Doctor examines patient

Credit: NCI

The risk of premature menopause among survivors of Hodgkin lymphoma (HL) may vary greatly, according to a study of more than 2000 women.

The results suggest that ovarian radiotherapy and certain chemotherapeutic regimens increase a woman’s risk of premature menopause.

And the radiation dose, number of treatment cycles, and patient age at treatment all influence that risk.

The findings appear in the Journal of the National Cancer Institute.

Previous research suggested that women with HL who receive certain types of chemotherapy or radiotherapy are at an increased risk of early menopause, but there was insufficient information to provide patients with detailed advice.

To gain more insight, Anthony Swerdlow, DSc, of The Institute of Cancer Research in London, UK, and his colleagues studied 2127 women who were treated for HL in England or Wales between 1960 and 2004.

All of the women were younger than 36 at the time of treatment, and all had received chest radiotherapy, sometimes alongside other treatments.

Some 605 of the women underwent non-surgical menopause before the age of 40. The researchers said this was a large enough number for them to estimate accurate risks of menopause, depending on the type and dose of treatments patients received and the age they received them.

The team found that several treatments caused a sharp increase in premature menopause risk, and menopause was more like among women treated at older ages.

The risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea, etoposide, cytarabine, melphalan) chemotherapy given prior to stem cell transplant.

However, there was no significant increase in risk after receiving adriamycin, bleomycin, vinblastine, dacarbazine (ABVD).

Within 5 years of treatment, menopause had occurred in 62.5% of patients who received ≥5 Gy of ovarian radiotherapy, 50.9% of patients who received BEAM, and 24.2% of patients who received ≥6 cycles of alkylating chemotherapy.

The cumulative risk of menopause by age 40 was 81.3% after ≥ 5 Gy of ovarian radiotherapy, 75.3% after BEAM, 49.1% after ≥ 6 cycles of alkylating chemotherapy, 3.0% after solely supradiaphragmatic radiotherapy, and 1.4% after ABVD.

“We hope our study will help women to understand better, in consultation with their doctors, their risks of future infertility following treatment for this malignancy,” Dr Swerdlow said.

“By looking in a much larger group of women than previous studies of this type, we were able to produce age- and treatment-specific risk estimates that we hope will be of practical use to individual women.”

Doctor examines patient

Credit: NCI

The risk of premature menopause among survivors of Hodgkin lymphoma (HL) may vary greatly, according to a study of more than 2000 women.

The results suggest that ovarian radiotherapy and certain chemotherapeutic regimens increase a woman’s risk of premature menopause.

And the radiation dose, number of treatment cycles, and patient age at treatment all influence that risk.

The findings appear in the Journal of the National Cancer Institute.

Previous research suggested that women with HL who receive certain types of chemotherapy or radiotherapy are at an increased risk of early menopause, but there was insufficient information to provide patients with detailed advice.

To gain more insight, Anthony Swerdlow, DSc, of The Institute of Cancer Research in London, UK, and his colleagues studied 2127 women who were treated for HL in England or Wales between 1960 and 2004.

All of the women were younger than 36 at the time of treatment, and all had received chest radiotherapy, sometimes alongside other treatments.

Some 605 of the women underwent non-surgical menopause before the age of 40. The researchers said this was a large enough number for them to estimate accurate risks of menopause, depending on the type and dose of treatments patients received and the age they received them.

The team found that several treatments caused a sharp increase in premature menopause risk, and menopause was more like among women treated at older ages.

The risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea, etoposide, cytarabine, melphalan) chemotherapy given prior to stem cell transplant.

However, there was no significant increase in risk after receiving adriamycin, bleomycin, vinblastine, dacarbazine (ABVD).

Within 5 years of treatment, menopause had occurred in 62.5% of patients who received ≥5 Gy of ovarian radiotherapy, 50.9% of patients who received BEAM, and 24.2% of patients who received ≥6 cycles of alkylating chemotherapy.

The cumulative risk of menopause by age 40 was 81.3% after ≥ 5 Gy of ovarian radiotherapy, 75.3% after BEAM, 49.1% after ≥ 6 cycles of alkylating chemotherapy, 3.0% after solely supradiaphragmatic radiotherapy, and 1.4% after ABVD.

“We hope our study will help women to understand better, in consultation with their doctors, their risks of future infertility following treatment for this malignancy,” Dr Swerdlow said.

“By looking in a much larger group of women than previous studies of this type, we were able to produce age- and treatment-specific risk estimates that we hope will be of practical use to individual women.”

Doctor examines patient

Credit: NCI

The risk of premature menopause among survivors of Hodgkin lymphoma (HL) may vary greatly, according to a study of more than 2000 women.

The results suggest that ovarian radiotherapy and certain chemotherapeutic regimens increase a woman’s risk of premature menopause.

And the radiation dose, number of treatment cycles, and patient age at treatment all influence that risk.

The findings appear in the Journal of the National Cancer Institute.

Previous research suggested that women with HL who receive certain types of chemotherapy or radiotherapy are at an increased risk of early menopause, but there was insufficient information to provide patients with detailed advice.

To gain more insight, Anthony Swerdlow, DSc, of The Institute of Cancer Research in London, UK, and his colleagues studied 2127 women who were treated for HL in England or Wales between 1960 and 2004.

All of the women were younger than 36 at the time of treatment, and all had received chest radiotherapy, sometimes alongside other treatments.

Some 605 of the women underwent non-surgical menopause before the age of 40. The researchers said this was a large enough number for them to estimate accurate risks of menopause, depending on the type and dose of treatments patients received and the age they received them.

The team found that several treatments caused a sharp increase in premature menopause risk, and menopause was more like among women treated at older ages.

The risk of premature menopause increased more than 20-fold after ovarian radiotherapy, alkylating chemotherapy other than dacarbazine, or BEAM (bis-chloroethylnitrosourea, etoposide, cytarabine, melphalan) chemotherapy given prior to stem cell transplant.

However, there was no significant increase in risk after receiving adriamycin, bleomycin, vinblastine, dacarbazine (ABVD).

Within 5 years of treatment, menopause had occurred in 62.5% of patients who received ≥5 Gy of ovarian radiotherapy, 50.9% of patients who received BEAM, and 24.2% of patients who received ≥6 cycles of alkylating chemotherapy.

The cumulative risk of menopause by age 40 was 81.3% after ≥ 5 Gy of ovarian radiotherapy, 75.3% after BEAM, 49.1% after ≥ 6 cycles of alkylating chemotherapy, 3.0% after solely supradiaphragmatic radiotherapy, and 1.4% after ABVD.

“We hope our study will help women to understand better, in consultation with their doctors, their risks of future infertility following treatment for this malignancy,” Dr Swerdlow said.

“By looking in a much larger group of women than previous studies of this type, we were able to produce age- and treatment-specific risk estimates that we hope will be of practical use to individual women.”

Blood smear showing

Plasmodium falciparum

Credit: CDC/Mae Melvin

A semi-automated system may allow healthcare professionals to diagnose malaria infection with more than 90% accuracy.

With this system, a computer algorithm analyzes red blood cells from a digitized slide, ranks them according to the likelihood of infection, and presents the user with more than 100 images from which to make a diagnosis.

Johan Lundin, MD, PhD, of the Institute for Molecular Medicine Finland, and his colleagues described the system in PLOS ONE.

The researchers noted that high-quality microscopy is still the most accurate method for detecting malaria infection. However, as microscopy can be time-consuming, the team wanted to streamline the process by developing a semi-automated system.

“We are not suggesting that the whole malaria diagnostic process could or should be automated,” Dr Lundin said. “Rather, our aim is to develop methods that are significantly less labor-intensive than the traditional ones and have a potential to considerably increase the throughput in malaria diagnostics.”

The group’s method is based on computer vision algorithms similar to those used in facial recognition software. First, a thin layer of blood smeared on a microscope slide is digitized. Then, a computer algorithm analyzes more than 50,000 red blood cells per sample and ranks them according to the probability of malaria infection.

Next, the program creates a panel containing images of more than a hundred cells that are the most likely to be infected and presents that panel to the user. The final diagnosis is made by a healthcare professional based on the images.

To test this system, Dr Lundin and his colleagues used a set of samples from 19 patients already diagnosed with malaria and 12 control subjects. From each sample, the researchers created a digitized slide, and the system generated 128 images of the most probable parasite candidate regions.

Two expert microscopists viewed the images on a tablet computer to determine whether a subject was infected with Plasmodium falciparum.

The diagnostic sensitivity was 90% with one viewer and 95% for the other. The specificity was 100% for both viewers.

Based on these results, the researchers said this system has the potential to increase the throughput in malaria diagnostics. However, it does require some tweaking, and the team would like to expand its capabilities.

“The equipment needed for digitization of the samples is a challenge in developed countries,” said study author Nina Linder, MD, PhD, also of the Institute for Molecular Medicine Finland. “In the next phase of our project, we will test the system in combination with inexpensive mobile microscopy devices that our group has also developed.”

“There is also a strong need for fast and accurate methods for measuring the malaria parasite load in a sample,” she added. “Various malaria drug screening programs are underway, and the parasite load in a large number of samples needs to be quantified for determining the efficacy of potential drugs. We are further developing the computer algorithms used in this study to meet this need as well.”

Lastly, the researchers said this system could be applied in various other fields of medicine. In addition to other infectious diseases such as tuberculosis, the group is planning to test the system’s utility in cancer diagnosis.

Blood smear showing

Plasmodium falciparum

Credit: CDC/Mae Melvin

A semi-automated system may allow healthcare professionals to diagnose malaria infection with more than 90% accuracy.

With this system, a computer algorithm analyzes red blood cells from a digitized slide, ranks them according to the likelihood of infection, and presents the user with more than 100 images from which to make a diagnosis.

Johan Lundin, MD, PhD, of the Institute for Molecular Medicine Finland, and his colleagues described the system in PLOS ONE.

The researchers noted that high-quality microscopy is still the most accurate method for detecting malaria infection. However, as microscopy can be time-consuming, the team wanted to streamline the process by developing a semi-automated system.

“We are not suggesting that the whole malaria diagnostic process could or should be automated,” Dr Lundin said. “Rather, our aim is to develop methods that are significantly less labor-intensive than the traditional ones and have a potential to considerably increase the throughput in malaria diagnostics.”

The group’s method is based on computer vision algorithms similar to those used in facial recognition software. First, a thin layer of blood smeared on a microscope slide is digitized. Then, a computer algorithm analyzes more than 50,000 red blood cells per sample and ranks them according to the probability of malaria infection.

Next, the program creates a panel containing images of more than a hundred cells that are the most likely to be infected and presents that panel to the user. The final diagnosis is made by a healthcare professional based on the images.

To test this system, Dr Lundin and his colleagues used a set of samples from 19 patients already diagnosed with malaria and 12 control subjects. From each sample, the researchers created a digitized slide, and the system generated 128 images of the most probable parasite candidate regions.

Two expert microscopists viewed the images on a tablet computer to determine whether a subject was infected with Plasmodium falciparum.

The diagnostic sensitivity was 90% with one viewer and 95% for the other. The specificity was 100% for both viewers.

Based on these results, the researchers said this system has the potential to increase the throughput in malaria diagnostics. However, it does require some tweaking, and the team would like to expand its capabilities.

“The equipment needed for digitization of the samples is a challenge in developed countries,” said study author Nina Linder, MD, PhD, also of the Institute for Molecular Medicine Finland. “In the next phase of our project, we will test the system in combination with inexpensive mobile microscopy devices that our group has also developed.”

“There is also a strong need for fast and accurate methods for measuring the malaria parasite load in a sample,” she added. “Various malaria drug screening programs are underway, and the parasite load in a large number of samples needs to be quantified for determining the efficacy of potential drugs. We are further developing the computer algorithms used in this study to meet this need as well.”

Lastly, the researchers said this system could be applied in various other fields of medicine. In addition to other infectious diseases such as tuberculosis, the group is planning to test the system’s utility in cancer diagnosis.

Blood smear showing

Plasmodium falciparum

Credit: CDC/Mae Melvin

A semi-automated system may allow healthcare professionals to diagnose malaria infection with more than 90% accuracy.

With this system, a computer algorithm analyzes red blood cells from a digitized slide, ranks them according to the likelihood of infection, and presents the user with more than 100 images from which to make a diagnosis.

Johan Lundin, MD, PhD, of the Institute for Molecular Medicine Finland, and his colleagues described the system in PLOS ONE.

The researchers noted that high-quality microscopy is still the most accurate method for detecting malaria infection. However, as microscopy can be time-consuming, the team wanted to streamline the process by developing a semi-automated system.

“We are not suggesting that the whole malaria diagnostic process could or should be automated,” Dr Lundin said. “Rather, our aim is to develop methods that are significantly less labor-intensive than the traditional ones and have a potential to considerably increase the throughput in malaria diagnostics.”

The group’s method is based on computer vision algorithms similar to those used in facial recognition software. First, a thin layer of blood smeared on a microscope slide is digitized. Then, a computer algorithm analyzes more than 50,000 red blood cells per sample and ranks them according to the probability of malaria infection.

Next, the program creates a panel containing images of more than a hundred cells that are the most likely to be infected and presents that panel to the user. The final diagnosis is made by a healthcare professional based on the images.

To test this system, Dr Lundin and his colleagues used a set of samples from 19 patients already diagnosed with malaria and 12 control subjects. From each sample, the researchers created a digitized slide, and the system generated 128 images of the most probable parasite candidate regions.

Two expert microscopists viewed the images on a tablet computer to determine whether a subject was infected with Plasmodium falciparum.

The diagnostic sensitivity was 90% with one viewer and 95% for the other. The specificity was 100% for both viewers.

Based on these results, the researchers said this system has the potential to increase the throughput in malaria diagnostics. However, it does require some tweaking, and the team would like to expand its capabilities.

“The equipment needed for digitization of the samples is a challenge in developed countries,” said study author Nina Linder, MD, PhD, also of the Institute for Molecular Medicine Finland. “In the next phase of our project, we will test the system in combination with inexpensive mobile microscopy devices that our group has also developed.”

“There is also a strong need for fast and accurate methods for measuring the malaria parasite load in a sample,” she added. “Various malaria drug screening programs are underway, and the parasite load in a large number of samples needs to be quantified for determining the efficacy of potential drugs. We are further developing the computer algorithms used in this study to meet this need as well.”

Lastly, the researchers said this system could be applied in various other fields of medicine. In addition to other infectious diseases such as tuberculosis, the group is planning to test the system’s utility in cancer diagnosis.

Antihemophilic factor

A recombinant factor VIII (rFVIII) product known as BAX 855 can prevent bleeding in hemophilia A patients, according to Baxter International, the company developing the product.

BAX 855 is a pegylated version of ADVATE, a full-length rFVIII product already approved to treat hemophilia A.

In a phase 3 study, BAX 855 met the primary endpoint of reducing annualized bleed rates (ABRs) among hemophilia A patients when used as prophylaxis rather than on-demand treatment.

The trial included 138 patients age 12 and older with previously treated hemophilia A. The patients received BAX 855 either twice weekly (45 IU/kg) or on-demand and were followed for 6 months.

The primary objective was to show that BAX 855 prophylaxis can reduce ABRs compared to on-demand treatment. The researchers’ other objectives were to evaluate the safety and immunogenicity of the compound when administered as prophylaxis or on-demand.

BAX 855 met its primary endpoint in the control and prevention of bleeding, routine prophylaxis, and perioperative management.

Patients in the twice-weekly prophylaxis arm experienced a 95% reduction in median ABR compared to those in the on-demand arm (1.9% vs 41.5%, respectively). BAX 855 was also effective in treating bleeding episodes, 96% of which were controlled with 1 or 2 infusions.

The half-life of BAX 855 was 1.4 to 1.5 times that of ADVATE, which is consistent with the findings from a phase 1 study.

No patients developed inhibitors to BAX 855 and no treatment-related serious adverse events, including hypersensitivity, were reported. The most common treatment-related adverse event was headache, which occurred in 3 patients.

Baxter said it expects to submit a biologics license application for BAX 855 to the US Food and Drug Administration before the end of 2014 and to present additional trial data in the coming months.

In addition to an ongoing continuation study for patients who have completed the pivotal trial, the company is starting a phase 3 study to evaluate the safety and efficacy of BAX 855 among 60 previously treated hemophilia A patients younger than 12 years of age.

Consistent with guidelines published by the European Medicines Agency that require a study in children less than 12 years of age prior to filing, Baxter expects to file a marketing authorization application with the agency upon the completing the pediatric study.

Antihemophilic factor

A recombinant factor VIII (rFVIII) product known as BAX 855 can prevent bleeding in hemophilia A patients, according to Baxter International, the company developing the product.

BAX 855 is a pegylated version of ADVATE, a full-length rFVIII product already approved to treat hemophilia A.

In a phase 3 study, BAX 855 met the primary endpoint of reducing annualized bleed rates (ABRs) among hemophilia A patients when used as prophylaxis rather than on-demand treatment.

The trial included 138 patients age 12 and older with previously treated hemophilia A. The patients received BAX 855 either twice weekly (45 IU/kg) or on-demand and were followed for 6 months.

The primary objective was to show that BAX 855 prophylaxis can reduce ABRs compared to on-demand treatment. The researchers’ other objectives were to evaluate the safety and immunogenicity of the compound when administered as prophylaxis or on-demand.

BAX 855 met its primary endpoint in the control and prevention of bleeding, routine prophylaxis, and perioperative management.

Patients in the twice-weekly prophylaxis arm experienced a 95% reduction in median ABR compared to those in the on-demand arm (1.9% vs 41.5%, respectively). BAX 855 was also effective in treating bleeding episodes, 96% of which were controlled with 1 or 2 infusions.

The half-life of BAX 855 was 1.4 to 1.5 times that of ADVATE, which is consistent with the findings from a phase 1 study.

No patients developed inhibitors to BAX 855 and no treatment-related serious adverse events, including hypersensitivity, were reported. The most common treatment-related adverse event was headache, which occurred in 3 patients.

Baxter said it expects to submit a biologics license application for BAX 855 to the US Food and Drug Administration before the end of 2014 and to present additional trial data in the coming months.

In addition to an ongoing continuation study for patients who have completed the pivotal trial, the company is starting a phase 3 study to evaluate the safety and efficacy of BAX 855 among 60 previously treated hemophilia A patients younger than 12 years of age.

Consistent with guidelines published by the European Medicines Agency that require a study in children less than 12 years of age prior to filing, Baxter expects to file a marketing authorization application with the agency upon the completing the pediatric study.

Antihemophilic factor

A recombinant factor VIII (rFVIII) product known as BAX 855 can prevent bleeding in hemophilia A patients, according to Baxter International, the company developing the product.

BAX 855 is a pegylated version of ADVATE, a full-length rFVIII product already approved to treat hemophilia A.

In a phase 3 study, BAX 855 met the primary endpoint of reducing annualized bleed rates (ABRs) among hemophilia A patients when used as prophylaxis rather than on-demand treatment.

The trial included 138 patients age 12 and older with previously treated hemophilia A. The patients received BAX 855 either twice weekly (45 IU/kg) or on-demand and were followed for 6 months.

The primary objective was to show that BAX 855 prophylaxis can reduce ABRs compared to on-demand treatment. The researchers’ other objectives were to evaluate the safety and immunogenicity of the compound when administered as prophylaxis or on-demand.

BAX 855 met its primary endpoint in the control and prevention of bleeding, routine prophylaxis, and perioperative management.

Patients in the twice-weekly prophylaxis arm experienced a 95% reduction in median ABR compared to those in the on-demand arm (1.9% vs 41.5%, respectively). BAX 855 was also effective in treating bleeding episodes, 96% of which were controlled with 1 or 2 infusions.

The half-life of BAX 855 was 1.4 to 1.5 times that of ADVATE, which is consistent with the findings from a phase 1 study.

No patients developed inhibitors to BAX 855 and no treatment-related serious adverse events, including hypersensitivity, were reported. The most common treatment-related adverse event was headache, which occurred in 3 patients.

Baxter said it expects to submit a biologics license application for BAX 855 to the US Food and Drug Administration before the end of 2014 and to present additional trial data in the coming months.

In addition to an ongoing continuation study for patients who have completed the pivotal trial, the company is starting a phase 3 study to evaluate the safety and efficacy of BAX 855 among 60 previously treated hemophilia A patients younger than 12 years of age.

Consistent with guidelines published by the European Medicines Agency that require a study in children less than 12 years of age prior to filing, Baxter expects to file a marketing authorization application with the agency upon the completing the pediatric study.

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

Researchers say they’ve developed a new computational method to predict the function of disease-causing genes and proteins, and this has enabled an important discovery.

The team used the method to study EXP1, a protein known to be essential to the malaria parasite Plasmodium falciparum, although its exact mechanism has been unclear.

The research revealed that EXP1 enables the parasite to detoxify the main metabolic byproducts it creates in red blood cells.

The researchers also found that EXP1 has a direct role in drug action and susceptibility to artesunate, an important member of the artemisinin drug family.

“Through this multiyear collaborative effort, we now have an improved understanding of the protective molecular mechanisms of the malaria parasite and its drug susceptibility to artesunate,” said study author Olivier Lichtarge, MD, PhD, of the Baylor College of Medicine in Houston, Texas.

“As we are witnessing a rise of resistance to artemisinins, these results may help [us in] finding new pathways to successor drugs.”

Dr Lichtarge and his colleagues described this research in Cell.

The team devised a computational method that allows biological information to flow from gene to gene across the supergenomic network.

“The network connects millions of genes from hundreds of species based on their interactions within the organism or based on their ancestral relations between different species,” said study author Andreas Martin Lisewski, PhD, also of the Baylor College of Medicine.

“Normally, computing the flow of functional information would be costly and slow, but we developed a compression method that reduces this gigantic network into one that is much smaller and now computationally tractable. The surprise is that these biological networks are compressible, much like digital data in today’s computers.”

To test their method, the researchers looked at functional predictions of P falciparum. It’s been more than 10 years since this parasite’s genome was fully sequenced, but little is known about the function for most of its genes.

“To better understand this disease, we need to identify more functions of the parasite’s genes,” Dr Lisewski said. “This understanding may eventually help us to stem the rise of drug-resistant malaria, such as the emerging resistance to artemisinins.”

With that in mind, the researchers used their computational method to study EXP1. And they discovered the protein is a membrane glutathione S-transferase that degrades cytotoxic hematin but is inhibited by artesunate.

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

Researchers say they’ve developed a new computational method to predict the function of disease-causing genes and proteins, and this has enabled an important discovery.

The team used the method to study EXP1, a protein known to be essential to the malaria parasite Plasmodium falciparum, although its exact mechanism has been unclear.

The research revealed that EXP1 enables the parasite to detoxify the main metabolic byproducts it creates in red blood cells.

The researchers also found that EXP1 has a direct role in drug action and susceptibility to artesunate, an important member of the artemisinin drug family.

“Through this multiyear collaborative effort, we now have an improved understanding of the protective molecular mechanisms of the malaria parasite and its drug susceptibility to artesunate,” said study author Olivier Lichtarge, MD, PhD, of the Baylor College of Medicine in Houston, Texas.

“As we are witnessing a rise of resistance to artemisinins, these results may help [us in] finding new pathways to successor drugs.”

Dr Lichtarge and his colleagues described this research in Cell.

The team devised a computational method that allows biological information to flow from gene to gene across the supergenomic network.

“The network connects millions of genes from hundreds of species based on their interactions within the organism or based on their ancestral relations between different species,” said study author Andreas Martin Lisewski, PhD, also of the Baylor College of Medicine.

“Normally, computing the flow of functional information would be costly and slow, but we developed a compression method that reduces this gigantic network into one that is much smaller and now computationally tractable. The surprise is that these biological networks are compressible, much like digital data in today’s computers.”

To test their method, the researchers looked at functional predictions of P falciparum. It’s been more than 10 years since this parasite’s genome was fully sequenced, but little is known about the function for most of its genes.

“To better understand this disease, we need to identify more functions of the parasite’s genes,” Dr Lisewski said. “This understanding may eventually help us to stem the rise of drug-resistant malaria, such as the emerging resistance to artemisinins.”

With that in mind, the researchers used their computational method to study EXP1. And they discovered the protein is a membrane glutathione S-transferase that degrades cytotoxic hematin but is inhibited by artesunate.

Plasmodium sporozoite

Credit: Ute Frevert

and Margaret Shear

Researchers say they’ve developed a new computational method to predict the function of disease-causing genes and proteins, and this has enabled an important discovery.

The team used the method to study EXP1, a protein known to be essential to the malaria parasite Plasmodium falciparum, although its exact mechanism has been unclear.

The research revealed that EXP1 enables the parasite to detoxify the main metabolic byproducts it creates in red blood cells.

The researchers also found that EXP1 has a direct role in drug action and susceptibility to artesunate, an important member of the artemisinin drug family.

“Through this multiyear collaborative effort, we now have an improved understanding of the protective molecular mechanisms of the malaria parasite and its drug susceptibility to artesunate,” said study author Olivier Lichtarge, MD, PhD, of the Baylor College of Medicine in Houston, Texas.

“As we are witnessing a rise of resistance to artemisinins, these results may help [us in] finding new pathways to successor drugs.”

Dr Lichtarge and his colleagues described this research in Cell.

The team devised a computational method that allows biological information to flow from gene to gene across the supergenomic network.

“The network connects millions of genes from hundreds of species based on their interactions within the organism or based on their ancestral relations between different species,” said study author Andreas Martin Lisewski, PhD, also of the Baylor College of Medicine.

“Normally, computing the flow of functional information would be costly and slow, but we developed a compression method that reduces this gigantic network into one that is much smaller and now computationally tractable. The surprise is that these biological networks are compressible, much like digital data in today’s computers.”

To test their method, the researchers looked at functional predictions of P falciparum. It’s been more than 10 years since this parasite’s genome was fully sequenced, but little is known about the function for most of its genes.

“To better understand this disease, we need to identify more functions of the parasite’s genes,” Dr Lisewski said. “This understanding may eventually help us to stem the rise of drug-resistant malaria, such as the emerging resistance to artemisinins.”

With that in mind, the researchers used their computational method to study EXP1. And they discovered the protein is a membrane glutathione S-transferase that degrades cytotoxic hematin but is inhibited by artesunate.

CML cells

Credit: UC San Diego

In vitro experiments have revealed new insight into tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML).

Though it’s now possible to overcome TKI resistance resulting from single BCR-ABL1 mutants, targeting compound mutants remains a challenge.

So researchers tested several TKIs on various BCR-ABL1 compound mutants to determine which drug, if any, would be most effective for each combination.

The results appear in Cancer Cell.

Thomas O’Hare, PhD, of the Huntsman Cancer Institute at the University of Utah, and his colleagues first took an inventory of clinical BCR-ABL1 compound mutations associated with TKI resistance that had been reported in the literature.

The team identified 12 kinase domain positions that account for most clinical BCR-ABL1 TKI resistance—M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396.

All of the clinically reported compound mutations include at least 1 of the 12 key positions, and most (65%) include 2. Each position has been implicated in resistance to 1 or more TKIs, including imatinib, nilotinib, dasatinib, bosutinib, rebastinib, and ponatinib.

The researchers found that some of the compound mutations they studied conferred resistance several-fold higher than that of either contributing mutation alone.

“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, also of the Huntsman Cancer Institute.

“One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”

The researchers had focused their testing on ponatinib, as the drug has proven effective against resistant CML, particularly cases with the T315I mutation. Unfortunately, ponatinib was often no match for compound mutations including T315I.

Tests did suggest that a 30 mg/day dose of ponatinib would maintain efficacy against 7 of the 8 non-T315I compound mutants tested, though the Y253H/E255V mutant proved resistant.

The researchers also found that a 15 mg/day dose of ponatinib could pre-empt outgrowth of 5 of the 8 non-T315I compound mutants, though Y253H/E255V, E255V/V299L, and F317L/F359V might be problematic.

But ponatinib proved substantially less effective against T315I-inclusive compound mutants. Nine of 10 T315I-inclusive compound mutants showed little or no sensitivity to ponatinib or any of the other TKIs tested. M244V/T315I was the only compound mutant not resistant to ponatinib.

The researchers noted that because ponatinib has proven effective against the T315I mutant in isolation, many patients treated with ponatinib are likely to have this mutation.

So it may be necessary to perform more sensitive screening on these patients to determine whether they might have T315I-inclusive compound mutants that could confer resistance.

“Fortunately, the problems we are studying affect a minority of CML patients,” Dr O’Hare said. “[S]till, this leaves some patients with no good treatment option at all. Our goal is to have a TKI option for every patient.”

According to Dr O’Hare, it’s only a matter of time until analogous compound mutations emerge in many other cancers, including acute myeloid leukemia and non-small cell lung cancer.

“Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he concluded.

CML cells

Credit: UC San Diego

In vitro experiments have revealed new insight into tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML).

Though it’s now possible to overcome TKI resistance resulting from single BCR-ABL1 mutants, targeting compound mutants remains a challenge.

So researchers tested several TKIs on various BCR-ABL1 compound mutants to determine which drug, if any, would be most effective for each combination.

The results appear in Cancer Cell.

Thomas O’Hare, PhD, of the Huntsman Cancer Institute at the University of Utah, and his colleagues first took an inventory of clinical BCR-ABL1 compound mutations associated with TKI resistance that had been reported in the literature.

The team identified 12 kinase domain positions that account for most clinical BCR-ABL1 TKI resistance—M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396.

All of the clinically reported compound mutations include at least 1 of the 12 key positions, and most (65%) include 2. Each position has been implicated in resistance to 1 or more TKIs, including imatinib, nilotinib, dasatinib, bosutinib, rebastinib, and ponatinib.

The researchers found that some of the compound mutations they studied conferred resistance several-fold higher than that of either contributing mutation alone.

“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, also of the Huntsman Cancer Institute.

“One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”

The researchers had focused their testing on ponatinib, as the drug has proven effective against resistant CML, particularly cases with the T315I mutation. Unfortunately, ponatinib was often no match for compound mutations including T315I.

Tests did suggest that a 30 mg/day dose of ponatinib would maintain efficacy against 7 of the 8 non-T315I compound mutants tested, though the Y253H/E255V mutant proved resistant.

The researchers also found that a 15 mg/day dose of ponatinib could pre-empt outgrowth of 5 of the 8 non-T315I compound mutants, though Y253H/E255V, E255V/V299L, and F317L/F359V might be problematic.

But ponatinib proved substantially less effective against T315I-inclusive compound mutants. Nine of 10 T315I-inclusive compound mutants showed little or no sensitivity to ponatinib or any of the other TKIs tested. M244V/T315I was the only compound mutant not resistant to ponatinib.

The researchers noted that because ponatinib has proven effective against the T315I mutant in isolation, many patients treated with ponatinib are likely to have this mutation.

So it may be necessary to perform more sensitive screening on these patients to determine whether they might have T315I-inclusive compound mutants that could confer resistance.

“Fortunately, the problems we are studying affect a minority of CML patients,” Dr O’Hare said. “[S]till, this leaves some patients with no good treatment option at all. Our goal is to have a TKI option for every patient.”

According to Dr O’Hare, it’s only a matter of time until analogous compound mutations emerge in many other cancers, including acute myeloid leukemia and non-small cell lung cancer.

“Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he concluded.

CML cells

Credit: UC San Diego

In vitro experiments have revealed new insight into tyrosine kinase inhibitor (TKI) resistance among patients with chronic myeloid leukemia (CML).

Though it’s now possible to overcome TKI resistance resulting from single BCR-ABL1 mutants, targeting compound mutants remains a challenge.

So researchers tested several TKIs on various BCR-ABL1 compound mutants to determine which drug, if any, would be most effective for each combination.

The results appear in Cancer Cell.

Thomas O’Hare, PhD, of the Huntsman Cancer Institute at the University of Utah, and his colleagues first took an inventory of clinical BCR-ABL1 compound mutations associated with TKI resistance that had been reported in the literature.

The team identified 12 kinase domain positions that account for most clinical BCR-ABL1 TKI resistance—M244, G250, Q252, Y253, E255, V299, F311, T315, F317, M351, F359, and H396.

All of the clinically reported compound mutations include at least 1 of the 12 key positions, and most (65%) include 2. Each position has been implicated in resistance to 1 or more TKIs, including imatinib, nilotinib, dasatinib, bosutinib, rebastinib, and ponatinib.

The researchers found that some of the compound mutations they studied conferred resistance several-fold higher than that of either contributing mutation alone.

“We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop,” said Michael Deininger, MD, PhD, also of the Huntsman Cancer Institute.

“One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”

The researchers had focused their testing on ponatinib, as the drug has proven effective against resistant CML, particularly cases with the T315I mutation. Unfortunately, ponatinib was often no match for compound mutations including T315I.

Tests did suggest that a 30 mg/day dose of ponatinib would maintain efficacy against 7 of the 8 non-T315I compound mutants tested, though the Y253H/E255V mutant proved resistant.

The researchers also found that a 15 mg/day dose of ponatinib could pre-empt outgrowth of 5 of the 8 non-T315I compound mutants, though Y253H/E255V, E255V/V299L, and F317L/F359V might be problematic.

But ponatinib proved substantially less effective against T315I-inclusive compound mutants. Nine of 10 T315I-inclusive compound mutants showed little or no sensitivity to ponatinib or any of the other TKIs tested. M244V/T315I was the only compound mutant not resistant to ponatinib.

The researchers noted that because ponatinib has proven effective against the T315I mutant in isolation, many patients treated with ponatinib are likely to have this mutation.

So it may be necessary to perform more sensitive screening on these patients to determine whether they might have T315I-inclusive compound mutants that could confer resistance.

“Fortunately, the problems we are studying affect a minority of CML patients,” Dr O’Hare said. “[S]till, this leaves some patients with no good treatment option at all. Our goal is to have a TKI option for every patient.”

According to Dr O’Hare, it’s only a matter of time until analogous compound mutations emerge in many other cancers, including acute myeloid leukemia and non-small cell lung cancer.

“Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he concluded.

Researchers in the lab

Credit: Rhoda Baer

An analysis of university discoveries licensed to biotechnology firms has revealed early bottlenecks in the drug development process.

Typically, universities do most of the basic research and then license a discovery to a small biotech firm that advances the research. The small firm will then sublicense the discovery to a large firm that can run clinical trials.

But an analysis published in Science Translational Medicine suggests the process rarely follows this straightforward path.

Instead, it often zigzags across biotech firms and between research areas before a drug is finally commercialized.

“The timeline for commercialization is much longer than most people think,” said study author Jerry Thursby, PhD, of the Georgia Institute of Technology in Atlanta.

To study the path of drug development, Dr Thursby and his colleagues built a database of 835 patents in 342 university licenses with biotech firms.

They then traced the path of patents to document whether the inventions were sublicensed to another firm for testing in a new disease category or whether the sublicense was to a large firm for clinical trials or marketing.

In all, 27% of inventions appeared in a second license (sublicense). The average time between invention and first license was 5.5 years, and the average time between first and second license was 3.5 years.

This time span is substantial, the researchers said, given that the average time from discovery to drug approval in the US is 13 years.

The team also found that sublicensing often resets the development timeline because a drug must be tested for an entirely new indication or several new indications.

The disease categories in the licenses analyzed spanned 20 distinct indications, and individual licenses included up to 5 indications. But the categories were very broad, such as “cancer” or “infectious diseases.”

Nevertheless, the researchers saw substantial changes in disease indications from the first license to the second. Only 19% of the inventions remained completely unchanged between the first and second license.

For 44% of inventions, none of the first-license indications remained in the second license. Twenty-eight percent of inventions had indications added between the first and second license, and 9% had indications subtracted.

The researchers said these results suggest a need for policies and initiatives that enhance early translation by more efficiently driving more inventions into multiple disease pipelines.

One option might be the formation of an open-source translational research database that complements clinicaltrials.gov, where patents and licenses for biomedical research thought to be destined for eventual therapeutic use would be logged and shared.

Researchers in the lab

Credit: Rhoda Baer

An analysis of university discoveries licensed to biotechnology firms has revealed early bottlenecks in the drug development process.

Typically, universities do most of the basic research and then license a discovery to a small biotech firm that advances the research. The small firm will then sublicense the discovery to a large firm that can run clinical trials.

But an analysis published in Science Translational Medicine suggests the process rarely follows this straightforward path.

Instead, it often zigzags across biotech firms and between research areas before a drug is finally commercialized.

“The timeline for commercialization is much longer than most people think,” said study author Jerry Thursby, PhD, of the Georgia Institute of Technology in Atlanta.

To study the path of drug development, Dr Thursby and his colleagues built a database of 835 patents in 342 university licenses with biotech firms.

They then traced the path of patents to document whether the inventions were sublicensed to another firm for testing in a new disease category or whether the sublicense was to a large firm for clinical trials or marketing.

In all, 27% of inventions appeared in a second license (sublicense). The average time between invention and first license was 5.5 years, and the average time between first and second license was 3.5 years.

This time span is substantial, the researchers said, given that the average time from discovery to drug approval in the US is 13 years.

The team also found that sublicensing often resets the development timeline because a drug must be tested for an entirely new indication or several new indications.

The disease categories in the licenses analyzed spanned 20 distinct indications, and individual licenses included up to 5 indications. But the categories were very broad, such as “cancer” or “infectious diseases.”

Nevertheless, the researchers saw substantial changes in disease indications from the first license to the second. Only 19% of the inventions remained completely unchanged between the first and second license.

For 44% of inventions, none of the first-license indications remained in the second license. Twenty-eight percent of inventions had indications added between the first and second license, and 9% had indications subtracted.

The researchers said these results suggest a need for policies and initiatives that enhance early translation by more efficiently driving more inventions into multiple disease pipelines.

One option might be the formation of an open-source translational research database that complements clinicaltrials.gov, where patents and licenses for biomedical research thought to be destined for eventual therapeutic use would be logged and shared.

Researchers in the lab

Credit: Rhoda Baer

An analysis of university discoveries licensed to biotechnology firms has revealed early bottlenecks in the drug development process.

Typically, universities do most of the basic research and then license a discovery to a small biotech firm that advances the research. The small firm will then sublicense the discovery to a large firm that can run clinical trials.

But an analysis published in Science Translational Medicine suggests the process rarely follows this straightforward path.

Instead, it often zigzags across biotech firms and between research areas before a drug is finally commercialized.

“The timeline for commercialization is much longer than most people think,” said study author Jerry Thursby, PhD, of the Georgia Institute of Technology in Atlanta.

To study the path of drug development, Dr Thursby and his colleagues built a database of 835 patents in 342 university licenses with biotech firms.

They then traced the path of patents to document whether the inventions were sublicensed to another firm for testing in a new disease category or whether the sublicense was to a large firm for clinical trials or marketing.

In all, 27% of inventions appeared in a second license (sublicense). The average time between invention and first license was 5.5 years, and the average time between first and second license was 3.5 years.

This time span is substantial, the researchers said, given that the average time from discovery to drug approval in the US is 13 years.

The team also found that sublicensing often resets the development timeline because a drug must be tested for an entirely new indication or several new indications.

The disease categories in the licenses analyzed spanned 20 distinct indications, and individual licenses included up to 5 indications. But the categories were very broad, such as “cancer” or “infectious diseases.”

Nevertheless, the researchers saw substantial changes in disease indications from the first license to the second. Only 19% of the inventions remained completely unchanged between the first and second license.

For 44% of inventions, none of the first-license indications remained in the second license. Twenty-eight percent of inventions had indications added between the first and second license, and 9% had indications subtracted.

The researchers said these results suggest a need for policies and initiatives that enhance early translation by more efficiently driving more inventions into multiple disease pipelines.

One option might be the formation of an open-source translational research database that complements clinicaltrials.gov, where patents and licenses for biomedical research thought to be destined for eventual therapeutic use would be logged and shared.

Researcher using a pipette

Credit: Rhoda Baer

Researchers say they have developed a pipette that can transfer a single cell at a time.

The device, called the handheld single-cell pipette (hSCP), has 2 plungers. The first is used to wash and capture a single cell, and the second can release the cell in the desired location.

Lidong Qin, PhD, of Houston Methodist Research Institute in Texas, and his colleagues described the hSCP and reported preliminary results with the device in the Journal of the American Chemical Society.

“Studying single cells and their unique functions has become a frontier in current biomedical research,” Dr Qin said. “One of the biggest challenges for single-cell research is picking out only one cell from a collection of millions of cells.”

He noted that current techniques for withdrawing single cells from a tube or Petri dish can be cumbersome, expensive, and time-consuming.

“Some old and clumsy methods are used to capture single cells,” he explained. “Some researchers use their mouths at one end of the pipette, driven by their own mouth force, to try to ensure only a minimum amount of cell suspension collected. The sample is then checked with a microscope to find out the number of cells captured. The opportunity to get only one cell is hit-or-miss and a bit troublesome.”

“One company provides a million-dollar machine that can help biologists transfer single cells to 96-well plates. Each run costs an additional $1000 to purchase the plate. Such technology will not be widely accessible to biologists.”

With that in mind, Dr Qin and his colleagues developed their 2-plunger hSCP. The first plunger withdraws fluid from a suspension of cells.

Fluid travels through canals on either side of a nanoscopic, laser-sculpted “hook” that is just big enough to trap a single cell. This hook can be altered depending on the size and type of cells a researcher is using.

The first plunger is also used to wash and separate the captured cell from other cells that may have been extracted. The second plunger pushes the captured cell out of the pipette into growth medium or onto a slide or welled plate for study.

Dr Qin said one of his goals is to make the technology cost $10 or less per run. And future designs of the hSCP will be developed with mass production in mind.

Dr Qin said his group can also produce hSCPs that pick up virtually any small number of cells, depending on a scientist’s needs, by etching more hooks during the pipette’s construction.

Researcher using a pipette

Credit: Rhoda Baer

Researchers say they have developed a pipette that can transfer a single cell at a time.

The device, called the handheld single-cell pipette (hSCP), has 2 plungers. The first is used to wash and capture a single cell, and the second can release the cell in the desired location.

Lidong Qin, PhD, of Houston Methodist Research Institute in Texas, and his colleagues described the hSCP and reported preliminary results with the device in the Journal of the American Chemical Society.

“Studying single cells and their unique functions has become a frontier in current biomedical research,” Dr Qin said. “One of the biggest challenges for single-cell research is picking out only one cell from a collection of millions of cells.”

He noted that current techniques for withdrawing single cells from a tube or Petri dish can be cumbersome, expensive, and time-consuming.

“Some old and clumsy methods are used to capture single cells,” he explained. “Some researchers use their mouths at one end of the pipette, driven by their own mouth force, to try to ensure only a minimum amount of cell suspension collected. The sample is then checked with a microscope to find out the number of cells captured. The opportunity to get only one cell is hit-or-miss and a bit troublesome.”

“One company provides a million-dollar machine that can help biologists transfer single cells to 96-well plates. Each run costs an additional $1000 to purchase the plate. Such technology will not be widely accessible to biologists.”

With that in mind, Dr Qin and his colleagues developed their 2-plunger hSCP. The first plunger withdraws fluid from a suspension of cells.

Fluid travels through canals on either side of a nanoscopic, laser-sculpted “hook” that is just big enough to trap a single cell. This hook can be altered depending on the size and type of cells a researcher is using.

The first plunger is also used to wash and separate the captured cell from other cells that may have been extracted. The second plunger pushes the captured cell out of the pipette into growth medium or onto a slide or welled plate for study.

Dr Qin said one of his goals is to make the technology cost $10 or less per run. And future designs of the hSCP will be developed with mass production in mind.

Dr Qin said his group can also produce hSCPs that pick up virtually any small number of cells, depending on a scientist’s needs, by etching more hooks during the pipette’s construction.

Researcher using a pipette

Credit: Rhoda Baer

Researchers say they have developed a pipette that can transfer a single cell at a time.

The device, called the handheld single-cell pipette (hSCP), has 2 plungers. The first is used to wash and capture a single cell, and the second can release the cell in the desired location.

Lidong Qin, PhD, of Houston Methodist Research Institute in Texas, and his colleagues described the hSCP and reported preliminary results with the device in the Journal of the American Chemical Society.

“Studying single cells and their unique functions has become a frontier in current biomedical research,” Dr Qin said. “One of the biggest challenges for single-cell research is picking out only one cell from a collection of millions of cells.”

He noted that current techniques for withdrawing single cells from a tube or Petri dish can be cumbersome, expensive, and time-consuming.

“Some old and clumsy methods are used to capture single cells,” he explained. “Some researchers use their mouths at one end of the pipette, driven by their own mouth force, to try to ensure only a minimum amount of cell suspension collected. The sample is then checked with a microscope to find out the number of cells captured. The opportunity to get only one cell is hit-or-miss and a bit troublesome.”

“One company provides a million-dollar machine that can help biologists transfer single cells to 96-well plates. Each run costs an additional $1000 to purchase the plate. Such technology will not be widely accessible to biologists.”

With that in mind, Dr Qin and his colleagues developed their 2-plunger hSCP. The first plunger withdraws fluid from a suspension of cells.

Fluid travels through canals on either side of a nanoscopic, laser-sculpted “hook” that is just big enough to trap a single cell. This hook can be altered depending on the size and type of cells a researcher is using.

The first plunger is also used to wash and separate the captured cell from other cells that may have been extracted. The second plunger pushes the captured cell out of the pipette into growth medium or onto a slide or welled plate for study.

Dr Qin said one of his goals is to make the technology cost $10 or less per run. And future designs of the hSCP will be developed with mass production in mind.

Dr Qin said his group can also produce hSCPs that pick up virtually any small number of cells, depending on a scientist’s needs, by etching more hooks during the pipette’s construction.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) has approved apixaban (Eliquis) to treat venous thromboembolism (VTE) and prevent recurrent VTE after initial therapy.

Apixaban is an oral selective factor Xa inhibitor that is already FDA approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and to prevent VTE in patients who have undergone hip or knee replacement surgery.

Apixaban’s latest FDA approval was based on results of the AMPLIFY and AMPLIFY-EXT studies.

The AMPLIFY trial

AMPLIFY included 5395 patients with confirmed, symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) who required treatment for 6 months. They had a mean age of 56.9 years, and 89.8% of randomized patients had unprovoked VTE.

About half of patients (n=2691) were randomized to receive apixaban at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.

The other half (n=2704) were randomized to the standard of care—enoxaparin at 1 mg/kg twice daily for at least 5 days until they had an INR ≥ 2 and warfarin (target INR range 2.0-3.0) for 6 months.

Apixaban proved noninferior to standard therapy in the combined primary endpoint of recurrent, symptomatic VTE (nonfatal DVT or PE) or VTE-related death. This outcome occurred in 2.3% of patients in the apixaban arm and 2.7% of patients in the standard-therapy arm (P<0.0001 for noninferiority).

Apixaban also proved superior to standard therapy with regard to bleeding. The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).

The AMPLIFY-EXT trial

AMPLIFY-EXT included 2486 patients who had completed 6 to 12 months of anticoagulation treatment for DVT or PE. Their mean age was 56.7 years, and 91.7% of randomized patients had unprovoked VTE.

Patients were randomized to receive apixaban at 2.5 mg (n=842), apixaban at 5 mg (n=815), or placebo (n=829).

Both apixaban doses were significantly superior to placebo (P<0.001) with regard to the primary efficacy endpoint, which was recurrent VTE or all-cause death.

During the 12-month active study period, these events occurred in 3.8% of patients in the 2.5 mg arm, 4.2% of patients in the 5 mg arm, and 11.6% of patients in the placebo arm.

The primary safety endpoint was the incidence of major bleeding, and there was no significant difference among the treatment arms. Major bleeding occurred in 0.2% of patients in the 2.5 mg arm, 0.1% of patients in the 5 mg arm, and 0.5% of patients in the placebo arm.

Nevertheless, apixaban has been shown to increase the risk of bleeding and can cause serious, potentially fatal, bleeding.

Apixaban’s label includes boxed warnings detailing the increased risk of thrombotic events in patients who prematurely discontinue the drug, as well as the increased risk of epidural or spinal hematoma, which may cause long-term or permanent paralysis, in patients undergoing spinal epidural anesthesia or spinal puncture.

For more information, visit eliquis.com. The drug is under joint development by Pfizer and Bristol-Myers Squibb.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) has approved apixaban (Eliquis) to treat venous thromboembolism (VTE) and prevent recurrent VTE after initial therapy.

Apixaban is an oral selective factor Xa inhibitor that is already FDA approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and to prevent VTE in patients who have undergone hip or knee replacement surgery.

Apixaban’s latest FDA approval was based on results of the AMPLIFY and AMPLIFY-EXT studies.

The AMPLIFY trial

AMPLIFY included 5395 patients with confirmed, symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) who required treatment for 6 months. They had a mean age of 56.9 years, and 89.8% of randomized patients had unprovoked VTE.

About half of patients (n=2691) were randomized to receive apixaban at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.

The other half (n=2704) were randomized to the standard of care—enoxaparin at 1 mg/kg twice daily for at least 5 days until they had an INR ≥ 2 and warfarin (target INR range 2.0-3.0) for 6 months.

Apixaban proved noninferior to standard therapy in the combined primary endpoint of recurrent, symptomatic VTE (nonfatal DVT or PE) or VTE-related death. This outcome occurred in 2.3% of patients in the apixaban arm and 2.7% of patients in the standard-therapy arm (P<0.0001 for noninferiority).

Apixaban also proved superior to standard therapy with regard to bleeding. The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).

The AMPLIFY-EXT trial

AMPLIFY-EXT included 2486 patients who had completed 6 to 12 months of anticoagulation treatment for DVT or PE. Their mean age was 56.7 years, and 91.7% of randomized patients had unprovoked VTE.

Patients were randomized to receive apixaban at 2.5 mg (n=842), apixaban at 5 mg (n=815), or placebo (n=829).

Both apixaban doses were significantly superior to placebo (P<0.001) with regard to the primary efficacy endpoint, which was recurrent VTE or all-cause death.

During the 12-month active study period, these events occurred in 3.8% of patients in the 2.5 mg arm, 4.2% of patients in the 5 mg arm, and 11.6% of patients in the placebo arm.

The primary safety endpoint was the incidence of major bleeding, and there was no significant difference among the treatment arms. Major bleeding occurred in 0.2% of patients in the 2.5 mg arm, 0.1% of patients in the 5 mg arm, and 0.5% of patients in the placebo arm.

Nevertheless, apixaban has been shown to increase the risk of bleeding and can cause serious, potentially fatal, bleeding.

Apixaban’s label includes boxed warnings detailing the increased risk of thrombotic events in patients who prematurely discontinue the drug, as well as the increased risk of epidural or spinal hematoma, which may cause long-term or permanent paralysis, in patients undergoing spinal epidural anesthesia or spinal puncture.

For more information, visit eliquis.com. The drug is under joint development by Pfizer and Bristol-Myers Squibb.

Thrombus

Credit: Kevin MacKenzie

The US Food and Drug Administration (FDA) has approved apixaban (Eliquis) to treat venous thromboembolism (VTE) and prevent recurrent VTE after initial therapy.

Apixaban is an oral selective factor Xa inhibitor that is already FDA approved to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and to prevent VTE in patients who have undergone hip or knee replacement surgery.

Apixaban’s latest FDA approval was based on results of the AMPLIFY and AMPLIFY-EXT studies.

The AMPLIFY trial

AMPLIFY included 5395 patients with confirmed, symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) who required treatment for 6 months. They had a mean age of 56.9 years, and 89.8% of randomized patients had unprovoked VTE.

About half of patients (n=2691) were randomized to receive apixaban at 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.

The other half (n=2704) were randomized to the standard of care—enoxaparin at 1 mg/kg twice daily for at least 5 days until they had an INR ≥ 2 and warfarin (target INR range 2.0-3.0) for 6 months.

Apixaban proved noninferior to standard therapy in the combined primary endpoint of recurrent, symptomatic VTE (nonfatal DVT or PE) or VTE-related death. This outcome occurred in 2.3% of patients in the apixaban arm and 2.7% of patients in the standard-therapy arm (P<0.0001 for noninferiority).

Apixaban also proved superior to standard therapy with regard to bleeding. The composite endpoint of major bleeding and clinically relevant, nonmajor bleeding occurred in 4.3% of patients in the apixaban arm and 9.7% of patients in the standard-therapy arm (P<0.001).

The AMPLIFY-EXT trial

AMPLIFY-EXT included 2486 patients who had completed 6 to 12 months of anticoagulation treatment for DVT or PE. Their mean age was 56.7 years, and 91.7% of randomized patients had unprovoked VTE.

Patients were randomized to receive apixaban at 2.5 mg (n=842), apixaban at 5 mg (n=815), or placebo (n=829).

Both apixaban doses were significantly superior to placebo (P<0.001) with regard to the primary efficacy endpoint, which was recurrent VTE or all-cause death.

During the 12-month active study period, these events occurred in 3.8% of patients in the 2.5 mg arm, 4.2% of patients in the 5 mg arm, and 11.6% of patients in the placebo arm.

The primary safety endpoint was the incidence of major bleeding, and there was no significant difference among the treatment arms. Major bleeding occurred in 0.2% of patients in the 2.5 mg arm, 0.1% of patients in the 5 mg arm, and 0.5% of patients in the placebo arm.

Nevertheless, apixaban has been shown to increase the risk of bleeding and can cause serious, potentially fatal, bleeding.

Apixaban’s label includes boxed warnings detailing the increased risk of thrombotic events in patients who prematurely discontinue the drug, as well as the increased risk of epidural or spinal hematoma, which may cause long-term or permanent paralysis, in patients undergoing spinal epidural anesthesia or spinal puncture.

For more information, visit eliquis.com. The drug is under joint development by Pfizer and Bristol-Myers Squibb.

The oral factor Xa inhibitor apixaban is now approved for the treatment of deep vein thrombosis and pulmonary embolism, and for reducing the risk of recurrent DVT and PE following initial treatment, the manufacturers have announced.

This approval is based on the results of the AMPLIFY and AMPLIFY-EXT studies, according to the statement issued by Bristol-Myers Squibb and Pfizer Aug. 21.

Apixaban, initially approved in 2012 and marketed as Eliquis, is already approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of DVT, "which may lead to PE," after hip or knee surgery. The recommended dose for the treatment of DVT and PE is 10 mg twice a day for 7 days, followed by 5 mg twice a day. The recommended dose for reducing the risk for recurrent DVT and PE, after initial therapy, is 2.5 mg twice a day.

AMPLIFY was a noninferiority study of about 5,200 patients with symptomatic DVT or PE. It compared apixaban (10 mg twice a day for 1 week, followed by 5 mg twice a day for 6 months) with standard care using enoxaparin (1 mg/kg administered subcutaneously twice a day for at least 5 days [until the international normalized ratio was at least 2], followed by warfarin for at least 5 days [target INR range of 2.0-3.0] for 6 months). The primary efficacy endpoint, a composite of recurrent symptomatic VTE or VTE-related death over 6 months, was comparable in the two groups: 2.3% among those on apixaban and 2.7% among those on enoxaparin/warfarin, according to the prescribing information.

The primary safety endpoint, major bleeding, was 0.6% among those on apixaban vs. 1.8% among those on enoxaparin/warfarin, a statistically significant difference. Rates of clinically relevant nonmajor bleeding, a secondary safety endpoint, was 3.9% among those on apixaban vs. 8% among those on enoxaparin/warfarin.

In Amplify-EXT, almost 2,500 patients who had received anticoagulant therapy for DVT and/or PE for 6-12 months and had not had a recurrent event were randomized to treatment with apixaban 2.5 or 5 mg twice a day, or placebo, followed for a mean of almost 1 year. The rate of recurrent VTE or all-cause death was 3.8% among those on 2.5 mg twice daily and 4.2% among those on 5 mg twice daily, vs. 11.6% among those on placebo; the effects of both doses were significantly more effective in reducing risk than was placebo.

In this study, the rate of bleeding-related adverse reactions was 13.3% among those on apixaban vs. 8.7% among those on placebo. The rate of major bleeding was 0.2% among those on the 2.5 mg twice-daily dose and 0.1% among those on the 5 mg twice-daily dose, vs. 0.5% among those on placebo.

The apixaban label includes a boxed warning about an increased risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture while on the drug.

Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program.

[email protected]

The oral factor Xa inhibitor apixaban is now approved for the treatment of deep vein thrombosis and pulmonary embolism, and for reducing the risk of recurrent DVT and PE following initial treatment, the manufacturers have announced.

This approval is based on the results of the AMPLIFY and AMPLIFY-EXT studies, according to the statement issued by Bristol-Myers Squibb and Pfizer Aug. 21.

Apixaban, initially approved in 2012 and marketed as Eliquis, is already approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of DVT, "which may lead to PE," after hip or knee surgery. The recommended dose for the treatment of DVT and PE is 10 mg twice a day for 7 days, followed by 5 mg twice a day. The recommended dose for reducing the risk for recurrent DVT and PE, after initial therapy, is 2.5 mg twice a day.

AMPLIFY was a noninferiority study of about 5,200 patients with symptomatic DVT or PE. It compared apixaban (10 mg twice a day for 1 week, followed by 5 mg twice a day for 6 months) with standard care using enoxaparin (1 mg/kg administered subcutaneously twice a day for at least 5 days [until the international normalized ratio was at least 2], followed by warfarin for at least 5 days [target INR range of 2.0-3.0] for 6 months). The primary efficacy endpoint, a composite of recurrent symptomatic VTE or VTE-related death over 6 months, was comparable in the two groups: 2.3% among those on apixaban and 2.7% among those on enoxaparin/warfarin, according to the prescribing information.

The primary safety endpoint, major bleeding, was 0.6% among those on apixaban vs. 1.8% among those on enoxaparin/warfarin, a statistically significant difference. Rates of clinically relevant nonmajor bleeding, a secondary safety endpoint, was 3.9% among those on apixaban vs. 8% among those on enoxaparin/warfarin.

In Amplify-EXT, almost 2,500 patients who had received anticoagulant therapy for DVT and/or PE for 6-12 months and had not had a recurrent event were randomized to treatment with apixaban 2.5 or 5 mg twice a day, or placebo, followed for a mean of almost 1 year. The rate of recurrent VTE or all-cause death was 3.8% among those on 2.5 mg twice daily and 4.2% among those on 5 mg twice daily, vs. 11.6% among those on placebo; the effects of both doses were significantly more effective in reducing risk than was placebo.

In this study, the rate of bleeding-related adverse reactions was 13.3% among those on apixaban vs. 8.7% among those on placebo. The rate of major bleeding was 0.2% among those on the 2.5 mg twice-daily dose and 0.1% among those on the 5 mg twice-daily dose, vs. 0.5% among those on placebo.

The apixaban label includes a boxed warning about an increased risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture while on the drug.

Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program.

[email protected]

The oral factor Xa inhibitor apixaban is now approved for the treatment of deep vein thrombosis and pulmonary embolism, and for reducing the risk of recurrent DVT and PE following initial treatment, the manufacturers have announced.

This approval is based on the results of the AMPLIFY and AMPLIFY-EXT studies, according to the statement issued by Bristol-Myers Squibb and Pfizer Aug. 21.

Apixaban, initially approved in 2012 and marketed as Eliquis, is already approved for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of DVT, "which may lead to PE," after hip or knee surgery. The recommended dose for the treatment of DVT and PE is 10 mg twice a day for 7 days, followed by 5 mg twice a day. The recommended dose for reducing the risk for recurrent DVT and PE, after initial therapy, is 2.5 mg twice a day.

AMPLIFY was a noninferiority study of about 5,200 patients with symptomatic DVT or PE. It compared apixaban (10 mg twice a day for 1 week, followed by 5 mg twice a day for 6 months) with standard care using enoxaparin (1 mg/kg administered subcutaneously twice a day for at least 5 days [until the international normalized ratio was at least 2], followed by warfarin for at least 5 days [target INR range of 2.0-3.0] for 6 months). The primary efficacy endpoint, a composite of recurrent symptomatic VTE or VTE-related death over 6 months, was comparable in the two groups: 2.3% among those on apixaban and 2.7% among those on enoxaparin/warfarin, according to the prescribing information.

The primary safety endpoint, major bleeding, was 0.6% among those on apixaban vs. 1.8% among those on enoxaparin/warfarin, a statistically significant difference. Rates of clinically relevant nonmajor bleeding, a secondary safety endpoint, was 3.9% among those on apixaban vs. 8% among those on enoxaparin/warfarin.

In Amplify-EXT, almost 2,500 patients who had received anticoagulant therapy for DVT and/or PE for 6-12 months and had not had a recurrent event were randomized to treatment with apixaban 2.5 or 5 mg twice a day, or placebo, followed for a mean of almost 1 year. The rate of recurrent VTE or all-cause death was 3.8% among those on 2.5 mg twice daily and 4.2% among those on 5 mg twice daily, vs. 11.6% among those on placebo; the effects of both doses were significantly more effective in reducing risk than was placebo.

In this study, the rate of bleeding-related adverse reactions was 13.3% among those on apixaban vs. 8.7% among those on placebo. The rate of major bleeding was 0.2% among those on the 2.5 mg twice-daily dose and 0.1% among those on the 5 mg twice-daily dose, vs. 0.5% among those on placebo.

The apixaban label includes a boxed warning about an increased risk of spinal/epidural hematoma in patients undergoing neuraxial anesthesia or spinal puncture while on the drug.

Serious adverse events associated with apixaban should be reported to the FDA’s MedWatch program.

[email protected]

Clinical question

For patients receiving mechanical ventilation, does routine oral care with chlorhexidine improve outcomes?

Bottom line

Oral care with chlorhexidine decreases the incidence of respiratory tract infections in mechanically ventilated cardiac surgery patients, but not in noncardiac surgery patients. Additionally, the use of chlorhexidine does not have a statistically significant effect on mortality, length of stay (LOS), or duration of mechanical ventilation in either population. Further research is needed to determine the benefit and safety of this common intervention in different patient populations. (LOE = 1a)

Reference

Klompas M, Speck K, Howell MD, Greene LR, Berenholtz SM. Reappraisal of routine oral care with chlorhexidine gluconate for patients receiving mechanical ventilation. JAMA Intern Med 2014;174(5):751-761.

Study design

Meta-analysis (randomized controlled trials)

Funding source

Unknown/not stated

Allocation

Uncertain

Setting

Inpatient (ICU only)

Synopsis

Previous meta-analyses demonstrated the effectiveness of chlorhexidine in the intensive care unit (ICU) for the prevention of ventilator-associated pneumonia, but did not distinguish between cardiac surgery and noncardiac surgery populations. These investigators searched multiple databases including PubMed and Embase, as well as reviewed reference lists of retrieved articles, to find randomized controlled trials that evaluated oral care with chlorhexidine versus oral care with placebo in mechanically ventilated patients for the prevention of nosocomial pneumonia, mortality, LOS, duration of mechanical ventilation, and antibiotic exposure. Two authors independently assessed the studies for inclusion and abstraction of data. The included studies were then rated for quality based on randomization strategy, allocation concealment, blinding, and completeness of follow-up. Of the 16 studies included in the review, 7 took place in combined medical–surgical units, 3 were in cardiac surgery units, and the rest were in other surgical or medical units. The presence of double-blinding in a study correlated with a higher quality rating. Data from the 3 studies of cardiac surgery patients showed fewer respiratory infections in patients receiving chlorhexidine (relative risk [RR] = 0.56; 95% CI, 0.41-0.77), but no association with mortality. The 13 studies involving noncardiac surgery patients, all of which focused specifically on ventilator-associated pneumonia, showed no significant difference in risk, even when the data was limited to the higher quality double-blind studies. However, there was a nonsignificant trend toward higher mortality with chlorhexidine use in this group of trials (RR = 1.13; 0.99-1.29). No significant differences were noted for the duration of mechanical ventilation, ICU LOS, hospital LOS, or antibiotic exposure, though data was limited for the latter 2 outcomes. The authors note that decreased exposure to an endotracheal tube in cardiac surgery patients, as compared with noncardiac surgery patients, may account for the decreased risk of pneumonia seen in this population. The potential increase in mortality in noncardiac surgery patients is harder to explain, but the authors postulate that this may be due to aspiration of chlorhexidine leading to acute lung injury.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

For patients receiving mechanical ventilation, does routine oral care with chlorhexidine improve outcomes?

Bottom line

Oral care with chlorhexidine decreases the incidence of respiratory tract infections in mechanically ventilated cardiac surgery patients, but not in noncardiac surgery patients. Additionally, the use of chlorhexidine does not have a statistically significant effect on mortality, length of stay (LOS), or duration of mechanical ventilation in either population. Further research is needed to determine the benefit and safety of this common intervention in different patient populations. (LOE = 1a)

Reference

Klompas M, Speck K, Howell MD, Greene LR, Berenholtz SM. Reappraisal of routine oral care with chlorhexidine gluconate for patients receiving mechanical ventilation. JAMA Intern Med 2014;174(5):751-761.

Study design

Meta-analysis (randomized controlled trials)

Funding source

Unknown/not stated

Allocation

Uncertain

Setting

Inpatient (ICU only)

Synopsis

Previous meta-analyses demonstrated the effectiveness of chlorhexidine in the intensive care unit (ICU) for the prevention of ventilator-associated pneumonia, but did not distinguish between cardiac surgery and noncardiac surgery populations. These investigators searched multiple databases including PubMed and Embase, as well as reviewed reference lists of retrieved articles, to find randomized controlled trials that evaluated oral care with chlorhexidine versus oral care with placebo in mechanically ventilated patients for the prevention of nosocomial pneumonia, mortality, LOS, duration of mechanical ventilation, and antibiotic exposure. Two authors independently assessed the studies for inclusion and abstraction of data. The included studies were then rated for quality based on randomization strategy, allocation concealment, blinding, and completeness of follow-up. Of the 16 studies included in the review, 7 took place in combined medical–surgical units, 3 were in cardiac surgery units, and the rest were in other surgical or medical units. The presence of double-blinding in a study correlated with a higher quality rating. Data from the 3 studies of cardiac surgery patients showed fewer respiratory infections in patients receiving chlorhexidine (relative risk [RR] = 0.56; 95% CI, 0.41-0.77), but no association with mortality. The 13 studies involving noncardiac surgery patients, all of which focused specifically on ventilator-associated pneumonia, showed no significant difference in risk, even when the data was limited to the higher quality double-blind studies. However, there was a nonsignificant trend toward higher mortality with chlorhexidine use in this group of trials (RR = 1.13; 0.99-1.29). No significant differences were noted for the duration of mechanical ventilation, ICU LOS, hospital LOS, or antibiotic exposure, though data was limited for the latter 2 outcomes. The authors note that decreased exposure to an endotracheal tube in cardiac surgery patients, as compared with noncardiac surgery patients, may account for the decreased risk of pneumonia seen in this population. The potential increase in mortality in noncardiac surgery patients is harder to explain, but the authors postulate that this may be due to aspiration of chlorhexidine leading to acute lung injury.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.

Clinical question

For patients receiving mechanical ventilation, does routine oral care with chlorhexidine improve outcomes?

Bottom line

Oral care with chlorhexidine decreases the incidence of respiratory tract infections in mechanically ventilated cardiac surgery patients, but not in noncardiac surgery patients. Additionally, the use of chlorhexidine does not have a statistically significant effect on mortality, length of stay (LOS), or duration of mechanical ventilation in either population. Further research is needed to determine the benefit and safety of this common intervention in different patient populations. (LOE = 1a)

Reference

Klompas M, Speck K, Howell MD, Greene LR, Berenholtz SM. Reappraisal of routine oral care with chlorhexidine gluconate for patients receiving mechanical ventilation. JAMA Intern Med 2014;174(5):751-761.

Study design

Meta-analysis (randomized controlled trials)

Funding source

Unknown/not stated

Allocation

Uncertain

Setting

Inpatient (ICU only)

Synopsis

Previous meta-analyses demonstrated the effectiveness of chlorhexidine in the intensive care unit (ICU) for the prevention of ventilator-associated pneumonia, but did not distinguish between cardiac surgery and noncardiac surgery populations. These investigators searched multiple databases including PubMed and Embase, as well as reviewed reference lists of retrieved articles, to find randomized controlled trials that evaluated oral care with chlorhexidine versus oral care with placebo in mechanically ventilated patients for the prevention of nosocomial pneumonia, mortality, LOS, duration of mechanical ventilation, and antibiotic exposure. Two authors independently assessed the studies for inclusion and abstraction of data. The included studies were then rated for quality based on randomization strategy, allocation concealment, blinding, and completeness of follow-up. Of the 16 studies included in the review, 7 took place in combined medical–surgical units, 3 were in cardiac surgery units, and the rest were in other surgical or medical units. The presence of double-blinding in a study correlated with a higher quality rating. Data from the 3 studies of cardiac surgery patients showed fewer respiratory infections in patients receiving chlorhexidine (relative risk [RR] = 0.56; 95% CI, 0.41-0.77), but no association with mortality. The 13 studies involving noncardiac surgery patients, all of which focused specifically on ventilator-associated pneumonia, showed no significant difference in risk, even when the data was limited to the higher quality double-blind studies. However, there was a nonsignificant trend toward higher mortality with chlorhexidine use in this group of trials (RR = 1.13; 0.99-1.29). No significant differences were noted for the duration of mechanical ventilation, ICU LOS, hospital LOS, or antibiotic exposure, though data was limited for the latter 2 outcomes. The authors note that decreased exposure to an endotracheal tube in cardiac surgery patients, as compared with noncardiac surgery patients, may account for the decreased risk of pneumonia seen in this population. The potential increase in mortality in noncardiac surgery patients is harder to explain, but the authors postulate that this may be due to aspiration of chlorhexidine leading to acute lung injury.

Dr. Kulkarni is an assistant professor of hospital medicine at Northwestern University in Chicago.