Hematology Times

Photo courtesy of Merck

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for the anti-PD-1 therapy pembrolizumab (Keytruda) as a treatment for patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

The recommendation pertains specifically to adults with cHL who have failed autologous hematopoietic stem cell transplant (auto-HSCT) and treatment with brentuximab vedotin (BV) or adults with cHL who are transplant-ineligible and have failed treatment with BV.

The CHMP’s recommendation will be reviewed by the European Commission, which is expected to make a decision about the drug in the second quarter of 2017.

Pembrolizumab is already approved for use in the European Union as a treatment for melanoma and non-small-cell lung cancer.

The CHMP’s positive opinion of pembrolizumab for cHL was based on data from the KEYNOTE-087 and KEYNOTE-013 trials. Results from both trials were presented at ASH 2016 (abstract 1107 and abstract 1108).

KEYNOTE-087

KEYNOTE-087 is a phase 2 trial in which researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:

• Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
• Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
• Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.

Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.

In Cohort 1 (n=69), the ORR was 73.9%. The CR rate was 21.7%, the partial response (PR) rate was 52.2%, 15.9% of patients had stable disease (SD), and 7.2% progressed. In 82.2% of responders, the response lasted 6 months or more.

In Cohort 2 (n=81), the ORR was 64.2%. The CR rate was 24.7%, the PR rate was 39.5%, 12.3% of patients had SD, and 21.0% progressed. In 70.0% of responders, the response lasted 6 months or more.

In Cohort 3 (n=60), the ORR was 70.0%. Twenty percent of patients had a CR, 50.0% had a PR, 16.7% had SD, and 13.3% progressed. In 75.6% of responders, the response lasted 6 months or more.

Results also included an analysis of patients with primary refractory disease (n=73), which was defined as failure to achieve CR or PR with first-line treatment. In this patient population, the ORR was 79.5%.

An ORR of 67.8% was reported in patients who relapsed after 3 or more lines of prior therapy (99/146).

The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).

The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).

There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.

KEYNOTE-013

KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.

Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.

The ORR was 58%. Nineteen percent of patients achieved a CR, 39% had a PR, and 23% had SD.

The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.

The median progression-free survival (PFS) was 11.4 months (range, 4.9-27.8 months). The six-month PFS rate was 66%, and the 12-month PFS rate was 48%.

The median overall survival was not reached. Six-month and 12-month overall survival rates were 100% and 87%, respectively.

The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).

The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).

AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths.

Photo courtesy of Merck

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for the anti-PD-1 therapy pembrolizumab (Keytruda) as a treatment for patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

The recommendation pertains specifically to adults with cHL who have failed autologous hematopoietic stem cell transplant (auto-HSCT) and treatment with brentuximab vedotin (BV) or adults with cHL who are transplant-ineligible and have failed treatment with BV.

The CHMP’s recommendation will be reviewed by the European Commission, which is expected to make a decision about the drug in the second quarter of 2017.

Pembrolizumab is already approved for use in the European Union as a treatment for melanoma and non-small-cell lung cancer.

The CHMP’s positive opinion of pembrolizumab for cHL was based on data from the KEYNOTE-087 and KEYNOTE-013 trials. Results from both trials were presented at ASH 2016 (abstract 1107 and abstract 1108).

KEYNOTE-087

KEYNOTE-087 is a phase 2 trial in which researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:

• Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
• Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
• Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.

Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.

In Cohort 1 (n=69), the ORR was 73.9%. The CR rate was 21.7%, the partial response (PR) rate was 52.2%, 15.9% of patients had stable disease (SD), and 7.2% progressed. In 82.2% of responders, the response lasted 6 months or more.

In Cohort 2 (n=81), the ORR was 64.2%. The CR rate was 24.7%, the PR rate was 39.5%, 12.3% of patients had SD, and 21.0% progressed. In 70.0% of responders, the response lasted 6 months or more.

In Cohort 3 (n=60), the ORR was 70.0%. Twenty percent of patients had a CR, 50.0% had a PR, 16.7% had SD, and 13.3% progressed. In 75.6% of responders, the response lasted 6 months or more.

Results also included an analysis of patients with primary refractory disease (n=73), which was defined as failure to achieve CR or PR with first-line treatment. In this patient population, the ORR was 79.5%.

An ORR of 67.8% was reported in patients who relapsed after 3 or more lines of prior therapy (99/146).

The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).

The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).

There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.

KEYNOTE-013

KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.

Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.

The ORR was 58%. Nineteen percent of patients achieved a CR, 39% had a PR, and 23% had SD.

The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.

The median progression-free survival (PFS) was 11.4 months (range, 4.9-27.8 months). The six-month PFS rate was 66%, and the 12-month PFS rate was 48%.

The median overall survival was not reached. Six-month and 12-month overall survival rates were 100% and 87%, respectively.

The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).

The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).

AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths.

Photo courtesy of Merck

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval for the anti-PD-1 therapy pembrolizumab (Keytruda) as a treatment for patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

The recommendation pertains specifically to adults with cHL who have failed autologous hematopoietic stem cell transplant (auto-HSCT) and treatment with brentuximab vedotin (BV) or adults with cHL who are transplant-ineligible and have failed treatment with BV.

The CHMP’s recommendation will be reviewed by the European Commission, which is expected to make a decision about the drug in the second quarter of 2017.

Pembrolizumab is already approved for use in the European Union as a treatment for melanoma and non-small-cell lung cancer.

The CHMP’s positive opinion of pembrolizumab for cHL was based on data from the KEYNOTE-087 and KEYNOTE-013 trials. Results from both trials were presented at ASH 2016 (abstract 1107 and abstract 1108).

KEYNOTE-087

KEYNOTE-087 is a phase 2 trial in which researchers evaluated pembrolizumab (a 200 mg fixed dose every 3 weeks) in patients with relapsed or refractory cHL across 3 cohorts:

• Cohort 1: Patients who progressed after auto-HSCT and subsequent treatment with BV
• Cohort 2: Patients who failed salvage chemotherapy, were ineligible for a transplant, and progressed after BV
• Cohort 3: Patients who progressed after auto-HSCT and did not receive BV after transplant.

Across all 210 enrolled patients, the overall response rate (ORR) was 69.0%, and the complete response (CR) rate was 22.4%.

In Cohort 1 (n=69), the ORR was 73.9%. The CR rate was 21.7%, the partial response (PR) rate was 52.2%, 15.9% of patients had stable disease (SD), and 7.2% progressed. In 82.2% of responders, the response lasted 6 months or more.

In Cohort 2 (n=81), the ORR was 64.2%. The CR rate was 24.7%, the PR rate was 39.5%, 12.3% of patients had SD, and 21.0% progressed. In 70.0% of responders, the response lasted 6 months or more.

In Cohort 3 (n=60), the ORR was 70.0%. Twenty percent of patients had a CR, 50.0% had a PR, 16.7% had SD, and 13.3% progressed. In 75.6% of responders, the response lasted 6 months or more.

Results also included an analysis of patients with primary refractory disease (n=73), which was defined as failure to achieve CR or PR with first-line treatment. In this patient population, the ORR was 79.5%.

An ORR of 67.8% was reported in patients who relapsed after 3 or more lines of prior therapy (99/146).

The most common treatment-related adverse events (AEs) were hypothyroidism (12.4%), pyrexia (10.5%), fatigue (9.0%), rash (7.6%), diarrhea (7.1%), headache (6.2%), nausea (5.7%), cough (5.7%), and neutropenia (5.2%).

The most common grade 3/4 treatment-related AEs were neutropenia (2.4%), diarrhea (1.0%), and dyspnea (1.0%). Immune-mediated AEs included pneumonitis (2.9%), hyperthyroidism (2.9%), colitis (1.0%), and myositis (1.0%).

There were 9 discontinuations because of treatment-related AEs and no treatment-related deaths.

KEYNOTE-013

KEYNOTE-013 is a phase 1b trial that has enrolled 31 patients with relapsed or refractory cHL who failed auto-HSCT and subsequent BV or who were transplant-ineligible.

Patients received pembrolizumab at 10 mg/kg every 2 weeks. The median duration of follow-up was 29 months.

The ORR was 58%. Nineteen percent of patients achieved a CR, 39% had a PR, and 23% had SD.

The median duration of response had not been reached at last follow-up (range, 0.0+ to 26.1+ months), and 70% of responding patients had a response lasting 12 months or more.

The median progression-free survival (PFS) was 11.4 months (range, 4.9-27.8 months). The six-month PFS rate was 66%, and the 12-month PFS rate was 48%.

The median overall survival was not reached. Six-month and 12-month overall survival rates were 100% and 87%, respectively.

The most common treatment-related AEs were diarrhea (19%), hypothyroidism (13%), pneumonitis (13%), nausea (13%), fatigue (10%), and dyspnea (10%).

The most common grade 3/4 treatment-related AEs were colitis (3%), axillary pain (3%), AST increase (3%), joint swelling (3%), nephrotic syndrome back pain (3%), and dyspnea (3%).

AEs leading to discontinuation were nephrotic syndrome (grade 3), interstitial lung disease (grade 2), and pneumonitis (grade 2). There were no treatment-related deaths.

General Medical Sciences

A new study supports the idea that most cancer-driving mutations are a result of DNA replication errors, not heredity or lifestyle/environmental factors.

For all 32 cancer types studied, researchers found that 66% of driver mutations resulted from DNA replication errors, 29% could be attributed to lifestyle or environmental factors, and the remaining 5% were inherited.

In hematologic malignancies, the percentage of mutations caused by DNA replication errors was even higher—70% in Hodgkin lymphoma, 85% in leukemias, 96% in non-Hodgkin lymphomas, and 99% in myeloma.

Cristian Tomasetti, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in Science.

“It is well-known that we must avoid environmental factors such as smoking to decrease our risk of getting cancer, but it is not as well-known that each time a normal cell divides and copies its DNA to produce 2 new cells, it makes multiple mistakes,” Dr Tomasetti said.

“These copying mistakes are a potent source of cancer mutations that, historically, have been scientifically undervalued, and this new work provides the first estimate of the fraction of mutations caused by these mistakes.”

In 2015, Dr Tomasetti and his colleagues reported that DNA replication errors could explain why certain cancers occur more often than others in the US.

The current study builds upon that research but includes additional cancers and encompasses an international population.

The researchers first studied the relationship between the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries representing 4.8 billion people, or more than half of the world’s population.

The team said they observed a strong correlation between cancer incidence and normal stem cell divisions in all countries, regardless of their environment.

Next, the researchers set out to determine the percentage of driver mutations caused by DNA replication errors in 32 cancer types. The team developed a mathematical model using DNA sequencing data from The Cancer Genome Atlas and epidemiologic data from the Cancer Research UK database.

According to the researchers, it generally takes 2 or more critical mutations for cancer to occur. In an individual, these mutations can be due to random DNA replication errors, the environment, or inherited genes.

Knowing this, the researchers used their mathematical model to show, for example, that when critical mutations in leukemia are added together, 85.2% of them are due to random DNA replication errors, 14.3% to environmental factors, and 0.5% to heredity.

In Hodgkin lymphoma, 69.5% are due to DNA replication errors, 30% to environmental factors, and 0.5% to heredity. In non-Hodgkin lymphoma, 95.6% are due to random DNA replication errors, 3.9% to environmental factors, and 0.5% to heredity.

In myeloma, 99.3% are due to DNA replication errors, 0.2% to environmental factors, and 0.5% to heredity.

Dr Tomasetti said these random DNA replication errors will only get more important as aging populations continue to grow, prolonging the opportunity for cells to make more and more errors.

“We need to continue to encourage people to avoid environmental agents and lifestyles that increase their risk of developing cancer mutations,” said study author Bert Vogelstein, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University.

“However, many people will still develop cancers due to these random DNA copying errors, and better methods to detect all cancers earlier, while they are still curable, are urgently needed.”

General Medical Sciences

A new study supports the idea that most cancer-driving mutations are a result of DNA replication errors, not heredity or lifestyle/environmental factors.

For all 32 cancer types studied, researchers found that 66% of driver mutations resulted from DNA replication errors, 29% could be attributed to lifestyle or environmental factors, and the remaining 5% were inherited.

In hematologic malignancies, the percentage of mutations caused by DNA replication errors was even higher—70% in Hodgkin lymphoma, 85% in leukemias, 96% in non-Hodgkin lymphomas, and 99% in myeloma.

Cristian Tomasetti, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in Science.

“It is well-known that we must avoid environmental factors such as smoking to decrease our risk of getting cancer, but it is not as well-known that each time a normal cell divides and copies its DNA to produce 2 new cells, it makes multiple mistakes,” Dr Tomasetti said.

“These copying mistakes are a potent source of cancer mutations that, historically, have been scientifically undervalued, and this new work provides the first estimate of the fraction of mutations caused by these mistakes.”

In 2015, Dr Tomasetti and his colleagues reported that DNA replication errors could explain why certain cancers occur more often than others in the US.

The current study builds upon that research but includes additional cancers and encompasses an international population.

The researchers first studied the relationship between the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries representing 4.8 billion people, or more than half of the world’s population.

The team said they observed a strong correlation between cancer incidence and normal stem cell divisions in all countries, regardless of their environment.

Next, the researchers set out to determine the percentage of driver mutations caused by DNA replication errors in 32 cancer types. The team developed a mathematical model using DNA sequencing data from The Cancer Genome Atlas and epidemiologic data from the Cancer Research UK database.

According to the researchers, it generally takes 2 or more critical mutations for cancer to occur. In an individual, these mutations can be due to random DNA replication errors, the environment, or inherited genes.

Knowing this, the researchers used their mathematical model to show, for example, that when critical mutations in leukemia are added together, 85.2% of them are due to random DNA replication errors, 14.3% to environmental factors, and 0.5% to heredity.

In Hodgkin lymphoma, 69.5% are due to DNA replication errors, 30% to environmental factors, and 0.5% to heredity. In non-Hodgkin lymphoma, 95.6% are due to random DNA replication errors, 3.9% to environmental factors, and 0.5% to heredity.

In myeloma, 99.3% are due to DNA replication errors, 0.2% to environmental factors, and 0.5% to heredity.

Dr Tomasetti said these random DNA replication errors will only get more important as aging populations continue to grow, prolonging the opportunity for cells to make more and more errors.

“We need to continue to encourage people to avoid environmental agents and lifestyles that increase their risk of developing cancer mutations,” said study author Bert Vogelstein, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University.

“However, many people will still develop cancers due to these random DNA copying errors, and better methods to detect all cancers earlier, while they are still curable, are urgently needed.”

General Medical Sciences

A new study supports the idea that most cancer-driving mutations are a result of DNA replication errors, not heredity or lifestyle/environmental factors.

For all 32 cancer types studied, researchers found that 66% of driver mutations resulted from DNA replication errors, 29% could be attributed to lifestyle or environmental factors, and the remaining 5% were inherited.

In hematologic malignancies, the percentage of mutations caused by DNA replication errors was even higher—70% in Hodgkin lymphoma, 85% in leukemias, 96% in non-Hodgkin lymphomas, and 99% in myeloma.

Cristian Tomasetti, PhD, of Johns Hopkins University School of Medicine in Baltimore, Maryland, and his colleagues reported these findings in Science.

“It is well-known that we must avoid environmental factors such as smoking to decrease our risk of getting cancer, but it is not as well-known that each time a normal cell divides and copies its DNA to produce 2 new cells, it makes multiple mistakes,” Dr Tomasetti said.

“These copying mistakes are a potent source of cancer mutations that, historically, have been scientifically undervalued, and this new work provides the first estimate of the fraction of mutations caused by these mistakes.”

In 2015, Dr Tomasetti and his colleagues reported that DNA replication errors could explain why certain cancers occur more often than others in the US.

The current study builds upon that research but includes additional cancers and encompasses an international population.

The researchers first studied the relationship between the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries representing 4.8 billion people, or more than half of the world’s population.

The team said they observed a strong correlation between cancer incidence and normal stem cell divisions in all countries, regardless of their environment.

Next, the researchers set out to determine the percentage of driver mutations caused by DNA replication errors in 32 cancer types. The team developed a mathematical model using DNA sequencing data from The Cancer Genome Atlas and epidemiologic data from the Cancer Research UK database.

According to the researchers, it generally takes 2 or more critical mutations for cancer to occur. In an individual, these mutations can be due to random DNA replication errors, the environment, or inherited genes.

Knowing this, the researchers used their mathematical model to show, for example, that when critical mutations in leukemia are added together, 85.2% of them are due to random DNA replication errors, 14.3% to environmental factors, and 0.5% to heredity.

In Hodgkin lymphoma, 69.5% are due to DNA replication errors, 30% to environmental factors, and 0.5% to heredity. In non-Hodgkin lymphoma, 95.6% are due to random DNA replication errors, 3.9% to environmental factors, and 0.5% to heredity.

In myeloma, 99.3% are due to DNA replication errors, 0.2% to environmental factors, and 0.5% to heredity.

Dr Tomasetti said these random DNA replication errors will only get more important as aging populations continue to grow, prolonging the opportunity for cells to make more and more errors.

“We need to continue to encourage people to avoid environmental agents and lifestyles that increase their risk of developing cancer mutations,” said study author Bert Vogelstein, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University.

“However, many people will still develop cancers due to these random DNA copying errors, and better methods to detect all cancers earlier, while they are still curable, are urgently needed.”

Photo by Nina Matthews

Women diagnosed with cancer during their childbearing years have an increased risk of preterm births, according to research published in JAMA Oncology.

The study showed that cancer survivors were more likely than women who never had cancer to give birth prematurely, have underweight babies, and undergo cesarean section deliveries.

The researchers said women diagnosed with cancer during pregnancy may be delivering early in order to start their cancer treatment, but that does not fully explain these findings.

The team also detected an increased risk of preterm delivery in women who had already received cancer treatment.

“We found that women were more likely to deliver preterm if they’ve been treated for cancer overall, with greater risks for women who had chemotherapy,” said study author Hazel B. Nichols, PhD, of University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

“While we believe these findings are something women should be aware of, we still have a lot of work to do to understand why this risk is becoming apparent and whether or not the children who are born preterm to these women go on to develop any health concerns.”

Dr Nichols and her colleagues analyzed data on 2598 births to female adolescent and young adult cancer survivors (ages 15 to 39) and 12,990 births to women without a cancer diagnosis.

Among cancer survivors, there was a significantly increased prevalence of preterm birth (prevalence ratio [PR]=1.52), low birth weight (PR=1.59), and cesarean delivery (PR=1.08), compared to women without a cancer diagnosis.

Timing of diagnosis and cancer type

When the researchers broke the data down by cancer diagnosis, they found a higher risk of preterm birth and low birth weight for women with lymphoma as well as breast and gynecologic cancers.

The PR for preterm birth was 1.59 for Hodgkin lymphoma, 1.98 for breast cancer, 2.11 for non-Hodgkin lymphoma, and 2.58 for gynecologic cancer. The PR for low birth weight was 1.59 for breast cancer, 2.41 for non-Hodgkin lymphoma, and 2.74 for gynecologic cancer.

The researchers found an increased risk of adverse birth outcomes among women who were diagnosed with cancer while pregnant and before pregnancy.

Among women diagnosed while pregnant, the PR was 2.97 for preterm birth, 2.82 for low birth weight, 1.21 for cesarean delivery, and 1.90 for low Apgar score. Among women diagnosed before pregnancy, the PR was 1.23 for preterm birth and 1.36 for low birth weight.

Role of treatment

Compared to women without a cancer diagnosis, cancer survivors who received chemotherapy but no radiation were more likely to have preterm births (PR=2.11), infants with low birth weight (PR=2.36), and cesarean deliveries (PR=1.16).

There was no significant increase in adverse birth outcomes among cancer survivors who received radiation but not chemotherapy.

Among the cancer survivors, women who received chemotherapy without radiation were more likely to have preterm births (PR=2.12), infants with low birth weight (PR=2.13), and infants who were small for their gestational age (PR=1.43) when compared to women treated with surgery only.

Dr Nichols said the role of treatment is an area of possible future research.

“We’d like to get better information about the types of chemotherapy women receive,” she said. “Chemotherapy is a very broad category, and the agents have very different effects on the body. In the future, we’d like to get more detailed information on the types of drugs that were involved in treatment.”

Photo by Nina Matthews

Women diagnosed with cancer during their childbearing years have an increased risk of preterm births, according to research published in JAMA Oncology.

The study showed that cancer survivors were more likely than women who never had cancer to give birth prematurely, have underweight babies, and undergo cesarean section deliveries.

The researchers said women diagnosed with cancer during pregnancy may be delivering early in order to start their cancer treatment, but that does not fully explain these findings.

The team also detected an increased risk of preterm delivery in women who had already received cancer treatment.

“We found that women were more likely to deliver preterm if they’ve been treated for cancer overall, with greater risks for women who had chemotherapy,” said study author Hazel B. Nichols, PhD, of University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

“While we believe these findings are something women should be aware of, we still have a lot of work to do to understand why this risk is becoming apparent and whether or not the children who are born preterm to these women go on to develop any health concerns.”

Dr Nichols and her colleagues analyzed data on 2598 births to female adolescent and young adult cancer survivors (ages 15 to 39) and 12,990 births to women without a cancer diagnosis.

Among cancer survivors, there was a significantly increased prevalence of preterm birth (prevalence ratio [PR]=1.52), low birth weight (PR=1.59), and cesarean delivery (PR=1.08), compared to women without a cancer diagnosis.

Timing of diagnosis and cancer type

When the researchers broke the data down by cancer diagnosis, they found a higher risk of preterm birth and low birth weight for women with lymphoma as well as breast and gynecologic cancers.

The PR for preterm birth was 1.59 for Hodgkin lymphoma, 1.98 for breast cancer, 2.11 for non-Hodgkin lymphoma, and 2.58 for gynecologic cancer. The PR for low birth weight was 1.59 for breast cancer, 2.41 for non-Hodgkin lymphoma, and 2.74 for gynecologic cancer.

The researchers found an increased risk of adverse birth outcomes among women who were diagnosed with cancer while pregnant and before pregnancy.

Among women diagnosed while pregnant, the PR was 2.97 for preterm birth, 2.82 for low birth weight, 1.21 for cesarean delivery, and 1.90 for low Apgar score. Among women diagnosed before pregnancy, the PR was 1.23 for preterm birth and 1.36 for low birth weight.

Role of treatment

Compared to women without a cancer diagnosis, cancer survivors who received chemotherapy but no radiation were more likely to have preterm births (PR=2.11), infants with low birth weight (PR=2.36), and cesarean deliveries (PR=1.16).

There was no significant increase in adverse birth outcomes among cancer survivors who received radiation but not chemotherapy.

Among the cancer survivors, women who received chemotherapy without radiation were more likely to have preterm births (PR=2.12), infants with low birth weight (PR=2.13), and infants who were small for their gestational age (PR=1.43) when compared to women treated with surgery only.

Dr Nichols said the role of treatment is an area of possible future research.

“We’d like to get better information about the types of chemotherapy women receive,” she said. “Chemotherapy is a very broad category, and the agents have very different effects on the body. In the future, we’d like to get more detailed information on the types of drugs that were involved in treatment.”

Photo by Nina Matthews

Women diagnosed with cancer during their childbearing years have an increased risk of preterm births, according to research published in JAMA Oncology.

The study showed that cancer survivors were more likely than women who never had cancer to give birth prematurely, have underweight babies, and undergo cesarean section deliveries.

The researchers said women diagnosed with cancer during pregnancy may be delivering early in order to start their cancer treatment, but that does not fully explain these findings.

The team also detected an increased risk of preterm delivery in women who had already received cancer treatment.

“We found that women were more likely to deliver preterm if they’ve been treated for cancer overall, with greater risks for women who had chemotherapy,” said study author Hazel B. Nichols, PhD, of University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill.

“While we believe these findings are something women should be aware of, we still have a lot of work to do to understand why this risk is becoming apparent and whether or not the children who are born preterm to these women go on to develop any health concerns.”

Dr Nichols and her colleagues analyzed data on 2598 births to female adolescent and young adult cancer survivors (ages 15 to 39) and 12,990 births to women without a cancer diagnosis.

Among cancer survivors, there was a significantly increased prevalence of preterm birth (prevalence ratio [PR]=1.52), low birth weight (PR=1.59), and cesarean delivery (PR=1.08), compared to women without a cancer diagnosis.

Timing of diagnosis and cancer type

When the researchers broke the data down by cancer diagnosis, they found a higher risk of preterm birth and low birth weight for women with lymphoma as well as breast and gynecologic cancers.

The PR for preterm birth was 1.59 for Hodgkin lymphoma, 1.98 for breast cancer, 2.11 for non-Hodgkin lymphoma, and 2.58 for gynecologic cancer. The PR for low birth weight was 1.59 for breast cancer, 2.41 for non-Hodgkin lymphoma, and 2.74 for gynecologic cancer.

The researchers found an increased risk of adverse birth outcomes among women who were diagnosed with cancer while pregnant and before pregnancy.

Among women diagnosed while pregnant, the PR was 2.97 for preterm birth, 2.82 for low birth weight, 1.21 for cesarean delivery, and 1.90 for low Apgar score. Among women diagnosed before pregnancy, the PR was 1.23 for preterm birth and 1.36 for low birth weight.

Role of treatment

Compared to women without a cancer diagnosis, cancer survivors who received chemotherapy but no radiation were more likely to have preterm births (PR=2.11), infants with low birth weight (PR=2.36), and cesarean deliveries (PR=1.16).

There was no significant increase in adverse birth outcomes among cancer survivors who received radiation but not chemotherapy.

Among the cancer survivors, women who received chemotherapy without radiation were more likely to have preterm births (PR=2.12), infants with low birth weight (PR=2.13), and infants who were small for their gestational age (PR=1.43) when compared to women treated with surgery only.

Dr Nichols said the role of treatment is an area of possible future research.

“We’d like to get better information about the types of chemotherapy women receive,” she said. “Chemotherapy is a very broad category, and the agents have very different effects on the body. In the future, we’d like to get more detailed information on the types of drugs that were involved in treatment.”

Photo by Rhoda Baer

The US cancer care delivery system is undergoing changes to better meet the needs of cancer patients, but persistent hurdles threaten to slow progress, according to the American Society of Clinical Oncology (ASCO).

ASCO’s “The State of Cancer Care in America, 2017” report describes areas of progress, including new approaches for cancer diagnosis and treatment, improved data sharing to drive innovation, and an increased focus on value-based healthcare.

However, the report also suggests that access and affordability challenges, along with increased practice burdens, continue to pose barriers to high-value, high-quality cancer care.

The report was published in the Journal of Oncology Practice.

Challenges

The report notes that the US population is growing rapidly, changing demographically, and living longer. And all of these factors contribute to a record number of cancer cases/survivors.

It has been estimated that the number of cancer survivors in the US will grow from 15.5 million to 20.3 million by 2026.

Unfortunately, the report says, cancer care is unaffordable for many patients, even those with health insurance.

And significant health disparities persist that are independent of insurance status. Socioeconomic status, geography, and race/ethnicity all impact patient health outcomes.

The report also suggests that oncology practices are facing increased administrative burdens that divert time and resources from their patients.

Progress

Despite the aforementioned challenges, the report paints an optimistic vision about the future of cancer care and highlights activity in the past year aimed at improving care.

For instance, the Food and Drug Administration approved 5 new anticancer therapies, expanded the use of 13, and approved several diagnostic tests in 2016.

In addition, overall cancer incidence and mortality rates were lower in 2016 than in previous decades.

“Since 1991, we’ve been able to save 2.1 million lives because of significant advances in prevention, diagnosis, and treatment—something unimaginable even a decade ago,” said ASCO President Daniel F. Hayes, MD.

“But there’s still more work to be done to ensure that every patient with cancer, no matter who they are or where they live, has access to high-quality, high-value cancer care.”

The report includes a list of recommendations that, ASCO believes, could help bring the US closer to achieving that goal.

Photo by Rhoda Baer

The US cancer care delivery system is undergoing changes to better meet the needs of cancer patients, but persistent hurdles threaten to slow progress, according to the American Society of Clinical Oncology (ASCO).

ASCO’s “The State of Cancer Care in America, 2017” report describes areas of progress, including new approaches for cancer diagnosis and treatment, improved data sharing to drive innovation, and an increased focus on value-based healthcare.

However, the report also suggests that access and affordability challenges, along with increased practice burdens, continue to pose barriers to high-value, high-quality cancer care.

The report was published in the Journal of Oncology Practice.

Challenges

The report notes that the US population is growing rapidly, changing demographically, and living longer. And all of these factors contribute to a record number of cancer cases/survivors.

It has been estimated that the number of cancer survivors in the US will grow from 15.5 million to 20.3 million by 2026.

Unfortunately, the report says, cancer care is unaffordable for many patients, even those with health insurance.

And significant health disparities persist that are independent of insurance status. Socioeconomic status, geography, and race/ethnicity all impact patient health outcomes.

The report also suggests that oncology practices are facing increased administrative burdens that divert time and resources from their patients.

Progress

Despite the aforementioned challenges, the report paints an optimistic vision about the future of cancer care and highlights activity in the past year aimed at improving care.

For instance, the Food and Drug Administration approved 5 new anticancer therapies, expanded the use of 13, and approved several diagnostic tests in 2016.

In addition, overall cancer incidence and mortality rates were lower in 2016 than in previous decades.

“Since 1991, we’ve been able to save 2.1 million lives because of significant advances in prevention, diagnosis, and treatment—something unimaginable even a decade ago,” said ASCO President Daniel F. Hayes, MD.

“But there’s still more work to be done to ensure that every patient with cancer, no matter who they are or where they live, has access to high-quality, high-value cancer care.”

The report includes a list of recommendations that, ASCO believes, could help bring the US closer to achieving that goal.

Photo by Rhoda Baer

The US cancer care delivery system is undergoing changes to better meet the needs of cancer patients, but persistent hurdles threaten to slow progress, according to the American Society of Clinical Oncology (ASCO).

ASCO’s “The State of Cancer Care in America, 2017” report describes areas of progress, including new approaches for cancer diagnosis and treatment, improved data sharing to drive innovation, and an increased focus on value-based healthcare.

However, the report also suggests that access and affordability challenges, along with increased practice burdens, continue to pose barriers to high-value, high-quality cancer care.

The report was published in the Journal of Oncology Practice.

Challenges

The report notes that the US population is growing rapidly, changing demographically, and living longer. And all of these factors contribute to a record number of cancer cases/survivors.

It has been estimated that the number of cancer survivors in the US will grow from 15.5 million to 20.3 million by 2026.

Unfortunately, the report says, cancer care is unaffordable for many patients, even those with health insurance.

And significant health disparities persist that are independent of insurance status. Socioeconomic status, geography, and race/ethnicity all impact patient health outcomes.

The report also suggests that oncology practices are facing increased administrative burdens that divert time and resources from their patients.

Progress

Despite the aforementioned challenges, the report paints an optimistic vision about the future of cancer care and highlights activity in the past year aimed at improving care.

For instance, the Food and Drug Administration approved 5 new anticancer therapies, expanded the use of 13, and approved several diagnostic tests in 2016.

In addition, overall cancer incidence and mortality rates were lower in 2016 than in previous decades.

“Since 1991, we’ve been able to save 2.1 million lives because of significant advances in prevention, diagnosis, and treatment—something unimaginable even a decade ago,” said ASCO President Daniel F. Hayes, MD.

“But there’s still more work to be done to ensure that every patient with cancer, no matter who they are or where they live, has access to high-quality, high-value cancer care.”

The report includes a list of recommendations that, ASCO believes, could help bring the US closer to achieving that goal.

Photo courtesy of NHS

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has recommended that NiCord® receive orphan designation as a treatment for patients who require a hematopoietic stem cell transplant.

NiCord is a stand-alone graft derived from a single umbilical cord blood unit that has been expanded in culture and enriched with stem and progenitor cells.

NiCord already has orphan designation in the European Union as a treatment for patients with acute myeloid leukemia.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days.

NiCord also has orphan designation and breakthrough designation from the US Food and Drug Administration for the treatment of hematologic malignancies.

NiCord research

Data from the pilot study of NiCord suggested the therapy can provide a clinically meaningful improvement in time to neutrophil engraftment over traditional cord blood transplant.

And research presented at EBMT 2016 showed that patients who received NiCord had fewer infections, shorter hospital stays, quicker platelet engraftment, and improved non-relapse mortality when compared to patients who received a traditional cord blood transplant.

NiCord is currently being studied in a phase 3 registration study as a graft for patients with hematologic malignancies who do not have a rapidly available, fully matched donor.

Gamida Cell, the company developing NiCord, announced last month that the first patient in the study had been transplanted.

Photo courtesy of NHS

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has recommended that NiCord® receive orphan designation as a treatment for patients who require a hematopoietic stem cell transplant.

NiCord is a stand-alone graft derived from a single umbilical cord blood unit that has been expanded in culture and enriched with stem and progenitor cells.

NiCord already has orphan designation in the European Union as a treatment for patients with acute myeloid leukemia.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days.

NiCord also has orphan designation and breakthrough designation from the US Food and Drug Administration for the treatment of hematologic malignancies.

NiCord research

Data from the pilot study of NiCord suggested the therapy can provide a clinically meaningful improvement in time to neutrophil engraftment over traditional cord blood transplant.

And research presented at EBMT 2016 showed that patients who received NiCord had fewer infections, shorter hospital stays, quicker platelet engraftment, and improved non-relapse mortality when compared to patients who received a traditional cord blood transplant.

NiCord is currently being studied in a phase 3 registration study as a graft for patients with hematologic malignancies who do not have a rapidly available, fully matched donor.

Gamida Cell, the company developing NiCord, announced last month that the first patient in the study had been transplanted.

Photo courtesy of NHS

The European Medicines Agency’s (EMA’s) Committee for Orphan Medicinal Products has recommended that NiCord® receive orphan designation as a treatment for patients who require a hematopoietic stem cell transplant.

NiCord is a stand-alone graft derived from a single umbilical cord blood unit that has been expanded in culture and enriched with stem and progenitor cells.

NiCord already has orphan designation in the European Union as a treatment for patients with acute myeloid leukemia.

Orphan designation provides regulatory and financial incentives for companies to develop and market therapies that treat life-threatening or chronically debilitating conditions affecting no more than 5 in 10,000 people in the European Union, and where no satisfactory treatment is available.

Orphan designation provides a 10-year period of marketing exclusivity if the drug receives regulatory approval. The designation also provides incentives for companies seeking protocol assistance from the EMA during the product development phase and direct access to the centralized authorization procedure.

The EMA adopts an opinion on the granting of orphan drug designation, and that opinion is submitted to the European Commission for a final decision. The European Commission typically makes a decision within 30 days.

NiCord also has orphan designation and breakthrough designation from the US Food and Drug Administration for the treatment of hematologic malignancies.

NiCord research

Data from the pilot study of NiCord suggested the therapy can provide a clinically meaningful improvement in time to neutrophil engraftment over traditional cord blood transplant.

And research presented at EBMT 2016 showed that patients who received NiCord had fewer infections, shorter hospital stays, quicker platelet engraftment, and improved non-relapse mortality when compared to patients who received a traditional cord blood transplant.

NiCord is currently being studied in a phase 3 registration study as a graft for patients with hematologic malignancies who do not have a rapidly available, fully matched donor.

Gamida Cell, the company developing NiCord, announced last month that the first patient in the study had been transplanted.

Lab mouse

The lungs may play a previously unrecognized role in blood production, according to preclinical research published in Nature.

Researchers discovered large numbers of megakaryocytes in the lungs of mice and found these cells produced roughly half of the animals’ platelets.

The team also identified a pool of hematopoietic progenitors in the extravascular spaces of mouse lungs that were capable of multi-lineage bone marrow reconstitution.

“This finding definitely suggests a more sophisticated view of the lungs—that they’re not just for respiration but also a key partner in formation of crucial aspects of the blood,” said study author Mark R. Looney, MD, of the University of California - San Francisco.

“What we’ve observed here in mice strongly suggests the lung may play a key role in blood formation in humans as well.”

The researchers believe these findings could have major implications for understanding diseases in which patients suffer from thrombocytopenia.

Imaging reveals surprise

This research was made possible by a refinement of a technique known as 2-photon intravital imaging. This approach allowed the researchers to visualize the behavior of individual cells within the blood vessels of a living mouse lung.

Dr Looney and his colleagues used the technique to examine interactions between the immune system and circulating platelets in the lungs in a mouse strain engineered so that platelets emit bright green fluorescence (GFP+).

In this way, the team noticed a large population of megakaryocytes in the lung vasculature. Though megakaryocytes had been observed in the lung before, they were generally thought to live and produce platelets primarily in the bone marrow.

“When we discovered this massive population of megakaryocytes that appeared to be living in the lung, we realized we had to follow this up,” said study author Emma Lefrançais, PhD, a postdoctoral researcher in Dr Looney’s lab.

More detailed imaging sessions revealed megakaryocytes in the act of producing more than 10 million platelets per hour within the lung vasculature. This suggests that roughly half of a mouse’s total platelet production occurs in the lung, not the bone marrow, as researchers had long presumed.

Subsequent experiments also revealed a variety of previously overlooked hematopoietic progenitors outside the lung vasculature.

Transplants provide more insight

The discovery of megakaryocytes and hematopoietic progenitors in the lung raised questions about how these cells move back and forth between the lung and bone marrow. To address these questions, the researchers conducted a set of lung transplant studies.

The team transplanted lungs from wild-type mice into mice with GFP+ megakaryocytes and vice-versa. The researchers said they observed proplatelet formation from GFP+ megakaryocytes in the lung vasculature of the GFP+ mice but not in the wild-type mice.

This suggests the megakaryocytes releasing platelets in the lung circulation originate from outside the lungs, the researchers said. And subsequent experiments suggested the megakaryocytes originate in the bone marrow.

“It’s fascinating that megakaryocytes travel all the way from the bone marrow to the lungs to produce platelets,” said Guadalupe Ortiz-Muñoz, PhD, a postdoctoral researcher in Dr Looney’s lab.

“It’s possible that the lung is an ideal bioreactor for platelet production because of the mechanical force of the blood, or perhaps because of some molecular signaling we don’t yet know about.”

In another experiment, the researchers transplanted lungs with GFP+ megakaryocyte progenitors into mutant mice with low platelet counts.

The transplants successfully restored platelet levels to normal, an effect that persisted over a few months of observation—much longer than the lifespan of individual megakaryocytes or platelets.

To the researchers, this indicated that resident megakaryocyte progenitors in the transplanted lungs had become activated by the recipient mouse’s low platelet counts and had produced healthy megakaryocytes to restore proper platelet production.

Finally, the researchers tested whether lung hematopoietic progenitors were capable of multi-lineage bone marrow reconstitution.

They found that cells originating from transplanted lungs traveled to damaged bone marrow and contributed to the production of platelets and other blood cells, including neutrophils, B cells, and T cells.

The researchers said these experiments suggest the lungs play host to a variety of hematopoietic progenitors capable of reconstituting damaged bone marrow and restoring the production of many components of the blood.

“To our knowledge, this is the first description of blood progenitors resident in the lung, and it raises a lot of questions with clinical relevance for the millions of people who suffer from thrombocytopenia,” Dr Looney said.

In particular, the study suggests that researchers who have proposed treating platelet diseases with platelets produced from engineered megakaryocytes should look to the lungs as a resource for platelet production, Dr Looney noted.

The study also presents new avenues of research for stem cell biologists to explore how the bone marrow and lung collaborate to produce a healthy blood system through the mutual exchange of stem cells.

“These observations alter existing paradigms regarding blood cell formation, lung biology and disease, and transplantation,” said pulmonologist Guy A. Zimmerman, MD, who is associate chair of the Department of Internal Medicine at the University of Utah School of Medicine and was an independent reviewer of this study for Nature.

“The findings have direct clinical relevance and provide a rich group of questions for future studies of platelet genesis and megakaryocyte function in lung inflammation and other inflammatory conditions, bleeding and thrombotic disorders, and transplantation.”

Lab mouse

The lungs may play a previously unrecognized role in blood production, according to preclinical research published in Nature.

Researchers discovered large numbers of megakaryocytes in the lungs of mice and found these cells produced roughly half of the animals’ platelets.

The team also identified a pool of hematopoietic progenitors in the extravascular spaces of mouse lungs that were capable of multi-lineage bone marrow reconstitution.

“This finding definitely suggests a more sophisticated view of the lungs—that they’re not just for respiration but also a key partner in formation of crucial aspects of the blood,” said study author Mark R. Looney, MD, of the University of California - San Francisco.

“What we’ve observed here in mice strongly suggests the lung may play a key role in blood formation in humans as well.”

The researchers believe these findings could have major implications for understanding diseases in which patients suffer from thrombocytopenia.

Imaging reveals surprise

This research was made possible by a refinement of a technique known as 2-photon intravital imaging. This approach allowed the researchers to visualize the behavior of individual cells within the blood vessels of a living mouse lung.

Dr Looney and his colleagues used the technique to examine interactions between the immune system and circulating platelets in the lungs in a mouse strain engineered so that platelets emit bright green fluorescence (GFP+).

In this way, the team noticed a large population of megakaryocytes in the lung vasculature. Though megakaryocytes had been observed in the lung before, they were generally thought to live and produce platelets primarily in the bone marrow.

“When we discovered this massive population of megakaryocytes that appeared to be living in the lung, we realized we had to follow this up,” said study author Emma Lefrançais, PhD, a postdoctoral researcher in Dr Looney’s lab.

More detailed imaging sessions revealed megakaryocytes in the act of producing more than 10 million platelets per hour within the lung vasculature. This suggests that roughly half of a mouse’s total platelet production occurs in the lung, not the bone marrow, as researchers had long presumed.

Subsequent experiments also revealed a variety of previously overlooked hematopoietic progenitors outside the lung vasculature.

Transplants provide more insight

The discovery of megakaryocytes and hematopoietic progenitors in the lung raised questions about how these cells move back and forth between the lung and bone marrow. To address these questions, the researchers conducted a set of lung transplant studies.

The team transplanted lungs from wild-type mice into mice with GFP+ megakaryocytes and vice-versa. The researchers said they observed proplatelet formation from GFP+ megakaryocytes in the lung vasculature of the GFP+ mice but not in the wild-type mice.

This suggests the megakaryocytes releasing platelets in the lung circulation originate from outside the lungs, the researchers said. And subsequent experiments suggested the megakaryocytes originate in the bone marrow.

“It’s fascinating that megakaryocytes travel all the way from the bone marrow to the lungs to produce platelets,” said Guadalupe Ortiz-Muñoz, PhD, a postdoctoral researcher in Dr Looney’s lab.

“It’s possible that the lung is an ideal bioreactor for platelet production because of the mechanical force of the blood, or perhaps because of some molecular signaling we don’t yet know about.”

In another experiment, the researchers transplanted lungs with GFP+ megakaryocyte progenitors into mutant mice with low platelet counts.

The transplants successfully restored platelet levels to normal, an effect that persisted over a few months of observation—much longer than the lifespan of individual megakaryocytes or platelets.

To the researchers, this indicated that resident megakaryocyte progenitors in the transplanted lungs had become activated by the recipient mouse’s low platelet counts and had produced healthy megakaryocytes to restore proper platelet production.

Finally, the researchers tested whether lung hematopoietic progenitors were capable of multi-lineage bone marrow reconstitution.

They found that cells originating from transplanted lungs traveled to damaged bone marrow and contributed to the production of platelets and other blood cells, including neutrophils, B cells, and T cells.

The researchers said these experiments suggest the lungs play host to a variety of hematopoietic progenitors capable of reconstituting damaged bone marrow and restoring the production of many components of the blood.

“To our knowledge, this is the first description of blood progenitors resident in the lung, and it raises a lot of questions with clinical relevance for the millions of people who suffer from thrombocytopenia,” Dr Looney said.

In particular, the study suggests that researchers who have proposed treating platelet diseases with platelets produced from engineered megakaryocytes should look to the lungs as a resource for platelet production, Dr Looney noted.

The study also presents new avenues of research for stem cell biologists to explore how the bone marrow and lung collaborate to produce a healthy blood system through the mutual exchange of stem cells.

“These observations alter existing paradigms regarding blood cell formation, lung biology and disease, and transplantation,” said pulmonologist Guy A. Zimmerman, MD, who is associate chair of the Department of Internal Medicine at the University of Utah School of Medicine and was an independent reviewer of this study for Nature.

“The findings have direct clinical relevance and provide a rich group of questions for future studies of platelet genesis and megakaryocyte function in lung inflammation and other inflammatory conditions, bleeding and thrombotic disorders, and transplantation.”

Lab mouse

The lungs may play a previously unrecognized role in blood production, according to preclinical research published in Nature.

Researchers discovered large numbers of megakaryocytes in the lungs of mice and found these cells produced roughly half of the animals’ platelets.

The team also identified a pool of hematopoietic progenitors in the extravascular spaces of mouse lungs that were capable of multi-lineage bone marrow reconstitution.

“This finding definitely suggests a more sophisticated view of the lungs—that they’re not just for respiration but also a key partner in formation of crucial aspects of the blood,” said study author Mark R. Looney, MD, of the University of California - San Francisco.

“What we’ve observed here in mice strongly suggests the lung may play a key role in blood formation in humans as well.”

The researchers believe these findings could have major implications for understanding diseases in which patients suffer from thrombocytopenia.

Imaging reveals surprise

This research was made possible by a refinement of a technique known as 2-photon intravital imaging. This approach allowed the researchers to visualize the behavior of individual cells within the blood vessels of a living mouse lung.

Dr Looney and his colleagues used the technique to examine interactions between the immune system and circulating platelets in the lungs in a mouse strain engineered so that platelets emit bright green fluorescence (GFP+).

In this way, the team noticed a large population of megakaryocytes in the lung vasculature. Though megakaryocytes had been observed in the lung before, they were generally thought to live and produce platelets primarily in the bone marrow.

“When we discovered this massive population of megakaryocytes that appeared to be living in the lung, we realized we had to follow this up,” said study author Emma Lefrançais, PhD, a postdoctoral researcher in Dr Looney’s lab.

More detailed imaging sessions revealed megakaryocytes in the act of producing more than 10 million platelets per hour within the lung vasculature. This suggests that roughly half of a mouse’s total platelet production occurs in the lung, not the bone marrow, as researchers had long presumed.

Subsequent experiments also revealed a variety of previously overlooked hematopoietic progenitors outside the lung vasculature.

Transplants provide more insight

The discovery of megakaryocytes and hematopoietic progenitors in the lung raised questions about how these cells move back and forth between the lung and bone marrow. To address these questions, the researchers conducted a set of lung transplant studies.

The team transplanted lungs from wild-type mice into mice with GFP+ megakaryocytes and vice-versa. The researchers said they observed proplatelet formation from GFP+ megakaryocytes in the lung vasculature of the GFP+ mice but not in the wild-type mice.

This suggests the megakaryocytes releasing platelets in the lung circulation originate from outside the lungs, the researchers said. And subsequent experiments suggested the megakaryocytes originate in the bone marrow.

“It’s fascinating that megakaryocytes travel all the way from the bone marrow to the lungs to produce platelets,” said Guadalupe Ortiz-Muñoz, PhD, a postdoctoral researcher in Dr Looney’s lab.

“It’s possible that the lung is an ideal bioreactor for platelet production because of the mechanical force of the blood, or perhaps because of some molecular signaling we don’t yet know about.”

In another experiment, the researchers transplanted lungs with GFP+ megakaryocyte progenitors into mutant mice with low platelet counts.

The transplants successfully restored platelet levels to normal, an effect that persisted over a few months of observation—much longer than the lifespan of individual megakaryocytes or platelets.

To the researchers, this indicated that resident megakaryocyte progenitors in the transplanted lungs had become activated by the recipient mouse’s low platelet counts and had produced healthy megakaryocytes to restore proper platelet production.

Finally, the researchers tested whether lung hematopoietic progenitors were capable of multi-lineage bone marrow reconstitution.

They found that cells originating from transplanted lungs traveled to damaged bone marrow and contributed to the production of platelets and other blood cells, including neutrophils, B cells, and T cells.

The researchers said these experiments suggest the lungs play host to a variety of hematopoietic progenitors capable of reconstituting damaged bone marrow and restoring the production of many components of the blood.

“To our knowledge, this is the first description of blood progenitors resident in the lung, and it raises a lot of questions with clinical relevance for the millions of people who suffer from thrombocytopenia,” Dr Looney said.

In particular, the study suggests that researchers who have proposed treating platelet diseases with platelets produced from engineered megakaryocytes should look to the lungs as a resource for platelet production, Dr Looney noted.

The study also presents new avenues of research for stem cell biologists to explore how the bone marrow and lung collaborate to produce a healthy blood system through the mutual exchange of stem cells.

“These observations alter existing paradigms regarding blood cell formation, lung biology and disease, and transplantation,” said pulmonologist Guy A. Zimmerman, MD, who is associate chair of the Department of Internal Medicine at the University of Utah School of Medicine and was an independent reviewer of this study for Nature.

“The findings have direct clinical relevance and provide a rich group of questions for future studies of platelet genesis and megakaryocyte function in lung inflammation and other inflammatory conditions, bleeding and thrombotic disorders, and transplantation.”

Image by Andre E.X. Brown

New research has revealed sex-based differences in utilization and outcomes of catheter-directed thrombolysis (CDT) in patients with deep vein thrombosis (DVT).

The study showed that CDT use was more common in men than women, although use of the procedure increased over time for both sexes.

There were significant between-sex differences in the rates of some bleeding complications and certain in-hospital outcomes, but in-hospital mortality rates were similar between the sexes.

Riyaz Bashir, MD, of Temple University in Philadelphia, Pennsylvania, and his colleagues reported these findings in Vascular Medicine.

“The data provided some interesting findings,” Dr Bashir said. “In addition to differences in utilization, we were able to find variations in the incidence of a number of complications, including bleeding that requires blood transfusion, intracranial hemorrhage, gastrointestinal bleeding, and acute kidney injury, as well as the incidence of angioplasty, stenting, and adjunctive IVC filter placement.”

For this study, Dr Bashir and his colleagues analyzed data from the Nationwide Inpatient Sample database.

The team identified 108,243 patients age 18 or older with a primary discharge diagnosis of proximal lower extremity or caval DVT between January 2005 and December 2011. Of those patients, 4826 (4.5%) were treated with CDT.

The researchers found that women underwent CDT less often than men—4.1% and 4.9%, respectively (P<0.01).

But the rates of CDT use increased between 2005 and 2011 for both sexes—from 2.1% to 5.9% in women (P<0.01) and from 2.5% to 7.5% (P<0.01) in men.

The rate of in-hospital mortality was similar between women (1.2%) and men (1.3%, P=0.76).

Likewise, there was no significant between-sex difference in length of hospital stay or total hospital charges. The average length of stay was 7.0 ± 5.7 days for men and 7.1 ± 5.5 days for women (P=0.55).

Average total hospital charges were $88,837 ± 68,284 for men and $91,487 ± 77,129 for women (P=0.28).

Women were more likely than men to:

• Require blood transfusions—11.7% and 8.8%, respectively, (P<0.01)
• Undergo angioplasty—64.1% and 54.3%, respectively (P<0.01)
• Undergo stenting—32.2% and 19.9%, respectively (P<0.01)
• Receive an inferior vena cava filter—37.0% and 32.1%, respectively (P<0.01).

Men were more likely than women to:

• Experience acute kidney injury—9.9% and 6.5%, respectively (P<0.01)
• Have an intracranial hemorrhage (ICH)—1.2% and 0.5%, respectively (P=0.03)
• Experience gastrointestinal bleeding—2.2% and 0.9%, respectively (P<0.01).

The researchers noted that the higher rate of ICH among men overall was due to a higher incidence of ICH among men over the age of 75.

There was no significant difference between men and women when it came to procedure-related hemorrhage—1.4% and 1.2%, respectively (P=0.45).

“Future research should focus on uncovering why these sex-based differences exist,” Dr Bashir said. “The answers to those questions could help shape future treatment guidelines for patients who are suitable candidates for CDT.”

Image by Andre E.X. Brown

New research has revealed sex-based differences in utilization and outcomes of catheter-directed thrombolysis (CDT) in patients with deep vein thrombosis (DVT).

The study showed that CDT use was more common in men than women, although use of the procedure increased over time for both sexes.

There were significant between-sex differences in the rates of some bleeding complications and certain in-hospital outcomes, but in-hospital mortality rates were similar between the sexes.

Riyaz Bashir, MD, of Temple University in Philadelphia, Pennsylvania, and his colleagues reported these findings in Vascular Medicine.

“The data provided some interesting findings,” Dr Bashir said. “In addition to differences in utilization, we were able to find variations in the incidence of a number of complications, including bleeding that requires blood transfusion, intracranial hemorrhage, gastrointestinal bleeding, and acute kidney injury, as well as the incidence of angioplasty, stenting, and adjunctive IVC filter placement.”

For this study, Dr Bashir and his colleagues analyzed data from the Nationwide Inpatient Sample database.

The team identified 108,243 patients age 18 or older with a primary discharge diagnosis of proximal lower extremity or caval DVT between January 2005 and December 2011. Of those patients, 4826 (4.5%) were treated with CDT.

The researchers found that women underwent CDT less often than men—4.1% and 4.9%, respectively (P<0.01).

But the rates of CDT use increased between 2005 and 2011 for both sexes—from 2.1% to 5.9% in women (P<0.01) and from 2.5% to 7.5% (P<0.01) in men.

The rate of in-hospital mortality was similar between women (1.2%) and men (1.3%, P=0.76).

Likewise, there was no significant between-sex difference in length of hospital stay or total hospital charges. The average length of stay was 7.0 ± 5.7 days for men and 7.1 ± 5.5 days for women (P=0.55).

Average total hospital charges were $88,837 ± 68,284 for men and $91,487 ± 77,129 for women (P=0.28).

Women were more likely than men to:

• Require blood transfusions—11.7% and 8.8%, respectively, (P<0.01)
• Undergo angioplasty—64.1% and 54.3%, respectively (P<0.01)
• Undergo stenting—32.2% and 19.9%, respectively (P<0.01)
• Receive an inferior vena cava filter—37.0% and 32.1%, respectively (P<0.01).

Men were more likely than women to:

• Experience acute kidney injury—9.9% and 6.5%, respectively (P<0.01)
• Have an intracranial hemorrhage (ICH)—1.2% and 0.5%, respectively (P=0.03)
• Experience gastrointestinal bleeding—2.2% and 0.9%, respectively (P<0.01).

The researchers noted that the higher rate of ICH among men overall was due to a higher incidence of ICH among men over the age of 75.

There was no significant difference between men and women when it came to procedure-related hemorrhage—1.4% and 1.2%, respectively (P=0.45).

“Future research should focus on uncovering why these sex-based differences exist,” Dr Bashir said. “The answers to those questions could help shape future treatment guidelines for patients who are suitable candidates for CDT.”

Image by Andre E.X. Brown

New research has revealed sex-based differences in utilization and outcomes of catheter-directed thrombolysis (CDT) in patients with deep vein thrombosis (DVT).

The study showed that CDT use was more common in men than women, although use of the procedure increased over time for both sexes.

There were significant between-sex differences in the rates of some bleeding complications and certain in-hospital outcomes, but in-hospital mortality rates were similar between the sexes.

Riyaz Bashir, MD, of Temple University in Philadelphia, Pennsylvania, and his colleagues reported these findings in Vascular Medicine.

“The data provided some interesting findings,” Dr Bashir said. “In addition to differences in utilization, we were able to find variations in the incidence of a number of complications, including bleeding that requires blood transfusion, intracranial hemorrhage, gastrointestinal bleeding, and acute kidney injury, as well as the incidence of angioplasty, stenting, and adjunctive IVC filter placement.”

For this study, Dr Bashir and his colleagues analyzed data from the Nationwide Inpatient Sample database.

The team identified 108,243 patients age 18 or older with a primary discharge diagnosis of proximal lower extremity or caval DVT between January 2005 and December 2011. Of those patients, 4826 (4.5%) were treated with CDT.

The researchers found that women underwent CDT less often than men—4.1% and 4.9%, respectively (P<0.01).

But the rates of CDT use increased between 2005 and 2011 for both sexes—from 2.1% to 5.9% in women (P<0.01) and from 2.5% to 7.5% (P<0.01) in men.

The rate of in-hospital mortality was similar between women (1.2%) and men (1.3%, P=0.76).

Likewise, there was no significant between-sex difference in length of hospital stay or total hospital charges. The average length of stay was 7.0 ± 5.7 days for men and 7.1 ± 5.5 days for women (P=0.55).

Average total hospital charges were $88,837 ± 68,284 for men and $91,487 ± 77,129 for women (P=0.28).

Women were more likely than men to:

• Require blood transfusions—11.7% and 8.8%, respectively, (P<0.01)
• Undergo angioplasty—64.1% and 54.3%, respectively (P<0.01)
• Undergo stenting—32.2% and 19.9%, respectively (P<0.01)
• Receive an inferior vena cava filter—37.0% and 32.1%, respectively (P<0.01).

Men were more likely than women to:

• Experience acute kidney injury—9.9% and 6.5%, respectively (P<0.01)
• Have an intracranial hemorrhage (ICH)—1.2% and 0.5%, respectively (P=0.03)
• Experience gastrointestinal bleeding—2.2% and 0.9%, respectively (P<0.01).

The researchers noted that the higher rate of ICH among men overall was due to a higher incidence of ICH among men over the age of 75.

There was no significant difference between men and women when it came to procedure-related hemorrhage—1.4% and 1.2%, respectively (P=0.45).

“Future research should focus on uncovering why these sex-based differences exist,” Dr Bashir said. “The answers to those questions could help shape future treatment guidelines for patients who are suitable candidates for CDT.”

Photo by Rhoda Baer

The Hematology/Oncology Pharmacy Association (HOPA) has announced the release of a toolkit intended to help prevent chemotherapy-induced nausea and vomiting (CINV) in cancer patients.

The Time to Talk CINV™ toolkit was designed to facilitate dialogue between patients and their healthcare teams to ensure no patient is needlessly suffering from CINV.

The tools in the kit, which are targeted to both patients and healthcare providers, were created with guidance from patients, caregivers, pharmacists, and nurses.

The entire toolkit is available for free download at TimeToTalkCINV.com.

The toolkit is part of the Time to Talk CINV™ campaign, which is a collaboration between HOPA, Eisai Inc., and Helsinn Therapeutics (US), Inc. (funded by Eisai and Helsinn Therapeutics).

The campaign began in response to results from a survey of cancer patients.

“Our research revealed a vast majority of patients on chemotherapy who experience nausea and vomiting expect to have this side effect, and 95% of these patients said, at some point, chemo-induced nausea and vomiting had an impact on their daily lives,” said Sarah Peters, PharmD, president of HOPA.

“In response to these findings, as well as the finding that healthcare team members are looking for better communication tools, the Time to Talk CINV toolkit was created to facilitate efficient and effective conversations about nausea and vomiting from chemotherapy to ensure that each patient is receiving the right information and effective management approaches.”

The Time to Talk CINV toolkit includes the following resources:

• A list of myths and truths about CINV intended to eliminate common misperceptions
• A checklist of questions patients can ask healthcare providers to better understand CINV
• A chemotherapy side effect tracker, which enables patients to track their experience and report back to their healthcare team
• A communication checklist for the healthcare team outlining best practices for communicating with patients to prevent CINV.

Each tool can be printed or filled out digitally.

Additional information about CINV, including videos and infographics, can be found on the Time to Talk CINV website.

Photo by Rhoda Baer

The Hematology/Oncology Pharmacy Association (HOPA) has announced the release of a toolkit intended to help prevent chemotherapy-induced nausea and vomiting (CINV) in cancer patients.

The Time to Talk CINV™ toolkit was designed to facilitate dialogue between patients and their healthcare teams to ensure no patient is needlessly suffering from CINV.

The tools in the kit, which are targeted to both patients and healthcare providers, were created with guidance from patients, caregivers, pharmacists, and nurses.

The entire toolkit is available for free download at TimeToTalkCINV.com.

The toolkit is part of the Time to Talk CINV™ campaign, which is a collaboration between HOPA, Eisai Inc., and Helsinn Therapeutics (US), Inc. (funded by Eisai and Helsinn Therapeutics).

The campaign began in response to results from a survey of cancer patients.

“Our research revealed a vast majority of patients on chemotherapy who experience nausea and vomiting expect to have this side effect, and 95% of these patients said, at some point, chemo-induced nausea and vomiting had an impact on their daily lives,” said Sarah Peters, PharmD, president of HOPA.

“In response to these findings, as well as the finding that healthcare team members are looking for better communication tools, the Time to Talk CINV toolkit was created to facilitate efficient and effective conversations about nausea and vomiting from chemotherapy to ensure that each patient is receiving the right information and effective management approaches.”

The Time to Talk CINV toolkit includes the following resources:

• A list of myths and truths about CINV intended to eliminate common misperceptions
• A checklist of questions patients can ask healthcare providers to better understand CINV
• A chemotherapy side effect tracker, which enables patients to track their experience and report back to their healthcare team
• A communication checklist for the healthcare team outlining best practices for communicating with patients to prevent CINV.

Each tool can be printed or filled out digitally.

Additional information about CINV, including videos and infographics, can be found on the Time to Talk CINV website.

Photo by Rhoda Baer

The Hematology/Oncology Pharmacy Association (HOPA) has announced the release of a toolkit intended to help prevent chemotherapy-induced nausea and vomiting (CINV) in cancer patients.

The Time to Talk CINV™ toolkit was designed to facilitate dialogue between patients and their healthcare teams to ensure no patient is needlessly suffering from CINV.

The tools in the kit, which are targeted to both patients and healthcare providers, were created with guidance from patients, caregivers, pharmacists, and nurses.

The entire toolkit is available for free download at TimeToTalkCINV.com.

The toolkit is part of the Time to Talk CINV™ campaign, which is a collaboration between HOPA, Eisai Inc., and Helsinn Therapeutics (US), Inc. (funded by Eisai and Helsinn Therapeutics).

The campaign began in response to results from a survey of cancer patients.

“Our research revealed a vast majority of patients on chemotherapy who experience nausea and vomiting expect to have this side effect, and 95% of these patients said, at some point, chemo-induced nausea and vomiting had an impact on their daily lives,” said Sarah Peters, PharmD, president of HOPA.

“In response to these findings, as well as the finding that healthcare team members are looking for better communication tools, the Time to Talk CINV toolkit was created to facilitate efficient and effective conversations about nausea and vomiting from chemotherapy to ensure that each patient is receiving the right information and effective management approaches.”

The Time to Talk CINV toolkit includes the following resources:

• A list of myths and truths about CINV intended to eliminate common misperceptions
• A checklist of questions patients can ask healthcare providers to better understand CINV
• A chemotherapy side effect tracker, which enables patients to track their experience and report back to their healthcare team
• A communication checklist for the healthcare team outlining best practices for communicating with patients to prevent CINV.

Each tool can be printed or filled out digitally.

Additional information about CINV, including videos and infographics, can be found on the Time to Talk CINV website.

Medical Center

WASHINGTON, DC—Using genetic testing to guide warfarin dosing can lower the risk of combined adverse events (AEs) after elective orthopedic surgery, according to the GIFT trial.

In this trial, investigators found that genotype-guided warfarin dosing was associated with a lower risk of combined AEs—confirmed venous thromboembolism (VTE), warfarin overdose, major bleeding, and death—when compared to clinically based warfarin dosing.

There were no deaths during this trial, so the researchers were unable to assess whether genotype-guided dosing actually reduced mortality risk.

However, they believe these findings could have implications for a broad population of patients starting warfarin therapy.

The findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 411-14).

“The way we dose warfarin clinically is trial-and-error dosing,” said study investigator Brian F. Gage, MD, of Washington University School of Medicine in St. Louis, Missouri.

“We often start patients on 5 mg daily and don’t find out who is very sensitive to warfarin until their INR is 4 or more, indicating an overdose. Based on our results, as compared with optimized clinical dosing, pharmacogenetic dosing did better overall, meaning this group of patients had a lower rate of adverse events.”

Dr Gage also noted that the clinical dosing used in this trial was likely better than standard dosing used in clinical practice.

In this trial, the researchers used a computer-based, real-time interface that estimated the therapeutic dose and provided recommendations for adjusting dose based on a patient’s age, height, weight, interactions with other medications, and other clinical factors.

Trial interventions

GIFT included 1597 patients age 65 and older who were undergoing elective knee or hip replacement surgery. Most patients were female (63.8%) and Caucasian (91.1%).

The patients were genotyped for genetic variants that influence warfarin sensitivity (CYP2C9*2, CYP2C9*3), warfarin metabolism (VKORC1), and vitamin K recycling (CYP4F2).

They were randomized to receive clinical dosing or genotype-guided dosing (in addition to clinical factors being taken into account). The patients were also randomly assigned to a target international normalized ratio (INR) of either 1.8 or 2.5.

For the first 11 days of therapy, warfarin dosing in both arms was guided by a web application that incorporated clinical factors in all patients and genotype in patients randomized to genotype-guided dosing.

Most (94%) of the time, prescribers gave the dose that was recommended. After 11 days of therapy, they were free to continue the current warfarin dose or make adjustments.

Patients were monitored using standard INR testing, and most underwent screening with lower extremity Doppler ultrasound 3 to 7 weeks after arthroplasty to check for clots.

The investigators followed patients for 90 days and assessed the primary outcome through day 30, although VTEs detected through day 60 were also included in the primary outcome.

Results

The primary outcome—a composite of confirmed VTE, warfarin overdose (INR ≥ 4), major bleeding, and death—occurred in 14.7% of patients in the clinical arm and 10.8% in the genotype-guided arm (P=0.018).

The relative rate of the primary outcome was 0.73 (95% CI, 0.56 - 0.95). The relative rate was 0.24 (95% CI, 0.05 - 1.14) for major bleeding, 0.71 (95% CI, 0.51 - 0.99) for INR ≥ 4.0, and 0.85 (95% CI, 0.54 - 1.34) for VTE.

There were no deaths at the 30-day follow-up point, and 1 patient was lost to follow-up.

“Before GIFT, we had a good idea of how these genes and clinical factors affected the dose of warfarin,” Dr Gage said. “What we didn’t know is whether taking genotype into account improved outcomes. It turns out that the genes that regulate warfarin metabolism and sensitivity and vitamin K use are highly variable, so we can’t simply look at patients and predict their therapeutic warfarin dose.”

“The GIFT trial is an example of personalized medicine. If the patient stays in a safe INR range, warfarin is an incredibly effective and safe drug. By getting the dose approximately right from the get-go, we’re less likely to have the patient overdose and can lower the risk of complications.”

Dr Gage said future research could combine GIFT with prior pharmacogenetic trials in a meta-analysis and should determine what other genetic variations predict response to anticoagulants.

Additionally, as clinical and genetic factors affecting warfarin dose requirements vary by race, dosing algorithms tailored to ancestry may be beneficial.

Dr Gage also said he hopes genetic and clinical dosing algorithms will be integrated within electronic medical records.

“The hope is that when a physician starts a prescription of warfarin, electronic medical records will seamlessly give a prudent recommendation to help the doctor come up with the right dose,” he said.

Medical Center

WASHINGTON, DC—Using genetic testing to guide warfarin dosing can lower the risk of combined adverse events (AEs) after elective orthopedic surgery, according to the GIFT trial.

In this trial, investigators found that genotype-guided warfarin dosing was associated with a lower risk of combined AEs—confirmed venous thromboembolism (VTE), warfarin overdose, major bleeding, and death—when compared to clinically based warfarin dosing.

There were no deaths during this trial, so the researchers were unable to assess whether genotype-guided dosing actually reduced mortality risk.

However, they believe these findings could have implications for a broad population of patients starting warfarin therapy.

The findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 411-14).

“The way we dose warfarin clinically is trial-and-error dosing,” said study investigator Brian F. Gage, MD, of Washington University School of Medicine in St. Louis, Missouri.

“We often start patients on 5 mg daily and don’t find out who is very sensitive to warfarin until their INR is 4 or more, indicating an overdose. Based on our results, as compared with optimized clinical dosing, pharmacogenetic dosing did better overall, meaning this group of patients had a lower rate of adverse events.”

Dr Gage also noted that the clinical dosing used in this trial was likely better than standard dosing used in clinical practice.

In this trial, the researchers used a computer-based, real-time interface that estimated the therapeutic dose and provided recommendations for adjusting dose based on a patient’s age, height, weight, interactions with other medications, and other clinical factors.

Trial interventions

GIFT included 1597 patients age 65 and older who were undergoing elective knee or hip replacement surgery. Most patients were female (63.8%) and Caucasian (91.1%).

The patients were genotyped for genetic variants that influence warfarin sensitivity (CYP2C9*2, CYP2C9*3), warfarin metabolism (VKORC1), and vitamin K recycling (CYP4F2).

They were randomized to receive clinical dosing or genotype-guided dosing (in addition to clinical factors being taken into account). The patients were also randomly assigned to a target international normalized ratio (INR) of either 1.8 or 2.5.

For the first 11 days of therapy, warfarin dosing in both arms was guided by a web application that incorporated clinical factors in all patients and genotype in patients randomized to genotype-guided dosing.

Most (94%) of the time, prescribers gave the dose that was recommended. After 11 days of therapy, they were free to continue the current warfarin dose or make adjustments.

Patients were monitored using standard INR testing, and most underwent screening with lower extremity Doppler ultrasound 3 to 7 weeks after arthroplasty to check for clots.

The investigators followed patients for 90 days and assessed the primary outcome through day 30, although VTEs detected through day 60 were also included in the primary outcome.

Results

The primary outcome—a composite of confirmed VTE, warfarin overdose (INR ≥ 4), major bleeding, and death—occurred in 14.7% of patients in the clinical arm and 10.8% in the genotype-guided arm (P=0.018).

The relative rate of the primary outcome was 0.73 (95% CI, 0.56 - 0.95). The relative rate was 0.24 (95% CI, 0.05 - 1.14) for major bleeding, 0.71 (95% CI, 0.51 - 0.99) for INR ≥ 4.0, and 0.85 (95% CI, 0.54 - 1.34) for VTE.

There were no deaths at the 30-day follow-up point, and 1 patient was lost to follow-up.

“Before GIFT, we had a good idea of how these genes and clinical factors affected the dose of warfarin,” Dr Gage said. “What we didn’t know is whether taking genotype into account improved outcomes. It turns out that the genes that regulate warfarin metabolism and sensitivity and vitamin K use are highly variable, so we can’t simply look at patients and predict their therapeutic warfarin dose.”

“The GIFT trial is an example of personalized medicine. If the patient stays in a safe INR range, warfarin is an incredibly effective and safe drug. By getting the dose approximately right from the get-go, we’re less likely to have the patient overdose and can lower the risk of complications.”

Dr Gage said future research could combine GIFT with prior pharmacogenetic trials in a meta-analysis and should determine what other genetic variations predict response to anticoagulants.

Additionally, as clinical and genetic factors affecting warfarin dose requirements vary by race, dosing algorithms tailored to ancestry may be beneficial.

Dr Gage also said he hopes genetic and clinical dosing algorithms will be integrated within electronic medical records.

“The hope is that when a physician starts a prescription of warfarin, electronic medical records will seamlessly give a prudent recommendation to help the doctor come up with the right dose,” he said.

Medical Center

WASHINGTON, DC—Using genetic testing to guide warfarin dosing can lower the risk of combined adverse events (AEs) after elective orthopedic surgery, according to the GIFT trial.

In this trial, investigators found that genotype-guided warfarin dosing was associated with a lower risk of combined AEs—confirmed venous thromboembolism (VTE), warfarin overdose, major bleeding, and death—when compared to clinically based warfarin dosing.

There were no deaths during this trial, so the researchers were unable to assess whether genotype-guided dosing actually reduced mortality risk.

However, they believe these findings could have implications for a broad population of patients starting warfarin therapy.

The findings were presented at the American College of Cardiology’s 66th Annual Scientific Session (abstract 411-14).

“The way we dose warfarin clinically is trial-and-error dosing,” said study investigator Brian F. Gage, MD, of Washington University School of Medicine in St. Louis, Missouri.

“We often start patients on 5 mg daily and don’t find out who is very sensitive to warfarin until their INR is 4 or more, indicating an overdose. Based on our results, as compared with optimized clinical dosing, pharmacogenetic dosing did better overall, meaning this group of patients had a lower rate of adverse events.”

Dr Gage also noted that the clinical dosing used in this trial was likely better than standard dosing used in clinical practice.

In this trial, the researchers used a computer-based, real-time interface that estimated the therapeutic dose and provided recommendations for adjusting dose based on a patient’s age, height, weight, interactions with other medications, and other clinical factors.

Trial interventions

GIFT included 1597 patients age 65 and older who were undergoing elective knee or hip replacement surgery. Most patients were female (63.8%) and Caucasian (91.1%).

The patients were genotyped for genetic variants that influence warfarin sensitivity (CYP2C9*2, CYP2C9*3), warfarin metabolism (VKORC1), and vitamin K recycling (CYP4F2).

They were randomized to receive clinical dosing or genotype-guided dosing (in addition to clinical factors being taken into account). The patients were also randomly assigned to a target international normalized ratio (INR) of either 1.8 or 2.5.

For the first 11 days of therapy, warfarin dosing in both arms was guided by a web application that incorporated clinical factors in all patients and genotype in patients randomized to genotype-guided dosing.

Most (94%) of the time, prescribers gave the dose that was recommended. After 11 days of therapy, they were free to continue the current warfarin dose or make adjustments.

Patients were monitored using standard INR testing, and most underwent screening with lower extremity Doppler ultrasound 3 to 7 weeks after arthroplasty to check for clots.

The investigators followed patients for 90 days and assessed the primary outcome through day 30, although VTEs detected through day 60 were also included in the primary outcome.

Results

The primary outcome—a composite of confirmed VTE, warfarin overdose (INR ≥ 4), major bleeding, and death—occurred in 14.7% of patients in the clinical arm and 10.8% in the genotype-guided arm (P=0.018).

The relative rate of the primary outcome was 0.73 (95% CI, 0.56 - 0.95). The relative rate was 0.24 (95% CI, 0.05 - 1.14) for major bleeding, 0.71 (95% CI, 0.51 - 0.99) for INR ≥ 4.0, and 0.85 (95% CI, 0.54 - 1.34) for VTE.

There were no deaths at the 30-day follow-up point, and 1 patient was lost to follow-up.

“Before GIFT, we had a good idea of how these genes and clinical factors affected the dose of warfarin,” Dr Gage said. “What we didn’t know is whether taking genotype into account improved outcomes. It turns out that the genes that regulate warfarin metabolism and sensitivity and vitamin K use are highly variable, so we can’t simply look at patients and predict their therapeutic warfarin dose.”

“The GIFT trial is an example of personalized medicine. If the patient stays in a safe INR range, warfarin is an incredibly effective and safe drug. By getting the dose approximately right from the get-go, we’re less likely to have the patient overdose and can lower the risk of complications.”

Dr Gage said future research could combine GIFT with prior pharmacogenetic trials in a meta-analysis and should determine what other genetic variations predict response to anticoagulants.

Additionally, as clinical and genetic factors affecting warfarin dose requirements vary by race, dosing algorithms tailored to ancestry may be beneficial.

Dr Gage also said he hopes genetic and clinical dosing algorithms will be integrated within electronic medical records.

“The hope is that when a physician starts a prescription of warfarin, electronic medical records will seamlessly give a prudent recommendation to help the doctor come up with the right dose,” he said.

Photo courtesy of the FDA

The US Food and Drug Administration (FDA) has issued an update on breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).

The agency said that, as of February 1, it has received 359 reports of BIA-ALCL.

However, the actual number of BIA-ALCL cases remains difficult to determine due to limitations in reporting and a lack of implant sales data.

The FDA also noted that most of the available data suggest BIA-ALCL occurs more frequently in patients who receive implants with textured surfaces rather than smooth surfaces.

The full FDA update includes background information on BIA-ALCL, a summary of medical device reports (MDRs) and the medical literature, as well as recommendations for patient care.

Background and MDRs

The FDA first identified a possible association between ALCL and breast implants in 2011.

The agency now concurs with the World Health Organization’s designation of BIA-ALCL as a rare T-cell lymphoma occurring in patients with breast implants.

The FDA continues to collect and review information about BIA-ALCL. This includes reviewing MDRs and the medical literature, as well as exchanging information with other international regulators and scientific experts.

The FDA said it has received 359 MDRs of BIA-ALCL, including 9 cases in which the patient died.

Information on the implant surface was available for 239 cases, and 203 of these cases involved textured implants.

Information on the implant filling was available in 312 cases. Of these, 186 patients had implants filled with silicone gel, and 126 had implants filled with saline.

Recommendations

The FDA said healthcare providers performing breast implant surgery should provide patients with the manufacturers’ labeling as well as any other educational materials before surgery and discuss with patients the benefits and risks of the different types of implants.

Providers should consider the possibility of BIA-ALCL when a patient presents with late-onset, persistent peri-implant seroma. The FDA noted that, in some cases, patients presented with capsular contracture or masses adjacent to the breast implant.

Patients with suspected BIA-ALCL should be referred to an appropriate specialist.

When testing for BIA-ALCL, providers should collect fresh seroma fluid and representative portions of the capsule and send these samples for pathology tests.

Diagnostic evaluation of patients with suspected BIA-ALCL should include cytological evaluation of seroma fluid with Wright Giemsa stained smears and cell block immunohistochemistry testing for cluster of differentiation and anaplastic lymphoma kinase markers.

When choosing a treatment approach for patients with BIA-ALCL, providers should consider current clinical practice guidelines, such as those from the National Comprehensive Cancer Network (included in the guidelines for T-cell lymphomas) or the Plastic Surgery Foundation.

Finally, providers should report all confirmed cases of BIA-ALCL to the FDA and to the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (ALCL) Etiology and Epidemiology (PROFILE Registry).

Photo courtesy of the FDA

The US Food and Drug Administration (FDA) has issued an update on breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).

The agency said that, as of February 1, it has received 359 reports of BIA-ALCL.

However, the actual number of BIA-ALCL cases remains difficult to determine due to limitations in reporting and a lack of implant sales data.

The FDA also noted that most of the available data suggest BIA-ALCL occurs more frequently in patients who receive implants with textured surfaces rather than smooth surfaces.

The full FDA update includes background information on BIA-ALCL, a summary of medical device reports (MDRs) and the medical literature, as well as recommendations for patient care.

Background and MDRs

The FDA first identified a possible association between ALCL and breast implants in 2011.

The agency now concurs with the World Health Organization’s designation of BIA-ALCL as a rare T-cell lymphoma occurring in patients with breast implants.

The FDA continues to collect and review information about BIA-ALCL. This includes reviewing MDRs and the medical literature, as well as exchanging information with other international regulators and scientific experts.

The FDA said it has received 359 MDRs of BIA-ALCL, including 9 cases in which the patient died.

Information on the implant surface was available for 239 cases, and 203 of these cases involved textured implants.

Information on the implant filling was available in 312 cases. Of these, 186 patients had implants filled with silicone gel, and 126 had implants filled with saline.

Recommendations

The FDA said healthcare providers performing breast implant surgery should provide patients with the manufacturers’ labeling as well as any other educational materials before surgery and discuss with patients the benefits and risks of the different types of implants.

Providers should consider the possibility of BIA-ALCL when a patient presents with late-onset, persistent peri-implant seroma. The FDA noted that, in some cases, patients presented with capsular contracture or masses adjacent to the breast implant.

Patients with suspected BIA-ALCL should be referred to an appropriate specialist.

When testing for BIA-ALCL, providers should collect fresh seroma fluid and representative portions of the capsule and send these samples for pathology tests.

Diagnostic evaluation of patients with suspected BIA-ALCL should include cytological evaluation of seroma fluid with Wright Giemsa stained smears and cell block immunohistochemistry testing for cluster of differentiation and anaplastic lymphoma kinase markers.

When choosing a treatment approach for patients with BIA-ALCL, providers should consider current clinical practice guidelines, such as those from the National Comprehensive Cancer Network (included in the guidelines for T-cell lymphomas) or the Plastic Surgery Foundation.

Finally, providers should report all confirmed cases of BIA-ALCL to the FDA and to the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (ALCL) Etiology and Epidemiology (PROFILE Registry).

Photo courtesy of the FDA

The US Food and Drug Administration (FDA) has issued an update on breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL).

The agency said that, as of February 1, it has received 359 reports of BIA-ALCL.

However, the actual number of BIA-ALCL cases remains difficult to determine due to limitations in reporting and a lack of implant sales data.

The FDA also noted that most of the available data suggest BIA-ALCL occurs more frequently in patients who receive implants with textured surfaces rather than smooth surfaces.

The full FDA update includes background information on BIA-ALCL, a summary of medical device reports (MDRs) and the medical literature, as well as recommendations for patient care.

Background and MDRs

The FDA first identified a possible association between ALCL and breast implants in 2011.

The agency now concurs with the World Health Organization’s designation of BIA-ALCL as a rare T-cell lymphoma occurring in patients with breast implants.

The FDA continues to collect and review information about BIA-ALCL. This includes reviewing MDRs and the medical literature, as well as exchanging information with other international regulators and scientific experts.

The FDA said it has received 359 MDRs of BIA-ALCL, including 9 cases in which the patient died.

Information on the implant surface was available for 239 cases, and 203 of these cases involved textured implants.

Information on the implant filling was available in 312 cases. Of these, 186 patients had implants filled with silicone gel, and 126 had implants filled with saline.

Recommendations

The FDA said healthcare providers performing breast implant surgery should provide patients with the manufacturers’ labeling as well as any other educational materials before surgery and discuss with patients the benefits and risks of the different types of implants.

Providers should consider the possibility of BIA-ALCL when a patient presents with late-onset, persistent peri-implant seroma. The FDA noted that, in some cases, patients presented with capsular contracture or masses adjacent to the breast implant.

Patients with suspected BIA-ALCL should be referred to an appropriate specialist.

When testing for BIA-ALCL, providers should collect fresh seroma fluid and representative portions of the capsule and send these samples for pathology tests.

Diagnostic evaluation of patients with suspected BIA-ALCL should include cytological evaluation of seroma fluid with Wright Giemsa stained smears and cell block immunohistochemistry testing for cluster of differentiation and anaplastic lymphoma kinase markers.

When choosing a treatment approach for patients with BIA-ALCL, providers should consider current clinical practice guidelines, such as those from the National Comprehensive Cancer Network (included in the guidelines for T-cell lymphomas) or the Plastic Surgery Foundation.

Finally, providers should report all confirmed cases of BIA-ALCL to the FDA and to the Patient Registry and Outcomes for Breast Implants and Anaplastic Large Cell Lymphoma (ALCL) Etiology and Epidemiology (PROFILE Registry).