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Trio wins Nobel Prize for parasite-related discoveries
Three researchers have won the 2015 Nobel Prize in Physiology or Medicine for discoveries related to parasitic diseases.
One half of the prize was awarded to Youyou Tu for discoveries concerning a novel therapy against malaria—artemisinin.
The other half of the prize was awarded to William C. Campbell, PhD, and Satoshi Ōmura, PhD, for their discoveries concerning a novel therapy against infections caused by roundworm parasites.
Drs Ōmura and Campbell discovered the drug avermectin. A derivative of this drug has lowered the incidence of river blindness and lymphatic filariasis and demonstrated efficacy against other parasitic diseases.
Artemisinin
Before artemisinin came into use, malaria was treated with chloroquine or quinine—with declining success. By the late 1960s, efforts to eradicate malaria had failed, and the disease was on the rise.
At that time, Tu turned to traditional herbal medicine to tackle the challenge of developing novel malaria therapies. From a large-scale screen of herbal remedies in malaria-infected animals, an extract from the plant Artemisia annua emerged as an interesting candidate.
However, the results were inconsistent. So Tu revisited the ancient literature and discovered clues that guided her in her quest to extract the active component from Artemisia annua. Tu was the first to show that this component, later called artemisinin, was effective against the malaria parasite in animals and humans.
Artemisinin is now used in all malaria-ridden parts of the world. When used in combination therapy, it is estimated to reduce mortality from malaria by more than 20% overall and by more than 30% in children.
Avermectin
The discovery of avermectin began with Streptomyces, bacteria that live in the soil and are known to produce agents with antibacterial activities.
Dr Ōmura isolated new strains of Streptomyces from soil samples and cultured them in the lab. He selected about 50 of the most promising cultures to analyze for their activity against harmful microorganisms. One of these cultures turned out to be Streptomyces avermitilis, the source of avermectin.
Dr Campbell acquired Dr Ōmura’s Streptomyces cultures and explored their efficacy. Dr Campbell showed that a component from one of the cultures could combat parasites in domestic and farm animals.
The bioactive agent was purified and named avermectin. It was subsequently modified to a more effective compound called ivermectin. Ivermectin turned out to be effective against a variety of parasites, including those that cause river blindness and lymphatic filariasis.
Today, ivermectin is used in all parts of the world that are plagued by parasitic diseases. The drug has proven effective against a range of parasites and has limited side effects. Thanks to ivermectin, river blindness and lymphatic filariasis are on the verge of eradication.
About the winners
Youyou Tu was born in 1930 in China. She graduated from Beijing Medical University in 1955. Tu has worked at the China Academy of Traditional Chinese Medicine since 1965. She has been chief professor there since 2000.
William C. Campbell was born in 1930 in Ramelton, Ireland. He received a BA from Trinity College, University of Dublin, in Ireland in 1952. He received a PhD from the University of Wisconsin in Madison, Wisconsin, in 1957.
From 1957 to 1990, Dr Campbell was with the Merck Institute for Therapeutic Research, from 1984 to 1990 as a senior scientist and director for assay research and development. Dr Campbell is currently a research fellow emeritus at Drew University in Madison, New Jersey.
Satoshi Ōmura was born in 1935 in the Yamanashi Prefecture, Japan. He received a PhD in pharmaceutical sciences in 1968 from the University of Tokyo and a PhD in chemistry in 1970 from Tokyo University of Science.
Dr Ōmura was a researcher at the Kitasato Institute in Japan from 1965 to 1971 and a professor at Kitasato University from 1975 to 2007. Since 2007, Dr Ōmura has been a professor emeritus at Kitasato University. 
Three researchers have won the 2015 Nobel Prize in Physiology or Medicine for discoveries related to parasitic diseases.
One half of the prize was awarded to Youyou Tu for discoveries concerning a novel therapy against malaria—artemisinin.
The other half of the prize was awarded to William C. Campbell, PhD, and Satoshi Ōmura, PhD, for their discoveries concerning a novel therapy against infections caused by roundworm parasites.
Drs Ōmura and Campbell discovered the drug avermectin. A derivative of this drug has lowered the incidence of river blindness and lymphatic filariasis and demonstrated efficacy against other parasitic diseases.
Artemisinin
Before artemisinin came into use, malaria was treated with chloroquine or quinine—with declining success. By the late 1960s, efforts to eradicate malaria had failed, and the disease was on the rise.
At that time, Tu turned to traditional herbal medicine to tackle the challenge of developing novel malaria therapies. From a large-scale screen of herbal remedies in malaria-infected animals, an extract from the plant Artemisia annua emerged as an interesting candidate.
However, the results were inconsistent. So Tu revisited the ancient literature and discovered clues that guided her in her quest to extract the active component from Artemisia annua. Tu was the first to show that this component, later called artemisinin, was effective against the malaria parasite in animals and humans.
Artemisinin is now used in all malaria-ridden parts of the world. When used in combination therapy, it is estimated to reduce mortality from malaria by more than 20% overall and by more than 30% in children.
Avermectin
The discovery of avermectin began with Streptomyces, bacteria that live in the soil and are known to produce agents with antibacterial activities.
Dr Ōmura isolated new strains of Streptomyces from soil samples and cultured them in the lab. He selected about 50 of the most promising cultures to analyze for their activity against harmful microorganisms. One of these cultures turned out to be Streptomyces avermitilis, the source of avermectin.
Dr Campbell acquired Dr Ōmura’s Streptomyces cultures and explored their efficacy. Dr Campbell showed that a component from one of the cultures could combat parasites in domestic and farm animals.
The bioactive agent was purified and named avermectin. It was subsequently modified to a more effective compound called ivermectin. Ivermectin turned out to be effective against a variety of parasites, including those that cause river blindness and lymphatic filariasis.
Today, ivermectin is used in all parts of the world that are plagued by parasitic diseases. The drug has proven effective against a range of parasites and has limited side effects. Thanks to ivermectin, river blindness and lymphatic filariasis are on the verge of eradication.
About the winners
Youyou Tu was born in 1930 in China. She graduated from Beijing Medical University in 1955. Tu has worked at the China Academy of Traditional Chinese Medicine since 1965. She has been chief professor there since 2000.
William C. Campbell was born in 1930 in Ramelton, Ireland. He received a BA from Trinity College, University of Dublin, in Ireland in 1952. He received a PhD from the University of Wisconsin in Madison, Wisconsin, in 1957.
From 1957 to 1990, Dr Campbell was with the Merck Institute for Therapeutic Research, from 1984 to 1990 as a senior scientist and director for assay research and development. Dr Campbell is currently a research fellow emeritus at Drew University in Madison, New Jersey.
Satoshi Ōmura was born in 1935 in the Yamanashi Prefecture, Japan. He received a PhD in pharmaceutical sciences in 1968 from the University of Tokyo and a PhD in chemistry in 1970 from Tokyo University of Science.
Dr Ōmura was a researcher at the Kitasato Institute in Japan from 1965 to 1971 and a professor at Kitasato University from 1975 to 2007. Since 2007, Dr Ōmura has been a professor emeritus at Kitasato University.
Three researchers have won the 2015 Nobel Prize in Physiology or Medicine for discoveries related to parasitic diseases.
One half of the prize was awarded to Youyou Tu for discoveries concerning a novel therapy against malaria—artemisinin.
The other half of the prize was awarded to William C. Campbell, PhD, and Satoshi Ōmura, PhD, for their discoveries concerning a novel therapy against infections caused by roundworm parasites.
Drs Ōmura and Campbell discovered the drug avermectin. A derivative of this drug has lowered the incidence of river blindness and lymphatic filariasis and demonstrated efficacy against other parasitic diseases.
Artemisinin
Before artemisinin came into use, malaria was treated with chloroquine or quinine—with declining success. By the late 1960s, efforts to eradicate malaria had failed, and the disease was on the rise.
At that time, Tu turned to traditional herbal medicine to tackle the challenge of developing novel malaria therapies. From a large-scale screen of herbal remedies in malaria-infected animals, an extract from the plant Artemisia annua emerged as an interesting candidate.
However, the results were inconsistent. So Tu revisited the ancient literature and discovered clues that guided her in her quest to extract the active component from Artemisia annua. Tu was the first to show that this component, later called artemisinin, was effective against the malaria parasite in animals and humans.
Artemisinin is now used in all malaria-ridden parts of the world. When used in combination therapy, it is estimated to reduce mortality from malaria by more than 20% overall and by more than 30% in children.
Avermectin
The discovery of avermectin began with Streptomyces, bacteria that live in the soil and are known to produce agents with antibacterial activities.
Dr Ōmura isolated new strains of Streptomyces from soil samples and cultured them in the lab. He selected about 50 of the most promising cultures to analyze for their activity against harmful microorganisms. One of these cultures turned out to be Streptomyces avermitilis, the source of avermectin.
Dr Campbell acquired Dr Ōmura’s Streptomyces cultures and explored their efficacy. Dr Campbell showed that a component from one of the cultures could combat parasites in domestic and farm animals.
The bioactive agent was purified and named avermectin. It was subsequently modified to a more effective compound called ivermectin. Ivermectin turned out to be effective against a variety of parasites, including those that cause river blindness and lymphatic filariasis.
Today, ivermectin is used in all parts of the world that are plagued by parasitic diseases. The drug has proven effective against a range of parasites and has limited side effects. Thanks to ivermectin, river blindness and lymphatic filariasis are on the verge of eradication.
About the winners
Youyou Tu was born in 1930 in China. She graduated from Beijing Medical University in 1955. Tu has worked at the China Academy of Traditional Chinese Medicine since 1965. She has been chief professor there since 2000.
William C. Campbell was born in 1930 in Ramelton, Ireland. He received a BA from Trinity College, University of Dublin, in Ireland in 1952. He received a PhD from the University of Wisconsin in Madison, Wisconsin, in 1957.
From 1957 to 1990, Dr Campbell was with the Merck Institute for Therapeutic Research, from 1984 to 1990 as a senior scientist and director for assay research and development. Dr Campbell is currently a research fellow emeritus at Drew University in Madison, New Jersey.
Satoshi Ōmura was born in 1935 in the Yamanashi Prefecture, Japan. He received a PhD in pharmaceutical sciences in 1968 from the University of Tokyo and a PhD in chemistry in 1970 from Tokyo University of Science.
Dr Ōmura was a researcher at the Kitasato Institute in Japan from 1965 to 1971 and a professor at Kitasato University from 1975 to 2007. Since 2007, Dr Ōmura has been a professor emeritus at Kitasato University.
Self-propelled particles stop bleeding
carbonate microparticle
in acidic solution
Image by James Baylis
Researchers say they’ve created self-propelled particles that can travel against the flow of blood to treat severe bleeding.
These calcium carbonate microparticles, which are applied as a powder, release carbon dioxide gas to propel them toward the source of bleeding.
They can be loaded with thrombin and transport the clotting protein through wounds and into damaged tissue in animals.
The researchers described the particles in Science Advances.
“People have developed hundreds of agents that can clot blood, but the issue is that it’s hard to push these therapies against severe blood flow, especially far enough upstream to reach the leaking vessels,” said study author Christian Kastrup, PhD, of the University of British Columbia in Vancouver, Canada.
“Here, for the first time, we’ve come up with an agent that can do that.”
After studying and modeling the movement of their microparticles in vitro, the researchers loaded the particles with thrombin and tested them in mouse and pig models of hemorrhage.
The particles helped clot blood and stopped hemorrhaging in both models. In fact, the gas-generating, thrombin-loaded particles stopped bleeding better than topical thrombin or thrombin-loaded particles that did not produce gas.
The researchers believe that, after more testing and development, their microparticles could have a wide range of uses. And they would be particularly useful for treating bleeding that originates internally, such as in the uterus, sinus, gastrointestinal tract, or abdomen, where traditional topical drugs are less effective.
“The area we’re really focusing on is postpartum hemorrhage: in the uterus, after childbirth, where you can’t see the damaged vessels but you can put the powder into that area and the particles can propel and find those damaged vessels,” Dr Kastrup said.
The researchers also believe the microparticles could be used to deliver a range of therapeutics to wound and hemorrhage sites.
carbonate microparticle
in acidic solution
Image by James Baylis
Researchers say they’ve created self-propelled particles that can travel against the flow of blood to treat severe bleeding.
These calcium carbonate microparticles, which are applied as a powder, release carbon dioxide gas to propel them toward the source of bleeding.
They can be loaded with thrombin and transport the clotting protein through wounds and into damaged tissue in animals.
The researchers described the particles in Science Advances.
“People have developed hundreds of agents that can clot blood, but the issue is that it’s hard to push these therapies against severe blood flow, especially far enough upstream to reach the leaking vessels,” said study author Christian Kastrup, PhD, of the University of British Columbia in Vancouver, Canada.
“Here, for the first time, we’ve come up with an agent that can do that.”
After studying and modeling the movement of their microparticles in vitro, the researchers loaded the particles with thrombin and tested them in mouse and pig models of hemorrhage.
The particles helped clot blood and stopped hemorrhaging in both models. In fact, the gas-generating, thrombin-loaded particles stopped bleeding better than topical thrombin or thrombin-loaded particles that did not produce gas.
The researchers believe that, after more testing and development, their microparticles could have a wide range of uses. And they would be particularly useful for treating bleeding that originates internally, such as in the uterus, sinus, gastrointestinal tract, or abdomen, where traditional topical drugs are less effective.
“The area we’re really focusing on is postpartum hemorrhage: in the uterus, after childbirth, where you can’t see the damaged vessels but you can put the powder into that area and the particles can propel and find those damaged vessels,” Dr Kastrup said.
The researchers also believe the microparticles could be used to deliver a range of therapeutics to wound and hemorrhage sites.
carbonate microparticle
in acidic solution
Image by James Baylis
Researchers say they’ve created self-propelled particles that can travel against the flow of blood to treat severe bleeding.
These calcium carbonate microparticles, which are applied as a powder, release carbon dioxide gas to propel them toward the source of bleeding.
They can be loaded with thrombin and transport the clotting protein through wounds and into damaged tissue in animals.
The researchers described the particles in Science Advances.
“People have developed hundreds of agents that can clot blood, but the issue is that it’s hard to push these therapies against severe blood flow, especially far enough upstream to reach the leaking vessels,” said study author Christian Kastrup, PhD, of the University of British Columbia in Vancouver, Canada.
“Here, for the first time, we’ve come up with an agent that can do that.”
After studying and modeling the movement of their microparticles in vitro, the researchers loaded the particles with thrombin and tested them in mouse and pig models of hemorrhage.
The particles helped clot blood and stopped hemorrhaging in both models. In fact, the gas-generating, thrombin-loaded particles stopped bleeding better than topical thrombin or thrombin-loaded particles that did not produce gas.
The researchers believe that, after more testing and development, their microparticles could have a wide range of uses. And they would be particularly useful for treating bleeding that originates internally, such as in the uterus, sinus, gastrointestinal tract, or abdomen, where traditional topical drugs are less effective.
“The area we’re really focusing on is postpartum hemorrhage: in the uterus, after childbirth, where you can’t see the damaged vessels but you can put the powder into that area and the particles can propel and find those damaged vessels,” Dr Kastrup said.
The researchers also believe the microparticles could be used to deliver a range of therapeutics to wound and hemorrhage sites.
Group issues guideline for iliofemoral DVT
Image by Andre E.X. Brown
A new guideline aims to help physicians identify and manage blood clots, specifically iliofemoral deep vein thrombosis (DVT), in the groin and thigh.
The guideline states that anticoagulant therapy remains the cornerstone of management, but certain patients with iliofemoral DVT may benefit from alternative strategies, such as inferior vena cava filters, compression therapy, and clot removal or reduction strategies.
The guideline, which is based on the latest evidence, was published in CMAJ.
It was developed by a team of hematologists, interventional radiologists, vascular surgeons, emergency department physicians, and primary care physicians.
“We think this clinical practice guideline fills an important gap in knowledge for care providers by providing a practical approach to a common problem that can have serious implications for patients,” said author David Liu, MD, of Vancouver General Hospital in British Columbia, Canada.
“Complications associated with DVT can occur years after the presentation of DVT if it is not managed at onset. DVT is a life-threatening condition in the short term, with long-term implications to the patient and society if not managed properly.”
The guideline team has created a summary of recommendations and a decision tool to help physicians. Highlights include:
- All hospital staff must have the tools to diagnose and determine the severity of iliofemoral DVT.
- Anticoagulants are recommended for all patients with iliofemoral DVT, but the type and length of treatment will vary according to presentation.
- For patients not able to take anticoagulants, use of inferior vena cava filters is recommended with regular follow-up. The filters should be removed as soon as possible.
- Immediate intervention with clot removal is recommended in patients with phlegmasia cerulea dolens to reduce the associated risks of amputation and death.
- Clot removal intervention can also be considered for patients who are at low risk of bleeding to minimize possible long-term complications from iliofemoral DVT that may decrease quality of life (such as post-thrombotic syndrome).
- To manage post-thrombotic syndrome, the use of compression stockings is recommended, although the evidence that this intervention is effective is weak.
- Patient follow-up by the primary care physician is important.
Image by Andre E.X. Brown
A new guideline aims to help physicians identify and manage blood clots, specifically iliofemoral deep vein thrombosis (DVT), in the groin and thigh.
The guideline states that anticoagulant therapy remains the cornerstone of management, but certain patients with iliofemoral DVT may benefit from alternative strategies, such as inferior vena cava filters, compression therapy, and clot removal or reduction strategies.
The guideline, which is based on the latest evidence, was published in CMAJ.
It was developed by a team of hematologists, interventional radiologists, vascular surgeons, emergency department physicians, and primary care physicians.
“We think this clinical practice guideline fills an important gap in knowledge for care providers by providing a practical approach to a common problem that can have serious implications for patients,” said author David Liu, MD, of Vancouver General Hospital in British Columbia, Canada.
“Complications associated with DVT can occur years after the presentation of DVT if it is not managed at onset. DVT is a life-threatening condition in the short term, with long-term implications to the patient and society if not managed properly.”
The guideline team has created a summary of recommendations and a decision tool to help physicians. Highlights include:
- All hospital staff must have the tools to diagnose and determine the severity of iliofemoral DVT.
- Anticoagulants are recommended for all patients with iliofemoral DVT, but the type and length of treatment will vary according to presentation.
- For patients not able to take anticoagulants, use of inferior vena cava filters is recommended with regular follow-up. The filters should be removed as soon as possible.
- Immediate intervention with clot removal is recommended in patients with phlegmasia cerulea dolens to reduce the associated risks of amputation and death.
- Clot removal intervention can also be considered for patients who are at low risk of bleeding to minimize possible long-term complications from iliofemoral DVT that may decrease quality of life (such as post-thrombotic syndrome).
- To manage post-thrombotic syndrome, the use of compression stockings is recommended, although the evidence that this intervention is effective is weak.
- Patient follow-up by the primary care physician is important.
Image by Andre E.X. Brown
A new guideline aims to help physicians identify and manage blood clots, specifically iliofemoral deep vein thrombosis (DVT), in the groin and thigh.
The guideline states that anticoagulant therapy remains the cornerstone of management, but certain patients with iliofemoral DVT may benefit from alternative strategies, such as inferior vena cava filters, compression therapy, and clot removal or reduction strategies.
The guideline, which is based on the latest evidence, was published in CMAJ.
It was developed by a team of hematologists, interventional radiologists, vascular surgeons, emergency department physicians, and primary care physicians.
“We think this clinical practice guideline fills an important gap in knowledge for care providers by providing a practical approach to a common problem that can have serious implications for patients,” said author David Liu, MD, of Vancouver General Hospital in British Columbia, Canada.
“Complications associated with DVT can occur years after the presentation of DVT if it is not managed at onset. DVT is a life-threatening condition in the short term, with long-term implications to the patient and society if not managed properly.”
The guideline team has created a summary of recommendations and a decision tool to help physicians. Highlights include:
- All hospital staff must have the tools to diagnose and determine the severity of iliofemoral DVT.
- Anticoagulants are recommended for all patients with iliofemoral DVT, but the type and length of treatment will vary according to presentation.
- For patients not able to take anticoagulants, use of inferior vena cava filters is recommended with regular follow-up. The filters should be removed as soon as possible.
- Immediate intervention with clot removal is recommended in patients with phlegmasia cerulea dolens to reduce the associated risks of amputation and death.
- Clot removal intervention can also be considered for patients who are at low risk of bleeding to minimize possible long-term complications from iliofemoral DVT that may decrease quality of life (such as post-thrombotic syndrome).
- To manage post-thrombotic syndrome, the use of compression stockings is recommended, although the evidence that this intervention is effective is weak.
- Patient follow-up by the primary care physician is important.
NICE can’t recommend new sepsis tests
Photo by William Weinert
The UK’s National Institute for Health and Care Excellence (NICE) has said there is not enough evidence to recommend 3 new blood tests for routine use in the National Health Service.
The tests are designed to identify bacteria and fungi in the bloodstream more rapidly than current tests.
According to NICE, there is too much uncertainty regarding the accuracy of the new tests and the size of benefit they might confer for patients with suspected sepsis.
The tests in question are LightCycler SeptiFast Test MGRADE (Roche Diagnostics), SepsiTest (Molzym Molecular Diagnostics), and IRIDICA BAC BSI assay (Abbott Diagnostics).
They are used to analyze whole blood samples for bacterial and fungal DNA, which may identify pathogens earlier than microbiology techniques. Microbiology techniques require blood samples to be incubated and cultured before pathogens can be identified.
The new tests are designed to enable earlier targeted treatment for patients with sepsis and reduce the use of broad-spectrum antimicrobials, which could help reduce future antimicrobial resistance.
“Rapid molecular tests that can identify which pathogens are the cause of an infection in hours rather than the days typically needed for traditional microbiology tests could ensure the right antibiotics are used much earlier in treatment,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
“This, in turn, could improve outcomes for patients with suspected sepsis as well as help to reduce the spread of resistant microbes. However, the committee [advising NICE] concluded that the tests may offer clinical benefit, but there is too much uncertainty in the size of the benefit to determine the effect of introducing the tests into clinical practice.”
“The committee also concluded that, although the rapid molecular tests might provide results more quickly, there was too much uncertainty in the accuracy of the tests for clinicians to be able to base a decision on whether to withdraw or continue antibiotics. The committee therefore decided that further research should be encouraged to determine the clinical scenarios in which the tests may offer most benefit.”
NICE’s draft diagnostics guidance on the LightCycler SeptiFast Test MGRADE, SepsiTest, and IRIDICA BAC BSI assay is available on the NICE website. The closing date for comments on this draft guidance is October 21, 2015.
Photo by William Weinert
The UK’s National Institute for Health and Care Excellence (NICE) has said there is not enough evidence to recommend 3 new blood tests for routine use in the National Health Service.
The tests are designed to identify bacteria and fungi in the bloodstream more rapidly than current tests.
According to NICE, there is too much uncertainty regarding the accuracy of the new tests and the size of benefit they might confer for patients with suspected sepsis.
The tests in question are LightCycler SeptiFast Test MGRADE (Roche Diagnostics), SepsiTest (Molzym Molecular Diagnostics), and IRIDICA BAC BSI assay (Abbott Diagnostics).
They are used to analyze whole blood samples for bacterial and fungal DNA, which may identify pathogens earlier than microbiology techniques. Microbiology techniques require blood samples to be incubated and cultured before pathogens can be identified.
The new tests are designed to enable earlier targeted treatment for patients with sepsis and reduce the use of broad-spectrum antimicrobials, which could help reduce future antimicrobial resistance.
“Rapid molecular tests that can identify which pathogens are the cause of an infection in hours rather than the days typically needed for traditional microbiology tests could ensure the right antibiotics are used much earlier in treatment,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
“This, in turn, could improve outcomes for patients with suspected sepsis as well as help to reduce the spread of resistant microbes. However, the committee [advising NICE] concluded that the tests may offer clinical benefit, but there is too much uncertainty in the size of the benefit to determine the effect of introducing the tests into clinical practice.”
“The committee also concluded that, although the rapid molecular tests might provide results more quickly, there was too much uncertainty in the accuracy of the tests for clinicians to be able to base a decision on whether to withdraw or continue antibiotics. The committee therefore decided that further research should be encouraged to determine the clinical scenarios in which the tests may offer most benefit.”
NICE’s draft diagnostics guidance on the LightCycler SeptiFast Test MGRADE, SepsiTest, and IRIDICA BAC BSI assay is available on the NICE website. The closing date for comments on this draft guidance is October 21, 2015.
Photo by William Weinert
The UK’s National Institute for Health and Care Excellence (NICE) has said there is not enough evidence to recommend 3 new blood tests for routine use in the National Health Service.
The tests are designed to identify bacteria and fungi in the bloodstream more rapidly than current tests.
According to NICE, there is too much uncertainty regarding the accuracy of the new tests and the size of benefit they might confer for patients with suspected sepsis.
The tests in question are LightCycler SeptiFast Test MGRADE (Roche Diagnostics), SepsiTest (Molzym Molecular Diagnostics), and IRIDICA BAC BSI assay (Abbott Diagnostics).
They are used to analyze whole blood samples for bacterial and fungal DNA, which may identify pathogens earlier than microbiology techniques. Microbiology techniques require blood samples to be incubated and cultured before pathogens can be identified.
The new tests are designed to enable earlier targeted treatment for patients with sepsis and reduce the use of broad-spectrum antimicrobials, which could help reduce future antimicrobial resistance.
“Rapid molecular tests that can identify which pathogens are the cause of an infection in hours rather than the days typically needed for traditional microbiology tests could ensure the right antibiotics are used much earlier in treatment,” said Carole Longson, NICE Health Technology Evaluation Centre Director.
“This, in turn, could improve outcomes for patients with suspected sepsis as well as help to reduce the spread of resistant microbes. However, the committee [advising NICE] concluded that the tests may offer clinical benefit, but there is too much uncertainty in the size of the benefit to determine the effect of introducing the tests into clinical practice.”
“The committee also concluded that, although the rapid molecular tests might provide results more quickly, there was too much uncertainty in the accuracy of the tests for clinicians to be able to base a decision on whether to withdraw or continue antibiotics. The committee therefore decided that further research should be encouraged to determine the clinical scenarios in which the tests may offer most benefit.”
NICE’s draft diagnostics guidance on the LightCycler SeptiFast Test MGRADE, SepsiTest, and IRIDICA BAC BSI assay is available on the NICE website. The closing date for comments on this draft guidance is October 21, 2015.
Living conditions linked to risk of Hodgkin lymphoma
Photo by Pavel Novak
VIENNA—Living in overcrowded conditions may affect a young person’s risk of developing certain subtypes of Hodgkin lymphoma (HL), according to researchers.
They studied more than 600 children and young adults with HL in England and found that patients who lived in areas with more overcrowded households had a lower incidence of nodular sclerosis (NS) HL but a higher incidence of the not-otherwise-specified (NOS) subtype of HL.
“Our findings related to the NS subtype may suggest that the recurrent infections to which children living in overcrowded conditions are likely to have been exposed stimulate their immune systems and, hence, protect them against developing this type of cancer later in their childhood and early adult life,” said Richard McNally, PhD, of Newcastle University in the UK.
“Those who have a genetic susceptibility to HL and have been less exposed to infection through not living in such overcrowded conditions may have less developed immune systems as a result and are therefore at greater risk of developing this subtype.”
Dr McNally and his colleagues added that it’s more difficult to interpret the findings in the NOS group because this subtype of HL is very heterogeneous. The team said the role of chance cannot be ruled out.
They presented this research at the 2015 European Cancer Congress (abstract 1414).
Dr McNally and his colleagues wanted to gain a better understanding of factors that cause HL, so they analyzed a cohort of young HL patients in Northern England, looking at factors such as sex, age, and socio-economic deprivation.
The researchers evaluated 621 cases of HL recorded in the Northern Region Young Persons’ Malignant Disease Registry. Patients were ages 0 to 24 at diagnosis and were diagnosed between 1968 and 2003.
There were 5 different subtypes of HL in this group:
- 247 cases of the NS type
- 143 NOS
- 105 of mixed cellularity
- 58 lymphocyte-rich cases
- 68 “others.”
Age and sex
Overall, more males than females had HL, but the male-female ratio varied by both age group and subtype. The age-standardized rate (ASR) of HL for males was 18.15 per million persons per year, and the ASR for females was 10.52 per million persons per year.
For the NS subtype, there were 130 males and 117 females, but this was reversed at ages 20 to 24, with 72 females and 55 males. The ASR for NS HL at 20 to 24 was 14.26 for males and 18.79 for females.
“That this change takes place after puberty seems to suggest that estrogens may be responsible in some way,” Dr McNally said. “There are a lot of genes directly regulated by sex hormones, and they are obvious suspects. Alternatively, epigenetic changes . . . influencing key genes, induced by sex hormones, may be responsible.”
Overcrowding
The researchers calculated socio-economic deprivation using the 4 components of the Townsend deprivation score: household overcrowding, non-home ownership, unemployment, and households with no car.
They observed a lower incidence of NS HL among those patients living in areas with more overcrowded households. The relative risk of NS HL was 0.88 for a 1% increase in household overcrowding (P<0.001).
For the NOS subtype, the reverse was seen. A 1% increase in household overcrowding was associated with an increased incidence of NOS HL—a relative risk of 1.17.
Overcrowding seemed to have no effect on the incidence of mixed-cellularity HL or lymphocyte-rich HL.
“We knew already that recurrent infections may protect against childhood leukemia, and now it looks as we can add Hodgkin lymphoma and, particularly its NS subtype, to the list,” Dr McNally said. “In order to further investigate the factors involved, prospective studies should investigate the hormonal changes and recurrent infections and their direct link to the risk of lymphoma, but such studies are difficult to do in rare diseases.”
“A practical follow-up would be case-control studies examining biological markers related to exposure to a multitude of infectious agents, and indeed to hormonal status itself, while genetic studies are another possibility.”
Photo by Pavel Novak
VIENNA—Living in overcrowded conditions may affect a young person’s risk of developing certain subtypes of Hodgkin lymphoma (HL), according to researchers.
They studied more than 600 children and young adults with HL in England and found that patients who lived in areas with more overcrowded households had a lower incidence of nodular sclerosis (NS) HL but a higher incidence of the not-otherwise-specified (NOS) subtype of HL.
“Our findings related to the NS subtype may suggest that the recurrent infections to which children living in overcrowded conditions are likely to have been exposed stimulate their immune systems and, hence, protect them against developing this type of cancer later in their childhood and early adult life,” said Richard McNally, PhD, of Newcastle University in the UK.
“Those who have a genetic susceptibility to HL and have been less exposed to infection through not living in such overcrowded conditions may have less developed immune systems as a result and are therefore at greater risk of developing this subtype.”
Dr McNally and his colleagues added that it’s more difficult to interpret the findings in the NOS group because this subtype of HL is very heterogeneous. The team said the role of chance cannot be ruled out.
They presented this research at the 2015 European Cancer Congress (abstract 1414).
Dr McNally and his colleagues wanted to gain a better understanding of factors that cause HL, so they analyzed a cohort of young HL patients in Northern England, looking at factors such as sex, age, and socio-economic deprivation.
The researchers evaluated 621 cases of HL recorded in the Northern Region Young Persons’ Malignant Disease Registry. Patients were ages 0 to 24 at diagnosis and were diagnosed between 1968 and 2003.
There were 5 different subtypes of HL in this group:
- 247 cases of the NS type
- 143 NOS
- 105 of mixed cellularity
- 58 lymphocyte-rich cases
- 68 “others.”
Age and sex
Overall, more males than females had HL, but the male-female ratio varied by both age group and subtype. The age-standardized rate (ASR) of HL for males was 18.15 per million persons per year, and the ASR for females was 10.52 per million persons per year.
For the NS subtype, there were 130 males and 117 females, but this was reversed at ages 20 to 24, with 72 females and 55 males. The ASR for NS HL at 20 to 24 was 14.26 for males and 18.79 for females.
“That this change takes place after puberty seems to suggest that estrogens may be responsible in some way,” Dr McNally said. “There are a lot of genes directly regulated by sex hormones, and they are obvious suspects. Alternatively, epigenetic changes . . . influencing key genes, induced by sex hormones, may be responsible.”
Overcrowding
The researchers calculated socio-economic deprivation using the 4 components of the Townsend deprivation score: household overcrowding, non-home ownership, unemployment, and households with no car.
They observed a lower incidence of NS HL among those patients living in areas with more overcrowded households. The relative risk of NS HL was 0.88 for a 1% increase in household overcrowding (P<0.001).
For the NOS subtype, the reverse was seen. A 1% increase in household overcrowding was associated with an increased incidence of NOS HL—a relative risk of 1.17.
Overcrowding seemed to have no effect on the incidence of mixed-cellularity HL or lymphocyte-rich HL.
“We knew already that recurrent infections may protect against childhood leukemia, and now it looks as we can add Hodgkin lymphoma and, particularly its NS subtype, to the list,” Dr McNally said. “In order to further investigate the factors involved, prospective studies should investigate the hormonal changes and recurrent infections and their direct link to the risk of lymphoma, but such studies are difficult to do in rare diseases.”
“A practical follow-up would be case-control studies examining biological markers related to exposure to a multitude of infectious agents, and indeed to hormonal status itself, while genetic studies are another possibility.”
Photo by Pavel Novak
VIENNA—Living in overcrowded conditions may affect a young person’s risk of developing certain subtypes of Hodgkin lymphoma (HL), according to researchers.
They studied more than 600 children and young adults with HL in England and found that patients who lived in areas with more overcrowded households had a lower incidence of nodular sclerosis (NS) HL but a higher incidence of the not-otherwise-specified (NOS) subtype of HL.
“Our findings related to the NS subtype may suggest that the recurrent infections to which children living in overcrowded conditions are likely to have been exposed stimulate their immune systems and, hence, protect them against developing this type of cancer later in their childhood and early adult life,” said Richard McNally, PhD, of Newcastle University in the UK.
“Those who have a genetic susceptibility to HL and have been less exposed to infection through not living in such overcrowded conditions may have less developed immune systems as a result and are therefore at greater risk of developing this subtype.”
Dr McNally and his colleagues added that it’s more difficult to interpret the findings in the NOS group because this subtype of HL is very heterogeneous. The team said the role of chance cannot be ruled out.
They presented this research at the 2015 European Cancer Congress (abstract 1414).
Dr McNally and his colleagues wanted to gain a better understanding of factors that cause HL, so they analyzed a cohort of young HL patients in Northern England, looking at factors such as sex, age, and socio-economic deprivation.
The researchers evaluated 621 cases of HL recorded in the Northern Region Young Persons’ Malignant Disease Registry. Patients were ages 0 to 24 at diagnosis and were diagnosed between 1968 and 2003.
There were 5 different subtypes of HL in this group:
- 247 cases of the NS type
- 143 NOS
- 105 of mixed cellularity
- 58 lymphocyte-rich cases
- 68 “others.”
Age and sex
Overall, more males than females had HL, but the male-female ratio varied by both age group and subtype. The age-standardized rate (ASR) of HL for males was 18.15 per million persons per year, and the ASR for females was 10.52 per million persons per year.
For the NS subtype, there were 130 males and 117 females, but this was reversed at ages 20 to 24, with 72 females and 55 males. The ASR for NS HL at 20 to 24 was 14.26 for males and 18.79 for females.
“That this change takes place after puberty seems to suggest that estrogens may be responsible in some way,” Dr McNally said. “There are a lot of genes directly regulated by sex hormones, and they are obvious suspects. Alternatively, epigenetic changes . . . influencing key genes, induced by sex hormones, may be responsible.”
Overcrowding
The researchers calculated socio-economic deprivation using the 4 components of the Townsend deprivation score: household overcrowding, non-home ownership, unemployment, and households with no car.
They observed a lower incidence of NS HL among those patients living in areas with more overcrowded households. The relative risk of NS HL was 0.88 for a 1% increase in household overcrowding (P<0.001).
For the NOS subtype, the reverse was seen. A 1% increase in household overcrowding was associated with an increased incidence of NOS HL—a relative risk of 1.17.
Overcrowding seemed to have no effect on the incidence of mixed-cellularity HL or lymphocyte-rich HL.
“We knew already that recurrent infections may protect against childhood leukemia, and now it looks as we can add Hodgkin lymphoma and, particularly its NS subtype, to the list,” Dr McNally said. “In order to further investigate the factors involved, prospective studies should investigate the hormonal changes and recurrent infections and their direct link to the risk of lymphoma, but such studies are difficult to do in rare diseases.”
“A practical follow-up would be case-control studies examining biological markers related to exposure to a multitude of infectious agents, and indeed to hormonal status itself, while genetic studies are another possibility.”
CHMP grants accelerated assessment for MM drug
Photo by Linda Bartlett
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has agreed to provide accelerated assessment for daratumumab.
The drug is under review as monotherapy for patients with relapsed and refractory multiple myeloma (MM).
The CHMP grants accelerated assessment when a product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.
Accelerated assessment shortens the review period from 210 days to 150 days.
About daratumumab
Daratumumab is an investigational monoclonal antibody that works by binding to CD38 on the surface of MM cells. In doing so, daratumumab triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.
In July 2013, daratumumab was granted orphan drug status by the European Medicines Agency for the treatment of plasma cell myeloma.
The drug has been accepted for priority review in the US as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an immunomodulatory agent or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.
In August 2012, Janssen Biotech, Inc. and Genmab entered an agreement that granted Janssen an exclusive worldwide license to develop, manufacture, and commercialize daratumumab.
Daratumumab trials
The marketing authorization application for daratumumab includes data from the phase 2 MMY2002 (SIRIUS) study, the phase 1/2 GEN501 study, and 3 additional supportive studies.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.
Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Photo by Linda Bartlett
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has agreed to provide accelerated assessment for daratumumab.
The drug is under review as monotherapy for patients with relapsed and refractory multiple myeloma (MM).
The CHMP grants accelerated assessment when a product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.
Accelerated assessment shortens the review period from 210 days to 150 days.
About daratumumab
Daratumumab is an investigational monoclonal antibody that works by binding to CD38 on the surface of MM cells. In doing so, daratumumab triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.
In July 2013, daratumumab was granted orphan drug status by the European Medicines Agency for the treatment of plasma cell myeloma.
The drug has been accepted for priority review in the US as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an immunomodulatory agent or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.
In August 2012, Janssen Biotech, Inc. and Genmab entered an agreement that granted Janssen an exclusive worldwide license to develop, manufacture, and commercialize daratumumab.
Daratumumab trials
The marketing authorization application for daratumumab includes data from the phase 2 MMY2002 (SIRIUS) study, the phase 1/2 GEN501 study, and 3 additional supportive studies.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.
Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Photo by Linda Bartlett
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has agreed to provide accelerated assessment for daratumumab.
The drug is under review as monotherapy for patients with relapsed and refractory multiple myeloma (MM).
The CHMP grants accelerated assessment when a product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.
Accelerated assessment shortens the review period from 210 days to 150 days.
About daratumumab
Daratumumab is an investigational monoclonal antibody that works by binding to CD38 on the surface of MM cells. In doing so, daratumumab triggers the patient’s own immune system to attack MM cells, resulting in cell death through multiple mechanisms of action.
In July 2013, daratumumab was granted orphan drug status by the European Medicines Agency for the treatment of plasma cell myeloma.
The drug has been accepted for priority review in the US as monotherapy for MM patients who are refractory to both a proteasome inhibitor and an immunomodulatory agent or who have received 3 or more prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent.
In August 2012, Janssen Biotech, Inc. and Genmab entered an agreement that granted Janssen an exclusive worldwide license to develop, manufacture, and commercialize daratumumab.
Daratumumab trials
The marketing authorization application for daratumumab includes data from the phase 2 MMY2002 (SIRIUS) study, the phase 1/2 GEN501 study, and 3 additional supportive studies.
The GEN501 study enrolled 102 patients with relapsed MM or relapsed MM that was refractory to 2 or more prior lines of therapy. The patients received daratumumab at a range of doses and on a number of different schedules.
The results suggested that daratumumab is most effective at a dose of 16 mg/kg. At this dose, the overall response rate was 36%.
Most adverse events in this study were grade 1 or 2, although serious events did occur.
The SIRIUS study enrolled 124 MM patients who had received 3 or more prior lines of therapy. They received daratumumab at different doses and on different schedules, but 106 of the patients received the drug at 16 mg/kg.
Twenty-nine percent of the 106 patients responded to treatment, and the median duration of response was 7 months. Thirty percent of patients experienced serious adverse events.
Group identifies malaria resistance locus
outside of Nairobi, Kenya
Photo by Gabrielle Tenenbaum
Researchers say they have identified genetic variants that protect African children from developing severe malaria, in some cases nearly halving a child’s chance of developing the disease.
The variants are at a locus located next to a cluster of genes that are responsible for creating the receptors the malaria parasite Plasmodium falciparum uses to infect red blood cells.
The researchers described their findings in a letter to Nature.
“The risk of developing severe malaria turns out to be strongly linked to the process by which the malaria parasite gains entry to the human red blood cell,” said Dr Kevin Marsh, of the Kemri-Wellcome Research Programme in Kilifi, Kenya.
“This study strengthens the argument for focusing on the malaria side of the parasite-human interaction in our search for new vaccine candidates.”
For this study, Dr Marsh and his colleagues analyzed data from 8 different African countries: Burkina Faso, Cameroon, Ghana, Kenya, Malawi, Mali, The Gambia, and Tanzania.
They compared the DNA of 5633 children with severe malaria and the DNA of 5919 children without severe malaria. The researchers then replicated their key findings in a further 14,000 children.
The locus the team identified is near a cluster of genes that code for glycophorins, which are involved in P falciparum’s invasion of red blood cells.
The researchers also found an allele that was common among children in Kenya. Having this allele reduced the risk of severe malaria by about 40% in Kenyan children, with a slightly smaller effect across all the other populations studied.
The team said this difference between populations could be due to the genetic features of the local malaria parasite in East Africa.
Balancing selection
The newly identified malaria resistance locus lies within a region of the genome where humans and chimpanzees have been known to share particular combinations of haplotypes.
This indicates that some of the variation seen in contemporary humans has been present for millions of years. The finding also suggests that this region of the genome is the subject of balancing selection.
Balancing selection happens when a particular genetic variant evolves because it confers health benefits, but it is carried by only a proportion of the population because it also has damaging consequences.
“These findings indicate that balancing selection and resistance to malaria are deeply intertwined themes in our ancient evolutionary history,” said Dr Dominic Kwiatkowski, of the Wellcome Trust Sanger Institute in Cambridge, UK.
“This new resistance locus is particularly interesting because it lies so close to genes that are gatekeepers for the malaria parasite’s invasion machinery. We now need to drill down at this locus to characterize these complex patterns of genetic variation more precisely and to understand the molecular mechanisms by which they act.”
outside of Nairobi, Kenya
Photo by Gabrielle Tenenbaum
Researchers say they have identified genetic variants that protect African children from developing severe malaria, in some cases nearly halving a child’s chance of developing the disease.
The variants are at a locus located next to a cluster of genes that are responsible for creating the receptors the malaria parasite Plasmodium falciparum uses to infect red blood cells.
The researchers described their findings in a letter to Nature.
“The risk of developing severe malaria turns out to be strongly linked to the process by which the malaria parasite gains entry to the human red blood cell,” said Dr Kevin Marsh, of the Kemri-Wellcome Research Programme in Kilifi, Kenya.
“This study strengthens the argument for focusing on the malaria side of the parasite-human interaction in our search for new vaccine candidates.”
For this study, Dr Marsh and his colleagues analyzed data from 8 different African countries: Burkina Faso, Cameroon, Ghana, Kenya, Malawi, Mali, The Gambia, and Tanzania.
They compared the DNA of 5633 children with severe malaria and the DNA of 5919 children without severe malaria. The researchers then replicated their key findings in a further 14,000 children.
The locus the team identified is near a cluster of genes that code for glycophorins, which are involved in P falciparum’s invasion of red blood cells.
The researchers also found an allele that was common among children in Kenya. Having this allele reduced the risk of severe malaria by about 40% in Kenyan children, with a slightly smaller effect across all the other populations studied.
The team said this difference between populations could be due to the genetic features of the local malaria parasite in East Africa.
Balancing selection
The newly identified malaria resistance locus lies within a region of the genome where humans and chimpanzees have been known to share particular combinations of haplotypes.
This indicates that some of the variation seen in contemporary humans has been present for millions of years. The finding also suggests that this region of the genome is the subject of balancing selection.
Balancing selection happens when a particular genetic variant evolves because it confers health benefits, but it is carried by only a proportion of the population because it also has damaging consequences.
“These findings indicate that balancing selection and resistance to malaria are deeply intertwined themes in our ancient evolutionary history,” said Dr Dominic Kwiatkowski, of the Wellcome Trust Sanger Institute in Cambridge, UK.
“This new resistance locus is particularly interesting because it lies so close to genes that are gatekeepers for the malaria parasite’s invasion machinery. We now need to drill down at this locus to characterize these complex patterns of genetic variation more precisely and to understand the molecular mechanisms by which they act.”
outside of Nairobi, Kenya
Photo by Gabrielle Tenenbaum
Researchers say they have identified genetic variants that protect African children from developing severe malaria, in some cases nearly halving a child’s chance of developing the disease.
The variants are at a locus located next to a cluster of genes that are responsible for creating the receptors the malaria parasite Plasmodium falciparum uses to infect red blood cells.
The researchers described their findings in a letter to Nature.
“The risk of developing severe malaria turns out to be strongly linked to the process by which the malaria parasite gains entry to the human red blood cell,” said Dr Kevin Marsh, of the Kemri-Wellcome Research Programme in Kilifi, Kenya.
“This study strengthens the argument for focusing on the malaria side of the parasite-human interaction in our search for new vaccine candidates.”
For this study, Dr Marsh and his colleagues analyzed data from 8 different African countries: Burkina Faso, Cameroon, Ghana, Kenya, Malawi, Mali, The Gambia, and Tanzania.
They compared the DNA of 5633 children with severe malaria and the DNA of 5919 children without severe malaria. The researchers then replicated their key findings in a further 14,000 children.
The locus the team identified is near a cluster of genes that code for glycophorins, which are involved in P falciparum’s invasion of red blood cells.
The researchers also found an allele that was common among children in Kenya. Having this allele reduced the risk of severe malaria by about 40% in Kenyan children, with a slightly smaller effect across all the other populations studied.
The team said this difference between populations could be due to the genetic features of the local malaria parasite in East Africa.
Balancing selection
The newly identified malaria resistance locus lies within a region of the genome where humans and chimpanzees have been known to share particular combinations of haplotypes.
This indicates that some of the variation seen in contemporary humans has been present for millions of years. The finding also suggests that this region of the genome is the subject of balancing selection.
Balancing selection happens when a particular genetic variant evolves because it confers health benefits, but it is carried by only a proportion of the population because it also has damaging consequences.
“These findings indicate that balancing selection and resistance to malaria are deeply intertwined themes in our ancient evolutionary history,” said Dr Dominic Kwiatkowski, of the Wellcome Trust Sanger Institute in Cambridge, UK.
“This new resistance locus is particularly interesting because it lies so close to genes that are gatekeepers for the malaria parasite’s invasion machinery. We now need to drill down at this locus to characterize these complex patterns of genetic variation more precisely and to understand the molecular mechanisms by which they act.”
Signature may predict progression to MM
Photo by Graham Colm
New research has revealed a microRNA (miRNA) signature in the bone marrow of patients with multiple myeloma (MM) that is also detectable in peripheral blood.
Investigators believe this signature may mark the onset of MM and predict progression to MM in patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM).
This research has been published in The Journal of Molecular Diagnostics.
“Currently, there is no single factor that can predict patients with MGUS or SMM who are likely to progress to myeloma,” said Katherine R. Calvo, MD, PhD, of the National Institutes of Health in Bethesda, Maryland.
“A biomarker of disease progression in the peripheral blood could assist in the early identification of patients evolving to multiple myeloma.”
With this in mind, Dr Calvo and her colleagues studied miRNAs as possible biomarkers of MM. Previous research has shown increased levels of specific miRNAs in the blood and plasma of MM patients.
In this study, the investigators analyzed bone marrow, plasma, and serum samples from healthy controls and patients with MM, MGUS, or SMM.
The team analyzed fluid from the bone marrow of 20 patients with MM and identified 111 miRNAs that showed a 2-fold or greater difference from levels observed in 8 control samples. Sixty-nine of the miRNAs were downregulated, and 42 were upregulated.
Further analysis revealed a unique miRNA signature indicative of MM. The bone marrow signature included 8 members of the let-7 family of miRNAs, each of which showed significant decreases ranging from 6-fold to 17-fold (P<0.03) in patients with MM.
Other experiments revealed the miRNA profiles characteristic of MM in peripheral blood, serum, and plasma samples.
Using quantitative real-time PCR, the investigators identified 18 miRNAs that were significantly decreased in bone marrow MM samples. Of these, 11 (60%) miRNAs were also significantly decreased in serum samples, and 6 of the 11 were also found to be lower in plasma samples (including 3 members of the let-7 miRNA family).
The investigators further explored whether the miRNA pattern of MM in precursor diseases changes as the disease progresses. They analyzed serum samples in 17 patients with MGUS, 17 with SMM, 13 with MM, and 12 healthy controls.
Only 4 of the 11 miRNAs (36%) that were reduced in the MM serum samples were lower in the MGUS samples.
“This suggests that aberrant expression of these [4] miRNAs may be associated with early events in plasma cell neoplasia,” Dr Calvo said.
Eight of the 11 (73%) miRNAs were decreased in SMM plasma samples. However, 3 (27%) were significantly reduced only in the MM samples, suggesting that downregulation of this group of miRNAs may be related to later events during evolution from precursor disease to MM.
“Our findings suggest that the antiproliferative and proapoptotic miRNAs, such as the let-7 family members, are downregulated in multiple myeloma’s microenvironment,” Dr Calvo said.
“These findings suggest that measuring expression of miRNAs associated with myeloma progression in the peripheral blood may hold promise for predicting disease progression in MGUS and SMM.”
Photo by Graham Colm
New research has revealed a microRNA (miRNA) signature in the bone marrow of patients with multiple myeloma (MM) that is also detectable in peripheral blood.
Investigators believe this signature may mark the onset of MM and predict progression to MM in patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM).
This research has been published in The Journal of Molecular Diagnostics.
“Currently, there is no single factor that can predict patients with MGUS or SMM who are likely to progress to myeloma,” said Katherine R. Calvo, MD, PhD, of the National Institutes of Health in Bethesda, Maryland.
“A biomarker of disease progression in the peripheral blood could assist in the early identification of patients evolving to multiple myeloma.”
With this in mind, Dr Calvo and her colleagues studied miRNAs as possible biomarkers of MM. Previous research has shown increased levels of specific miRNAs in the blood and plasma of MM patients.
In this study, the investigators analyzed bone marrow, plasma, and serum samples from healthy controls and patients with MM, MGUS, or SMM.
The team analyzed fluid from the bone marrow of 20 patients with MM and identified 111 miRNAs that showed a 2-fold or greater difference from levels observed in 8 control samples. Sixty-nine of the miRNAs were downregulated, and 42 were upregulated.
Further analysis revealed a unique miRNA signature indicative of MM. The bone marrow signature included 8 members of the let-7 family of miRNAs, each of which showed significant decreases ranging from 6-fold to 17-fold (P<0.03) in patients with MM.
Other experiments revealed the miRNA profiles characteristic of MM in peripheral blood, serum, and plasma samples.
Using quantitative real-time PCR, the investigators identified 18 miRNAs that were significantly decreased in bone marrow MM samples. Of these, 11 (60%) miRNAs were also significantly decreased in serum samples, and 6 of the 11 were also found to be lower in plasma samples (including 3 members of the let-7 miRNA family).
The investigators further explored whether the miRNA pattern of MM in precursor diseases changes as the disease progresses. They analyzed serum samples in 17 patients with MGUS, 17 with SMM, 13 with MM, and 12 healthy controls.
Only 4 of the 11 miRNAs (36%) that were reduced in the MM serum samples were lower in the MGUS samples.
“This suggests that aberrant expression of these [4] miRNAs may be associated with early events in plasma cell neoplasia,” Dr Calvo said.
Eight of the 11 (73%) miRNAs were decreased in SMM plasma samples. However, 3 (27%) were significantly reduced only in the MM samples, suggesting that downregulation of this group of miRNAs may be related to later events during evolution from precursor disease to MM.
“Our findings suggest that the antiproliferative and proapoptotic miRNAs, such as the let-7 family members, are downregulated in multiple myeloma’s microenvironment,” Dr Calvo said.
“These findings suggest that measuring expression of miRNAs associated with myeloma progression in the peripheral blood may hold promise for predicting disease progression in MGUS and SMM.”
Photo by Graham Colm
New research has revealed a microRNA (miRNA) signature in the bone marrow of patients with multiple myeloma (MM) that is also detectable in peripheral blood.
Investigators believe this signature may mark the onset of MM and predict progression to MM in patients with monoclonal gammopathy of undetermined significance (MGUS) or smoldering myeloma (SMM).
This research has been published in The Journal of Molecular Diagnostics.
“Currently, there is no single factor that can predict patients with MGUS or SMM who are likely to progress to myeloma,” said Katherine R. Calvo, MD, PhD, of the National Institutes of Health in Bethesda, Maryland.
“A biomarker of disease progression in the peripheral blood could assist in the early identification of patients evolving to multiple myeloma.”
With this in mind, Dr Calvo and her colleagues studied miRNAs as possible biomarkers of MM. Previous research has shown increased levels of specific miRNAs in the blood and plasma of MM patients.
In this study, the investigators analyzed bone marrow, plasma, and serum samples from healthy controls and patients with MM, MGUS, or SMM.
The team analyzed fluid from the bone marrow of 20 patients with MM and identified 111 miRNAs that showed a 2-fold or greater difference from levels observed in 8 control samples. Sixty-nine of the miRNAs were downregulated, and 42 were upregulated.
Further analysis revealed a unique miRNA signature indicative of MM. The bone marrow signature included 8 members of the let-7 family of miRNAs, each of which showed significant decreases ranging from 6-fold to 17-fold (P<0.03) in patients with MM.
Other experiments revealed the miRNA profiles characteristic of MM in peripheral blood, serum, and plasma samples.
Using quantitative real-time PCR, the investigators identified 18 miRNAs that were significantly decreased in bone marrow MM samples. Of these, 11 (60%) miRNAs were also significantly decreased in serum samples, and 6 of the 11 were also found to be lower in plasma samples (including 3 members of the let-7 miRNA family).
The investigators further explored whether the miRNA pattern of MM in precursor diseases changes as the disease progresses. They analyzed serum samples in 17 patients with MGUS, 17 with SMM, 13 with MM, and 12 healthy controls.
Only 4 of the 11 miRNAs (36%) that were reduced in the MM serum samples were lower in the MGUS samples.
“This suggests that aberrant expression of these [4] miRNAs may be associated with early events in plasma cell neoplasia,” Dr Calvo said.
Eight of the 11 (73%) miRNAs were decreased in SMM plasma samples. However, 3 (27%) were significantly reduced only in the MM samples, suggesting that downregulation of this group of miRNAs may be related to later events during evolution from precursor disease to MM.
“Our findings suggest that the antiproliferative and proapoptotic miRNAs, such as the let-7 family members, are downregulated in multiple myeloma’s microenvironment,” Dr Calvo said.
“These findings suggest that measuring expression of miRNAs associated with myeloma progression in the peripheral blood may hold promise for predicting disease progression in MGUS and SMM.”
CHMP recommends product for hemophilia A
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the recombinant factor VIII Fc fusion protein efmoroctocog alfa (Elocta) to treat patients with hemophilia A.
The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to
deliver its final decision within 3 months.
If approved by the EC, efmoroctocog alfa would be the first hemophilia A treatment with prolonged circulation available in the European Union (plus Iceland, Lichtenstein, and Norway).
The CHMP’s positive opinion of efmoroctocog alfa was based on results from 2 phase 3 studies—A-LONG and Kids A-LONG.
A-LONG
The A-LONG study included 165 previously treated males 12 years of age and older with severe hemophilia A. Researchers evaluated individualized and weekly prophylaxis to reduce or prevent bleeding episodes and on-demand dosing to treat bleeding episodes.
Prophylaxis with efmoroctocog alfa resulted in low annualized bleeding rates, and a majority of bleeding episodes were controlled with a single injection of efmoroctocog alfa.
None of the patients developed neutralizing antibodies, efmoroctocog alfa was considered well-tolerated, and the product had a prolonged half-life when compared with rFVIII.
Kids A-LONG
The Kids A-LONG study included 71 boys (younger than 12) with severe hemophilia A who had at least 50 prior exposure days to FVIII therapies.
The children saw their median annualized bleeding rate decrease with efmoroctocog alfa, and close to half of the children did not have any bleeding episodes while they were receiving efmoroctocog alfa.
None of the patients developed inhibitors, and researchers said adverse events were typical of a pediatric hemophilia population.
ASPIRE
Participants in both the A-LONG and Kids A-LONG trials were able to enroll in ASPIRE, a phase 3 extension study evaluating the long-term safety and efficacy of efmoroctocog alfa.
Interim results of ASPIRE suggested that extended treatment with efmoroctocog alfa was largely safe and effective.
Efmoroctocog alfa development
Elocta is the European trade name for efmoroctocog alfa, which is known as Eloctate in the US, Canada, Australia, New Zealand, and Japan, where it is approved for the treatment of hemophilia A.
Biogen and Sobi are collaboration partners in the development and commercialization of efmoroctocog alfa for hemophilia A.
Last year, Sobi exercised its opt-in right to assume final development and commercialization of efmoroctocog alfa in the Sobi territories (essentially, Europe, North Africa, Russia, and certain countries in the Middle East). Biogen leads development for efmoroctocog alfa, has manufacturing rights, and has commercialization rights in North America and all other regions in the world excluding the Sobi territories.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the recombinant factor VIII Fc fusion protein efmoroctocog alfa (Elocta) to treat patients with hemophilia A.
The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to
deliver its final decision within 3 months.
If approved by the EC, efmoroctocog alfa would be the first hemophilia A treatment with prolonged circulation available in the European Union (plus Iceland, Lichtenstein, and Norway).
The CHMP’s positive opinion of efmoroctocog alfa was based on results from 2 phase 3 studies—A-LONG and Kids A-LONG.
A-LONG
The A-LONG study included 165 previously treated males 12 years of age and older with severe hemophilia A. Researchers evaluated individualized and weekly prophylaxis to reduce or prevent bleeding episodes and on-demand dosing to treat bleeding episodes.
Prophylaxis with efmoroctocog alfa resulted in low annualized bleeding rates, and a majority of bleeding episodes were controlled with a single injection of efmoroctocog alfa.
None of the patients developed neutralizing antibodies, efmoroctocog alfa was considered well-tolerated, and the product had a prolonged half-life when compared with rFVIII.
Kids A-LONG
The Kids A-LONG study included 71 boys (younger than 12) with severe hemophilia A who had at least 50 prior exposure days to FVIII therapies.
The children saw their median annualized bleeding rate decrease with efmoroctocog alfa, and close to half of the children did not have any bleeding episodes while they were receiving efmoroctocog alfa.
None of the patients developed inhibitors, and researchers said adverse events were typical of a pediatric hemophilia population.
ASPIRE
Participants in both the A-LONG and Kids A-LONG trials were able to enroll in ASPIRE, a phase 3 extension study evaluating the long-term safety and efficacy of efmoroctocog alfa.
Interim results of ASPIRE suggested that extended treatment with efmoroctocog alfa was largely safe and effective.
Efmoroctocog alfa development
Elocta is the European trade name for efmoroctocog alfa, which is known as Eloctate in the US, Canada, Australia, New Zealand, and Japan, where it is approved for the treatment of hemophilia A.
Biogen and Sobi are collaboration partners in the development and commercialization of efmoroctocog alfa for hemophilia A.
Last year, Sobi exercised its opt-in right to assume final development and commercialization of efmoroctocog alfa in the Sobi territories (essentially, Europe, North Africa, Russia, and certain countries in the Middle East). Biogen leads development for efmoroctocog alfa, has manufacturing rights, and has commercialization rights in North America and all other regions in the world excluding the Sobi territories.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for the recombinant factor VIII Fc fusion protein efmoroctocog alfa (Elocta) to treat patients with hemophilia A.
The CHMP’s recommendation will be reviewed by the European Commission (EC). The EC usually follows the CHMP’s recommendations and is expected to
deliver its final decision within 3 months.
If approved by the EC, efmoroctocog alfa would be the first hemophilia A treatment with prolonged circulation available in the European Union (plus Iceland, Lichtenstein, and Norway).
The CHMP’s positive opinion of efmoroctocog alfa was based on results from 2 phase 3 studies—A-LONG and Kids A-LONG.
A-LONG
The A-LONG study included 165 previously treated males 12 years of age and older with severe hemophilia A. Researchers evaluated individualized and weekly prophylaxis to reduce or prevent bleeding episodes and on-demand dosing to treat bleeding episodes.
Prophylaxis with efmoroctocog alfa resulted in low annualized bleeding rates, and a majority of bleeding episodes were controlled with a single injection of efmoroctocog alfa.
None of the patients developed neutralizing antibodies, efmoroctocog alfa was considered well-tolerated, and the product had a prolonged half-life when compared with rFVIII.
Kids A-LONG
The Kids A-LONG study included 71 boys (younger than 12) with severe hemophilia A who had at least 50 prior exposure days to FVIII therapies.
The children saw their median annualized bleeding rate decrease with efmoroctocog alfa, and close to half of the children did not have any bleeding episodes while they were receiving efmoroctocog alfa.
None of the patients developed inhibitors, and researchers said adverse events were typical of a pediatric hemophilia population.
ASPIRE
Participants in both the A-LONG and Kids A-LONG trials were able to enroll in ASPIRE, a phase 3 extension study evaluating the long-term safety and efficacy of efmoroctocog alfa.
Interim results of ASPIRE suggested that extended treatment with efmoroctocog alfa was largely safe and effective.
Efmoroctocog alfa development
Elocta is the European trade name for efmoroctocog alfa, which is known as Eloctate in the US, Canada, Australia, New Zealand, and Japan, where it is approved for the treatment of hemophilia A.
Biogen and Sobi are collaboration partners in the development and commercialization of efmoroctocog alfa for hemophilia A.
Last year, Sobi exercised its opt-in right to assume final development and commercialization of efmoroctocog alfa in the Sobi territories (essentially, Europe, North Africa, Russia, and certain countries in the Middle East). Biogen leads development for efmoroctocog alfa, has manufacturing rights, and has commercialization rights in North America and all other regions in the world excluding the Sobi territories.
New chimeric CD19 antibody may reduce MRD in ALL
NEW YORK—Researchers have developed a pharmaceutical-grade, third-generation, CD19-specific antibody that reduced minimal residual disease (MRD) in pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
This chimerized, Fc-optimized antibody—4G7SDIE—was used on a compassionate-need basis in 14 patients with relapsed or refractory BCP-ALL. Nine of the patients had prior stem cell transplants.
Ursula JE Seidel, a PhD candidate at University Children’s Hospital Tubingen in Germany, discussed early results with the new antibody (poster B144) during the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
Patients received 4G7SDIE infusions ranging from 5 mg/m2 to 50 mg/m2 twice a week for a year or longer.
They rarely experienced fever, nausea, or headache, according to the investigators, and all had B-cell depletion.
“The good thing about this antibody is it has a very low toxicity profile,” Seidel noted.
Upon discontinuation of therapy, B-cell counts recovered rapidly to normal levels.
The researchers followed the patients for a median of 543 days after transplant (range, 208–1137) and a median of 720 days after administration of 4G7SDIE (range, 264–1115).
Nine of the 14 patients had a reduction in MRD by 1 log or more, 2 of whom were receiving additional therapy with tyrosine kinase inhibitors.
Five patients had a reduction in MRD below the quantifiable level, and 2 patients became MRD-negative.
Six patients relapsed, and 5 of them died from relapsed disease. Two patients died of sepsis or chemotoxicity while in complete molecular remission. And 6 patients remain in complete molecular remission.
Functional characterization of 4G7SDIE
Through analysis of cells from healthy volunteers and BCP-ALL blasts of untreated and treated patients, the researchers determined that 4G7SDIE mediates enhanced antibody‑dependent cellular cytotoxicity through its improved capability to recruit FcγRIIIa-bearing effector cells.
They identified natural killer cells and γδ T cells as the main effector cells. And they determined that the FcγRIIIa-V158F polymorphism did not influence the effect of 4G7SDIE-mediated antibody‑dependent cellular cytotoxicity.
The researchers believe that the promising anti-leukemic effects of 4G7SDIE both in vitro and in vivo call for additional exploration. They are currently planning a phase 1/2 study to further assess the therapeutic activity of 4G7SDIE.
NEW YORK—Researchers have developed a pharmaceutical-grade, third-generation, CD19-specific antibody that reduced minimal residual disease (MRD) in pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
This chimerized, Fc-optimized antibody—4G7SDIE—was used on a compassionate-need basis in 14 patients with relapsed or refractory BCP-ALL. Nine of the patients had prior stem cell transplants.
Ursula JE Seidel, a PhD candidate at University Children’s Hospital Tubingen in Germany, discussed early results with the new antibody (poster B144) during the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
Patients received 4G7SDIE infusions ranging from 5 mg/m2 to 50 mg/m2 twice a week for a year or longer.
They rarely experienced fever, nausea, or headache, according to the investigators, and all had B-cell depletion.
“The good thing about this antibody is it has a very low toxicity profile,” Seidel noted.
Upon discontinuation of therapy, B-cell counts recovered rapidly to normal levels.
The researchers followed the patients for a median of 543 days after transplant (range, 208–1137) and a median of 720 days after administration of 4G7SDIE (range, 264–1115).
Nine of the 14 patients had a reduction in MRD by 1 log or more, 2 of whom were receiving additional therapy with tyrosine kinase inhibitors.
Five patients had a reduction in MRD below the quantifiable level, and 2 patients became MRD-negative.
Six patients relapsed, and 5 of them died from relapsed disease. Two patients died of sepsis or chemotoxicity while in complete molecular remission. And 6 patients remain in complete molecular remission.
Functional characterization of 4G7SDIE
Through analysis of cells from healthy volunteers and BCP-ALL blasts of untreated and treated patients, the researchers determined that 4G7SDIE mediates enhanced antibody‑dependent cellular cytotoxicity through its improved capability to recruit FcγRIIIa-bearing effector cells.
They identified natural killer cells and γδ T cells as the main effector cells. And they determined that the FcγRIIIa-V158F polymorphism did not influence the effect of 4G7SDIE-mediated antibody‑dependent cellular cytotoxicity.
The researchers believe that the promising anti-leukemic effects of 4G7SDIE both in vitro and in vivo call for additional exploration. They are currently planning a phase 1/2 study to further assess the therapeutic activity of 4G7SDIE.
NEW YORK—Researchers have developed a pharmaceutical-grade, third-generation, CD19-specific antibody that reduced minimal residual disease (MRD) in pediatric patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
This chimerized, Fc-optimized antibody—4G7SDIE—was used on a compassionate-need basis in 14 patients with relapsed or refractory BCP-ALL. Nine of the patients had prior stem cell transplants.
Ursula JE Seidel, a PhD candidate at University Children’s Hospital Tubingen in Germany, discussed early results with the new antibody (poster B144) during the inaugural CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference.
Patients received 4G7SDIE infusions ranging from 5 mg/m2 to 50 mg/m2 twice a week for a year or longer.
They rarely experienced fever, nausea, or headache, according to the investigators, and all had B-cell depletion.
“The good thing about this antibody is it has a very low toxicity profile,” Seidel noted.
Upon discontinuation of therapy, B-cell counts recovered rapidly to normal levels.
The researchers followed the patients for a median of 543 days after transplant (range, 208–1137) and a median of 720 days after administration of 4G7SDIE (range, 264–1115).
Nine of the 14 patients had a reduction in MRD by 1 log or more, 2 of whom were receiving additional therapy with tyrosine kinase inhibitors.
Five patients had a reduction in MRD below the quantifiable level, and 2 patients became MRD-negative.
Six patients relapsed, and 5 of them died from relapsed disease. Two patients died of sepsis or chemotoxicity while in complete molecular remission. And 6 patients remain in complete molecular remission.
Functional characterization of 4G7SDIE
Through analysis of cells from healthy volunteers and BCP-ALL blasts of untreated and treated patients, the researchers determined that 4G7SDIE mediates enhanced antibody‑dependent cellular cytotoxicity through its improved capability to recruit FcγRIIIa-bearing effector cells.
They identified natural killer cells and γδ T cells as the main effector cells. And they determined that the FcγRIIIa-V158F polymorphism did not influence the effect of 4G7SDIE-mediated antibody‑dependent cellular cytotoxicity.
The researchers believe that the promising anti-leukemic effects of 4G7SDIE both in vitro and in vivo call for additional exploration. They are currently planning a phase 1/2 study to further assess the therapeutic activity of 4G7SDIE.