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Antibiotic recalled due to presence of particulates
Cubist Pharmaceuticals, Inc. is recalling 9 lots of the antibiotic Cubicin (daptomycin for injection), following complaints of foreign particulate matter in reconstituted vials.
Particulate matter in an intravenous drug poses a risk of thromboembolism and pulmonary embolism.
Other risks include phlebitis, the mechanical blocking of the capillaries or arterioles, the activation of platelets, the generation of microthrombi, and the formation of granulomas.
To date, there have been no adverse events associated with complaints of particulate matter from the 9 lots of Cubicin being recalled.
Cubicin is an intravenous product indicated for the treatment of skin infections and certain blood stream infections. The drug was distributed throughout the US, so the recall is nationwide.
The recall includes the following lots of Cubicin 500 mg (NDC 67919-011-01, UPC 3 67919-011-01 6):
Lot # Expiration date Ship dates
CDC203 DEC 2015 9/2/13 through 9/24/13
CDC207 JAN 2016 9/16/13 through 10/15/13
CDC213 FEB 2016 10/1/13 through 10/7/13
CDC217 MAR 2016 12/2/13 through 12/11/13
CDC226 APR 2016 7/29/13 through 8/26/13
CDC234 MAY 2016 8/26/13 through 9/19/13
CDC235 MAY 2016 9/19/13 through 10/17/13
CDC243 JUL 2016 10/17/13 through 11/12/13
CDC246 JUL 2016 11/12/13 through 12/2/13
Cubist Pharmaceuticals is notifying customers of this recall by letter and phone. Customers with product from the recalled lots should quarantine the product and discontinue distribution.
To arrange for the return and replacement of product, call Cubist at (855) 534-8309 between the hours of 9 am and 7 pm EDT, Monday through Friday.
Healthcare professionals and pharmacists with medical questions regarding this recall can contact Cubist Medical Information at (877) 282-4786 between the hours of 8 am and 5:30 pm EDT, Monday through Friday.
Adverse events or quality problems associated with the use of this product can be reported to the Food and Drug Administration’s MedWatch Adverse Events Program. 
Cubist Pharmaceuticals, Inc. is recalling 9 lots of the antibiotic Cubicin (daptomycin for injection), following complaints of foreign particulate matter in reconstituted vials.
Particulate matter in an intravenous drug poses a risk of thromboembolism and pulmonary embolism.
Other risks include phlebitis, the mechanical blocking of the capillaries or arterioles, the activation of platelets, the generation of microthrombi, and the formation of granulomas.
To date, there have been no adverse events associated with complaints of particulate matter from the 9 lots of Cubicin being recalled.
Cubicin is an intravenous product indicated for the treatment of skin infections and certain blood stream infections. The drug was distributed throughout the US, so the recall is nationwide.
The recall includes the following lots of Cubicin 500 mg (NDC 67919-011-01, UPC 3 67919-011-01 6):
Lot # Expiration date Ship dates
CDC203 DEC 2015 9/2/13 through 9/24/13
CDC207 JAN 2016 9/16/13 through 10/15/13
CDC213 FEB 2016 10/1/13 through 10/7/13
CDC217 MAR 2016 12/2/13 through 12/11/13
CDC226 APR 2016 7/29/13 through 8/26/13
CDC234 MAY 2016 8/26/13 through 9/19/13
CDC235 MAY 2016 9/19/13 through 10/17/13
CDC243 JUL 2016 10/17/13 through 11/12/13
CDC246 JUL 2016 11/12/13 through 12/2/13
Cubist Pharmaceuticals is notifying customers of this recall by letter and phone. Customers with product from the recalled lots should quarantine the product and discontinue distribution.
To arrange for the return and replacement of product, call Cubist at (855) 534-8309 between the hours of 9 am and 7 pm EDT, Monday through Friday.
Healthcare professionals and pharmacists with medical questions regarding this recall can contact Cubist Medical Information at (877) 282-4786 between the hours of 8 am and 5:30 pm EDT, Monday through Friday.
Adverse events or quality problems associated with the use of this product can be reported to the Food and Drug Administration’s MedWatch Adverse Events Program.
Cubist Pharmaceuticals, Inc. is recalling 9 lots of the antibiotic Cubicin (daptomycin for injection), following complaints of foreign particulate matter in reconstituted vials.
Particulate matter in an intravenous drug poses a risk of thromboembolism and pulmonary embolism.
Other risks include phlebitis, the mechanical blocking of the capillaries or arterioles, the activation of platelets, the generation of microthrombi, and the formation of granulomas.
To date, there have been no adverse events associated with complaints of particulate matter from the 9 lots of Cubicin being recalled.
Cubicin is an intravenous product indicated for the treatment of skin infections and certain blood stream infections. The drug was distributed throughout the US, so the recall is nationwide.
The recall includes the following lots of Cubicin 500 mg (NDC 67919-011-01, UPC 3 67919-011-01 6):
Lot # Expiration date Ship dates
CDC203 DEC 2015 9/2/13 through 9/24/13
CDC207 JAN 2016 9/16/13 through 10/15/13
CDC213 FEB 2016 10/1/13 through 10/7/13
CDC217 MAR 2016 12/2/13 through 12/11/13
CDC226 APR 2016 7/29/13 through 8/26/13
CDC234 MAY 2016 8/26/13 through 9/19/13
CDC235 MAY 2016 9/19/13 through 10/17/13
CDC243 JUL 2016 10/17/13 through 11/12/13
CDC246 JUL 2016 11/12/13 through 12/2/13
Cubist Pharmaceuticals is notifying customers of this recall by letter and phone. Customers with product from the recalled lots should quarantine the product and discontinue distribution.
To arrange for the return and replacement of product, call Cubist at (855) 534-8309 between the hours of 9 am and 7 pm EDT, Monday through Friday.
Healthcare professionals and pharmacists with medical questions regarding this recall can contact Cubist Medical Information at (877) 282-4786 between the hours of 8 am and 5:30 pm EDT, Monday through Friday.
Adverse events or quality problems associated with the use of this product can be reported to the Food and Drug Administration’s MedWatch Adverse Events Program.
Method reveals unexpected hematopoiesis discovery
in the bone marrow
A new epigenetic profiling technique has allowed researchers to chart histone dynamics during hematopoiesis, and it has produced some surprising results.
The researchers developed a high-sensitivity, indexing-first chromatin immunoprecipitation approach (iChIP) that requires as few as 500 cells for accurate analysis.
The techniques currently in use require millions of cells for accurate detection and analysis, but iCHIP overcomes this limitation.
David Lara-Astiaso, of the Weizmann Institute of Science in Rehovot, Israel, and his colleagues described the new method in Science.
The team used iCHIP to profile the dynamics of 4 chromatin modifications across 16 stages of hematopoietic differentiation.
“Using this powerful approach, we were able to identify the exact DNA regulatory sequences, as well as the various regulatory proteins, that are involved in controlling stem cell fate, casting light on previously unseen parts of the basic program of life,” said Nir Friedman, PhD, of the Hebrew University of Jerusalem in Israel.
The research also suggested that as many as 50% of these regulatory sequences are established and opened during intermediate stages of cell development. This means epigenetics are active at stages in which we thought cell destiny was already set.
“This changes our whole understanding of the process of blood stem cell fate decisions,” Lara-Astiaso said.
“[The discovery suggests] the process is more dynamic and flexible than previously thought, giving the cell slightly more leeway at the later stages in deciding what type of cell to turn into, in case its circumstances change.”
Although this research was conducted on mouse HSCs, the researchers believe the mechanism may hold true for other types of cells as well.
“This research creates a lot of excitement in the field, as it sets the groundwork to study these regulatory elements in humans,” said Assaf Weiner, of the Hebrew University of Jerusalem.
Discovering the exact regulatory DNA sequence controlling the fate of hematopoietic stem cells, as well as understanding the mechanism, holds promise for the development of diagnostic tools and therapeutic interventions, the researchers noted.
in the bone marrow
A new epigenetic profiling technique has allowed researchers to chart histone dynamics during hematopoiesis, and it has produced some surprising results.
The researchers developed a high-sensitivity, indexing-first chromatin immunoprecipitation approach (iChIP) that requires as few as 500 cells for accurate analysis.
The techniques currently in use require millions of cells for accurate detection and analysis, but iCHIP overcomes this limitation.
David Lara-Astiaso, of the Weizmann Institute of Science in Rehovot, Israel, and his colleagues described the new method in Science.
The team used iCHIP to profile the dynamics of 4 chromatin modifications across 16 stages of hematopoietic differentiation.
“Using this powerful approach, we were able to identify the exact DNA regulatory sequences, as well as the various regulatory proteins, that are involved in controlling stem cell fate, casting light on previously unseen parts of the basic program of life,” said Nir Friedman, PhD, of the Hebrew University of Jerusalem in Israel.
The research also suggested that as many as 50% of these regulatory sequences are established and opened during intermediate stages of cell development. This means epigenetics are active at stages in which we thought cell destiny was already set.
“This changes our whole understanding of the process of blood stem cell fate decisions,” Lara-Astiaso said.
“[The discovery suggests] the process is more dynamic and flexible than previously thought, giving the cell slightly more leeway at the later stages in deciding what type of cell to turn into, in case its circumstances change.”
Although this research was conducted on mouse HSCs, the researchers believe the mechanism may hold true for other types of cells as well.
“This research creates a lot of excitement in the field, as it sets the groundwork to study these regulatory elements in humans,” said Assaf Weiner, of the Hebrew University of Jerusalem.
Discovering the exact regulatory DNA sequence controlling the fate of hematopoietic stem cells, as well as understanding the mechanism, holds promise for the development of diagnostic tools and therapeutic interventions, the researchers noted.
in the bone marrow
A new epigenetic profiling technique has allowed researchers to chart histone dynamics during hematopoiesis, and it has produced some surprising results.
The researchers developed a high-sensitivity, indexing-first chromatin immunoprecipitation approach (iChIP) that requires as few as 500 cells for accurate analysis.
The techniques currently in use require millions of cells for accurate detection and analysis, but iCHIP overcomes this limitation.
David Lara-Astiaso, of the Weizmann Institute of Science in Rehovot, Israel, and his colleagues described the new method in Science.
The team used iCHIP to profile the dynamics of 4 chromatin modifications across 16 stages of hematopoietic differentiation.
“Using this powerful approach, we were able to identify the exact DNA regulatory sequences, as well as the various regulatory proteins, that are involved in controlling stem cell fate, casting light on previously unseen parts of the basic program of life,” said Nir Friedman, PhD, of the Hebrew University of Jerusalem in Israel.
The research also suggested that as many as 50% of these regulatory sequences are established and opened during intermediate stages of cell development. This means epigenetics are active at stages in which we thought cell destiny was already set.
“This changes our whole understanding of the process of blood stem cell fate decisions,” Lara-Astiaso said.
“[The discovery suggests] the process is more dynamic and flexible than previously thought, giving the cell slightly more leeway at the later stages in deciding what type of cell to turn into, in case its circumstances change.”
Although this research was conducted on mouse HSCs, the researchers believe the mechanism may hold true for other types of cells as well.
“This research creates a lot of excitement in the field, as it sets the groundwork to study these regulatory elements in humans,” said Assaf Weiner, of the Hebrew University of Jerusalem.
Discovering the exact regulatory DNA sequence controlling the fate of hematopoietic stem cells, as well as understanding the mechanism, holds promise for the development of diagnostic tools and therapeutic interventions, the researchers noted.
New insight into stem cell differentiation
Adam Engler, UC San Diego
Jacobs School of Engineering
The stiffness of the extracellular matrix may play a larger role in stem cell differentiation than we thought, according to a new study.
Scientists have recently suggested that protein tethering and matrix porosity, as well as matrix stiffness and ligand type, regulate stem cell differentiation.
However, new research published in Nature Materials indicates that matrix stiffness regulates stem cell differentiation independently of tethering and porosity.
Adam Engler, PhD, of the University of California, San Diego, and his colleagues discovered that human adipose stromal cells and mesenchymal stromal cells underwent osteogenic differentiation if placed in a stiff hydrogel. But the cells underwent adipogenesis if placed in a soft hydrogel.
The protein binding the stem cell to the hydrogel was not a factor in the differentiation process. Results suggested the protein layer was merely an adhesive.
The researchers found that stem cell differentiation is a response to the mechanical deformation of the hydrogel from the force exerted by the cell. With a series of experiments, the team showed that this happens whether the protein tethering the cell to the matrix is tight, loose, or nonexistent.
Across multiple samples using a stiff matrix, varying the degree of tethering made no significant difference in the rate of osteogenic or adipogenic differentiation.
Likewise, the size of the pores in the matrix had no effect on stem cell differentiation, as long as the stiffness of the hydrogel remained the same.
However, Dr Engler pointed out that matrix stiffness is only “one cue out of dozens that are important in stem cell differentiation.”
“That doesn’t mean the other cues are irrelevant,” he noted. “They may still push the cells into a specific cell type. We have just ruled out porosity and tethering, and further emphasized stiffness in this process.”
Adam Engler, UC San Diego
Jacobs School of Engineering
The stiffness of the extracellular matrix may play a larger role in stem cell differentiation than we thought, according to a new study.
Scientists have recently suggested that protein tethering and matrix porosity, as well as matrix stiffness and ligand type, regulate stem cell differentiation.
However, new research published in Nature Materials indicates that matrix stiffness regulates stem cell differentiation independently of tethering and porosity.
Adam Engler, PhD, of the University of California, San Diego, and his colleagues discovered that human adipose stromal cells and mesenchymal stromal cells underwent osteogenic differentiation if placed in a stiff hydrogel. But the cells underwent adipogenesis if placed in a soft hydrogel.
The protein binding the stem cell to the hydrogel was not a factor in the differentiation process. Results suggested the protein layer was merely an adhesive.
The researchers found that stem cell differentiation is a response to the mechanical deformation of the hydrogel from the force exerted by the cell. With a series of experiments, the team showed that this happens whether the protein tethering the cell to the matrix is tight, loose, or nonexistent.
Across multiple samples using a stiff matrix, varying the degree of tethering made no significant difference in the rate of osteogenic or adipogenic differentiation.
Likewise, the size of the pores in the matrix had no effect on stem cell differentiation, as long as the stiffness of the hydrogel remained the same.
However, Dr Engler pointed out that matrix stiffness is only “one cue out of dozens that are important in stem cell differentiation.”
“That doesn’t mean the other cues are irrelevant,” he noted. “They may still push the cells into a specific cell type. We have just ruled out porosity and tethering, and further emphasized stiffness in this process.”
Adam Engler, UC San Diego
Jacobs School of Engineering
The stiffness of the extracellular matrix may play a larger role in stem cell differentiation than we thought, according to a new study.
Scientists have recently suggested that protein tethering and matrix porosity, as well as matrix stiffness and ligand type, regulate stem cell differentiation.
However, new research published in Nature Materials indicates that matrix stiffness regulates stem cell differentiation independently of tethering and porosity.
Adam Engler, PhD, of the University of California, San Diego, and his colleagues discovered that human adipose stromal cells and mesenchymal stromal cells underwent osteogenic differentiation if placed in a stiff hydrogel. But the cells underwent adipogenesis if placed in a soft hydrogel.
The protein binding the stem cell to the hydrogel was not a factor in the differentiation process. Results suggested the protein layer was merely an adhesive.
The researchers found that stem cell differentiation is a response to the mechanical deformation of the hydrogel from the force exerted by the cell. With a series of experiments, the team showed that this happens whether the protein tethering the cell to the matrix is tight, loose, or nonexistent.
Across multiple samples using a stiff matrix, varying the degree of tethering made no significant difference in the rate of osteogenic or adipogenic differentiation.
Likewise, the size of the pores in the matrix had no effect on stem cell differentiation, as long as the stiffness of the hydrogel remained the same.
However, Dr Engler pointed out that matrix stiffness is only “one cue out of dozens that are important in stem cell differentiation.”
“That doesn’t mean the other cues are irrelevant,” he noted. “They may still push the cells into a specific cell type. We have just ruled out porosity and tethering, and further emphasized stiffness in this process.”
FDA approves bortezomib retreatment in MM
The US Food and Drug Administration (FDA) has approved bortezomib (Velcade) for the retreatment of adults with multiple myeloma (MM) who previously responded to bortezomib and relapsed at least 6 months after that treatment.
Bortezomib’s label has been updated to include dosing guidelines and safety and efficacy findings for single-agent bortezomib and bortezomib in combination with dexamethasone in patients previously treated with bortezomib.
Bortezomib retreatment may be started at the last dose the patient tolerated.
The FDA approved bortezomib retreatment based on results of the phase 2 RETRIEVE study and other supportive data.
The single-arm RETRIEVE trial included 130 MM patients aged 18 years and older who had previously responded to bortezomib-based therapy and relapsed at least 6 months after the treatment. The patients had received a median of 2 prior therapies (range, 1 to 7).
In this study, 94 of the patients received bortezomib in combination with dexamethasone.
One patient achieved complete response to treatment, and 49 achieved partial responses, for an overall response rate of 38.5%. The median duration of response was 6.5 months (range, 0.6 to 19.3 months).
The safety profile with bortezomib retreatment was consistent with the known safety profile of intravenous bortezomib in relapsed MM. Researchers did not observer cumulative toxicities upon retreatment.
The most common adverse event was thrombocytopenia, which occurred in 52% of patients. The incidence of grade 3 or higher thrombocytopenia was 24%.
Peripheral neuropathy was also common, occurring in 28% of patients. Grade 3 or higher peripheral neuropathy occurred in 6% of patients.
The rate of serious adverse events was 12.3%. The most commonly reported serious adverse events were thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster (1.5%), and pneumonia (1.5%). Adverse events leading to discontinuation occurred in 13% of patients.
Bortezomib is co-developed by Millennium/Takeda and Janssen Pharmaceutical Companies. Millennium is responsible for commercialization of bortezomib in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world.
Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote bortezomib in Japan. Bortezomib is approved in more than 90 countries.
The US Food and Drug Administration (FDA) has approved bortezomib (Velcade) for the retreatment of adults with multiple myeloma (MM) who previously responded to bortezomib and relapsed at least 6 months after that treatment.
Bortezomib’s label has been updated to include dosing guidelines and safety and efficacy findings for single-agent bortezomib and bortezomib in combination with dexamethasone in patients previously treated with bortezomib.
Bortezomib retreatment may be started at the last dose the patient tolerated.
The FDA approved bortezomib retreatment based on results of the phase 2 RETRIEVE study and other supportive data.
The single-arm RETRIEVE trial included 130 MM patients aged 18 years and older who had previously responded to bortezomib-based therapy and relapsed at least 6 months after the treatment. The patients had received a median of 2 prior therapies (range, 1 to 7).
In this study, 94 of the patients received bortezomib in combination with dexamethasone.
One patient achieved complete response to treatment, and 49 achieved partial responses, for an overall response rate of 38.5%. The median duration of response was 6.5 months (range, 0.6 to 19.3 months).
The safety profile with bortezomib retreatment was consistent with the known safety profile of intravenous bortezomib in relapsed MM. Researchers did not observer cumulative toxicities upon retreatment.
The most common adverse event was thrombocytopenia, which occurred in 52% of patients. The incidence of grade 3 or higher thrombocytopenia was 24%.
Peripheral neuropathy was also common, occurring in 28% of patients. Grade 3 or higher peripheral neuropathy occurred in 6% of patients.
The rate of serious adverse events was 12.3%. The most commonly reported serious adverse events were thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster (1.5%), and pneumonia (1.5%). Adverse events leading to discontinuation occurred in 13% of patients.
Bortezomib is co-developed by Millennium/Takeda and Janssen Pharmaceutical Companies. Millennium is responsible for commercialization of bortezomib in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world.
Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote bortezomib in Japan. Bortezomib is approved in more than 90 countries.
The US Food and Drug Administration (FDA) has approved bortezomib (Velcade) for the retreatment of adults with multiple myeloma (MM) who previously responded to bortezomib and relapsed at least 6 months after that treatment.
Bortezomib’s label has been updated to include dosing guidelines and safety and efficacy findings for single-agent bortezomib and bortezomib in combination with dexamethasone in patients previously treated with bortezomib.
Bortezomib retreatment may be started at the last dose the patient tolerated.
The FDA approved bortezomib retreatment based on results of the phase 2 RETRIEVE study and other supportive data.
The single-arm RETRIEVE trial included 130 MM patients aged 18 years and older who had previously responded to bortezomib-based therapy and relapsed at least 6 months after the treatment. The patients had received a median of 2 prior therapies (range, 1 to 7).
In this study, 94 of the patients received bortezomib in combination with dexamethasone.
One patient achieved complete response to treatment, and 49 achieved partial responses, for an overall response rate of 38.5%. The median duration of response was 6.5 months (range, 0.6 to 19.3 months).
The safety profile with bortezomib retreatment was consistent with the known safety profile of intravenous bortezomib in relapsed MM. Researchers did not observer cumulative toxicities upon retreatment.
The most common adverse event was thrombocytopenia, which occurred in 52% of patients. The incidence of grade 3 or higher thrombocytopenia was 24%.
Peripheral neuropathy was also common, occurring in 28% of patients. Grade 3 or higher peripheral neuropathy occurred in 6% of patients.
The rate of serious adverse events was 12.3%. The most commonly reported serious adverse events were thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster (1.5%), and pneumonia (1.5%). Adverse events leading to discontinuation occurred in 13% of patients.
Bortezomib is co-developed by Millennium/Takeda and Janssen Pharmaceutical Companies. Millennium is responsible for commercialization of bortezomib in the US. Janssen Pharmaceutical Companies are responsible for commercialization in Europe and the rest of the world.
Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. co-promote bortezomib in Japan. Bortezomib is approved in more than 90 countries.
Method could speed up cancer diagnosis
Credit: NIGMS
A new technique could enable faster diagnosis of cancer and various prenatal conditions, according to a paper published in Proceedings of the National Academy of Sciences.
The method, known as convex lens-induced confinement (CLIC), allows researchers to load long strands of DNA into a tunable, nanoscale imaging chamber in ways that maintain their structural identity and under conditions that are similar to those in the human body.
CLIC lets researchers map large genomes rapidly and identify specific gene sequences from single cells with single-molecule resolution, a process that is critical to diagnosing diseases like cancer.
“Current practices of genomic analysis typically require tens of thousands of cells worth of genomic material to obtain the information we need, but this new approach works with single cells,” said study author Rob Sladek, MD, of McGill University in Montreal, Canada.
“CLIC will allow researchers to avoid having to spend time stitching together maps of entire genomes, as we do under current techniques, and promises to make genomic analysis a much simpler and more efficient process.”
The CLIC imaging chamber can sit on top of a standard inverted fluorescence microscope, and strands of DNA can be loaded into the chamber from above, which allows the strands to maintain their integrity.
Existing tools used for genomic analysis rely on side-loading DNA under pressure into nanochannels in the imaging chamber. This breaks the DNA molecules into small pieces, making it a challenge to reconstruct the genome.
CLIC, on the other hand, is “like squeezing many soft spaghetti noodles into long, narrow tubes without breaking them,” according to study author Sabrina Leslie, PhD, also of McGill University.
“Once these long strands of DNA are gently squeezed down into nanochannels from a nanoscale bath above, they become effectively rigid, which means that we can map positions along uniformly stretched strands of DNA, while holding them still,” she said.
“This means diagnostics can be performed quickly, one cell at a time, which is critical for diagnosing many prenatal conditions and the onset of cancer.”
Credit: NIGMS
A new technique could enable faster diagnosis of cancer and various prenatal conditions, according to a paper published in Proceedings of the National Academy of Sciences.
The method, known as convex lens-induced confinement (CLIC), allows researchers to load long strands of DNA into a tunable, nanoscale imaging chamber in ways that maintain their structural identity and under conditions that are similar to those in the human body.
CLIC lets researchers map large genomes rapidly and identify specific gene sequences from single cells with single-molecule resolution, a process that is critical to diagnosing diseases like cancer.
“Current practices of genomic analysis typically require tens of thousands of cells worth of genomic material to obtain the information we need, but this new approach works with single cells,” said study author Rob Sladek, MD, of McGill University in Montreal, Canada.
“CLIC will allow researchers to avoid having to spend time stitching together maps of entire genomes, as we do under current techniques, and promises to make genomic analysis a much simpler and more efficient process.”
The CLIC imaging chamber can sit on top of a standard inverted fluorescence microscope, and strands of DNA can be loaded into the chamber from above, which allows the strands to maintain their integrity.
Existing tools used for genomic analysis rely on side-loading DNA under pressure into nanochannels in the imaging chamber. This breaks the DNA molecules into small pieces, making it a challenge to reconstruct the genome.
CLIC, on the other hand, is “like squeezing many soft spaghetti noodles into long, narrow tubes without breaking them,” according to study author Sabrina Leslie, PhD, also of McGill University.
“Once these long strands of DNA are gently squeezed down into nanochannels from a nanoscale bath above, they become effectively rigid, which means that we can map positions along uniformly stretched strands of DNA, while holding them still,” she said.
“This means diagnostics can be performed quickly, one cell at a time, which is critical for diagnosing many prenatal conditions and the onset of cancer.”
Credit: NIGMS
A new technique could enable faster diagnosis of cancer and various prenatal conditions, according to a paper published in Proceedings of the National Academy of Sciences.
The method, known as convex lens-induced confinement (CLIC), allows researchers to load long strands of DNA into a tunable, nanoscale imaging chamber in ways that maintain their structural identity and under conditions that are similar to those in the human body.
CLIC lets researchers map large genomes rapidly and identify specific gene sequences from single cells with single-molecule resolution, a process that is critical to diagnosing diseases like cancer.
“Current practices of genomic analysis typically require tens of thousands of cells worth of genomic material to obtain the information we need, but this new approach works with single cells,” said study author Rob Sladek, MD, of McGill University in Montreal, Canada.
“CLIC will allow researchers to avoid having to spend time stitching together maps of entire genomes, as we do under current techniques, and promises to make genomic analysis a much simpler and more efficient process.”
The CLIC imaging chamber can sit on top of a standard inverted fluorescence microscope, and strands of DNA can be loaded into the chamber from above, which allows the strands to maintain their integrity.
Existing tools used for genomic analysis rely on side-loading DNA under pressure into nanochannels in the imaging chamber. This breaks the DNA molecules into small pieces, making it a challenge to reconstruct the genome.
CLIC, on the other hand, is “like squeezing many soft spaghetti noodles into long, narrow tubes without breaking them,” according to study author Sabrina Leslie, PhD, also of McGill University.
“Once these long strands of DNA are gently squeezed down into nanochannels from a nanoscale bath above, they become effectively rigid, which means that we can map positions along uniformly stretched strands of DNA, while holding them still,” she said.
“This means diagnostics can be performed quickly, one cell at a time, which is critical for diagnosing many prenatal conditions and the onset of cancer.”
Drug gets fast track designation for MF
Credit: Peter Anderson
The US Food and Drug Administration (FDA) is expediting its review of pacritinib, a tyrosine kinase inhibitor with activity against JAK2 and FLT3, by granting the drug fast track designation.
Pacritinib is under review as a treatment for patients with intermediate- and high-risk myelofibrosis (MF), including those with disease-related or treatment-induced thrombocytopenia and those who cannot tolerate or do not respond well to other JAK2 therapy.
The FDA’s fast track process is designed to expedite the review of drugs to treat serious conditions and fill an unmet medical need.
The program enables a company—in this case, CTI BioPharma—to submit sections of a new drug application on a rolling basis as data becomes available.
That way, the FDA can review sections of the application as they are received, rather than waiting until every section of the application is completed before the entire application can be reviewed. This often leads to faster approval.
Pacritinib is currently under investigation in two phase 3 clinical trials, known as the PERSIST program, for patients with MF.
One of these trials, known as PERSIST-1, includes a broad set of patients without limitations on platelet counts. The other, PERSIST-2, includes patients with low platelet counts.
PERSIST-1
In July 2014, CTI Biopharma completed enrollment in the PERSIST-1 trial, which was designed to enroll approximately 320 patients.
This randomized trial was designed to compared the efficacy and safety of pacritinib with that of best available therapy, other than JAK inhibitors, in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, without exclusion for low platelet counts.
The primary endpoint is the percentage of patients achieving at least a 35% reduction in spleen volume, measured by MRI or CT from baseline to 24 weeks of treatment.
PERSIST-2
In March 2014, CTI announced the initiation of the PERSIST-2 trial, a comparison of pacritinib and best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with MF whose platelet counts are 100,000/uL or lower.
The trial is designed to enroll up to 300 patients in North America, Europe, Australia, and New Zealand. In October 2013, CTI reached agreement with the FDA on a special protocol assessment for the trial, a written agreement between CTI and the FDA regarding the planned design, endpoints, and statistical analysis approach of the trial to be used in support of a potential new drug application.
Under the special protocol assessment, the trial will have two primary endpoints. The first is the percentage of patients achieving a 35% or greater reduction in spleen volume, measured by MRI or CT scan from baseline to 24 weeks of treatment.
The second primary endpoint is the percentage of patients achieving a total symptom score reduction of 50% or greater using 6 key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.
More details on the PERSIST-1 and PERSIST-2 trials can be found at www.clinicaltrials.gov.
Credit: Peter Anderson
The US Food and Drug Administration (FDA) is expediting its review of pacritinib, a tyrosine kinase inhibitor with activity against JAK2 and FLT3, by granting the drug fast track designation.
Pacritinib is under review as a treatment for patients with intermediate- and high-risk myelofibrosis (MF), including those with disease-related or treatment-induced thrombocytopenia and those who cannot tolerate or do not respond well to other JAK2 therapy.
The FDA’s fast track process is designed to expedite the review of drugs to treat serious conditions and fill an unmet medical need.
The program enables a company—in this case, CTI BioPharma—to submit sections of a new drug application on a rolling basis as data becomes available.
That way, the FDA can review sections of the application as they are received, rather than waiting until every section of the application is completed before the entire application can be reviewed. This often leads to faster approval.
Pacritinib is currently under investigation in two phase 3 clinical trials, known as the PERSIST program, for patients with MF.
One of these trials, known as PERSIST-1, includes a broad set of patients without limitations on platelet counts. The other, PERSIST-2, includes patients with low platelet counts.
PERSIST-1
In July 2014, CTI Biopharma completed enrollment in the PERSIST-1 trial, which was designed to enroll approximately 320 patients.
This randomized trial was designed to compared the efficacy and safety of pacritinib with that of best available therapy, other than JAK inhibitors, in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, without exclusion for low platelet counts.
The primary endpoint is the percentage of patients achieving at least a 35% reduction in spleen volume, measured by MRI or CT from baseline to 24 weeks of treatment.
PERSIST-2
In March 2014, CTI announced the initiation of the PERSIST-2 trial, a comparison of pacritinib and best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with MF whose platelet counts are 100,000/uL or lower.
The trial is designed to enroll up to 300 patients in North America, Europe, Australia, and New Zealand. In October 2013, CTI reached agreement with the FDA on a special protocol assessment for the trial, a written agreement between CTI and the FDA regarding the planned design, endpoints, and statistical analysis approach of the trial to be used in support of a potential new drug application.
Under the special protocol assessment, the trial will have two primary endpoints. The first is the percentage of patients achieving a 35% or greater reduction in spleen volume, measured by MRI or CT scan from baseline to 24 weeks of treatment.
The second primary endpoint is the percentage of patients achieving a total symptom score reduction of 50% or greater using 6 key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.
More details on the PERSIST-1 and PERSIST-2 trials can be found at www.clinicaltrials.gov.
Credit: Peter Anderson
The US Food and Drug Administration (FDA) is expediting its review of pacritinib, a tyrosine kinase inhibitor with activity against JAK2 and FLT3, by granting the drug fast track designation.
Pacritinib is under review as a treatment for patients with intermediate- and high-risk myelofibrosis (MF), including those with disease-related or treatment-induced thrombocytopenia and those who cannot tolerate or do not respond well to other JAK2 therapy.
The FDA’s fast track process is designed to expedite the review of drugs to treat serious conditions and fill an unmet medical need.
The program enables a company—in this case, CTI BioPharma—to submit sections of a new drug application on a rolling basis as data becomes available.
That way, the FDA can review sections of the application as they are received, rather than waiting until every section of the application is completed before the entire application can be reviewed. This often leads to faster approval.
Pacritinib is currently under investigation in two phase 3 clinical trials, known as the PERSIST program, for patients with MF.
One of these trials, known as PERSIST-1, includes a broad set of patients without limitations on platelet counts. The other, PERSIST-2, includes patients with low platelet counts.
PERSIST-1
In July 2014, CTI Biopharma completed enrollment in the PERSIST-1 trial, which was designed to enroll approximately 320 patients.
This randomized trial was designed to compared the efficacy and safety of pacritinib with that of best available therapy, other than JAK inhibitors, in patients with primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF, without exclusion for low platelet counts.
The primary endpoint is the percentage of patients achieving at least a 35% reduction in spleen volume, measured by MRI or CT from baseline to 24 weeks of treatment.
PERSIST-2
In March 2014, CTI announced the initiation of the PERSIST-2 trial, a comparison of pacritinib and best available therapy, including approved JAK2 inhibitors that are dosed according to product label, in patients with MF whose platelet counts are 100,000/uL or lower.
The trial is designed to enroll up to 300 patients in North America, Europe, Australia, and New Zealand. In October 2013, CTI reached agreement with the FDA on a special protocol assessment for the trial, a written agreement between CTI and the FDA regarding the planned design, endpoints, and statistical analysis approach of the trial to be used in support of a potential new drug application.
Under the special protocol assessment, the trial will have two primary endpoints. The first is the percentage of patients achieving a 35% or greater reduction in spleen volume, measured by MRI or CT scan from baseline to 24 weeks of treatment.
The second primary endpoint is the percentage of patients achieving a total symptom score reduction of 50% or greater using 6 key symptoms, as measured by the modified Myeloproliferative Neoplasm Symptom Assessment (MPN-SAF TSS 2.0) diary from baseline to 24 weeks.
More details on the PERSIST-1 and PERSIST-2 trials can be found at www.clinicaltrials.gov.
Study challenges traditional cancer classification
a tumor sample in a test tube
Credit: Rhoda Baer
Defining cancers by molecular criteria rather than their tissue of origin can provide patients with more accurate diagnoses, researchers have reported in Cell.
The group analyzed the molecular characteristics of more than 3500 samples of 12 different cancers and reclassified them according to the new information.
For 5 of the cancer types, including acute myeloid leukemia (AML), the molecular classification largely matched the tissue-of-origin classification.
For the remaining malignancies, that was not the case.
“This genomic study not only challenges our existing system of classifying cancers based on tissue type, but also provides a massive new data resource for further exploration, as well as a comprehensive list of the molecular features distinguishing each of the newly described cancer classes,” said study author Christopher Benz, MD, of the University of California, San Francisco.
The researchers said each molecular subtype they identified may reflect tumors arising from distinct cell types. For example, the data showed a marked difference between cancers of epithelial and non-epithelial origins.
“We think the subtypes reflect, primarily, the cell of origin,” said study author Joshua Stuart, PhD, of the University of California, Santa Cruz.
“Another factor is the nature of the genomic lesion, and third is the microenvironment of the cell and how surrounding cells influence it. We are disentangling the signals from these different factors so we can gauge each one for its prognostic power.”
Identifying molecular subtypes
The researchers performed an integrative analysis using 5 genome-wide platforms and 1 proteomic platform on 3527 specimens from 12 cancer types.
This included AML, glioblastoma multiforme, serous ovarian carcinoma, colon and rectal adenocarcinomas, lung squamous cell carcinoma, breast cancer, endometrial cancer, renal cell carcinoma, bladder urothelial adenocarcinoma, lung adenocarcinoma, and head and neck squamous cell carcinoma.
The group’s analyses allowed them to classify these cancer types into 11 major cellular/molecular subtypes. Two of the initial 13 subtypes (numbers 11 and 12) were eliminated from further analysis because they included fewer than 10 samples.
Five of the classification types—C5-renal cell carcinoma, C6-endometrial cancer, C9-serous ovarian carcinoma, C10-glioblastoma multiforme, and C13-AML—showed near 1-to-1 relationships with the tissue site of origin. However, there were a few cases of reclassification here and there, such as a case of breast cancer that fell in the AML subtype.
Another subtype stayed pretty true to its tissues of origin. C7-colon adenocarcinoma/rectal adenocarcinoma was composed mainly of colon and rectal adenocarcinomas but also included a case of endometrial cancer.
The C1-lung adenocarcinoma-enriched subtype was predominantly composed of non-small cell lung adenocarcinoma samples. But it also included cases of bladder cancer, breast cancer, colon adenocarcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, renal cell carcinoma, lung squamous cell carcinoma , serous ovarian carcinoma, and endometrial cancer.
The C2-squamous-like subtype consisted largely of head and neck squamous cell carcinoma and lung squamous cell carcinoma but also included bladder urothelial adenocarcinoma and breast cancer.
Breast cancers were further divided into the C3-breast cancer/luminal subtype and the C4-breast cancer/basal subtype. The C4 subtype also included lung adenocarcinoma and lung squamous cell carcinoma.
The researchers noted that breast cancers were present in 7 of the subtype classifications. And while this study confirmed known differences between the subtypes of breast cancer, the team was surprised to discover that basal-like breast cancers actually constitute their own cancer class.
“Even though these basal-like cancers arise in the breast, on the molecular level, they have more in common with ovarian cancers and cancers of squamous-cell origin than with other subtypes of breast cancer,” said study author Christina Yau, PhD, of the University of California, San Francisco.
Like breast cancers, bladder cancers were present in 7 of the subtype classifications. There were 1 or 2 cases in C5, C10, C11, and C12. But most bladder cancer samples fell into 1 of 3 categories: C1-lung adenocarcinoma-enriched, C2-squamous-like, and C8-bladder urothelial adenocarcinoma.
Although the C8-bladder urothelial adenocarcinoma subtype consisted largely of bladder cancer, it also included breast cancer, head and neck squamous cell carcinoma, lung adenocarcinoma, and lung squamous cell carcinoma.
These findings may help explain why patients with bladder cancer “often respond very differently when treated with the same systemic therapy for their seemingly identical cancer type,” Dr Benz said.
In fact, the researchers found the bladder cancers that clustered with other tumor types had a worse prognosis.
Next steps
The researchers noted that follow-up studies are needed to validate these findings, but this analysis lays the groundwork for classifying tumors into molecularly defined subtypes. The new classification scheme could be used to enroll patients in clinical trials and could lead to different treatment options based on molecular subtypes.
“We can now say what the telltale signatures of the subtypes are, so you can classify a patient’s tumor just based on the gene expression data, or just based on mutation data, if that’s what you have,” Dr Stuart said. “Having a molecular map like this could help get a patient into the right clinical trial.”
The researchers believe the percentage of tumors that should be reclassified based on molecular signatures is likely to grow as more samples and tumor types are analyzed. This study suggested that 1 in 10 cancers could be reclassified in clinically meaningful ways, but the researchers said their next analysis will include 21 tumor types instead of 12.
“We’re just appreciating the tip of the iceberg when considering the potential of this multiplatform type of genomic analysis,” Dr Benz said. “It could be that as many as 30% or 50% of cancers need to be reclassified.”
The data sets and results from this study have been made available to other researchers through the Synapse website.
a tumor sample in a test tube
Credit: Rhoda Baer
Defining cancers by molecular criteria rather than their tissue of origin can provide patients with more accurate diagnoses, researchers have reported in Cell.
The group analyzed the molecular characteristics of more than 3500 samples of 12 different cancers and reclassified them according to the new information.
For 5 of the cancer types, including acute myeloid leukemia (AML), the molecular classification largely matched the tissue-of-origin classification.
For the remaining malignancies, that was not the case.
“This genomic study not only challenges our existing system of classifying cancers based on tissue type, but also provides a massive new data resource for further exploration, as well as a comprehensive list of the molecular features distinguishing each of the newly described cancer classes,” said study author Christopher Benz, MD, of the University of California, San Francisco.
The researchers said each molecular subtype they identified may reflect tumors arising from distinct cell types. For example, the data showed a marked difference between cancers of epithelial and non-epithelial origins.
“We think the subtypes reflect, primarily, the cell of origin,” said study author Joshua Stuart, PhD, of the University of California, Santa Cruz.
“Another factor is the nature of the genomic lesion, and third is the microenvironment of the cell and how surrounding cells influence it. We are disentangling the signals from these different factors so we can gauge each one for its prognostic power.”
Identifying molecular subtypes
The researchers performed an integrative analysis using 5 genome-wide platforms and 1 proteomic platform on 3527 specimens from 12 cancer types.
This included AML, glioblastoma multiforme, serous ovarian carcinoma, colon and rectal adenocarcinomas, lung squamous cell carcinoma, breast cancer, endometrial cancer, renal cell carcinoma, bladder urothelial adenocarcinoma, lung adenocarcinoma, and head and neck squamous cell carcinoma.
The group’s analyses allowed them to classify these cancer types into 11 major cellular/molecular subtypes. Two of the initial 13 subtypes (numbers 11 and 12) were eliminated from further analysis because they included fewer than 10 samples.
Five of the classification types—C5-renal cell carcinoma, C6-endometrial cancer, C9-serous ovarian carcinoma, C10-glioblastoma multiforme, and C13-AML—showed near 1-to-1 relationships with the tissue site of origin. However, there were a few cases of reclassification here and there, such as a case of breast cancer that fell in the AML subtype.
Another subtype stayed pretty true to its tissues of origin. C7-colon adenocarcinoma/rectal adenocarcinoma was composed mainly of colon and rectal adenocarcinomas but also included a case of endometrial cancer.
The C1-lung adenocarcinoma-enriched subtype was predominantly composed of non-small cell lung adenocarcinoma samples. But it also included cases of bladder cancer, breast cancer, colon adenocarcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, renal cell carcinoma, lung squamous cell carcinoma , serous ovarian carcinoma, and endometrial cancer.
The C2-squamous-like subtype consisted largely of head and neck squamous cell carcinoma and lung squamous cell carcinoma but also included bladder urothelial adenocarcinoma and breast cancer.
Breast cancers were further divided into the C3-breast cancer/luminal subtype and the C4-breast cancer/basal subtype. The C4 subtype also included lung adenocarcinoma and lung squamous cell carcinoma.
The researchers noted that breast cancers were present in 7 of the subtype classifications. And while this study confirmed known differences between the subtypes of breast cancer, the team was surprised to discover that basal-like breast cancers actually constitute their own cancer class.
“Even though these basal-like cancers arise in the breast, on the molecular level, they have more in common with ovarian cancers and cancers of squamous-cell origin than with other subtypes of breast cancer,” said study author Christina Yau, PhD, of the University of California, San Francisco.
Like breast cancers, bladder cancers were present in 7 of the subtype classifications. There were 1 or 2 cases in C5, C10, C11, and C12. But most bladder cancer samples fell into 1 of 3 categories: C1-lung adenocarcinoma-enriched, C2-squamous-like, and C8-bladder urothelial adenocarcinoma.
Although the C8-bladder urothelial adenocarcinoma subtype consisted largely of bladder cancer, it also included breast cancer, head and neck squamous cell carcinoma, lung adenocarcinoma, and lung squamous cell carcinoma.
These findings may help explain why patients with bladder cancer “often respond very differently when treated with the same systemic therapy for their seemingly identical cancer type,” Dr Benz said.
In fact, the researchers found the bladder cancers that clustered with other tumor types had a worse prognosis.
Next steps
The researchers noted that follow-up studies are needed to validate these findings, but this analysis lays the groundwork for classifying tumors into molecularly defined subtypes. The new classification scheme could be used to enroll patients in clinical trials and could lead to different treatment options based on molecular subtypes.
“We can now say what the telltale signatures of the subtypes are, so you can classify a patient’s tumor just based on the gene expression data, or just based on mutation data, if that’s what you have,” Dr Stuart said. “Having a molecular map like this could help get a patient into the right clinical trial.”
The researchers believe the percentage of tumors that should be reclassified based on molecular signatures is likely to grow as more samples and tumor types are analyzed. This study suggested that 1 in 10 cancers could be reclassified in clinically meaningful ways, but the researchers said their next analysis will include 21 tumor types instead of 12.
“We’re just appreciating the tip of the iceberg when considering the potential of this multiplatform type of genomic analysis,” Dr Benz said. “It could be that as many as 30% or 50% of cancers need to be reclassified.”
The data sets and results from this study have been made available to other researchers through the Synapse website.
a tumor sample in a test tube
Credit: Rhoda Baer
Defining cancers by molecular criteria rather than their tissue of origin can provide patients with more accurate diagnoses, researchers have reported in Cell.
The group analyzed the molecular characteristics of more than 3500 samples of 12 different cancers and reclassified them according to the new information.
For 5 of the cancer types, including acute myeloid leukemia (AML), the molecular classification largely matched the tissue-of-origin classification.
For the remaining malignancies, that was not the case.
“This genomic study not only challenges our existing system of classifying cancers based on tissue type, but also provides a massive new data resource for further exploration, as well as a comprehensive list of the molecular features distinguishing each of the newly described cancer classes,” said study author Christopher Benz, MD, of the University of California, San Francisco.
The researchers said each molecular subtype they identified may reflect tumors arising from distinct cell types. For example, the data showed a marked difference between cancers of epithelial and non-epithelial origins.
“We think the subtypes reflect, primarily, the cell of origin,” said study author Joshua Stuart, PhD, of the University of California, Santa Cruz.
“Another factor is the nature of the genomic lesion, and third is the microenvironment of the cell and how surrounding cells influence it. We are disentangling the signals from these different factors so we can gauge each one for its prognostic power.”
Identifying molecular subtypes
The researchers performed an integrative analysis using 5 genome-wide platforms and 1 proteomic platform on 3527 specimens from 12 cancer types.
This included AML, glioblastoma multiforme, serous ovarian carcinoma, colon and rectal adenocarcinomas, lung squamous cell carcinoma, breast cancer, endometrial cancer, renal cell carcinoma, bladder urothelial adenocarcinoma, lung adenocarcinoma, and head and neck squamous cell carcinoma.
The group’s analyses allowed them to classify these cancer types into 11 major cellular/molecular subtypes. Two of the initial 13 subtypes (numbers 11 and 12) were eliminated from further analysis because they included fewer than 10 samples.
Five of the classification types—C5-renal cell carcinoma, C6-endometrial cancer, C9-serous ovarian carcinoma, C10-glioblastoma multiforme, and C13-AML—showed near 1-to-1 relationships with the tissue site of origin. However, there were a few cases of reclassification here and there, such as a case of breast cancer that fell in the AML subtype.
Another subtype stayed pretty true to its tissues of origin. C7-colon adenocarcinoma/rectal adenocarcinoma was composed mainly of colon and rectal adenocarcinomas but also included a case of endometrial cancer.
The C1-lung adenocarcinoma-enriched subtype was predominantly composed of non-small cell lung adenocarcinoma samples. But it also included cases of bladder cancer, breast cancer, colon adenocarcinoma, glioblastoma multiforme, head and neck squamous cell carcinoma, renal cell carcinoma, lung squamous cell carcinoma , serous ovarian carcinoma, and endometrial cancer.
The C2-squamous-like subtype consisted largely of head and neck squamous cell carcinoma and lung squamous cell carcinoma but also included bladder urothelial adenocarcinoma and breast cancer.
Breast cancers were further divided into the C3-breast cancer/luminal subtype and the C4-breast cancer/basal subtype. The C4 subtype also included lung adenocarcinoma and lung squamous cell carcinoma.
The researchers noted that breast cancers were present in 7 of the subtype classifications. And while this study confirmed known differences between the subtypes of breast cancer, the team was surprised to discover that basal-like breast cancers actually constitute their own cancer class.
“Even though these basal-like cancers arise in the breast, on the molecular level, they have more in common with ovarian cancers and cancers of squamous-cell origin than with other subtypes of breast cancer,” said study author Christina Yau, PhD, of the University of California, San Francisco.
Like breast cancers, bladder cancers were present in 7 of the subtype classifications. There were 1 or 2 cases in C5, C10, C11, and C12. But most bladder cancer samples fell into 1 of 3 categories: C1-lung adenocarcinoma-enriched, C2-squamous-like, and C8-bladder urothelial adenocarcinoma.
Although the C8-bladder urothelial adenocarcinoma subtype consisted largely of bladder cancer, it also included breast cancer, head and neck squamous cell carcinoma, lung adenocarcinoma, and lung squamous cell carcinoma.
These findings may help explain why patients with bladder cancer “often respond very differently when treated with the same systemic therapy for their seemingly identical cancer type,” Dr Benz said.
In fact, the researchers found the bladder cancers that clustered with other tumor types had a worse prognosis.
Next steps
The researchers noted that follow-up studies are needed to validate these findings, but this analysis lays the groundwork for classifying tumors into molecularly defined subtypes. The new classification scheme could be used to enroll patients in clinical trials and could lead to different treatment options based on molecular subtypes.
“We can now say what the telltale signatures of the subtypes are, so you can classify a patient’s tumor just based on the gene expression data, or just based on mutation data, if that’s what you have,” Dr Stuart said. “Having a molecular map like this could help get a patient into the right clinical trial.”
The researchers believe the percentage of tumors that should be reclassified based on molecular signatures is likely to grow as more samples and tumor types are analyzed. This study suggested that 1 in 10 cancers could be reclassified in clinically meaningful ways, but the researchers said their next analysis will include 21 tumor types instead of 12.
“We’re just appreciating the tip of the iceberg when considering the potential of this multiplatform type of genomic analysis,” Dr Benz said. “It could be that as many as 30% or 50% of cancers need to be reclassified.”
The data sets and results from this study have been made available to other researchers through the Synapse website.
Two new tests can detect CJD
Credit: Elise Amendola
Two groups of scientists have developed new tests to diagnose Creutzfeldt-Jakob disease (CJD).
One test uses samples collected from nasal passages to detect sporadic CJD, and the other uses urine samples to identify variant CJD.
The researchers said these tests provide simple methods for differentiating CJD from other diseases and could help prevent the transmission of CJD via blood
transfusions, transplants, or contaminated surgical instruments.
Both tests are described in The New England Journal of Medicine.
Nasal test for sporadic CJD
In one NEJM article, Byron Caughey, PhD, of the National Institute of Allergy and Infectious Diseases in Rockville, Maryland, and his colleagues detailed their results with the nasal test.
The researchers collected 31 nasal samples from patients with sporadic CJD and 43 samples from patients who had other neurologic diseases or no neurologic disease. The team brushed the inside of a subject’s nose to collect olfactory neurons connected to the brain.
Testing these samples allowed the researchers to correctly identify 30 of the 31 sporadic CJD patients (97% sensitivity). The tests also correctly showed negative results for all 43 of the non-CJD patients (100% specificity).
By comparison, tests using cerebral spinal fluid, which is currently used to detect sporadic CJD, were 77% sensitive and 100% specific. And these results took twice as long to obtain.
While continuing to validate the new testing method in CJD patients, the scientists are looking to expand their research to diagnose forms of prion diseases in sheep, cattle, and wildlife. The team also hopes to replace the nasal brush with an even simpler swabbing approach.
Urine test for variant CJD
In another NEJM article, Fabio Moda, PhD, of the University of Texas Medical School at Houston, and his colleagues described results observed with their urine test.
The team noted that the infectious agent in transmissible spongiform encephalopathies appears to be composed exclusively of the misfolded form of the prion protein, PrPSc. So they set out to determine if they could detect PrPSc in the urine of patients with CJD.
The researchers analyzed urine samples from healthy individuals (n=52) and patients with variant CJD (n=68), sporadic CJD (n=14), genetic forms of prion disease (n=4), other neurodegenerative disorders (n=50), and nondegenerative neurologic disorders (n=50).
The group found they could only detect PrPSc in samples from patients with variant CJD. They found “minute quantities” of PrPSc in 13 of the 14 urine samples from variant CJD patients, but PrPSc was not present in any of the samples from the other patients or the healthy individuals.
This suggests the test has a sensitivity of 92.9% and a specificity of 100%.
Credit: Elise Amendola
Two groups of scientists have developed new tests to diagnose Creutzfeldt-Jakob disease (CJD).
One test uses samples collected from nasal passages to detect sporadic CJD, and the other uses urine samples to identify variant CJD.
The researchers said these tests provide simple methods for differentiating CJD from other diseases and could help prevent the transmission of CJD via blood
transfusions, transplants, or contaminated surgical instruments.
Both tests are described in The New England Journal of Medicine.
Nasal test for sporadic CJD
In one NEJM article, Byron Caughey, PhD, of the National Institute of Allergy and Infectious Diseases in Rockville, Maryland, and his colleagues detailed their results with the nasal test.
The researchers collected 31 nasal samples from patients with sporadic CJD and 43 samples from patients who had other neurologic diseases or no neurologic disease. The team brushed the inside of a subject’s nose to collect olfactory neurons connected to the brain.
Testing these samples allowed the researchers to correctly identify 30 of the 31 sporadic CJD patients (97% sensitivity). The tests also correctly showed negative results for all 43 of the non-CJD patients (100% specificity).
By comparison, tests using cerebral spinal fluid, which is currently used to detect sporadic CJD, were 77% sensitive and 100% specific. And these results took twice as long to obtain.
While continuing to validate the new testing method in CJD patients, the scientists are looking to expand their research to diagnose forms of prion diseases in sheep, cattle, and wildlife. The team also hopes to replace the nasal brush with an even simpler swabbing approach.
Urine test for variant CJD
In another NEJM article, Fabio Moda, PhD, of the University of Texas Medical School at Houston, and his colleagues described results observed with their urine test.
The team noted that the infectious agent in transmissible spongiform encephalopathies appears to be composed exclusively of the misfolded form of the prion protein, PrPSc. So they set out to determine if they could detect PrPSc in the urine of patients with CJD.
The researchers analyzed urine samples from healthy individuals (n=52) and patients with variant CJD (n=68), sporadic CJD (n=14), genetic forms of prion disease (n=4), other neurodegenerative disorders (n=50), and nondegenerative neurologic disorders (n=50).
The group found they could only detect PrPSc in samples from patients with variant CJD. They found “minute quantities” of PrPSc in 13 of the 14 urine samples from variant CJD patients, but PrPSc was not present in any of the samples from the other patients or the healthy individuals.
This suggests the test has a sensitivity of 92.9% and a specificity of 100%.
Credit: Elise Amendola
Two groups of scientists have developed new tests to diagnose Creutzfeldt-Jakob disease (CJD).
One test uses samples collected from nasal passages to detect sporadic CJD, and the other uses urine samples to identify variant CJD.
The researchers said these tests provide simple methods for differentiating CJD from other diseases and could help prevent the transmission of CJD via blood
transfusions, transplants, or contaminated surgical instruments.
Both tests are described in The New England Journal of Medicine.
Nasal test for sporadic CJD
In one NEJM article, Byron Caughey, PhD, of the National Institute of Allergy and Infectious Diseases in Rockville, Maryland, and his colleagues detailed their results with the nasal test.
The researchers collected 31 nasal samples from patients with sporadic CJD and 43 samples from patients who had other neurologic diseases or no neurologic disease. The team brushed the inside of a subject’s nose to collect olfactory neurons connected to the brain.
Testing these samples allowed the researchers to correctly identify 30 of the 31 sporadic CJD patients (97% sensitivity). The tests also correctly showed negative results for all 43 of the non-CJD patients (100% specificity).
By comparison, tests using cerebral spinal fluid, which is currently used to detect sporadic CJD, were 77% sensitive and 100% specific. And these results took twice as long to obtain.
While continuing to validate the new testing method in CJD patients, the scientists are looking to expand their research to diagnose forms of prion diseases in sheep, cattle, and wildlife. The team also hopes to replace the nasal brush with an even simpler swabbing approach.
Urine test for variant CJD
In another NEJM article, Fabio Moda, PhD, of the University of Texas Medical School at Houston, and his colleagues described results observed with their urine test.
The team noted that the infectious agent in transmissible spongiform encephalopathies appears to be composed exclusively of the misfolded form of the prion protein, PrPSc. So they set out to determine if they could detect PrPSc in the urine of patients with CJD.
The researchers analyzed urine samples from healthy individuals (n=52) and patients with variant CJD (n=68), sporadic CJD (n=14), genetic forms of prion disease (n=4), other neurodegenerative disorders (n=50), and nondegenerative neurologic disorders (n=50).
The group found they could only detect PrPSc in samples from patients with variant CJD. They found “minute quantities” of PrPSc in 13 of the 14 urine samples from variant CJD patients, but PrPSc was not present in any of the samples from the other patients or the healthy individuals.
This suggests the test has a sensitivity of 92.9% and a specificity of 100%.
Gene plays crucial role in cancer development, team says
Credit: Beth A. Sullivan
New research suggests DNA ligase 3 is crucial for the evolutionary processes that drive cancer.
“We have identified a gene that, as cells age, seems to regulate whether the cells become cancerous or not,” said Eric A. Hendrickson, PhD, of the University of Minnesota in Minneapolis.
“This gene has never been identified before in this role, so this makes it a potentially very important therapeutic target.”
Dr Hendrickson and his colleagues recounted this discovery in Cell Reports.
The researchers noted that short, dysfunctional telomeres can fuse, thereby generating dicentric chromosomes and initiating breakage-fusion-bridge cycles. The cells that manage to escape the subsequent crisis have genomic rearrangements that drive clonal evolution and malignant progression.
The team wanted to determine exactly what allows these malignant cells to escape telomere-driven crisis and avoid death.
To find out, the group disabled certain genes in human cells and then studied the impact this had on telomere fusion.
They found that cells escaped death when ligase 3 was active but not when its action, which appears to promote fusion within like chromosomes rather than between different chromosomes, was inhibited.
“Telomere dysfunction has been identified in many human cancers,” said study author Duncan Baird, PhD, of Cardiff University in the UK.
“And, as we have shown previously, short telomeres can predict the outcome of patients with [chronic lymphocytic leukemia] and probably many other tumor types. Thus, the discovery that ligase 3 is required for this process is fundamentally important.”
This research was made possible by a chance meeting between Dr Baird and Dr Hendrickson at an international conference. The pair discovered they were both looking at the role of ligase 3 in cancer and decided to collaborate.
“The collaboration paid off, as we were able to uncover something that neither one of us could have done on our own,” Dr Hendrickson said.
Additional studies are already underway. The researchers are investigating the discovery that the reliance on ligase 3 appears to be dependent upon the activity of another key DNA repair gene, p53.
“Since p53 is the most commonly mutated gene in human cancer, it now behooves us to discover how these two genes are interacting and to see if we can’t use that information to develop synergistic treatment modalities,” Dr Hendrickson concluded.
Credit: Beth A. Sullivan
New research suggests DNA ligase 3 is crucial for the evolutionary processes that drive cancer.
“We have identified a gene that, as cells age, seems to regulate whether the cells become cancerous or not,” said Eric A. Hendrickson, PhD, of the University of Minnesota in Minneapolis.
“This gene has never been identified before in this role, so this makes it a potentially very important therapeutic target.”
Dr Hendrickson and his colleagues recounted this discovery in Cell Reports.
The researchers noted that short, dysfunctional telomeres can fuse, thereby generating dicentric chromosomes and initiating breakage-fusion-bridge cycles. The cells that manage to escape the subsequent crisis have genomic rearrangements that drive clonal evolution and malignant progression.
The team wanted to determine exactly what allows these malignant cells to escape telomere-driven crisis and avoid death.
To find out, the group disabled certain genes in human cells and then studied the impact this had on telomere fusion.
They found that cells escaped death when ligase 3 was active but not when its action, which appears to promote fusion within like chromosomes rather than between different chromosomes, was inhibited.
“Telomere dysfunction has been identified in many human cancers,” said study author Duncan Baird, PhD, of Cardiff University in the UK.
“And, as we have shown previously, short telomeres can predict the outcome of patients with [chronic lymphocytic leukemia] and probably many other tumor types. Thus, the discovery that ligase 3 is required for this process is fundamentally important.”
This research was made possible by a chance meeting between Dr Baird and Dr Hendrickson at an international conference. The pair discovered they were both looking at the role of ligase 3 in cancer and decided to collaborate.
“The collaboration paid off, as we were able to uncover something that neither one of us could have done on our own,” Dr Hendrickson said.
Additional studies are already underway. The researchers are investigating the discovery that the reliance on ligase 3 appears to be dependent upon the activity of another key DNA repair gene, p53.
“Since p53 is the most commonly mutated gene in human cancer, it now behooves us to discover how these two genes are interacting and to see if we can’t use that information to develop synergistic treatment modalities,” Dr Hendrickson concluded.
Credit: Beth A. Sullivan
New research suggests DNA ligase 3 is crucial for the evolutionary processes that drive cancer.
“We have identified a gene that, as cells age, seems to regulate whether the cells become cancerous or not,” said Eric A. Hendrickson, PhD, of the University of Minnesota in Minneapolis.
“This gene has never been identified before in this role, so this makes it a potentially very important therapeutic target.”
Dr Hendrickson and his colleagues recounted this discovery in Cell Reports.
The researchers noted that short, dysfunctional telomeres can fuse, thereby generating dicentric chromosomes and initiating breakage-fusion-bridge cycles. The cells that manage to escape the subsequent crisis have genomic rearrangements that drive clonal evolution and malignant progression.
The team wanted to determine exactly what allows these malignant cells to escape telomere-driven crisis and avoid death.
To find out, the group disabled certain genes in human cells and then studied the impact this had on telomere fusion.
They found that cells escaped death when ligase 3 was active but not when its action, which appears to promote fusion within like chromosomes rather than between different chromosomes, was inhibited.
“Telomere dysfunction has been identified in many human cancers,” said study author Duncan Baird, PhD, of Cardiff University in the UK.
“And, as we have shown previously, short telomeres can predict the outcome of patients with [chronic lymphocytic leukemia] and probably many other tumor types. Thus, the discovery that ligase 3 is required for this process is fundamentally important.”
This research was made possible by a chance meeting between Dr Baird and Dr Hendrickson at an international conference. The pair discovered they were both looking at the role of ligase 3 in cancer and decided to collaborate.
“The collaboration paid off, as we were able to uncover something that neither one of us could have done on our own,” Dr Hendrickson said.
Additional studies are already underway. The researchers are investigating the discovery that the reliance on ligase 3 appears to be dependent upon the activity of another key DNA repair gene, p53.
“Since p53 is the most commonly mutated gene in human cancer, it now behooves us to discover how these two genes are interacting and to see if we can’t use that information to develop synergistic treatment modalities,” Dr Hendrickson concluded.
Interim data appear positive for MM drug
Interim results of the phase 3 ASPIRE trial suggest carfilzomib can improve progression-free survival (PFS) in patients with relapsed multiple myeloma (MM).
Patients who received carfilzomib, lenalidomide, and dexamethasone lived 8.7 months longer without progression than patients who received only lenalidomide and dexamethasone.
The companies developing carfilzomib, Amgen and its subsidiary, Onyx Pharmaceuticals, Inc., recently shared these results.
They said additional results will be submitted for presentation at the 56th Annual ASH Meeting in December.
The companies also said data from the ASPIRE trial will form the basis for regulatory submissions for carfilzomib throughout the world.
In the US, the data may support the conversion of accelerated approval to full approval and expand the current indication for carfilzomib.
The ASPIRE trial includes 792 patients with relapsed MM who were randomized to treatment at sites in North America, Europe, and Israel. Prior to study treatment, the patients had received 1 to 3 therapeutic regimens.
The patients were randomized to receive carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1 only, then 27 mg/m2), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, 7 days off) and low-dose dexamethasone (40 mg per week in 4-week cycles), or lenalidomide and low-dose dexamethasone alone.
The primary endpoint was PFS, and secondary endpoints included overall survival, overall response rate, duration of response, disease control rate, health-related quality of life, and safety.
At a planned interim analysis, patients in the carfilzomib arm had a significantly longer median PFS than patients in the other arm—26.3 months and 17.6 months, respectively (P<0.0001).
The data for overall survival are not yet mature, but the analysis showed a trend in favor of carfilzomib that did not reach statistical significance, according to Amgen and Onyx.
The companies said the safety profile in this study is consistent with previous studies, including the rate of cardiac events.
Treatment discontinuation due to adverse events and on-study deaths were comparable between the 2 arms, and researchers did not identify any new safety signals.
Interim results of the phase 3 ASPIRE trial suggest carfilzomib can improve progression-free survival (PFS) in patients with relapsed multiple myeloma (MM).
Patients who received carfilzomib, lenalidomide, and dexamethasone lived 8.7 months longer without progression than patients who received only lenalidomide and dexamethasone.
The companies developing carfilzomib, Amgen and its subsidiary, Onyx Pharmaceuticals, Inc., recently shared these results.
They said additional results will be submitted for presentation at the 56th Annual ASH Meeting in December.
The companies also said data from the ASPIRE trial will form the basis for regulatory submissions for carfilzomib throughout the world.
In the US, the data may support the conversion of accelerated approval to full approval and expand the current indication for carfilzomib.
The ASPIRE trial includes 792 patients with relapsed MM who were randomized to treatment at sites in North America, Europe, and Israel. Prior to study treatment, the patients had received 1 to 3 therapeutic regimens.
The patients were randomized to receive carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1 only, then 27 mg/m2), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, 7 days off) and low-dose dexamethasone (40 mg per week in 4-week cycles), or lenalidomide and low-dose dexamethasone alone.
The primary endpoint was PFS, and secondary endpoints included overall survival, overall response rate, duration of response, disease control rate, health-related quality of life, and safety.
At a planned interim analysis, patients in the carfilzomib arm had a significantly longer median PFS than patients in the other arm—26.3 months and 17.6 months, respectively (P<0.0001).
The data for overall survival are not yet mature, but the analysis showed a trend in favor of carfilzomib that did not reach statistical significance, according to Amgen and Onyx.
The companies said the safety profile in this study is consistent with previous studies, including the rate of cardiac events.
Treatment discontinuation due to adverse events and on-study deaths were comparable between the 2 arms, and researchers did not identify any new safety signals.
Interim results of the phase 3 ASPIRE trial suggest carfilzomib can improve progression-free survival (PFS) in patients with relapsed multiple myeloma (MM).
Patients who received carfilzomib, lenalidomide, and dexamethasone lived 8.7 months longer without progression than patients who received only lenalidomide and dexamethasone.
The companies developing carfilzomib, Amgen and its subsidiary, Onyx Pharmaceuticals, Inc., recently shared these results.
They said additional results will be submitted for presentation at the 56th Annual ASH Meeting in December.
The companies also said data from the ASPIRE trial will form the basis for regulatory submissions for carfilzomib throughout the world.
In the US, the data may support the conversion of accelerated approval to full approval and expand the current indication for carfilzomib.
The ASPIRE trial includes 792 patients with relapsed MM who were randomized to treatment at sites in North America, Europe, and Israel. Prior to study treatment, the patients had received 1 to 3 therapeutic regimens.
The patients were randomized to receive carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1 only, then 27 mg/m2), in addition to a standard dosing schedule of lenalidomide (25 mg per day for 21 days on, 7 days off) and low-dose dexamethasone (40 mg per week in 4-week cycles), or lenalidomide and low-dose dexamethasone alone.
The primary endpoint was PFS, and secondary endpoints included overall survival, overall response rate, duration of response, disease control rate, health-related quality of life, and safety.
At a planned interim analysis, patients in the carfilzomib arm had a significantly longer median PFS than patients in the other arm—26.3 months and 17.6 months, respectively (P<0.0001).
The data for overall survival are not yet mature, but the analysis showed a trend in favor of carfilzomib that did not reach statistical significance, according to Amgen and Onyx.
The companies said the safety profile in this study is consistent with previous studies, including the rate of cardiac events.
Treatment discontinuation due to adverse events and on-study deaths were comparable between the 2 arms, and researchers did not identify any new safety signals.