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.

DNA helices

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.”

DNA helices

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.”

DNA helices

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.”

Micrograph showing 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.

Micrograph showing 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.

Micrograph showing 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.

The effectiveness of influenza vaccine is recognized to vary widely from season to season. At least two factors are critical for determining the likelihood that flu vaccine will be successful in preventing illness.

First, the demographics of who is being immunized (primarily age and presence of comorbidity) and second, the "match" between the circulating flu viruses and that year’s flu vaccine. When the flu vaccine is a poor match with circulating viruses, less benefit from flu vaccination will be observed; in years when the "match" between vaccine and circulating virus is good, substantial reduction in influenza respiratory illness in children and adults is observed. Recently, a second influenza B antigen has been added (creating quadrivalent vaccines) to improve the match with influenza B strains that may circulate in the community.

In February 2014, the Centers for Disease Control and Prevention reported midseason vaccine effectiveness estimates (MMWR 2014 Feb 21;63:137-42).

The major circulating virus was influenza A "2009 H1N1" virus and the "match" between vaccine strains and circulating strains was considered good. The CDC’s midseason vaccine effectiveness estimate was 61% for all age groups (95% confidence interval, 52%-68%), reinforcing the value of influenza vaccine for disease prevention in both children and adults. Flu vaccine reduced the risk of seeking medical attention for flulike illness by 60% for both children and adults.

Another factor that may determine the effectiveness of influenza vaccine in children is whether the individual receives live attenuated influenza vaccine (LAIV) or trivalent or quadrivalent inactivated influenza vaccine (IIV). The CDC has been considering the question "should LAIV be recommended preferentially over IIV in healthy children 2-8 years of age?" based on data from a limited number of studies. Canada, United Kingdom, Israel, and Germany have each expressed a preference for LAIV in their recent recommendations. The CDC working group evaluated published studies primarily restricted to those focused on healthy children, those with both LAIV and IIV cohorts, those studying the U.S. licensed and similar vaccines, and those in English. Their literature review identified five randomized trials and five additional observational studies. Lab-confirmed influenza in symptomatic children was the primary outcome; influenza related mortality and hospitalization also were considered.

The efficacy of LAIV was originally established in four randomized, placebo-controlled clinical trials. Each study was completed over two influenza seasons.

In the Belshe study (N. Engl. J. Med. 1998;338:1405-12), the efficacy compared with placebo was 93% in the first season and 100% in the second (after revaccination).

In a second study (Pediatrics 2006;118:2298-312), efficacy compared to placebo was 85% in the first season and 89% in the second (after revaccination).

Subsequently, randomized studies comparing LAIV with IIV in children younger than 8 years of age demonstrating the relative benefits of LAIV were reported (N. Engl. J. Med. 2007;356:685-96; Pediatr. Infect. Dis. J. 2006 ;25:870-9). A reduction greater than or equal to 50% in laboratory-confirmed influenza cases in the LAIV cohorts compared with the trivalent inactivated vaccine groups was observed. Greater efficacy was reported both in groups that were influenza vaccine naive as well as those with prior immunization. No reductions in hospitalization and medically-attended acute respiratory illness were reported for the LAIV cohorts; however, the quality of the data was judged to be less robust than for laboratory-confirmed disease. For children aged 9-18 years, no differences in laboratory-confirmed influenza were reported.

The mechanism for improved efficacy of LAIV in young children (2-8 years) is largely unknown. LAIV may elicit long-lasting and broader humoral and cellular responses that more closely resembles natural immunity. It also has been hypothesized that LAIV is more immunogenic than IIV as a priming vaccine, and IIV is more effective in boosting preexisting immunity. It is possible that is one explanation for why LAIV is more effective in young children, and that no differences are observed in older children and adults. It also has been suggested that LAIV may elicit an antibody that is more broadly protective against mismatched influenza strains.

In June, the Advisory Committee on Immunization Practices (ACIP) proposed new recommendations regarding the use of LAIV and IIV for young healthy children. ACIP affirmed that both LAIV and IIV are effective in prevention of influenza in children, but recommended that LAIV be used for healthy children aged 2-8 years when both vaccines are available and there are no contraindications or precautions to its use. When LAIV is not immediately available, IIV should be used. Vaccination should not be delayed to procure LAIV.

ACIP restated previous contraindications and precautions to administration of LAIV. Those with contraindications to LAIV should receive inactivated vaccine. These include:

• Children less than 2 years of age and adults older than 49 years of age.

• Children aged 2-17 years receiving aspirin, persons with allergic reactions to vaccine or vaccine components, pregnant women, immunosuppressed persons, and persons with egg allergy.

• Children aged 2-4 years who have had a wheezing episode noted in the medical record or whose parents report that a health care provider informed them of wheezing or asthma within the last 12 months.

• Individuals who have taken antiviral medications within the previous 48 hours.

Administration to children less than 8 years of age with chronic medical conditions (specifically those associated with increased risk of influenza complications) is considered a precaution as safety has not been established.

Immunization for all children beginning at 6 months of age is still the essential message. However, when both LAIV and IIV (trivalent [TIV] or quadrivalent inactivated influenza vaccines [QIV]) are available, the advisory committee recommended LAIV as a preference in healthy children aged 2-8 years. If only TIV or QIV is available, administration of either one is recommended as delays in receipt are of greater concern than are the differences in vaccine formulations. This recommendation, if approved by the CDC director, will not be official until it is published in the 2014-2015 influenza prevention and control recommendations in the MMWR. In anticipation of this new recommendation, the manufacturer has stated that it will be producing 18 million doses of quadrivalent LAIV for the U.S. market for the 2014-2015 season, up from the 13 million it produced last season. More information when available also will be posted on the CDC influenza website and the American Academy of Pediatrics website.

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

The effectiveness of influenza vaccine is recognized to vary widely from season to season. At least two factors are critical for determining the likelihood that flu vaccine will be successful in preventing illness.

First, the demographics of who is being immunized (primarily age and presence of comorbidity) and second, the "match" between the circulating flu viruses and that year’s flu vaccine. When the flu vaccine is a poor match with circulating viruses, less benefit from flu vaccination will be observed; in years when the "match" between vaccine and circulating virus is good, substantial reduction in influenza respiratory illness in children and adults is observed. Recently, a second influenza B antigen has been added (creating quadrivalent vaccines) to improve the match with influenza B strains that may circulate in the community.

In February 2014, the Centers for Disease Control and Prevention reported midseason vaccine effectiveness estimates (MMWR 2014 Feb 21;63:137-42).

The major circulating virus was influenza A "2009 H1N1" virus and the "match" between vaccine strains and circulating strains was considered good. The CDC’s midseason vaccine effectiveness estimate was 61% for all age groups (95% confidence interval, 52%-68%), reinforcing the value of influenza vaccine for disease prevention in both children and adults. Flu vaccine reduced the risk of seeking medical attention for flulike illness by 60% for both children and adults.

Another factor that may determine the effectiveness of influenza vaccine in children is whether the individual receives live attenuated influenza vaccine (LAIV) or trivalent or quadrivalent inactivated influenza vaccine (IIV). The CDC has been considering the question "should LAIV be recommended preferentially over IIV in healthy children 2-8 years of age?" based on data from a limited number of studies. Canada, United Kingdom, Israel, and Germany have each expressed a preference for LAIV in their recent recommendations. The CDC working group evaluated published studies primarily restricted to those focused on healthy children, those with both LAIV and IIV cohorts, those studying the U.S. licensed and similar vaccines, and those in English. Their literature review identified five randomized trials and five additional observational studies. Lab-confirmed influenza in symptomatic children was the primary outcome; influenza related mortality and hospitalization also were considered.

The efficacy of LAIV was originally established in four randomized, placebo-controlled clinical trials. Each study was completed over two influenza seasons.

In the Belshe study (N. Engl. J. Med. 1998;338:1405-12), the efficacy compared with placebo was 93% in the first season and 100% in the second (after revaccination).

In a second study (Pediatrics 2006;118:2298-312), efficacy compared to placebo was 85% in the first season and 89% in the second (after revaccination).

Subsequently, randomized studies comparing LAIV with IIV in children younger than 8 years of age demonstrating the relative benefits of LAIV were reported (N. Engl. J. Med. 2007;356:685-96; Pediatr. Infect. Dis. J. 2006 ;25:870-9). A reduction greater than or equal to 50% in laboratory-confirmed influenza cases in the LAIV cohorts compared with the trivalent inactivated vaccine groups was observed. Greater efficacy was reported both in groups that were influenza vaccine naive as well as those with prior immunization. No reductions in hospitalization and medically-attended acute respiratory illness were reported for the LAIV cohorts; however, the quality of the data was judged to be less robust than for laboratory-confirmed disease. For children aged 9-18 years, no differences in laboratory-confirmed influenza were reported.

The mechanism for improved efficacy of LAIV in young children (2-8 years) is largely unknown. LAIV may elicit long-lasting and broader humoral and cellular responses that more closely resembles natural immunity. It also has been hypothesized that LAIV is more immunogenic than IIV as a priming vaccine, and IIV is more effective in boosting preexisting immunity. It is possible that is one explanation for why LAIV is more effective in young children, and that no differences are observed in older children and adults. It also has been suggested that LAIV may elicit an antibody that is more broadly protective against mismatched influenza strains.

In June, the Advisory Committee on Immunization Practices (ACIP) proposed new recommendations regarding the use of LAIV and IIV for young healthy children. ACIP affirmed that both LAIV and IIV are effective in prevention of influenza in children, but recommended that LAIV be used for healthy children aged 2-8 years when both vaccines are available and there are no contraindications or precautions to its use. When LAIV is not immediately available, IIV should be used. Vaccination should not be delayed to procure LAIV.

ACIP restated previous contraindications and precautions to administration of LAIV. Those with contraindications to LAIV should receive inactivated vaccine. These include:

• Children less than 2 years of age and adults older than 49 years of age.

• Children aged 2-17 years receiving aspirin, persons with allergic reactions to vaccine or vaccine components, pregnant women, immunosuppressed persons, and persons with egg allergy.

• Children aged 2-4 years who have had a wheezing episode noted in the medical record or whose parents report that a health care provider informed them of wheezing or asthma within the last 12 months.

• Individuals who have taken antiviral medications within the previous 48 hours.

Administration to children less than 8 years of age with chronic medical conditions (specifically those associated with increased risk of influenza complications) is considered a precaution as safety has not been established.

Immunization for all children beginning at 6 months of age is still the essential message. However, when both LAIV and IIV (trivalent [TIV] or quadrivalent inactivated influenza vaccines [QIV]) are available, the advisory committee recommended LAIV as a preference in healthy children aged 2-8 years. If only TIV or QIV is available, administration of either one is recommended as delays in receipt are of greater concern than are the differences in vaccine formulations. This recommendation, if approved by the CDC director, will not be official until it is published in the 2014-2015 influenza prevention and control recommendations in the MMWR. In anticipation of this new recommendation, the manufacturer has stated that it will be producing 18 million doses of quadrivalent LAIV for the U.S. market for the 2014-2015 season, up from the 13 million it produced last season. More information when available also will be posted on the CDC influenza website and the American Academy of Pediatrics website.

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

The effectiveness of influenza vaccine is recognized to vary widely from season to season. At least two factors are critical for determining the likelihood that flu vaccine will be successful in preventing illness.

First, the demographics of who is being immunized (primarily age and presence of comorbidity) and second, the "match" between the circulating flu viruses and that year’s flu vaccine. When the flu vaccine is a poor match with circulating viruses, less benefit from flu vaccination will be observed; in years when the "match" between vaccine and circulating virus is good, substantial reduction in influenza respiratory illness in children and adults is observed. Recently, a second influenza B antigen has been added (creating quadrivalent vaccines) to improve the match with influenza B strains that may circulate in the community.

In February 2014, the Centers for Disease Control and Prevention reported midseason vaccine effectiveness estimates (MMWR 2014 Feb 21;63:137-42).

The major circulating virus was influenza A "2009 H1N1" virus and the "match" between vaccine strains and circulating strains was considered good. The CDC’s midseason vaccine effectiveness estimate was 61% for all age groups (95% confidence interval, 52%-68%), reinforcing the value of influenza vaccine for disease prevention in both children and adults. Flu vaccine reduced the risk of seeking medical attention for flulike illness by 60% for both children and adults.

Another factor that may determine the effectiveness of influenza vaccine in children is whether the individual receives live attenuated influenza vaccine (LAIV) or trivalent or quadrivalent inactivated influenza vaccine (IIV). The CDC has been considering the question "should LAIV be recommended preferentially over IIV in healthy children 2-8 years of age?" based on data from a limited number of studies. Canada, United Kingdom, Israel, and Germany have each expressed a preference for LAIV in their recent recommendations. The CDC working group evaluated published studies primarily restricted to those focused on healthy children, those with both LAIV and IIV cohorts, those studying the U.S. licensed and similar vaccines, and those in English. Their literature review identified five randomized trials and five additional observational studies. Lab-confirmed influenza in symptomatic children was the primary outcome; influenza related mortality and hospitalization also were considered.

The efficacy of LAIV was originally established in four randomized, placebo-controlled clinical trials. Each study was completed over two influenza seasons.

In the Belshe study (N. Engl. J. Med. 1998;338:1405-12), the efficacy compared with placebo was 93% in the first season and 100% in the second (after revaccination).

In a second study (Pediatrics 2006;118:2298-312), efficacy compared to placebo was 85% in the first season and 89% in the second (after revaccination).

Subsequently, randomized studies comparing LAIV with IIV in children younger than 8 years of age demonstrating the relative benefits of LAIV were reported (N. Engl. J. Med. 2007;356:685-96; Pediatr. Infect. Dis. J. 2006 ;25:870-9). A reduction greater than or equal to 50% in laboratory-confirmed influenza cases in the LAIV cohorts compared with the trivalent inactivated vaccine groups was observed. Greater efficacy was reported both in groups that were influenza vaccine naive as well as those with prior immunization. No reductions in hospitalization and medically-attended acute respiratory illness were reported for the LAIV cohorts; however, the quality of the data was judged to be less robust than for laboratory-confirmed disease. For children aged 9-18 years, no differences in laboratory-confirmed influenza were reported.

The mechanism for improved efficacy of LAIV in young children (2-8 years) is largely unknown. LAIV may elicit long-lasting and broader humoral and cellular responses that more closely resembles natural immunity. It also has been hypothesized that LAIV is more immunogenic than IIV as a priming vaccine, and IIV is more effective in boosting preexisting immunity. It is possible that is one explanation for why LAIV is more effective in young children, and that no differences are observed in older children and adults. It also has been suggested that LAIV may elicit an antibody that is more broadly protective against mismatched influenza strains.

In June, the Advisory Committee on Immunization Practices (ACIP) proposed new recommendations regarding the use of LAIV and IIV for young healthy children. ACIP affirmed that both LAIV and IIV are effective in prevention of influenza in children, but recommended that LAIV be used for healthy children aged 2-8 years when both vaccines are available and there are no contraindications or precautions to its use. When LAIV is not immediately available, IIV should be used. Vaccination should not be delayed to procure LAIV.

ACIP restated previous contraindications and precautions to administration of LAIV. Those with contraindications to LAIV should receive inactivated vaccine. These include:

• Children less than 2 years of age and adults older than 49 years of age.

• Children aged 2-17 years receiving aspirin, persons with allergic reactions to vaccine or vaccine components, pregnant women, immunosuppressed persons, and persons with egg allergy.

• Children aged 2-4 years who have had a wheezing episode noted in the medical record or whose parents report that a health care provider informed them of wheezing or asthma within the last 12 months.

• Individuals who have taken antiviral medications within the previous 48 hours.

Administration to children less than 8 years of age with chronic medical conditions (specifically those associated with increased risk of influenza complications) is considered a precaution as safety has not been established.

Immunization for all children beginning at 6 months of age is still the essential message. However, when both LAIV and IIV (trivalent [TIV] or quadrivalent inactivated influenza vaccines [QIV]) are available, the advisory committee recommended LAIV as a preference in healthy children aged 2-8 years. If only TIV or QIV is available, administration of either one is recommended as delays in receipt are of greater concern than are the differences in vaccine formulations. This recommendation, if approved by the CDC director, will not be official until it is published in the 2014-2015 influenza prevention and control recommendations in the MMWR. In anticipation of this new recommendation, the manufacturer has stated that it will be producing 18 million doses of quadrivalent LAIV for the U.S. market for the 2014-2015 season, up from the 13 million it produced last season. More information when available also will be posted on the CDC influenza website and the American Academy of Pediatrics website.

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

A researchers examining

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 researchers examining

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 researchers examining

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.

Blood for transfusion

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, PrP^Sc. So they set out to determine if they could detect PrP^Sc 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 PrP^Sc in samples from patients with variant CJD. They found “minute quantities” of PrP^Sc in 13 of the 14 urine samples from variant CJD patients, but PrP^Sc 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%.

Blood for transfusion

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, PrP^Sc. So they set out to determine if they could detect PrP^Sc 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 PrP^Sc in samples from patients with variant CJD. They found “minute quantities” of PrP^Sc in 13 of the 14 urine samples from variant CJD patients, but PrP^Sc 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%.

Blood for transfusion

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, PrP^Sc. So they set out to determine if they could detect PrP^Sc 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 PrP^Sc in samples from patients with variant CJD. They found “minute quantities” of PrP^Sc in 13 of the 14 urine samples from variant CJD patients, but PrP^Sc 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%.

Chromosomes

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.

Chromosomes

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.

Chromosomes

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 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.