levels and varying the timing and number of doses.
The experimental vaccine is also being examined in demographic groups other than healthy adults, including adolescents, children, and infants.
In a placebo-controlled trial, an investigational vaccine protected a small but statistically significant proportion of healthy volunteers against naturally acquired malaria infection for the duration of the malaria season in Mali.
The vaccine, known as the PfSPZ Vaccine, contains live but weakened Plasmodium falciparum sporozoites and was developed by scientists at Sanaria Inc.
Results of the phase 1 trial were published in The Lancet Infectious Diseases.
Sanaria was the regulatory sponsor of the trial. The National Institute of Allergy and Infectious Diseases (NIAID) supported the development of the vaccine.
Earlier research suggested the PfSPZ Vaccine was safe and could protect against malaria infection for up to a year in healthy US adults who had not been previously exposed to malaria.
The Mali study was launched in January 2014 to provide additional safety data for the PfSPZ Vaccine and determine if it could protect adults living in a malaria-endemic area against naturally occurring malaria infection.
The study enrolled 109 healthy African men and non-pregnant women ages 18 to 35. Subjects received either 5 doses of the intravenous PfSPZ Vaccine (2.7 × 10⁵) or 5 doses of placebo (saline) over 5 months of the dry season at the study’s clinical site in the Donéguébougou village in rural Mali.
The subjects also received combined artemether and lumefantrine (4 tablets twice per day over 3 days) to eliminate P falciparum before the first and last vaccinations.
Clinical staff monitored the subjects during the 6-month malaria-transmission season for the presence of malaria parasites in the blood. The team collected blood smears every 2 weeks and during any illness for 24 weeks after the fifth vaccination.
The investigators said they detected no significant differences in local or systemic adverse events or laboratory abnormalities between the PfSPZ Vaccine group and the placebo group.
The most common solicited systemic adverse events were headache (7% in the vaccine group and 9% in the placebo group), fatigue (2% in the placebo group), fever (2% in the placebo group), and myalgia (2% in each group).
Efficacy
Ninety-three percent of evaluable subjects in the placebo group (37/40) and 66% of evaluable subjects in the PfSPZ Vaccine group (27/41) developed P falciparum malaria infections.
The investigators said the PfSPZ Vaccine demonstrated a 48% protective efficacy by time to first positive malaria blood smear and 29% efficacy by the proportion of participants with at least 1 positive malaria blood smear during a full 20-week malaria transmission season.
By both measures of protective efficacy, there was statistically significant protection in the vaccine group compared to the placebo group.
“This level of sustained efficacy against malaria infection in a region with an intense transmission season has not been seen in previous malaria vaccine studies in Africa,” said Sara Healy, MD, of NIAID in Bethesda, Maryland.
“It is a very encouraging finding that we can, hopefully, build upon.”
The investigators noted that the vaccine-induced antibody response was considerably lower in the Mali study than in the US trial, even though subjects received the same vaccine regimen.
“The poor antibody response to PfSPZ Vaccine among Malians could have been because of the participants’ lifelong exposure to P falciparum,” said Patrick E. Duffy, MD, of NIAID.
Feasibility
The investigators reported that there was no problem administering the PfSPZ Vaccine in a rural, malaria-endemic area—an initial concern about the vaccine’s design.
“Direct venous inoculation is not currently used for any licensed vaccines to prevent an infectious disease,” said Ogobara Doumbo, MD, PhD, of the University of Science, Techniques and Technologies of Bamako in Bamako, Mali.
“In this study, we administered 491 inoculations in a rural setting without a problem, and the dosages were delivered in a matter of seconds. It shows that this approach is feasible from both a logistical and public health standpoint.”
According to the investigators, a malaria vaccine employed in mass vaccination programs to eliminate P falciparum from geographically defined areas would need to prevent malaria infection or transmission in at least 80% of recipients throughout the malaria transmission season.
Clinical trials now underway in Africa, Europe, and the US have been designed to boost the PfSPZ Vaccine’s efficacy by increasing dosage levels and varying the timing and number of doses.
The experimental vaccine is also being examined in demographic groups other than healthy adults, including adolescents, children, and infants.
Group ranks TKIs according to cardiotoxicity
Researchers say they have devised a way to rank tyrosine kinase inhibitors (TKIs) based on their likelihood of causing lasting heart damage in patients.
The team found they could accurately identify those TKIs already known to be the most dangerous.
The researchers believe that, in the future, their system may prove useful in the early stages of drug development to screen new compounds for cardiotoxicity.
“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients,” said study author Joseph Wu, MD, PhD, of Stanford University School of Medicine in California.
“It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects.”
Dr Wu and his colleagues described this research in Science Translational Medicine.
The researchers began with human induced pluripotent stem cell-derived cardiomyocytes generated from the cells of 11 healthy people and 2 patients with kidney cancer.
The team grew the cardiomyocytes in a dish and tested the effects of 21 commonly used TKIs on the cells.
Treatment with drug levels equivalent to those taken by patients often caused the cells to beat irregularly and begin to die. The cells also displayed differences in the electrophysiological signaling that controls their contraction.
The researchers used these and other measurements to develop a cardiac safety index for each drug. They found that TKIs known to be particularly dangerous to heart function had the lowest safety indices, and TKIs known to be better tolerated by patients ranked higher on the safety index.
High cardiotoxicity
Seven of the 21 TKIs tested were assigned cardiac safety indices at or below 0.1—the threshold limit at which the researchers designated a drug highly cardiotoxic.
These TKIs (from lowest to highest safety score) were vemurafenib, sorafenib, doxorubicin, regorafenib, vandetanib, crizotinib, and nilotinib.
Three of the most cardiotoxic TKIs (regorafenib, sorafenib, and vandetanib) are known to inhibit the same 2 signaling pathways: VEGFR2 and PDGFR.
The researchers noticed that cells treated with these 3 drugs ramped up the activity of a cellular signaling pathway that responds to insulin or IGF1, an insulin-like growth factor.
This discovery, coupled with the fact that treatment with insulin or IGF1 is known to enhance heart function during adverse cardiac events such as heart attacks, led the researchers to experiment further.
They found that exposing the cells to insulin or IGF1 made it less likely they would die due to TKIs blocking the VEGFR2 and PDGFR pathways. Although more research is needed, these findings suggest it may be possible to alleviate some of the heart damage in patients receiving these TKIs.
“There is a critical need for a way to ‘safety test’ all drugs earlier in development before they are administered to patients,” Dr Wu said. “Our drug safety index is a step in that direction.”
Researchers say they have devised a way to rank tyrosine kinase inhibitors (TKIs) based on their likelihood of causing lasting heart damage in patients.
The team found they could accurately identify those TKIs already known to be the most dangerous.
The researchers believe that, in the future, their system may prove useful in the early stages of drug development to screen new compounds for cardiotoxicity.
“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients,” said study author Joseph Wu, MD, PhD, of Stanford University School of Medicine in California.
“It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects.”
Dr Wu and his colleagues described this research in Science Translational Medicine.
The researchers began with human induced pluripotent stem cell-derived cardiomyocytes generated from the cells of 11 healthy people and 2 patients with kidney cancer.
The team grew the cardiomyocytes in a dish and tested the effects of 21 commonly used TKIs on the cells.
Treatment with drug levels equivalent to those taken by patients often caused the cells to beat irregularly and begin to die. The cells also displayed differences in the electrophysiological signaling that controls their contraction.
The researchers used these and other measurements to develop a cardiac safety index for each drug. They found that TKIs known to be particularly dangerous to heart function had the lowest safety indices, and TKIs known to be better tolerated by patients ranked higher on the safety index.
High cardiotoxicity
Seven of the 21 TKIs tested were assigned cardiac safety indices at or below 0.1—the threshold limit at which the researchers designated a drug highly cardiotoxic.
These TKIs (from lowest to highest safety score) were vemurafenib, sorafenib, doxorubicin, regorafenib, vandetanib, crizotinib, and nilotinib.
Three of the most cardiotoxic TKIs (regorafenib, sorafenib, and vandetanib) are known to inhibit the same 2 signaling pathways: VEGFR2 and PDGFR.
The researchers noticed that cells treated with these 3 drugs ramped up the activity of a cellular signaling pathway that responds to insulin or IGF1, an insulin-like growth factor.
This discovery, coupled with the fact that treatment with insulin or IGF1 is known to enhance heart function during adverse cardiac events such as heart attacks, led the researchers to experiment further.
They found that exposing the cells to insulin or IGF1 made it less likely they would die due to TKIs blocking the VEGFR2 and PDGFR pathways. Although more research is needed, these findings suggest it may be possible to alleviate some of the heart damage in patients receiving these TKIs.
“There is a critical need for a way to ‘safety test’ all drugs earlier in development before they are administered to patients,” Dr Wu said. “Our drug safety index is a step in that direction.”
Researchers say they have devised a way to rank tyrosine kinase inhibitors (TKIs) based on their likelihood of causing lasting heart damage in patients.
The team found they could accurately identify those TKIs already known to be the most dangerous.
The researchers believe that, in the future, their system may prove useful in the early stages of drug development to screen new compounds for cardiotoxicity.
“This type of study represents a critical step forward from the usual process running from initial drug discovery and clinical trials in human patients,” said study author Joseph Wu, MD, PhD, of Stanford University School of Medicine in California.
“It will help pharmaceutical companies better focus their efforts on developing safer drugs, and it will provide patients more effective drugs with fewer side effects.”
Dr Wu and his colleagues described this research in Science Translational Medicine.
The researchers began with human induced pluripotent stem cell-derived cardiomyocytes generated from the cells of 11 healthy people and 2 patients with kidney cancer.
The team grew the cardiomyocytes in a dish and tested the effects of 21 commonly used TKIs on the cells.
Treatment with drug levels equivalent to those taken by patients often caused the cells to beat irregularly and begin to die. The cells also displayed differences in the electrophysiological signaling that controls their contraction.
The researchers used these and other measurements to develop a cardiac safety index for each drug. They found that TKIs known to be particularly dangerous to heart function had the lowest safety indices, and TKIs known to be better tolerated by patients ranked higher on the safety index.
High cardiotoxicity
Seven of the 21 TKIs tested were assigned cardiac safety indices at or below 0.1—the threshold limit at which the researchers designated a drug highly cardiotoxic.
These TKIs (from lowest to highest safety score) were vemurafenib, sorafenib, doxorubicin, regorafenib, vandetanib, crizotinib, and nilotinib.
Three of the most cardiotoxic TKIs (regorafenib, sorafenib, and vandetanib) are known to inhibit the same 2 signaling pathways: VEGFR2 and PDGFR.
The researchers noticed that cells treated with these 3 drugs ramped up the activity of a cellular signaling pathway that responds to insulin or IGF1, an insulin-like growth factor.
This discovery, coupled with the fact that treatment with insulin or IGF1 is known to enhance heart function during adverse cardiac events such as heart attacks, led the researchers to experiment further.
They found that exposing the cells to insulin or IGF1 made it less likely they would die due to TKIs blocking the VEGFR2 and PDGFR pathways. Although more research is needed, these findings suggest it may be possible to alleviate some of the heart damage in patients receiving these TKIs.
“There is a critical need for a way to ‘safety test’ all drugs earlier in development before they are administered to patients,” Dr Wu said. “Our drug safety index is a step in that direction.”
Proximity to oil, gas wells linked to ALL
A pumpjack is used to lift
liquid from an oil well.
Photo by Eric Kounce
Living in an area of high-density oil and gas development may increase a young person’s risk of developing acute lymphoblastic leukemia (ALL), according to research published in PLOS ONE.
The study showed that children and young adults in Colorado who had been diagnosed with ALL were more likely than young people with non-hematologic cancers to live in areas of high-density oil and gas development.
However, there was no such association for young people with non-Hodgkin lymphoma (NHL).
“Over 378,000 Coloradans and millions of Americans currently live within a mile of at least one oil and gas well, and petroleum development continues to expand into residential areas,” said study author Lisa McKenzie, PhD, of the University of Colorado Anschutz Campus in Aurora.
“The findings from our registry-based, case-control study indicate that young Coloradans diagnosed with one type of childhood leukemia are more likely to live in the densest areas of oil and gas sites. More comprehensive research that can address our study’s limitations is needed to understand and explain these results.”
Dr McKenzie and her colleagues said they conducted this study because oil and gas development emits known hematological carcinogens, such as benzene, and increasingly occurs in residential areas.
The team wanted to determine whether living near areas of oil and gas development was associated with risk for hematologic cancers. So they analyzed data from the Colorado Central Cancer Registry and the Colorado Oil and Gas Information System.
The study included 743 subjects, ages 0 to 24, living in rural Colorado and diagnosed with cancer between 2001 and 2013. This included 87 ALL cases, 50 NHL cases, and 528 controls with non-hematologic cancers. (Other hematologic malignancies were not included in the analysis due to small numbers.)
Data analysis
The researchers used information from the Colorado Oil and Gas Information System to build a geocoded dataset with coordinates of all oil and gas wells in rural Colorado and determined dates for when each well was active.
Geocoded residential addresses of cancer patients at the time of diagnosis were linked to active well locations in the year of diagnosis and active well locations in each of the 10 years preceding the cancer diagnosis.
The researchers then took the inverse of each distance and summed the inverse distances to calculate inverse distance weighted (IDW) oil and gas well counts within a 16.1 km radius of each participant’s residence at cancer diagnosis for each of the 10 years prior to the date of diagnosis. (The IDW well count method gives greater weight to the wells nearer the home.)
The team used logistic regression to estimate associations for cancers across IDW well count tertiles. The first tertile had less than 4.9 wells per 1.6 km, the second had 4.9 to 33.6 wells per 1.6 km, and the third had more than 33.6 wells per 1.6 km.
Results
The researchers found an increase in the odds of living near oil and gas development at the time of ALL diagnosis, even after adjusting for age, race, gender, income, elevation, and year of cancer diagnosis.
ALL patients ages 0 to 24 were twice as likely as controls to live in the densest area of active oil and gas wells (highest IDW well count tertile).
ALL patients ages 5 to 24 were 4.6 times more likely than controls to live in areas included in the highest IDW well count tertile.
However, there was no significant association between ALL and proximity to oil and gas development in ALL patients ages 0 to 4. The adjusted odds ratio was 0.51 for the highest IDW well count tertile.
Likewise, there were no significant associations between density of oil and gas development and NHL. The adjusted odds ratio was 0.99 for the highest IDW well count tertile.
Limitations and next steps
The researchers said this study was limited by the low occurrence of ALL and NHL in rural Colorado, lack of specific age at cancer diagnosis, and the fact that all study participants had been diagnosed with cancer.
In addition, the study was limited by the lack of information on specific activities at the well sites, place of residence before cancer diagnosis, other sources of pollution around the residence, and individual characteristics such as common infections and family history of cancer.
The team said future research should incorporate information on oil and gas development activities and production levels, as well as levels of specific pollutants of interest such as benzene, near homes, schools, and day care centers.
They recommended that such research consider specific ages and residential histories, compare cases to controls without cancer, and address other potential confounders and and environmental stressors.
A pumpjack is used to lift
liquid from an oil well.
Photo by Eric Kounce
Living in an area of high-density oil and gas development may increase a young person’s risk of developing acute lymphoblastic leukemia (ALL), according to research published in PLOS ONE.
The study showed that children and young adults in Colorado who had been diagnosed with ALL were more likely than young people with non-hematologic cancers to live in areas of high-density oil and gas development.
However, there was no such association for young people with non-Hodgkin lymphoma (NHL).
“Over 378,000 Coloradans and millions of Americans currently live within a mile of at least one oil and gas well, and petroleum development continues to expand into residential areas,” said study author Lisa McKenzie, PhD, of the University of Colorado Anschutz Campus in Aurora.
“The findings from our registry-based, case-control study indicate that young Coloradans diagnosed with one type of childhood leukemia are more likely to live in the densest areas of oil and gas sites. More comprehensive research that can address our study’s limitations is needed to understand and explain these results.”
Dr McKenzie and her colleagues said they conducted this study because oil and gas development emits known hematological carcinogens, such as benzene, and increasingly occurs in residential areas.
The team wanted to determine whether living near areas of oil and gas development was associated with risk for hematologic cancers. So they analyzed data from the Colorado Central Cancer Registry and the Colorado Oil and Gas Information System.
The study included 743 subjects, ages 0 to 24, living in rural Colorado and diagnosed with cancer between 2001 and 2013. This included 87 ALL cases, 50 NHL cases, and 528 controls with non-hematologic cancers. (Other hematologic malignancies were not included in the analysis due to small numbers.)
Data analysis
The researchers used information from the Colorado Oil and Gas Information System to build a geocoded dataset with coordinates of all oil and gas wells in rural Colorado and determined dates for when each well was active.
Geocoded residential addresses of cancer patients at the time of diagnosis were linked to active well locations in the year of diagnosis and active well locations in each of the 10 years preceding the cancer diagnosis.
The researchers then took the inverse of each distance and summed the inverse distances to calculate inverse distance weighted (IDW) oil and gas well counts within a 16.1 km radius of each participant’s residence at cancer diagnosis for each of the 10 years prior to the date of diagnosis. (The IDW well count method gives greater weight to the wells nearer the home.)
The team used logistic regression to estimate associations for cancers across IDW well count tertiles. The first tertile had less than 4.9 wells per 1.6 km, the second had 4.9 to 33.6 wells per 1.6 km, and the third had more than 33.6 wells per 1.6 km.
Results
The researchers found an increase in the odds of living near oil and gas development at the time of ALL diagnosis, even after adjusting for age, race, gender, income, elevation, and year of cancer diagnosis.
ALL patients ages 0 to 24 were twice as likely as controls to live in the densest area of active oil and gas wells (highest IDW well count tertile).
ALL patients ages 5 to 24 were 4.6 times more likely than controls to live in areas included in the highest IDW well count tertile.
However, there was no significant association between ALL and proximity to oil and gas development in ALL patients ages 0 to 4. The adjusted odds ratio was 0.51 for the highest IDW well count tertile.
Likewise, there were no significant associations between density of oil and gas development and NHL. The adjusted odds ratio was 0.99 for the highest IDW well count tertile.
Limitations and next steps
The researchers said this study was limited by the low occurrence of ALL and NHL in rural Colorado, lack of specific age at cancer diagnosis, and the fact that all study participants had been diagnosed with cancer.
In addition, the study was limited by the lack of information on specific activities at the well sites, place of residence before cancer diagnosis, other sources of pollution around the residence, and individual characteristics such as common infections and family history of cancer.
The team said future research should incorporate information on oil and gas development activities and production levels, as well as levels of specific pollutants of interest such as benzene, near homes, schools, and day care centers.
They recommended that such research consider specific ages and residential histories, compare cases to controls without cancer, and address other potential confounders and and environmental stressors.
A pumpjack is used to lift
liquid from an oil well.
Photo by Eric Kounce
Living in an area of high-density oil and gas development may increase a young person’s risk of developing acute lymphoblastic leukemia (ALL), according to research published in PLOS ONE.
The study showed that children and young adults in Colorado who had been diagnosed with ALL were more likely than young people with non-hematologic cancers to live in areas of high-density oil and gas development.
However, there was no such association for young people with non-Hodgkin lymphoma (NHL).
“Over 378,000 Coloradans and millions of Americans currently live within a mile of at least one oil and gas well, and petroleum development continues to expand into residential areas,” said study author Lisa McKenzie, PhD, of the University of Colorado Anschutz Campus in Aurora.
“The findings from our registry-based, case-control study indicate that young Coloradans diagnosed with one type of childhood leukemia are more likely to live in the densest areas of oil and gas sites. More comprehensive research that can address our study’s limitations is needed to understand and explain these results.”
Dr McKenzie and her colleagues said they conducted this study because oil and gas development emits known hematological carcinogens, such as benzene, and increasingly occurs in residential areas.
The team wanted to determine whether living near areas of oil and gas development was associated with risk for hematologic cancers. So they analyzed data from the Colorado Central Cancer Registry and the Colorado Oil and Gas Information System.
The study included 743 subjects, ages 0 to 24, living in rural Colorado and diagnosed with cancer between 2001 and 2013. This included 87 ALL cases, 50 NHL cases, and 528 controls with non-hematologic cancers. (Other hematologic malignancies were not included in the analysis due to small numbers.)
Data analysis
The researchers used information from the Colorado Oil and Gas Information System to build a geocoded dataset with coordinates of all oil and gas wells in rural Colorado and determined dates for when each well was active.
Geocoded residential addresses of cancer patients at the time of diagnosis were linked to active well locations in the year of diagnosis and active well locations in each of the 10 years preceding the cancer diagnosis.
The researchers then took the inverse of each distance and summed the inverse distances to calculate inverse distance weighted (IDW) oil and gas well counts within a 16.1 km radius of each participant’s residence at cancer diagnosis for each of the 10 years prior to the date of diagnosis. (The IDW well count method gives greater weight to the wells nearer the home.)
The team used logistic regression to estimate associations for cancers across IDW well count tertiles. The first tertile had less than 4.9 wells per 1.6 km, the second had 4.9 to 33.6 wells per 1.6 km, and the third had more than 33.6 wells per 1.6 km.
Results
The researchers found an increase in the odds of living near oil and gas development at the time of ALL diagnosis, even after adjusting for age, race, gender, income, elevation, and year of cancer diagnosis.
ALL patients ages 0 to 24 were twice as likely as controls to live in the densest area of active oil and gas wells (highest IDW well count tertile).
ALL patients ages 5 to 24 were 4.6 times more likely than controls to live in areas included in the highest IDW well count tertile.
However, there was no significant association between ALL and proximity to oil and gas development in ALL patients ages 0 to 4. The adjusted odds ratio was 0.51 for the highest IDW well count tertile.
Likewise, there were no significant associations between density of oil and gas development and NHL. The adjusted odds ratio was 0.99 for the highest IDW well count tertile.
Limitations and next steps
The researchers said this study was limited by the low occurrence of ALL and NHL in rural Colorado, lack of specific age at cancer diagnosis, and the fact that all study participants had been diagnosed with cancer.
In addition, the study was limited by the lack of information on specific activities at the well sites, place of residence before cancer diagnosis, other sources of pollution around the residence, and individual characteristics such as common infections and family history of cancer.
The team said future research should incorporate information on oil and gas development activities and production levels, as well as levels of specific pollutants of interest such as benzene, near homes, schools, and day care centers.
They recommended that such research consider specific ages and residential histories, compare cases to controls without cancer, and address other potential confounders and and environmental stressors.
Magnetic implant may offer new drug delivery method
A tiny magnetic implant could provide a new method of drug delivery, according to research published in Advanced Functional Materials.
The device is a silicone sponge with magnetic carbonyl iron particles wrapped in a round polymer layer. It measures 6 mm in diameter.
A drug is injected into the device, which is surgically implanted in the area being treated.
Passing a magnet over the implant activates the device by deforming the sponge and triggering the release of the drug into surrounding tissue through a tiny opening.
“Drug implants can be safe and effective for treating many conditions, and magnetically controlled implants are particularly interesting because you can adjust the dose after implantation by using different magnet strengths,” said study author Ali Shademani, a PhD student at the University of British Columbia (UBC) in Vancouver, British Columbia, Canada.
“This device lets you release the actual dose that the patient needs when they need it, and it’s sufficiently easy to use that patients could administer their own medication one day without having to go to a hospital,” added John K. Jackson, also of UBC.
The researchers tested the device on animal tissue in the lab using the prostate cancer drug docetaxel. The device was able to deliver the drug on demand even after repeated use.
The drug also produced an effect on cancer cells comparable to that of freshly administered docetaxel, suggesting that drugs stored in the device stay effective.
The researchers are now working on refining the device and narrowing down the conditions for its use.
“This could one day be used for administering painkillers, hormones, chemotherapy drugs, and other treatments for a wide range of health conditions,” said Mu Chiao, PhD, of UBC. “In the next few years, we hope to be able to test it for long-term use and for viability in living models.”
A tiny magnetic implant could provide a new method of drug delivery, according to research published in Advanced Functional Materials.
The device is a silicone sponge with magnetic carbonyl iron particles wrapped in a round polymer layer. It measures 6 mm in diameter.
A drug is injected into the device, which is surgically implanted in the area being treated.
Passing a magnet over the implant activates the device by deforming the sponge and triggering the release of the drug into surrounding tissue through a tiny opening.
“Drug implants can be safe and effective for treating many conditions, and magnetically controlled implants are particularly interesting because you can adjust the dose after implantation by using different magnet strengths,” said study author Ali Shademani, a PhD student at the University of British Columbia (UBC) in Vancouver, British Columbia, Canada.
“This device lets you release the actual dose that the patient needs when they need it, and it’s sufficiently easy to use that patients could administer their own medication one day without having to go to a hospital,” added John K. Jackson, also of UBC.
The researchers tested the device on animal tissue in the lab using the prostate cancer drug docetaxel. The device was able to deliver the drug on demand even after repeated use.
The drug also produced an effect on cancer cells comparable to that of freshly administered docetaxel, suggesting that drugs stored in the device stay effective.
The researchers are now working on refining the device and narrowing down the conditions for its use.
“This could one day be used for administering painkillers, hormones, chemotherapy drugs, and other treatments for a wide range of health conditions,” said Mu Chiao, PhD, of UBC. “In the next few years, we hope to be able to test it for long-term use and for viability in living models.”
A tiny magnetic implant could provide a new method of drug delivery, according to research published in Advanced Functional Materials.
The device is a silicone sponge with magnetic carbonyl iron particles wrapped in a round polymer layer. It measures 6 mm in diameter.
A drug is injected into the device, which is surgically implanted in the area being treated.
Passing a magnet over the implant activates the device by deforming the sponge and triggering the release of the drug into surrounding tissue through a tiny opening.
“Drug implants can be safe and effective for treating many conditions, and magnetically controlled implants are particularly interesting because you can adjust the dose after implantation by using different magnet strengths,” said study author Ali Shademani, a PhD student at the University of British Columbia (UBC) in Vancouver, British Columbia, Canada.
“This device lets you release the actual dose that the patient needs when they need it, and it’s sufficiently easy to use that patients could administer their own medication one day without having to go to a hospital,” added John K. Jackson, also of UBC.
The researchers tested the device on animal tissue in the lab using the prostate cancer drug docetaxel. The device was able to deliver the drug on demand even after repeated use.
The drug also produced an effect on cancer cells comparable to that of freshly administered docetaxel, suggesting that drugs stored in the device stay effective.
The researchers are now working on refining the device and narrowing down the conditions for its use.
“This could one day be used for administering painkillers, hormones, chemotherapy drugs, and other treatments for a wide range of health conditions,” said Mu Chiao, PhD, of UBC. “In the next few years, we hope to be able to test it for long-term use and for viability in living models.”
Styrene exposure linked to myeloid leukemia, HL
A new study links styrene—a chemical used in the manufacture of plastics, rubber, and resins—to certain cancers.
The research showed that, contrary to previous suggestions, employees who have worked with styrene do not have an increased incidence of esophageal, pancreatic, lung, kidney, or bladder cancer.
On the other hand, they may have an increased risk of nasal and paranasal cancer, as well as myeloid leukemia and Hodgkin lymphoma (HL).
The research was published in Epidemiology.
“It is important to know for present and former workers exposed to styrene that they are unlikely to have become ill by doing their job if they have developed cancer of the esophagus, pancreas, lungs, kidneys, bladder, or a wide range of other types of cancer,” said study author Henrik A. Kolstad, MD, PhD, of Aarhus University in Denmark.
“This is also new and important knowledge in the USA, where styrene was added to the list of carcinogenic substances in 2011.”
In relation to the cancers for which the study shows a possible increased risk, Dr Kolstad emphasized that additional research is needed to determine if styrene is the actual cause of the employees’ disease.
For the current study, Dr Kolstad and his colleagues analyzed data on 72,292 employees who worked for 1 of 443 small and medium-sized companies in Denmark that used styrene for the production of wind turbines, pleasure boats, and other products from 1964 to 2007.
There were 8961 incident cases of cancer in this cohort from 1968 to 2012. The standardized incidence rate ratio (SIR) for all cancers was 1.04. When the researchers included a 10-year lag period, the SIR for all cancers was still 1.04.
As for hematologic malignancies, the researchers said they observed increased rate ratios associated with increased duration of employment for HL and myeloid leukemia.
For HL, the SIRs were 1.21 with no lag and 1.22 with a 10-year lag. For myeloid leukemia, the SIRs were 1.06 and 1.13, respectively.
The SIRs for non-Hodgkin lymphoma were 0.97 with no lag and 0.94 with a 10-year lag. The SIRs for multiple myeloma were 0.79 and 0.77, respectively.
For cancers of lymphatic and hematopoietic tissue, the SIRs were 0.97 with no lag and 0.96 with a 10-year lag. For lymphatic leukemia, the SIR was 0.96 for both time points.
The SIRs for monocytic leukemia were 0.77 with no lag and 0.56 with a 10-year lag. The SIRs for other and unspecified leukemias were 1.05 and 1.26, respectively.
The researchers noted that workers first employed in the 1960s had a higher risk of HL than workers first employed in subsequent years.
The SIRs were 2.12 for those first employed in 1964-1969, 0.82 for 1970-1979, 1.07 for 1980-1989, 1.52 for 1990-1999, and 1.10 for those first employed in 2000-2007.
There were no such associations for other cancer sites.
A new study links styrene—a chemical used in the manufacture of plastics, rubber, and resins—to certain cancers.
The research showed that, contrary to previous suggestions, employees who have worked with styrene do not have an increased incidence of esophageal, pancreatic, lung, kidney, or bladder cancer.
On the other hand, they may have an increased risk of nasal and paranasal cancer, as well as myeloid leukemia and Hodgkin lymphoma (HL).
The research was published in Epidemiology.
“It is important to know for present and former workers exposed to styrene that they are unlikely to have become ill by doing their job if they have developed cancer of the esophagus, pancreas, lungs, kidneys, bladder, or a wide range of other types of cancer,” said study author Henrik A. Kolstad, MD, PhD, of Aarhus University in Denmark.
“This is also new and important knowledge in the USA, where styrene was added to the list of carcinogenic substances in 2011.”
In relation to the cancers for which the study shows a possible increased risk, Dr Kolstad emphasized that additional research is needed to determine if styrene is the actual cause of the employees’ disease.
For the current study, Dr Kolstad and his colleagues analyzed data on 72,292 employees who worked for 1 of 443 small and medium-sized companies in Denmark that used styrene for the production of wind turbines, pleasure boats, and other products from 1964 to 2007.
There were 8961 incident cases of cancer in this cohort from 1968 to 2012. The standardized incidence rate ratio (SIR) for all cancers was 1.04. When the researchers included a 10-year lag period, the SIR for all cancers was still 1.04.
As for hematologic malignancies, the researchers said they observed increased rate ratios associated with increased duration of employment for HL and myeloid leukemia.
For HL, the SIRs were 1.21 with no lag and 1.22 with a 10-year lag. For myeloid leukemia, the SIRs were 1.06 and 1.13, respectively.
The SIRs for non-Hodgkin lymphoma were 0.97 with no lag and 0.94 with a 10-year lag. The SIRs for multiple myeloma were 0.79 and 0.77, respectively.
For cancers of lymphatic and hematopoietic tissue, the SIRs were 0.97 with no lag and 0.96 with a 10-year lag. For lymphatic leukemia, the SIR was 0.96 for both time points.
The SIRs for monocytic leukemia were 0.77 with no lag and 0.56 with a 10-year lag. The SIRs for other and unspecified leukemias were 1.05 and 1.26, respectively.
The researchers noted that workers first employed in the 1960s had a higher risk of HL than workers first employed in subsequent years.
The SIRs were 2.12 for those first employed in 1964-1969, 0.82 for 1970-1979, 1.07 for 1980-1989, 1.52 for 1990-1999, and 1.10 for those first employed in 2000-2007.
There were no such associations for other cancer sites.
A new study links styrene—a chemical used in the manufacture of plastics, rubber, and resins—to certain cancers.
The research showed that, contrary to previous suggestions, employees who have worked with styrene do not have an increased incidence of esophageal, pancreatic, lung, kidney, or bladder cancer.
On the other hand, they may have an increased risk of nasal and paranasal cancer, as well as myeloid leukemia and Hodgkin lymphoma (HL).
The research was published in Epidemiology.
“It is important to know for present and former workers exposed to styrene that they are unlikely to have become ill by doing their job if they have developed cancer of the esophagus, pancreas, lungs, kidneys, bladder, or a wide range of other types of cancer,” said study author Henrik A. Kolstad, MD, PhD, of Aarhus University in Denmark.
“This is also new and important knowledge in the USA, where styrene was added to the list of carcinogenic substances in 2011.”
In relation to the cancers for which the study shows a possible increased risk, Dr Kolstad emphasized that additional research is needed to determine if styrene is the actual cause of the employees’ disease.
For the current study, Dr Kolstad and his colleagues analyzed data on 72,292 employees who worked for 1 of 443 small and medium-sized companies in Denmark that used styrene for the production of wind turbines, pleasure boats, and other products from 1964 to 2007.
There were 8961 incident cases of cancer in this cohort from 1968 to 2012. The standardized incidence rate ratio (SIR) for all cancers was 1.04. When the researchers included a 10-year lag period, the SIR for all cancers was still 1.04.
As for hematologic malignancies, the researchers said they observed increased rate ratios associated with increased duration of employment for HL and myeloid leukemia.
For HL, the SIRs were 1.21 with no lag and 1.22 with a 10-year lag. For myeloid leukemia, the SIRs were 1.06 and 1.13, respectively.
The SIRs for non-Hodgkin lymphoma were 0.97 with no lag and 0.94 with a 10-year lag. The SIRs for multiple myeloma were 0.79 and 0.77, respectively.
For cancers of lymphatic and hematopoietic tissue, the SIRs were 0.97 with no lag and 0.96 with a 10-year lag. For lymphatic leukemia, the SIR was 0.96 for both time points.
The SIRs for monocytic leukemia were 0.77 with no lag and 0.56 with a 10-year lag. The SIRs for other and unspecified leukemias were 1.05 and 1.26, respectively.
The researchers noted that workers first employed in the 1960s had a higher risk of HL than workers first employed in subsequent years.
The SIRs were 2.12 for those first employed in 1964-1969, 0.82 for 1970-1979, 1.07 for 1980-1989, 1.52 for 1990-1999, and 1.10 for those first employed in 2000-2007.
There were no such associations for other cancer sites.
Vaccination approach prevents malaria
A novel vaccination approach can offer 100% protection against malaria, according to research published in Nature.
The approach involved direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated Plasmodium falciparum sporozoites (PfSPZ) in healthy adults taking chloroquine for antimalarial chemoprophylaxis (PfSPZ-CVac).
At the optimal dose and schedule, PfSPZ-CVac prevented infection in 9 of 9 volunteers, and this protection lasted 10 weeks after the last dose.
In addition, researchers said PfSPZ-CVac was well-tolerated.
PfSPZ was provided by Sanaria. This research was supported by federal funding and the Bill and Melinda Gates Foundation.
Treatment and challenge
The researchers tested PfSPZ-CVac in healthy adults, ages 18 to 45, who were malaria-naive. They received different doses of PfSPZ at different intervals and different doses/schedules of chloroquine.
In the first part of the study, test subjects received 3 doses of PfSPZ at 3.2 × 103 (n=9), 1.28 × 104 (n=9), or 5.12 × 104 (n=9), and controls (n=13) received 3 doses of normal saline.
Doses were given at 28-day intervals, and controlled human malaria infection (CHMI) was performed at 8 to 10 weeks after immunization.
In the second part of the study, test subjects received 3 doses of PfSPZ at 5.12 × 104 at 14-day intervals (n=9) or 5-day intervals (n=9), and controls (n=6) received 3 doses of normal saline.
CHMI was performed at 10 weeks post-immunization.
Most subjects received chloroquine at a base loading dose of 10 mg kg-1 or 620 mg two days before the first dose of PfSPZ, whichever dose was less, followed by weekly doses of 5 mg kg-1 or 310 mg through 5 days after the last dose of PfSPZ. Subjects who were immunized on days 0, 5, and 10 received chloroquine on days 0, 5, 10, and 15.
Results
All controls, who received normal saline plus chloroquine, developed parasitemia.
However, 3 doses of PfSPZ at 5.12 × 104, given at 28-day intervals, prevented infection in 9 of 9 subjects (100%).
The 3.2 × 103 dose of PfSPZ (also given at 28-day intervals) protected 3 of 9 subjects (33%), and the 1.28 × 104 dose protected 6 of 9 subjects (67%).
Three doses of PfSPZ at 5.12 × 104, given at 5-day intervals, protected 5 of 8 subjects (63%). And 3 doses of PfSPZ at 5.12 × 104, given at 14-day intervals, protected 6 of 9 subjects (67%).
“By vaccinating with a live, fully active pathogen, it seems clear that we were able to set off a very strong immune response,” said study author Benjamin Mordmüller, of the University of Tübingen in Germany.
“Additionally, all the data we have so far indicate that what we have here is relatively stable, long-lasting protection.”
“That protection was probably caused by specific T lymphocytes and antibody responses to the parasites in the liver,” added Peter Kremsner, also of the University of Tübingen.
The researchers said there were no serious adverse events, and the frequencies of grade 1-3 events were similar in subjects who received PfSPZ-CVac and controls.
Chloroquine was considered well-tolerated, although 2 subjects discontinued the trial after the loading dose because they experienced nausea and vomiting.
A novel vaccination approach can offer 100% protection against malaria, according to research published in Nature.
The approach involved direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated Plasmodium falciparum sporozoites (PfSPZ) in healthy adults taking chloroquine for antimalarial chemoprophylaxis (PfSPZ-CVac).
At the optimal dose and schedule, PfSPZ-CVac prevented infection in 9 of 9 volunteers, and this protection lasted 10 weeks after the last dose.
In addition, researchers said PfSPZ-CVac was well-tolerated.
PfSPZ was provided by Sanaria. This research was supported by federal funding and the Bill and Melinda Gates Foundation.
Treatment and challenge
The researchers tested PfSPZ-CVac in healthy adults, ages 18 to 45, who were malaria-naive. They received different doses of PfSPZ at different intervals and different doses/schedules of chloroquine.
In the first part of the study, test subjects received 3 doses of PfSPZ at 3.2 × 103 (n=9), 1.28 × 104 (n=9), or 5.12 × 104 (n=9), and controls (n=13) received 3 doses of normal saline.
Doses were given at 28-day intervals, and controlled human malaria infection (CHMI) was performed at 8 to 10 weeks after immunization.
In the second part of the study, test subjects received 3 doses of PfSPZ at 5.12 × 104 at 14-day intervals (n=9) or 5-day intervals (n=9), and controls (n=6) received 3 doses of normal saline.
CHMI was performed at 10 weeks post-immunization.
Most subjects received chloroquine at a base loading dose of 10 mg kg-1 or 620 mg two days before the first dose of PfSPZ, whichever dose was less, followed by weekly doses of 5 mg kg-1 or 310 mg through 5 days after the last dose of PfSPZ. Subjects who were immunized on days 0, 5, and 10 received chloroquine on days 0, 5, 10, and 15.
Results
All controls, who received normal saline plus chloroquine, developed parasitemia.
However, 3 doses of PfSPZ at 5.12 × 104, given at 28-day intervals, prevented infection in 9 of 9 subjects (100%).
The 3.2 × 103 dose of PfSPZ (also given at 28-day intervals) protected 3 of 9 subjects (33%), and the 1.28 × 104 dose protected 6 of 9 subjects (67%).
Three doses of PfSPZ at 5.12 × 104, given at 5-day intervals, protected 5 of 8 subjects (63%). And 3 doses of PfSPZ at 5.12 × 104, given at 14-day intervals, protected 6 of 9 subjects (67%).
“By vaccinating with a live, fully active pathogen, it seems clear that we were able to set off a very strong immune response,” said study author Benjamin Mordmüller, of the University of Tübingen in Germany.
“Additionally, all the data we have so far indicate that what we have here is relatively stable, long-lasting protection.”
“That protection was probably caused by specific T lymphocytes and antibody responses to the parasites in the liver,” added Peter Kremsner, also of the University of Tübingen.
The researchers said there were no serious adverse events, and the frequencies of grade 1-3 events were similar in subjects who received PfSPZ-CVac and controls.
Chloroquine was considered well-tolerated, although 2 subjects discontinued the trial after the loading dose because they experienced nausea and vomiting.
A novel vaccination approach can offer 100% protection against malaria, according to research published in Nature.
The approach involved direct venous inoculation of aseptic, purified, cryopreserved, non-irradiated Plasmodium falciparum sporozoites (PfSPZ) in healthy adults taking chloroquine for antimalarial chemoprophylaxis (PfSPZ-CVac).
At the optimal dose and schedule, PfSPZ-CVac prevented infection in 9 of 9 volunteers, and this protection lasted 10 weeks after the last dose.
In addition, researchers said PfSPZ-CVac was well-tolerated.
PfSPZ was provided by Sanaria. This research was supported by federal funding and the Bill and Melinda Gates Foundation.
Treatment and challenge
The researchers tested PfSPZ-CVac in healthy adults, ages 18 to 45, who were malaria-naive. They received different doses of PfSPZ at different intervals and different doses/schedules of chloroquine.
In the first part of the study, test subjects received 3 doses of PfSPZ at 3.2 × 103 (n=9), 1.28 × 104 (n=9), or 5.12 × 104 (n=9), and controls (n=13) received 3 doses of normal saline.
Doses were given at 28-day intervals, and controlled human malaria infection (CHMI) was performed at 8 to 10 weeks after immunization.
In the second part of the study, test subjects received 3 doses of PfSPZ at 5.12 × 104 at 14-day intervals (n=9) or 5-day intervals (n=9), and controls (n=6) received 3 doses of normal saline.
CHMI was performed at 10 weeks post-immunization.
Most subjects received chloroquine at a base loading dose of 10 mg kg-1 or 620 mg two days before the first dose of PfSPZ, whichever dose was less, followed by weekly doses of 5 mg kg-1 or 310 mg through 5 days after the last dose of PfSPZ. Subjects who were immunized on days 0, 5, and 10 received chloroquine on days 0, 5, 10, and 15.
Results
All controls, who received normal saline plus chloroquine, developed parasitemia.
However, 3 doses of PfSPZ at 5.12 × 104, given at 28-day intervals, prevented infection in 9 of 9 subjects (100%).
The 3.2 × 103 dose of PfSPZ (also given at 28-day intervals) protected 3 of 9 subjects (33%), and the 1.28 × 104 dose protected 6 of 9 subjects (67%).
Three doses of PfSPZ at 5.12 × 104, given at 5-day intervals, protected 5 of 8 subjects (63%). And 3 doses of PfSPZ at 5.12 × 104, given at 14-day intervals, protected 6 of 9 subjects (67%).
“By vaccinating with a live, fully active pathogen, it seems clear that we were able to set off a very strong immune response,” said study author Benjamin Mordmüller, of the University of Tübingen in Germany.
“Additionally, all the data we have so far indicate that what we have here is relatively stable, long-lasting protection.”
“That protection was probably caused by specific T lymphocytes and antibody responses to the parasites in the liver,” added Peter Kremsner, also of the University of Tübingen.
The researchers said there were no serious adverse events, and the frequencies of grade 1-3 events were similar in subjects who received PfSPZ-CVac and controls.
Chloroquine was considered well-tolerated, although 2 subjects discontinued the trial after the loading dose because they experienced nausea and vomiting.
Drug produces high response rates in AITL
Photo by Larry Young
SAN FRANCISCO—Treatment with 5-azacitidine (5-AZA) can produce a high response rate in patients with relapsed/refractory angioimmunoblastic T-cell lymphoma (AITL), according to a small study.
The overall response rate (ORR) among AITL patients was 75%, and the complete response (CR) rate was 42%.
However, this study also included patients with other types of peripheral T-cell lymphoma (PTCL), and most of these patients did not respond to 5-AZA.
Richard Delarue, MD, of Necker University Hospital in Paris, France, presented these results at the 9th Annual T-cell Lymphoma Forum.
Results were also presented at the 2016 ASH Annual Meeting (abstract 4164). Dr Delarue reported receiving honoraria from Celgene.
Patients
The study included 19 patients with relapsed/refractory PTCL. Twelve patients had AITL, 3 had adult T-cell leukemia/lymphoma (ATLL), 2 had PTCL not otherwise specified, 1 had enteropathy-associated T-cell lymphoma, and 1 had transformed mycosis fungoides.
At diagnosis, the median age was 71 (range, 39-85) for AITL patients and 59 (range, 32-83) for the other PTCL patients. Seventy-five percent of AITL patients had an IPI score of 3 to 5 and a PIT score of 3 to 4. Eighty-six percent of the other PTCL patients had an IPI score of 3 to 5, and 57% had a PIT score of 3 to 4.
At the time of 5-AZA treatment, all patients had stage III/IV disease. The AITL patients had received a median of 2 (range, 0-6) prior lines of therapy, and the other PTCL patients had received a median of 3 (range, 0-7).
Two patients did not receive chemotherapy before 5-AZA because of the presence of associated chronic myelomonocytic leukemia (CMML) that required treatment first.
Ninety-two percent of AITL patients had TET2 mutations (n=11), 33% had DNMT3A mutations (n=4), and 0% had IDH2 mutations. One of the non-AITL patients had a TET2 mutation.
Treatment
Patients received a subcutaneous injection of 5-AZA at 75 mg/m² for 7 consecutive days every 28 days until progression or unacceptable toxicity. Six patients also received 4 to 8 infusions of rituximab because of EBV-DNA positivity.
The patients received a median of 3 cycles of 5-AZA. At the time of analysis, 4 patients were still receiving therapy.
The median follow-up was 84 days (range, 19 to 1236).
Toxicity
“Hematological toxicity was as expected with 5-azacitidine,” Dr Delarue said.
However, 2 patients had “unusual” adverse reactions. One patient had grade 2 polyneuropathy, which was considered related to a paraneoplastic syndrome.
The other patient had grade 3 diarrhea related to colitis of unknown origin, and this led to treatment interruption.
There were no treatment-related deaths.
Efficacy
Dr Delarue noted that the ORR was significantly higher in AITL patients than in patients with the other PTCL subtypes (P=0.0198).
The ORR was 53% in the entire cohort (10/19), 75% (9/12) among AITL patients, and 14% among patients with other PTCLs (1/7).
“The only patient with a response in the ‘other PTCL’ group was a patient with HTLV1-associated ATLL . . . , but he relapsed a couple of weeks after the second cycle,” Dr Delarue explained.
Among the AITL patients, the CR rate was 42% (5/12), the partial response rate was 33% (4/12), and the rate of stable disease was 25% (3/12).
Six AITL patients eventually progressed—after 2, 2, 3, 4, 4, and 20 cycles of therapy, respectively.
Two AITL patients are off therapy but remain in CR after 9 and 10 months (5 and 6 cycles of treatment), respectively.
The median progression-free survival for AITL patients was 16 months, and the median overall survival was 17 months.
Dr DeLarue noted that 4 of the AITL patients had CMML, 1 had non-CMML myelodysplastic syndrome, 3 had monocytosis without CMML, and 4 had normal monocyte counts.
He also said that, at present, it’s not possible to correlate the results observed in the AITL patients with their mutational status.
However, he and his colleagues are planning a prospective study of 5-AZA in patients with relapsed/refractory AITL and T follicular helper cell PTCL not otherwise specified. 5-AZA will be compared to investigator’s choice in this study.
Dr DeLarue said this trial will provide an opportunity to use the new oral formulation of 5-AZA (CC-486). And he and his colleagues welcome collaborators.
Photo by Larry Young
SAN FRANCISCO—Treatment with 5-azacitidine (5-AZA) can produce a high response rate in patients with relapsed/refractory angioimmunoblastic T-cell lymphoma (AITL), according to a small study.
The overall response rate (ORR) among AITL patients was 75%, and the complete response (CR) rate was 42%.
However, this study also included patients with other types of peripheral T-cell lymphoma (PTCL), and most of these patients did not respond to 5-AZA.
Richard Delarue, MD, of Necker University Hospital in Paris, France, presented these results at the 9th Annual T-cell Lymphoma Forum.
Results were also presented at the 2016 ASH Annual Meeting (abstract 4164). Dr Delarue reported receiving honoraria from Celgene.
Patients
The study included 19 patients with relapsed/refractory PTCL. Twelve patients had AITL, 3 had adult T-cell leukemia/lymphoma (ATLL), 2 had PTCL not otherwise specified, 1 had enteropathy-associated T-cell lymphoma, and 1 had transformed mycosis fungoides.
At diagnosis, the median age was 71 (range, 39-85) for AITL patients and 59 (range, 32-83) for the other PTCL patients. Seventy-five percent of AITL patients had an IPI score of 3 to 5 and a PIT score of 3 to 4. Eighty-six percent of the other PTCL patients had an IPI score of 3 to 5, and 57% had a PIT score of 3 to 4.
At the time of 5-AZA treatment, all patients had stage III/IV disease. The AITL patients had received a median of 2 (range, 0-6) prior lines of therapy, and the other PTCL patients had received a median of 3 (range, 0-7).
Two patients did not receive chemotherapy before 5-AZA because of the presence of associated chronic myelomonocytic leukemia (CMML) that required treatment first.
Ninety-two percent of AITL patients had TET2 mutations (n=11), 33% had DNMT3A mutations (n=4), and 0% had IDH2 mutations. One of the non-AITL patients had a TET2 mutation.
Treatment
Patients received a subcutaneous injection of 5-AZA at 75 mg/m² for 7 consecutive days every 28 days until progression or unacceptable toxicity. Six patients also received 4 to 8 infusions of rituximab because of EBV-DNA positivity.
The patients received a median of 3 cycles of 5-AZA. At the time of analysis, 4 patients were still receiving therapy.
The median follow-up was 84 days (range, 19 to 1236).
Toxicity
“Hematological toxicity was as expected with 5-azacitidine,” Dr Delarue said.
However, 2 patients had “unusual” adverse reactions. One patient had grade 2 polyneuropathy, which was considered related to a paraneoplastic syndrome.
The other patient had grade 3 diarrhea related to colitis of unknown origin, and this led to treatment interruption.
There were no treatment-related deaths.
Efficacy
Dr Delarue noted that the ORR was significantly higher in AITL patients than in patients with the other PTCL subtypes (P=0.0198).
The ORR was 53% in the entire cohort (10/19), 75% (9/12) among AITL patients, and 14% among patients with other PTCLs (1/7).
“The only patient with a response in the ‘other PTCL’ group was a patient with HTLV1-associated ATLL . . . , but he relapsed a couple of weeks after the second cycle,” Dr Delarue explained.
Among the AITL patients, the CR rate was 42% (5/12), the partial response rate was 33% (4/12), and the rate of stable disease was 25% (3/12).
Six AITL patients eventually progressed—after 2, 2, 3, 4, 4, and 20 cycles of therapy, respectively.
Two AITL patients are off therapy but remain in CR after 9 and 10 months (5 and 6 cycles of treatment), respectively.
The median progression-free survival for AITL patients was 16 months, and the median overall survival was 17 months.
Dr DeLarue noted that 4 of the AITL patients had CMML, 1 had non-CMML myelodysplastic syndrome, 3 had monocytosis without CMML, and 4 had normal monocyte counts.
He also said that, at present, it’s not possible to correlate the results observed in the AITL patients with their mutational status.
However, he and his colleagues are planning a prospective study of 5-AZA in patients with relapsed/refractory AITL and T follicular helper cell PTCL not otherwise specified. 5-AZA will be compared to investigator’s choice in this study.
Dr DeLarue said this trial will provide an opportunity to use the new oral formulation of 5-AZA (CC-486). And he and his colleagues welcome collaborators.
Photo by Larry Young
SAN FRANCISCO—Treatment with 5-azacitidine (5-AZA) can produce a high response rate in patients with relapsed/refractory angioimmunoblastic T-cell lymphoma (AITL), according to a small study.
The overall response rate (ORR) among AITL patients was 75%, and the complete response (CR) rate was 42%.
However, this study also included patients with other types of peripheral T-cell lymphoma (PTCL), and most of these patients did not respond to 5-AZA.
Richard Delarue, MD, of Necker University Hospital in Paris, France, presented these results at the 9th Annual T-cell Lymphoma Forum.
Results were also presented at the 2016 ASH Annual Meeting (abstract 4164). Dr Delarue reported receiving honoraria from Celgene.
Patients
The study included 19 patients with relapsed/refractory PTCL. Twelve patients had AITL, 3 had adult T-cell leukemia/lymphoma (ATLL), 2 had PTCL not otherwise specified, 1 had enteropathy-associated T-cell lymphoma, and 1 had transformed mycosis fungoides.
At diagnosis, the median age was 71 (range, 39-85) for AITL patients and 59 (range, 32-83) for the other PTCL patients. Seventy-five percent of AITL patients had an IPI score of 3 to 5 and a PIT score of 3 to 4. Eighty-six percent of the other PTCL patients had an IPI score of 3 to 5, and 57% had a PIT score of 3 to 4.
At the time of 5-AZA treatment, all patients had stage III/IV disease. The AITL patients had received a median of 2 (range, 0-6) prior lines of therapy, and the other PTCL patients had received a median of 3 (range, 0-7).
Two patients did not receive chemotherapy before 5-AZA because of the presence of associated chronic myelomonocytic leukemia (CMML) that required treatment first.
Ninety-two percent of AITL patients had TET2 mutations (n=11), 33% had DNMT3A mutations (n=4), and 0% had IDH2 mutations. One of the non-AITL patients had a TET2 mutation.
Treatment
Patients received a subcutaneous injection of 5-AZA at 75 mg/m² for 7 consecutive days every 28 days until progression or unacceptable toxicity. Six patients also received 4 to 8 infusions of rituximab because of EBV-DNA positivity.
The patients received a median of 3 cycles of 5-AZA. At the time of analysis, 4 patients were still receiving therapy.
The median follow-up was 84 days (range, 19 to 1236).
Toxicity
“Hematological toxicity was as expected with 5-azacitidine,” Dr Delarue said.
However, 2 patients had “unusual” adverse reactions. One patient had grade 2 polyneuropathy, which was considered related to a paraneoplastic syndrome.
The other patient had grade 3 diarrhea related to colitis of unknown origin, and this led to treatment interruption.
There were no treatment-related deaths.
Efficacy
Dr Delarue noted that the ORR was significantly higher in AITL patients than in patients with the other PTCL subtypes (P=0.0198).
The ORR was 53% in the entire cohort (10/19), 75% (9/12) among AITL patients, and 14% among patients with other PTCLs (1/7).
“The only patient with a response in the ‘other PTCL’ group was a patient with HTLV1-associated ATLL . . . , but he relapsed a couple of weeks after the second cycle,” Dr Delarue explained.
Among the AITL patients, the CR rate was 42% (5/12), the partial response rate was 33% (4/12), and the rate of stable disease was 25% (3/12).
Six AITL patients eventually progressed—after 2, 2, 3, 4, 4, and 20 cycles of therapy, respectively.
Two AITL patients are off therapy but remain in CR after 9 and 10 months (5 and 6 cycles of treatment), respectively.
The median progression-free survival for AITL patients was 16 months, and the median overall survival was 17 months.
Dr DeLarue noted that 4 of the AITL patients had CMML, 1 had non-CMML myelodysplastic syndrome, 3 had monocytosis without CMML, and 4 had normal monocyte counts.
He also said that, at present, it’s not possible to correlate the results observed in the AITL patients with their mutational status.
However, he and his colleagues are planning a prospective study of 5-AZA in patients with relapsed/refractory AITL and T follicular helper cell PTCL not otherwise specified. 5-AZA will be compared to investigator’s choice in this study.
Dr DeLarue said this trial will provide an opportunity to use the new oral formulation of 5-AZA (CC-486). And he and his colleagues welcome collaborators.