Due to many reasons, the healthcare paradigm has shifted, dictating alternative staffing models to manage the burgeoning inpatient census of hospital-based physicians. Herein, we will briefly describe the Emory University Division of Hospital Medicine (EDHM) approach to utilizing advanced practice providers (APPs) in the care of inpatients and summarize key components of the program that improve sustainability for providers.

The EDHM in Atlanta matriculated APPs into its service in 2004. Currently, there are 22 APPs across all Emory HM sites. The largest group is at Emory University Hospital Midtown (EUHM).

At EUHM, the addition of a renal service created concern for increased workload for the physicians. APPs were recruited to bridge the gap in 2011. Initially, the role was ill-defined, but over time, with physician and administrative leadership buy-in and support, the role has evolved. Currently at EUHM, APPs are practicing in other HM services, allowing them to practice near or at the top of their scope of practice. The 12 hospitalist APPs at EUHM practice in four roles: nocturnist, frontline provider in the observation unit, dedicated renal service, and generalist on an overflow team.

Along with the rapid growth of APPs on the service came the need for structured leadership, improved onboarding procedures, competency maintenance, advocacy, and professional development activities. Essentially, we needed to create a career track parallel to that of the physicians without compromising the portion of our scopes of our practice that overlap (i.e., patient care) while supporting our regulatory differences.

The professional development plans incorporated findings from APP exit interviews at the University of Maryland Medical Center highlighting the following retention issues:1

1. Length of time for credentialing
2. Role clarity
3. Inadequate clinical orientation
4. Feelings of clinical incompetence
5. Feelings of isolation

With the instillation of APP leadership, the team created a comprehensive APP program. The Hospital Medicine APP program at EUHM includes the following components:

• APP representation at monthly clinical operation meetings and quarterly education council meetings to ensure that APP competency and regulatory issues are always represented.
• Orientation personally tailored to the APP’s level of clinical expertise, with a post-orientation meeting with leadership and remediation, if needed.
• APP incentives to teach NP or PA students, conduct in-services, join committees, or participate in other leadership opportunities.
• APPs invited to attend and/or present at all divisional small and large group learning opportunities (e.g., Grand Rounds, Lunch and Learn, Journal Club).
• APPs allocated time and space to meet and discuss practice issues.
• Newly developed Mini-Hospitalist Academy, which offers monthly workshops to all hospitalist physicians and APPs, from novice to expert.
• Dedicated APP Ongoing Professional Performance Evaluation (OPPE) program.
• In addition to the annual monetary support offered for educational opportunities, the division offers an annual Faculty Development Award. This award is by application for eligible educational opportunities; APPs are welcome to apply and have consistently been awarded support to pursue myriad opportunities.

This successful APP-physician collaboration is driven by a committed group of professionals who are sensitive to the shifting healthcare paradigm. Our APPs and physicians are constantly adapting their practice so that our collaboration is safe, evidence-based, and professionally fulfilling. TH

Yvonne Brown, DNP, MSN, ACNP-C, FNP-C, nurse practitioner, lead advanced practice provider, Division of Hospital Medicine, Emory Healthcare, Emory University Hospital Midtown, Atlanta

Reference

1. Bahouth MN, Esposito-Herr MB. Orientation program for hospital-based nurse practitioners. AACN Adv Crit Care. 2009;20(1):82-90.

Due to many reasons, the healthcare paradigm has shifted, dictating alternative staffing models to manage the burgeoning inpatient census of hospital-based physicians. Herein, we will briefly describe the Emory University Division of Hospital Medicine (EDHM) approach to utilizing advanced practice providers (APPs) in the care of inpatients and summarize key components of the program that improve sustainability for providers.

The EDHM in Atlanta matriculated APPs into its service in 2004. Currently, there are 22 APPs across all Emory HM sites. The largest group is at Emory University Hospital Midtown (EUHM).

At EUHM, the addition of a renal service created concern for increased workload for the physicians. APPs were recruited to bridge the gap in 2011. Initially, the role was ill-defined, but over time, with physician and administrative leadership buy-in and support, the role has evolved. Currently at EUHM, APPs are practicing in other HM services, allowing them to practice near or at the top of their scope of practice. The 12 hospitalist APPs at EUHM practice in four roles: nocturnist, frontline provider in the observation unit, dedicated renal service, and generalist on an overflow team.

Along with the rapid growth of APPs on the service came the need for structured leadership, improved onboarding procedures, competency maintenance, advocacy, and professional development activities. Essentially, we needed to create a career track parallel to that of the physicians without compromising the portion of our scopes of our practice that overlap (i.e., patient care) while supporting our regulatory differences.

The professional development plans incorporated findings from APP exit interviews at the University of Maryland Medical Center highlighting the following retention issues:1

1. Length of time for credentialing
2. Role clarity
3. Inadequate clinical orientation
4. Feelings of clinical incompetence
5. Feelings of isolation

With the instillation of APP leadership, the team created a comprehensive APP program. The Hospital Medicine APP program at EUHM includes the following components:

• APP representation at monthly clinical operation meetings and quarterly education council meetings to ensure that APP competency and regulatory issues are always represented.
• Orientation personally tailored to the APP’s level of clinical expertise, with a post-orientation meeting with leadership and remediation, if needed.
• APP incentives to teach NP or PA students, conduct in-services, join committees, or participate in other leadership opportunities.
• APPs invited to attend and/or present at all divisional small and large group learning opportunities (e.g., Grand Rounds, Lunch and Learn, Journal Club).
• APPs allocated time and space to meet and discuss practice issues.
• Newly developed Mini-Hospitalist Academy, which offers monthly workshops to all hospitalist physicians and APPs, from novice to expert.
• Dedicated APP Ongoing Professional Performance Evaluation (OPPE) program.
• In addition to the annual monetary support offered for educational opportunities, the division offers an annual Faculty Development Award. This award is by application for eligible educational opportunities; APPs are welcome to apply and have consistently been awarded support to pursue myriad opportunities.

This successful APP-physician collaboration is driven by a committed group of professionals who are sensitive to the shifting healthcare paradigm. Our APPs and physicians are constantly adapting their practice so that our collaboration is safe, evidence-based, and professionally fulfilling. TH

Yvonne Brown, DNP, MSN, ACNP-C, FNP-C, nurse practitioner, lead advanced practice provider, Division of Hospital Medicine, Emory Healthcare, Emory University Hospital Midtown, Atlanta

Reference

1. Bahouth MN, Esposito-Herr MB. Orientation program for hospital-based nurse practitioners. AACN Adv Crit Care. 2009;20(1):82-90.

Due to many reasons, the healthcare paradigm has shifted, dictating alternative staffing models to manage the burgeoning inpatient census of hospital-based physicians. Herein, we will briefly describe the Emory University Division of Hospital Medicine (EDHM) approach to utilizing advanced practice providers (APPs) in the care of inpatients and summarize key components of the program that improve sustainability for providers.

The EDHM in Atlanta matriculated APPs into its service in 2004. Currently, there are 22 APPs across all Emory HM sites. The largest group is at Emory University Hospital Midtown (EUHM).

At EUHM, the addition of a renal service created concern for increased workload for the physicians. APPs were recruited to bridge the gap in 2011. Initially, the role was ill-defined, but over time, with physician and administrative leadership buy-in and support, the role has evolved. Currently at EUHM, APPs are practicing in other HM services, allowing them to practice near or at the top of their scope of practice. The 12 hospitalist APPs at EUHM practice in four roles: nocturnist, frontline provider in the observation unit, dedicated renal service, and generalist on an overflow team.

Along with the rapid growth of APPs on the service came the need for structured leadership, improved onboarding procedures, competency maintenance, advocacy, and professional development activities. Essentially, we needed to create a career track parallel to that of the physicians without compromising the portion of our scopes of our practice that overlap (i.e., patient care) while supporting our regulatory differences.

The professional development plans incorporated findings from APP exit interviews at the University of Maryland Medical Center highlighting the following retention issues:1

1. Length of time for credentialing
2. Role clarity
3. Inadequate clinical orientation
4. Feelings of clinical incompetence
5. Feelings of isolation

With the instillation of APP leadership, the team created a comprehensive APP program. The Hospital Medicine APP program at EUHM includes the following components:

• APP representation at monthly clinical operation meetings and quarterly education council meetings to ensure that APP competency and regulatory issues are always represented.
• Orientation personally tailored to the APP’s level of clinical expertise, with a post-orientation meeting with leadership and remediation, if needed.
• APP incentives to teach NP or PA students, conduct in-services, join committees, or participate in other leadership opportunities.
• APPs invited to attend and/or present at all divisional small and large group learning opportunities (e.g., Grand Rounds, Lunch and Learn, Journal Club).
• APPs allocated time and space to meet and discuss practice issues.
• Newly developed Mini-Hospitalist Academy, which offers monthly workshops to all hospitalist physicians and APPs, from novice to expert.
• Dedicated APP Ongoing Professional Performance Evaluation (OPPE) program.
• In addition to the annual monetary support offered for educational opportunities, the division offers an annual Faculty Development Award. This award is by application for eligible educational opportunities; APPs are welcome to apply and have consistently been awarded support to pursue myriad opportunities.

This successful APP-physician collaboration is driven by a committed group of professionals who are sensitive to the shifting healthcare paradigm. Our APPs and physicians are constantly adapting their practice so that our collaboration is safe, evidence-based, and professionally fulfilling. TH

Yvonne Brown, DNP, MSN, ACNP-C, FNP-C, nurse practitioner, lead advanced practice provider, Division of Hospital Medicine, Emory Healthcare, Emory University Hospital Midtown, Atlanta

Reference

1. Bahouth MN, Esposito-Herr MB. Orientation program for hospital-based nurse practitioners. AACN Adv Crit Care. 2009;20(1):82-90.

Laura Franco, MD

COPENHAGEN—Results of a new study suggest that vitamin K antagonists (VKAs) and non-VKA oral anticoagulants (NOACs) can both confer an increased risk of major bleeding, but the type of bleeding tends to differ with the type of anticoagulant.

The research showed that patients taking VKAs were more likely to be hospitalized for intracranial hemorrhage (ICH), while patients taking NOACs were more likely to be hospitalized for gastrointestinal (GI) bleeding.

In addition, the 30-day mortality rate was significantly lower in patients who were taking NOACs than in those who were taking VKAs. However, there was no significant difference between the 2 treatment groups when the researchers assessed mortality according to the type of major bleeding.

Laura Franco, MD, of the University of Perugia in Italy, presented these findings at the 21st Congress of the European Hematology Association (abstract S139*).

For this study, Dr Franco and her colleagues wanted to evaluate the real-life clinical presentation, management, and outcome of major bleeding in patients on anticoagulants.

So the team analyzed a cohort of patients treated at 9 Italian hospitals and a group of patients enrolled in Germany’s Dresden NOAC registry.

Between September 2013 and May 2016, there were 874 patients who were hospitalized for major bleeding—220 of whom who were taking NOACs and 654 of whom were taking VKAs.

Overall, 44% (n=386) of patients were hospitalized for an ICH, and 30% (n=261) were hospitalized for GI bleeding.

The incidence of ICH was 22% (n=48) among patients who received NOACs and 52% (n=338) among patients who received VKAs. The odds ratio was 0.26 (95% CI, 0.18-0.37; P<0.001).

The incidence of GI major bleeding was 46% (n=102) in the NOAC group and 24% (n=159) in the VKA group. The odds ratio was 2.69 (95% CI, 1.95-3.70; P<0.001).

The incidence of 30-day mortality was significantly higher in the VKA group than the NOAC group—17% and 10%, respectively. The adjusted hazard ratio (aHR) was 0.59 (95% CI, 0.36-0.94, P=0.012).

However, when the researchers looked at 30-day mortality according to the site of major bleeding, they observed no significant differences between the NOAC and VKA groups.

The incidence of 30-day mortality among patients with ICH was 25% in both the NOAC and VKA groups (aHR=1.07; 95% CI, 0.57-1.97). And the incidence of 30-day mortality among patients with GI bleeding was 7% in the NOAC group and 10% in the VKA group (aHR=0.66; 95% CI, 0.26-1.68).

*Data in the abstract differ from data presented at the meeting.

Laura Franco, MD

COPENHAGEN—Results of a new study suggest that vitamin K antagonists (VKAs) and non-VKA oral anticoagulants (NOACs) can both confer an increased risk of major bleeding, but the type of bleeding tends to differ with the type of anticoagulant.

The research showed that patients taking VKAs were more likely to be hospitalized for intracranial hemorrhage (ICH), while patients taking NOACs were more likely to be hospitalized for gastrointestinal (GI) bleeding.

In addition, the 30-day mortality rate was significantly lower in patients who were taking NOACs than in those who were taking VKAs. However, there was no significant difference between the 2 treatment groups when the researchers assessed mortality according to the type of major bleeding.

Laura Franco, MD, of the University of Perugia in Italy, presented these findings at the 21st Congress of the European Hematology Association (abstract S139*).

For this study, Dr Franco and her colleagues wanted to evaluate the real-life clinical presentation, management, and outcome of major bleeding in patients on anticoagulants.

So the team analyzed a cohort of patients treated at 9 Italian hospitals and a group of patients enrolled in Germany’s Dresden NOAC registry.

Between September 2013 and May 2016, there were 874 patients who were hospitalized for major bleeding—220 of whom who were taking NOACs and 654 of whom were taking VKAs.

Overall, 44% (n=386) of patients were hospitalized for an ICH, and 30% (n=261) were hospitalized for GI bleeding.

The incidence of ICH was 22% (n=48) among patients who received NOACs and 52% (n=338) among patients who received VKAs. The odds ratio was 0.26 (95% CI, 0.18-0.37; P<0.001).

The incidence of GI major bleeding was 46% (n=102) in the NOAC group and 24% (n=159) in the VKA group. The odds ratio was 2.69 (95% CI, 1.95-3.70; P<0.001).

The incidence of 30-day mortality was significantly higher in the VKA group than the NOAC group—17% and 10%, respectively. The adjusted hazard ratio (aHR) was 0.59 (95% CI, 0.36-0.94, P=0.012).

However, when the researchers looked at 30-day mortality according to the site of major bleeding, they observed no significant differences between the NOAC and VKA groups.

The incidence of 30-day mortality among patients with ICH was 25% in both the NOAC and VKA groups (aHR=1.07; 95% CI, 0.57-1.97). And the incidence of 30-day mortality among patients with GI bleeding was 7% in the NOAC group and 10% in the VKA group (aHR=0.66; 95% CI, 0.26-1.68).

*Data in the abstract differ from data presented at the meeting.

Laura Franco, MD

COPENHAGEN—Results of a new study suggest that vitamin K antagonists (VKAs) and non-VKA oral anticoagulants (NOACs) can both confer an increased risk of major bleeding, but the type of bleeding tends to differ with the type of anticoagulant.

The research showed that patients taking VKAs were more likely to be hospitalized for intracranial hemorrhage (ICH), while patients taking NOACs were more likely to be hospitalized for gastrointestinal (GI) bleeding.

In addition, the 30-day mortality rate was significantly lower in patients who were taking NOACs than in those who were taking VKAs. However, there was no significant difference between the 2 treatment groups when the researchers assessed mortality according to the type of major bleeding.

Laura Franco, MD, of the University of Perugia in Italy, presented these findings at the 21st Congress of the European Hematology Association (abstract S139*).

For this study, Dr Franco and her colleagues wanted to evaluate the real-life clinical presentation, management, and outcome of major bleeding in patients on anticoagulants.

So the team analyzed a cohort of patients treated at 9 Italian hospitals and a group of patients enrolled in Germany’s Dresden NOAC registry.

Between September 2013 and May 2016, there were 874 patients who were hospitalized for major bleeding—220 of whom who were taking NOACs and 654 of whom were taking VKAs.

Overall, 44% (n=386) of patients were hospitalized for an ICH, and 30% (n=261) were hospitalized for GI bleeding.

The incidence of ICH was 22% (n=48) among patients who received NOACs and 52% (n=338) among patients who received VKAs. The odds ratio was 0.26 (95% CI, 0.18-0.37; P<0.001).

The incidence of GI major bleeding was 46% (n=102) in the NOAC group and 24% (n=159) in the VKA group. The odds ratio was 2.69 (95% CI, 1.95-3.70; P<0.001).

The incidence of 30-day mortality was significantly higher in the VKA group than the NOAC group—17% and 10%, respectively. The adjusted hazard ratio (aHR) was 0.59 (95% CI, 0.36-0.94, P=0.012).

However, when the researchers looked at 30-day mortality according to the site of major bleeding, they observed no significant differences between the NOAC and VKA groups.

The incidence of 30-day mortality among patients with ICH was 25% in both the NOAC and VKA groups (aHR=1.07; 95% CI, 0.57-1.97). And the incidence of 30-day mortality among patients with GI bleeding was 7% in the NOAC group and 10% in the VKA group (aHR=0.66; 95% CI, 0.26-1.68).

*Data in the abstract differ from data presented at the meeting.

CML cells

Image by Difu Wu

Researchers have used a tiny force probe to compare how healthy hematopoietic cells and cancerous ones respond to stress.

They found that cells harvested from the bone marrow of 5 patients with chronic myeloid leukemia (CML) appeared much stiffer than comparable samples taken from 5 healthy volunteers.

In addition, the researchers were able to identify areas of localized brittle failure events in the CML cells.

“What makes this work so exciting to us is not simply seeing a difference between the stiffness of healthy and cancerous cells but observing that the cancerous cells also lost their dynamic ductility and behaved as more breakable objects,” said study author Françoise Argoul, PhD, of the French National Centre for Research (CNRS) in Lyon, France.

Dr Argoul and her colleagues described this work in Physical Biology.

The researchers believe the mechanical signatures obtained by squeezing or deforming cells could potentially assist physicians in determining the presence of CML and other hematologic malignancies.

The mechanical data might also provide clues as to how long the cells have been affected by the cancer.

“We would like to construct a hematopoietic cancer cell chart where the loss of cell mechanical functions could be graded, depending on the leukemia and its stage of evolution,” Dr Argoul said.

Thinking about how the technique might be applied in a hospital setting, she added that biopsy needles could, in principle, be adapted to allow local sensing of internal soft tissue structures.

However, before the researchers can even progress to testing cells inside the body and preparing for clinical trials, they must first build up sufficient information from their measurements on isolated cells under a range of conditions in the lab.

CML cells

Image by Difu Wu

Researchers have used a tiny force probe to compare how healthy hematopoietic cells and cancerous ones respond to stress.

They found that cells harvested from the bone marrow of 5 patients with chronic myeloid leukemia (CML) appeared much stiffer than comparable samples taken from 5 healthy volunteers.

In addition, the researchers were able to identify areas of localized brittle failure events in the CML cells.

“What makes this work so exciting to us is not simply seeing a difference between the stiffness of healthy and cancerous cells but observing that the cancerous cells also lost their dynamic ductility and behaved as more breakable objects,” said study author Françoise Argoul, PhD, of the French National Centre for Research (CNRS) in Lyon, France.

Dr Argoul and her colleagues described this work in Physical Biology.

The researchers believe the mechanical signatures obtained by squeezing or deforming cells could potentially assist physicians in determining the presence of CML and other hematologic malignancies.

The mechanical data might also provide clues as to how long the cells have been affected by the cancer.

“We would like to construct a hematopoietic cancer cell chart where the loss of cell mechanical functions could be graded, depending on the leukemia and its stage of evolution,” Dr Argoul said.

Thinking about how the technique might be applied in a hospital setting, she added that biopsy needles could, in principle, be adapted to allow local sensing of internal soft tissue structures.

However, before the researchers can even progress to testing cells inside the body and preparing for clinical trials, they must first build up sufficient information from their measurements on isolated cells under a range of conditions in the lab.

CML cells

Image by Difu Wu

Researchers have used a tiny force probe to compare how healthy hematopoietic cells and cancerous ones respond to stress.

They found that cells harvested from the bone marrow of 5 patients with chronic myeloid leukemia (CML) appeared much stiffer than comparable samples taken from 5 healthy volunteers.

In addition, the researchers were able to identify areas of localized brittle failure events in the CML cells.

“What makes this work so exciting to us is not simply seeing a difference between the stiffness of healthy and cancerous cells but observing that the cancerous cells also lost their dynamic ductility and behaved as more breakable objects,” said study author Françoise Argoul, PhD, of the French National Centre for Research (CNRS) in Lyon, France.

Dr Argoul and her colleagues described this work in Physical Biology.

The researchers believe the mechanical signatures obtained by squeezing or deforming cells could potentially assist physicians in determining the presence of CML and other hematologic malignancies.

The mechanical data might also provide clues as to how long the cells have been affected by the cancer.

“We would like to construct a hematopoietic cancer cell chart where the loss of cell mechanical functions could be graded, depending on the leukemia and its stage of evolution,” Dr Argoul said.

Thinking about how the technique might be applied in a hospital setting, she added that biopsy needles could, in principle, be adapted to allow local sensing of internal soft tissue structures.

However, before the researchers can even progress to testing cells inside the body and preparing for clinical trials, they must first build up sufficient information from their measurements on isolated cells under a range of conditions in the lab.

Skin biopsy showing GVHD

Image courtesy of PLOS ONE

A study published in Blood has revealed a protein that could be used to diagnose chronic graft-versus-host disease (cGVHD).

Investigators found elevated levels of the protein, CXCL10, in the blood of transplant recipients around the time they developed cGVHD.

The team therefore believes that testing a transplant patient for this protein could potentially enable early diagnosis of cGVHD.

“Diagnostic tests are desperately needed to make blood and marrow transplants safer,” said study author Kirk Schultz, of BC Children’s Hospital in Vancouver, British Columbia, Canada.

“At this time, there are no good tests to diagnose cGVHD, and the disease can only be identified too late—when it is already established. If we can diagnose it earlier and better, then treatments can be used to stop it before it becomes a chronic, disabling disease.”

For this study, Dr Schultz and his colleagues searched for cGVHD biomarkers in blood samples from 2 groups of adult patients—36 cGVHD patients who were at least 1 month from diagnosis and 31 time-matched control subjects without cGVHD.

This revealed 11 potential biomarkers. The investigators went on to test the validity of these biomarkers in 2 replication cohorts, which included a total of 134 patients with cGVHD and 154 control subjects.

Results showed that the inflammatory protein CXCL10 was consistently elevated in patients with cGVHD. This protein appears to impact a patient’s normal immune cells, preventing the body from fighting cGVHD.

The investigators also found evidence to suggest that another protein, sBAFF, is a biomarker of cGVHD.

Although these results may bring us one step closer to a diagnostic test for cGVHD, the team said further study is needed in larger patient groups.

Skin biopsy showing GVHD

Image courtesy of PLOS ONE

A study published in Blood has revealed a protein that could be used to diagnose chronic graft-versus-host disease (cGVHD).

Investigators found elevated levels of the protein, CXCL10, in the blood of transplant recipients around the time they developed cGVHD.

The team therefore believes that testing a transplant patient for this protein could potentially enable early diagnosis of cGVHD.

“Diagnostic tests are desperately needed to make blood and marrow transplants safer,” said study author Kirk Schultz, of BC Children’s Hospital in Vancouver, British Columbia, Canada.

“At this time, there are no good tests to diagnose cGVHD, and the disease can only be identified too late—when it is already established. If we can diagnose it earlier and better, then treatments can be used to stop it before it becomes a chronic, disabling disease.”

For this study, Dr Schultz and his colleagues searched for cGVHD biomarkers in blood samples from 2 groups of adult patients—36 cGVHD patients who were at least 1 month from diagnosis and 31 time-matched control subjects without cGVHD.

This revealed 11 potential biomarkers. The investigators went on to test the validity of these biomarkers in 2 replication cohorts, which included a total of 134 patients with cGVHD and 154 control subjects.

Results showed that the inflammatory protein CXCL10 was consistently elevated in patients with cGVHD. This protein appears to impact a patient’s normal immune cells, preventing the body from fighting cGVHD.

The investigators also found evidence to suggest that another protein, sBAFF, is a biomarker of cGVHD.

Although these results may bring us one step closer to a diagnostic test for cGVHD, the team said further study is needed in larger patient groups.

Skin biopsy showing GVHD

Image courtesy of PLOS ONE

A study published in Blood has revealed a protein that could be used to diagnose chronic graft-versus-host disease (cGVHD).

Investigators found elevated levels of the protein, CXCL10, in the blood of transplant recipients around the time they developed cGVHD.

The team therefore believes that testing a transplant patient for this protein could potentially enable early diagnosis of cGVHD.

“Diagnostic tests are desperately needed to make blood and marrow transplants safer,” said study author Kirk Schultz, of BC Children’s Hospital in Vancouver, British Columbia, Canada.

“At this time, there are no good tests to diagnose cGVHD, and the disease can only be identified too late—when it is already established. If we can diagnose it earlier and better, then treatments can be used to stop it before it becomes a chronic, disabling disease.”

For this study, Dr Schultz and his colleagues searched for cGVHD biomarkers in blood samples from 2 groups of adult patients—36 cGVHD patients who were at least 1 month from diagnosis and 31 time-matched control subjects without cGVHD.

This revealed 11 potential biomarkers. The investigators went on to test the validity of these biomarkers in 2 replication cohorts, which included a total of 134 patients with cGVHD and 154 control subjects.

Results showed that the inflammatory protein CXCL10 was consistently elevated in patients with cGVHD. This protein appears to impact a patient’s normal immune cells, preventing the body from fighting cGVHD.

The investigators also found evidence to suggest that another protein, sBAFF, is a biomarker of cGVHD.

Although these results may bring us one step closer to a diagnostic test for cGVHD, the team said further study is needed in larger patient groups.

Bottles of thalidomide

Researchers say they have identified the molecular mechanism of thalidomide and other immunomodulatory drugs (IMiDs), a finding that is relevant to the treatment of multiple myeloma and other hematologic malignancies.

Previous research showed that cereblon, a cellular protein, plays an important role in the function of IMiDs.

However, the exact details of how cereblon mediates the effects of IMiDs were not clear.

The new study, published in Nature Medicine, provides an explanation.

Researchers found that, inside cells, cereblon usually binds to the proteins CD147 and MCT1. Among other things, these 2 proteins promote proliferation, metabolism, and the formation of new blood vessels. In cancers such as multiple myeloma, tumor cells contain particularly high levels of CD147 and MCT1.

As a protein complex, CD147 and MCT1 always occur as a pair. However, to find their other half and become activated, the proteins require the help of cereblon.

Binding to cereblon promotes development and stability of the complex, which, in return, stimulates cell growth and facilitates the excretion of metabolic products like lactate.

In diseases such as multiple myeloma, an increased abundance of this protein complex enables tumor cells to multiply and spread rapidly.

If such a cancer is treated with IMiDs, the drug virtually displaces the complex from its binding to cereblon. As a result, CD147 and MCT1 can no longer be activated, and they vanish.

“Ultimately, this causes the tumor cells to die,” said study author Ruth Eichner, MD, of Technische Universität München in Munich, Germany.

But the disruption of the protein complex is also responsible for the severe birth defects that can occur in the children of women who take thalidomide and other IMiDs when pregnant.

“The mechanisms are identical,” said study author Florian Bassermann, MD, PhD, of Technische Universität München.

“A specific inactivation of the protein complex resulted in the same developmental defects observed after thalidomide treatment.”

The researchers said this confirms the prevailing hypothesis that the typical IMiD-induced birth defects are related to the reduced and abnormal formation of new blood vessels. That’s because, without CD147 and MCT1, blood vessels cannot develop properly.

The team also said these findings could be used to assess the efficacy of IMiD treatment before actually giving an IMiD to the patient.

“The disappearance of the protein complex could only be observed in patients that had responded well to this type of treatment,” Dr Bassermann explained.

Therefore, he and his colleagues believe this information could be used to assess a patient’s response before starting an IMiD. A sample of the patient’s tumor cells could be cultured and treated with IMiDs. If the cells showed a disruption of the complex, the patient would most likely benefit from IMiD treatment.

The researchers also think the results of this study could lead to the development of new anticancer therapies.

The team said the CD147-MCT1 protein complex is a particularly attractive target for tumor treatment, as it is mainly found on the surface of cells and virtually links the inside to the outside of the cell.

Therefore, inactivation of the complex might be achieved using specifically produced antibodies and other distinctive drugs—a possibility Dr Bassermann and his team are now exploring.

Bottles of thalidomide

Researchers say they have identified the molecular mechanism of thalidomide and other immunomodulatory drugs (IMiDs), a finding that is relevant to the treatment of multiple myeloma and other hematologic malignancies.

Previous research showed that cereblon, a cellular protein, plays an important role in the function of IMiDs.

However, the exact details of how cereblon mediates the effects of IMiDs were not clear.

The new study, published in Nature Medicine, provides an explanation.

Researchers found that, inside cells, cereblon usually binds to the proteins CD147 and MCT1. Among other things, these 2 proteins promote proliferation, metabolism, and the formation of new blood vessels. In cancers such as multiple myeloma, tumor cells contain particularly high levels of CD147 and MCT1.

As a protein complex, CD147 and MCT1 always occur as a pair. However, to find their other half and become activated, the proteins require the help of cereblon.

Binding to cereblon promotes development and stability of the complex, which, in return, stimulates cell growth and facilitates the excretion of metabolic products like lactate.

In diseases such as multiple myeloma, an increased abundance of this protein complex enables tumor cells to multiply and spread rapidly.

If such a cancer is treated with IMiDs, the drug virtually displaces the complex from its binding to cereblon. As a result, CD147 and MCT1 can no longer be activated, and they vanish.

“Ultimately, this causes the tumor cells to die,” said study author Ruth Eichner, MD, of Technische Universität München in Munich, Germany.

But the disruption of the protein complex is also responsible for the severe birth defects that can occur in the children of women who take thalidomide and other IMiDs when pregnant.

“The mechanisms are identical,” said study author Florian Bassermann, MD, PhD, of Technische Universität München.

“A specific inactivation of the protein complex resulted in the same developmental defects observed after thalidomide treatment.”

The researchers said this confirms the prevailing hypothesis that the typical IMiD-induced birth defects are related to the reduced and abnormal formation of new blood vessels. That’s because, without CD147 and MCT1, blood vessels cannot develop properly.

The team also said these findings could be used to assess the efficacy of IMiD treatment before actually giving an IMiD to the patient.

“The disappearance of the protein complex could only be observed in patients that had responded well to this type of treatment,” Dr Bassermann explained.

Therefore, he and his colleagues believe this information could be used to assess a patient’s response before starting an IMiD. A sample of the patient’s tumor cells could be cultured and treated with IMiDs. If the cells showed a disruption of the complex, the patient would most likely benefit from IMiD treatment.

The researchers also think the results of this study could lead to the development of new anticancer therapies.

The team said the CD147-MCT1 protein complex is a particularly attractive target for tumor treatment, as it is mainly found on the surface of cells and virtually links the inside to the outside of the cell.

Therefore, inactivation of the complex might be achieved using specifically produced antibodies and other distinctive drugs—a possibility Dr Bassermann and his team are now exploring.

Bottles of thalidomide

Researchers say they have identified the molecular mechanism of thalidomide and other immunomodulatory drugs (IMiDs), a finding that is relevant to the treatment of multiple myeloma and other hematologic malignancies.

Previous research showed that cereblon, a cellular protein, plays an important role in the function of IMiDs.

However, the exact details of how cereblon mediates the effects of IMiDs were not clear.

The new study, published in Nature Medicine, provides an explanation.

Researchers found that, inside cells, cereblon usually binds to the proteins CD147 and MCT1. Among other things, these 2 proteins promote proliferation, metabolism, and the formation of new blood vessels. In cancers such as multiple myeloma, tumor cells contain particularly high levels of CD147 and MCT1.

As a protein complex, CD147 and MCT1 always occur as a pair. However, to find their other half and become activated, the proteins require the help of cereblon.

Binding to cereblon promotes development and stability of the complex, which, in return, stimulates cell growth and facilitates the excretion of metabolic products like lactate.

In diseases such as multiple myeloma, an increased abundance of this protein complex enables tumor cells to multiply and spread rapidly.

If such a cancer is treated with IMiDs, the drug virtually displaces the complex from its binding to cereblon. As a result, CD147 and MCT1 can no longer be activated, and they vanish.

“Ultimately, this causes the tumor cells to die,” said study author Ruth Eichner, MD, of Technische Universität München in Munich, Germany.

But the disruption of the protein complex is also responsible for the severe birth defects that can occur in the children of women who take thalidomide and other IMiDs when pregnant.

“The mechanisms are identical,” said study author Florian Bassermann, MD, PhD, of Technische Universität München.

“A specific inactivation of the protein complex resulted in the same developmental defects observed after thalidomide treatment.”

The researchers said this confirms the prevailing hypothesis that the typical IMiD-induced birth defects are related to the reduced and abnormal formation of new blood vessels. That’s because, without CD147 and MCT1, blood vessels cannot develop properly.

The team also said these findings could be used to assess the efficacy of IMiD treatment before actually giving an IMiD to the patient.

“The disappearance of the protein complex could only be observed in patients that had responded well to this type of treatment,” Dr Bassermann explained.

Therefore, he and his colleagues believe this information could be used to assess a patient’s response before starting an IMiD. A sample of the patient’s tumor cells could be cultured and treated with IMiDs. If the cells showed a disruption of the complex, the patient would most likely benefit from IMiD treatment.

The researchers also think the results of this study could lead to the development of new anticancer therapies.

The team said the CD147-MCT1 protein complex is a particularly attractive target for tumor treatment, as it is mainly found on the surface of cells and virtually links the inside to the outside of the cell.

Therefore, inactivation of the complex might be achieved using specifically produced antibodies and other distinctive drugs—a possibility Dr Bassermann and his team are now exploring.

Long-term pioglitazone is not only safe for patients with nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes but is associated with significant improvements in fatty liver disease outcomes, compared with placebo, research suggests.

Investigators randomized 101 individuals with biopsy-proven NASH and either prediabetes or type 2 diabetes to 18 months of 45 mg/day of pioglitazone or placebo, followed by an 18 month open-label phase of pioglitazone, in addition to a hypocaloric diet, according to a paper published online June 20 in the Annals of Internal Medicine.

©pixologicstudio/thinkstockphotos.com

Among patients randomized to pioglitazone, 58% achieved at least a two-point reduction in their NASH activity score, without a worsening of fibrosis, compared with only 17% of the placebo group (P less than .001).

The pioglitazone group also showed a significantly greater likelihood that their NASH would resolve, with 51% of the treatment group achieving resolution, compared with 19% of the placebo group (P less than .001).

Pioglitazone treatment was also associated with significantly greater improvements in steatosis, inflammation, and ballooning necrosis, as well as mean histologic scores and fibrosis scores (Ann Intern Med. 2016 Jun 20. doi: 10.7326/M15-1774).

The study also showed that only 12% of the pioglitazone group showed progression of any fibrosis, compared with 28% of the placebo group (P = .039), while pioglitazone was associated with significant 2.5 kg weight gain over placebo.

“Because thiazolidinediones target insulin resistance and adipose tissue dysfunction or inflammation that promotes hepatic ‘lipotoxicity’ in NASH (which is also a prominent feature of T2DM), they may be more helpful for treating steatohepatitis in this population,” wrote Dr. Kenneth Cusi, from the division of endocrinology at the University of Florida, Gainesville, and his coauthors.

However, the authors noted that there have been relatively few studies of pioglitazone and its effects on steatohepatitis in individuals with prediabetes or type 2 diabetes.

“This study also has implications for patients with prediabetes and NASH (about half of our participants) because hepatic steatosis is a risk factor for T2DM, even in nonobese patients,” the authors wrote. They suggested that future studies could explore whether the reversal of hepatic steatosis or nonalcoholic steatohepatitis in patients with prediabetes may help to halt the development of type 2 diabetes.

The study was supported by the Burroughs Wellcome Fund and the American Diabetes Association. One author reported nonfinancial support from Takeda Pharmaceuticals in the form of study medication and placebo, and grants and consultancies from pharmaceutical companies outside the submitted work. No other conflicts of interest were declared.

Long-term pioglitazone is not only safe for patients with nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes but is associated with significant improvements in fatty liver disease outcomes, compared with placebo, research suggests.

Investigators randomized 101 individuals with biopsy-proven NASH and either prediabetes or type 2 diabetes to 18 months of 45 mg/day of pioglitazone or placebo, followed by an 18 month open-label phase of pioglitazone, in addition to a hypocaloric diet, according to a paper published online June 20 in the Annals of Internal Medicine.

©pixologicstudio/thinkstockphotos.com

Among patients randomized to pioglitazone, 58% achieved at least a two-point reduction in their NASH activity score, without a worsening of fibrosis, compared with only 17% of the placebo group (P less than .001).

The pioglitazone group also showed a significantly greater likelihood that their NASH would resolve, with 51% of the treatment group achieving resolution, compared with 19% of the placebo group (P less than .001).

Pioglitazone treatment was also associated with significantly greater improvements in steatosis, inflammation, and ballooning necrosis, as well as mean histologic scores and fibrosis scores (Ann Intern Med. 2016 Jun 20. doi: 10.7326/M15-1774).

The study also showed that only 12% of the pioglitazone group showed progression of any fibrosis, compared with 28% of the placebo group (P = .039), while pioglitazone was associated with significant 2.5 kg weight gain over placebo.

“Because thiazolidinediones target insulin resistance and adipose tissue dysfunction or inflammation that promotes hepatic ‘lipotoxicity’ in NASH (which is also a prominent feature of T2DM), they may be more helpful for treating steatohepatitis in this population,” wrote Dr. Kenneth Cusi, from the division of endocrinology at the University of Florida, Gainesville, and his coauthors.

However, the authors noted that there have been relatively few studies of pioglitazone and its effects on steatohepatitis in individuals with prediabetes or type 2 diabetes.

“This study also has implications for patients with prediabetes and NASH (about half of our participants) because hepatic steatosis is a risk factor for T2DM, even in nonobese patients,” the authors wrote. They suggested that future studies could explore whether the reversal of hepatic steatosis or nonalcoholic steatohepatitis in patients with prediabetes may help to halt the development of type 2 diabetes.

The study was supported by the Burroughs Wellcome Fund and the American Diabetes Association. One author reported nonfinancial support from Takeda Pharmaceuticals in the form of study medication and placebo, and grants and consultancies from pharmaceutical companies outside the submitted work. No other conflicts of interest were declared.

Long-term pioglitazone is not only safe for patients with nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes but is associated with significant improvements in fatty liver disease outcomes, compared with placebo, research suggests.

Investigators randomized 101 individuals with biopsy-proven NASH and either prediabetes or type 2 diabetes to 18 months of 45 mg/day of pioglitazone or placebo, followed by an 18 month open-label phase of pioglitazone, in addition to a hypocaloric diet, according to a paper published online June 20 in the Annals of Internal Medicine.

©pixologicstudio/thinkstockphotos.com

Among patients randomized to pioglitazone, 58% achieved at least a two-point reduction in their NASH activity score, without a worsening of fibrosis, compared with only 17% of the placebo group (P less than .001).

The pioglitazone group also showed a significantly greater likelihood that their NASH would resolve, with 51% of the treatment group achieving resolution, compared with 19% of the placebo group (P less than .001).

Pioglitazone treatment was also associated with significantly greater improvements in steatosis, inflammation, and ballooning necrosis, as well as mean histologic scores and fibrosis scores (Ann Intern Med. 2016 Jun 20. doi: 10.7326/M15-1774).

The study also showed that only 12% of the pioglitazone group showed progression of any fibrosis, compared with 28% of the placebo group (P = .039), while pioglitazone was associated with significant 2.5 kg weight gain over placebo.

“Because thiazolidinediones target insulin resistance and adipose tissue dysfunction or inflammation that promotes hepatic ‘lipotoxicity’ in NASH (which is also a prominent feature of T2DM), they may be more helpful for treating steatohepatitis in this population,” wrote Dr. Kenneth Cusi, from the division of endocrinology at the University of Florida, Gainesville, and his coauthors.

However, the authors noted that there have been relatively few studies of pioglitazone and its effects on steatohepatitis in individuals with prediabetes or type 2 diabetes.

“This study also has implications for patients with prediabetes and NASH (about half of our participants) because hepatic steatosis is a risk factor for T2DM, even in nonobese patients,” the authors wrote. They suggested that future studies could explore whether the reversal of hepatic steatosis or nonalcoholic steatohepatitis in patients with prediabetes may help to halt the development of type 2 diabetes.

The study was supported by the Burroughs Wellcome Fund and the American Diabetes Association. One author reported nonfinancial support from Takeda Pharmaceuticals in the form of study medication and placebo, and grants and consultancies from pharmaceutical companies outside the submitted work. No other conflicts of interest were declared.

The U.S. Preventive Services Task Force has issued a draft recommendation opposing screening for obstructive sleep apnea (OSA) in adults who are asymptomatic for the breathing disorder.

The USPSTF’s opposition is based on its determination that there is insufficient evidence to assess the balance of benefits and harms of screening for OSA in asymptomatic adults in primary care settings, giving the service an “I” grade. The recommendation and a draft evidence review are available for public comment until July 11 at 8:00 p.m. EST.

The draft recommendation is the first that the USPSTF has ever made about sleep apnea, according to the draft evidence review. The recommendation “applies to asymptomatic adults (aged 18 years and older) and adults with unrecognized symptoms of OSA.” It does not apply to children, adolescents, pregnant women, persons presenting with symptoms of or concerns about OSA, those who are being referred for evaluation or treatment of suspected OSA, and those who have acute conditions that could trigger the onset of OSA.

“Reported estimates of OSA prevalence vary due to differing definitions of OSA, sampling bias, and year of study publication. A 2013 systematic review reported an estimated prevalence of 2%-14% based on four community-based studies, while two U.S.-based studies conducted in the 1990s reported an estimated prevalence of 10% for mild OSA and 3.8%-6.5% for moderate or severe OSA,” according to the recommendation.

The USPSTF was unable to find adequate evidence on the direct harms of screening for OSA or the benefits of screening for OSA in asymptomatic populations, including their magnitude.

Most primary care clinicians do not routinely screen for OSA, according to the recommendation. While the Epworth Sleepiness Scale, STOP Questionnaire, STOPBang Questionnaire, Berlin Questionnaire, and Wisconsin Sleep Questionnaire are potential screening tests for OSA, none of these questionnaires has been validated in a primary care setting.

“There is uncertainty about the clinical utility of all potential screening tools,” and the USPSTF found no studies that prospectively evaluated screening questionnaires or clinical prediction tools to report calibration or clinical utility for improving health outcomes,” the draft evidence review said.

The USPSTF also found no studies evaluating the effect of screening for OSA on health outcomes or that directly evaluated benefits or harms of screening for OSA.

The recommendation calls for further research on the health outcomes of screening for OSA in asymptomatic persons and the role of sleepiness in determining health outcomes. The following are needed:

• The identification of valid and reliable clinical prediction tools that could accurately determine which asymptomatic persons (or persons with unrecognized symptoms) would benefit from further evaluation and testing for OSA.

• Studies that evaluate the effect of OSA treatments or interventions on health outcomes that are adequately powered and have an appropriate length of follow-up.

• Studies that evaluate whether improvement in the apnea-hypopnea index leads to improvement in health outcomes.

• More data on the natural history of mild sleep apnea.

The final evidence review will be used to inform the final USPSTF recommendation statement.

[email protected]

The U.S. Preventive Services Task Force has issued a draft recommendation opposing screening for obstructive sleep apnea (OSA) in adults who are asymptomatic for the breathing disorder.

The USPSTF’s opposition is based on its determination that there is insufficient evidence to assess the balance of benefits and harms of screening for OSA in asymptomatic adults in primary care settings, giving the service an “I” grade. The recommendation and a draft evidence review are available for public comment until July 11 at 8:00 p.m. EST.

The draft recommendation is the first that the USPSTF has ever made about sleep apnea, according to the draft evidence review. The recommendation “applies to asymptomatic adults (aged 18 years and older) and adults with unrecognized symptoms of OSA.” It does not apply to children, adolescents, pregnant women, persons presenting with symptoms of or concerns about OSA, those who are being referred for evaluation or treatment of suspected OSA, and those who have acute conditions that could trigger the onset of OSA.

“Reported estimates of OSA prevalence vary due to differing definitions of OSA, sampling bias, and year of study publication. A 2013 systematic review reported an estimated prevalence of 2%-14% based on four community-based studies, while two U.S.-based studies conducted in the 1990s reported an estimated prevalence of 10% for mild OSA and 3.8%-6.5% for moderate or severe OSA,” according to the recommendation.

The USPSTF was unable to find adequate evidence on the direct harms of screening for OSA or the benefits of screening for OSA in asymptomatic populations, including their magnitude.

Most primary care clinicians do not routinely screen for OSA, according to the recommendation. While the Epworth Sleepiness Scale, STOP Questionnaire, STOPBang Questionnaire, Berlin Questionnaire, and Wisconsin Sleep Questionnaire are potential screening tests for OSA, none of these questionnaires has been validated in a primary care setting.

“There is uncertainty about the clinical utility of all potential screening tools,” and the USPSTF found no studies that prospectively evaluated screening questionnaires or clinical prediction tools to report calibration or clinical utility for improving health outcomes,” the draft evidence review said.

The USPSTF also found no studies evaluating the effect of screening for OSA on health outcomes or that directly evaluated benefits or harms of screening for OSA.

The recommendation calls for further research on the health outcomes of screening for OSA in asymptomatic persons and the role of sleepiness in determining health outcomes. The following are needed:

• The identification of valid and reliable clinical prediction tools that could accurately determine which asymptomatic persons (or persons with unrecognized symptoms) would benefit from further evaluation and testing for OSA.

• Studies that evaluate the effect of OSA treatments or interventions on health outcomes that are adequately powered and have an appropriate length of follow-up.

• Studies that evaluate whether improvement in the apnea-hypopnea index leads to improvement in health outcomes.

• More data on the natural history of mild sleep apnea.

The final evidence review will be used to inform the final USPSTF recommendation statement.

[email protected]

The U.S. Preventive Services Task Force has issued a draft recommendation opposing screening for obstructive sleep apnea (OSA) in adults who are asymptomatic for the breathing disorder.

The USPSTF’s opposition is based on its determination that there is insufficient evidence to assess the balance of benefits and harms of screening for OSA in asymptomatic adults in primary care settings, giving the service an “I” grade. The recommendation and a draft evidence review are available for public comment until July 11 at 8:00 p.m. EST.

The draft recommendation is the first that the USPSTF has ever made about sleep apnea, according to the draft evidence review. The recommendation “applies to asymptomatic adults (aged 18 years and older) and adults with unrecognized symptoms of OSA.” It does not apply to children, adolescents, pregnant women, persons presenting with symptoms of or concerns about OSA, those who are being referred for evaluation or treatment of suspected OSA, and those who have acute conditions that could trigger the onset of OSA.

“Reported estimates of OSA prevalence vary due to differing definitions of OSA, sampling bias, and year of study publication. A 2013 systematic review reported an estimated prevalence of 2%-14% based on four community-based studies, while two U.S.-based studies conducted in the 1990s reported an estimated prevalence of 10% for mild OSA and 3.8%-6.5% for moderate or severe OSA,” according to the recommendation.

The USPSTF was unable to find adequate evidence on the direct harms of screening for OSA or the benefits of screening for OSA in asymptomatic populations, including their magnitude.

Most primary care clinicians do not routinely screen for OSA, according to the recommendation. While the Epworth Sleepiness Scale, STOP Questionnaire, STOPBang Questionnaire, Berlin Questionnaire, and Wisconsin Sleep Questionnaire are potential screening tests for OSA, none of these questionnaires has been validated in a primary care setting.

“There is uncertainty about the clinical utility of all potential screening tools,” and the USPSTF found no studies that prospectively evaluated screening questionnaires or clinical prediction tools to report calibration or clinical utility for improving health outcomes,” the draft evidence review said.

The USPSTF also found no studies evaluating the effect of screening for OSA on health outcomes or that directly evaluated benefits or harms of screening for OSA.

The recommendation calls for further research on the health outcomes of screening for OSA in asymptomatic persons and the role of sleepiness in determining health outcomes. The following are needed:

• The identification of valid and reliable clinical prediction tools that could accurately determine which asymptomatic persons (or persons with unrecognized symptoms) would benefit from further evaluation and testing for OSA.

• Studies that evaluate the effect of OSA treatments or interventions on health outcomes that are adequately powered and have an appropriate length of follow-up.

• Studies that evaluate whether improvement in the apnea-hypopnea index leads to improvement in health outcomes.

• More data on the natural history of mild sleep apnea.

The final evidence review will be used to inform the final USPSTF recommendation statement.

[email protected]

Endometrioid endometrial tumors with DNA mismatch repair (MMR) defects were associated with lower progression-free survival than were tumors that lacked these epigenetic defects, according to a large prospective study published online June 20 in the Journal of Clinical Oncology.

“The overall effect was less than would be expected given the strong association [between MMR defects and] higher grade (66% grade 2 or 3), higher stage (22% stage III or IV), and frequent lymphovascular space invasion (33%),” Dr. Scott McMeekin of the University of Oklahoma Health Sciences Center, Oklahoma City, and his associates wrote. Perhaps MMR-deficient tumors “are eliciting an antitumor immune response, as has been described for POLE ultramutated tumors,” they suggested.

Endometrioid endometrial tumors comprise about 80% of uterine cancers, and about 20%-40% of endometrioid endometrial cancer (EEC) tumors show loss of MMR, but “the relationship between MMR defects and outcomes in patients with endometrial cancer has not been fully established,” the researchers wrote.

Their study looked for links between MMR classes, clinicopathologic features, and outcomes, including response to adjuvant therapy. Understanding these links “will be critical to the design and implementation of trials for treating advanced-stage and recurrent EEC, including biologic therapies such as immune checkpoint blockade,” they wrote (J Clin Oncol. 2016. doi: 10.1200/JCO.2016.67.8722).

The study included 1,043 women with primary EEC prospectively recruited between 2003 and 2007 by the NRG/Gynecologic Oncology Group.

Tumor slides and clinical reports for a total of 1,024 EECs were centrally reviewed, and the tumors were tested for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was classified as being either MMR normal, having an epigenetic defect, having a probable mutation (that is, an MMR defect not attributable to MLH1 methylation), or as being MSI-low.

Progression-free survival was significantly lower among women whose tumors had epigenetic defects, compared with women whose tumors were MMR normal (hazard ratio, 1.37; 95% confidence interval, 1.00-1.86; P less than .05).

However, trends in disease-specific survival were similar, regardless of MMR type, the researchers wrote. Importantly, an exploratory analysis revealed a possible link between MMR status and response to adjuvant therapy. Specifically, women classified as having probable MMR mutations who received adjuvant therapy had substantially better progression-free survival, with a P-value that trended toward significant (HR, 0.24; 95% CI, 0.05-1.16; P = .07).

“No such effect was seen in the epigenetic defect group, and the differences in outcomes for patients with the two different classes of MMR defect are highly suggestive,” the researchers wrote. “Despite the large size of our study, our power to detect differences in survival is limited by the modest number of cases whose tumors were classified as probable mutation (99, 10% of cohort) and further by the fact that only 26 subjects received adjuvant therapy.”

Since many cancer centers regularly test tumor specimens for MMR defects and MLH1 methylation, “it should be possible to rapidly undertake retrospective studies to validate the findings we report here,” the researchers noted.

Dr. McMeekin reported having no financial disclosures. His coauthors reported ties to several companies, including Repros Therapeutics, Ethicon, Vitatex, Genentech, Janssen Oncology, Tesaro, AstraZeneca, and OvaGene Oncology.

Endometrioid endometrial tumors with DNA mismatch repair (MMR) defects were associated with lower progression-free survival than were tumors that lacked these epigenetic defects, according to a large prospective study published online June 20 in the Journal of Clinical Oncology.

“The overall effect was less than would be expected given the strong association [between MMR defects and] higher grade (66% grade 2 or 3), higher stage (22% stage III or IV), and frequent lymphovascular space invasion (33%),” Dr. Scott McMeekin of the University of Oklahoma Health Sciences Center, Oklahoma City, and his associates wrote. Perhaps MMR-deficient tumors “are eliciting an antitumor immune response, as has been described for POLE ultramutated tumors,” they suggested.

Endometrioid endometrial tumors comprise about 80% of uterine cancers, and about 20%-40% of endometrioid endometrial cancer (EEC) tumors show loss of MMR, but “the relationship between MMR defects and outcomes in patients with endometrial cancer has not been fully established,” the researchers wrote.

Their study looked for links between MMR classes, clinicopathologic features, and outcomes, including response to adjuvant therapy. Understanding these links “will be critical to the design and implementation of trials for treating advanced-stage and recurrent EEC, including biologic therapies such as immune checkpoint blockade,” they wrote (J Clin Oncol. 2016. doi: 10.1200/JCO.2016.67.8722).

The study included 1,043 women with primary EEC prospectively recruited between 2003 and 2007 by the NRG/Gynecologic Oncology Group.

Tumor slides and clinical reports for a total of 1,024 EECs were centrally reviewed, and the tumors were tested for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was classified as being either MMR normal, having an epigenetic defect, having a probable mutation (that is, an MMR defect not attributable to MLH1 methylation), or as being MSI-low.

Progression-free survival was significantly lower among women whose tumors had epigenetic defects, compared with women whose tumors were MMR normal (hazard ratio, 1.37; 95% confidence interval, 1.00-1.86; P less than .05).

However, trends in disease-specific survival were similar, regardless of MMR type, the researchers wrote. Importantly, an exploratory analysis revealed a possible link between MMR status and response to adjuvant therapy. Specifically, women classified as having probable MMR mutations who received adjuvant therapy had substantially better progression-free survival, with a P-value that trended toward significant (HR, 0.24; 95% CI, 0.05-1.16; P = .07).

“No such effect was seen in the epigenetic defect group, and the differences in outcomes for patients with the two different classes of MMR defect are highly suggestive,” the researchers wrote. “Despite the large size of our study, our power to detect differences in survival is limited by the modest number of cases whose tumors were classified as probable mutation (99, 10% of cohort) and further by the fact that only 26 subjects received adjuvant therapy.”

Since many cancer centers regularly test tumor specimens for MMR defects and MLH1 methylation, “it should be possible to rapidly undertake retrospective studies to validate the findings we report here,” the researchers noted.

Dr. McMeekin reported having no financial disclosures. His coauthors reported ties to several companies, including Repros Therapeutics, Ethicon, Vitatex, Genentech, Janssen Oncology, Tesaro, AstraZeneca, and OvaGene Oncology.

Endometrioid endometrial tumors with DNA mismatch repair (MMR) defects were associated with lower progression-free survival than were tumors that lacked these epigenetic defects, according to a large prospective study published online June 20 in the Journal of Clinical Oncology.

“The overall effect was less than would be expected given the strong association [between MMR defects and] higher grade (66% grade 2 or 3), higher stage (22% stage III or IV), and frequent lymphovascular space invasion (33%),” Dr. Scott McMeekin of the University of Oklahoma Health Sciences Center, Oklahoma City, and his associates wrote. Perhaps MMR-deficient tumors “are eliciting an antitumor immune response, as has been described for POLE ultramutated tumors,” they suggested.

Endometrioid endometrial tumors comprise about 80% of uterine cancers, and about 20%-40% of endometrioid endometrial cancer (EEC) tumors show loss of MMR, but “the relationship between MMR defects and outcomes in patients with endometrial cancer has not been fully established,” the researchers wrote.

Their study looked for links between MMR classes, clinicopathologic features, and outcomes, including response to adjuvant therapy. Understanding these links “will be critical to the design and implementation of trials for treating advanced-stage and recurrent EEC, including biologic therapies such as immune checkpoint blockade,” they wrote (J Clin Oncol. 2016. doi: 10.1200/JCO.2016.67.8722).

The study included 1,043 women with primary EEC prospectively recruited between 2003 and 2007 by the NRG/Gynecologic Oncology Group.

Tumor slides and clinical reports for a total of 1,024 EECs were centrally reviewed, and the tumors were tested for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was classified as being either MMR normal, having an epigenetic defect, having a probable mutation (that is, an MMR defect not attributable to MLH1 methylation), or as being MSI-low.

Progression-free survival was significantly lower among women whose tumors had epigenetic defects, compared with women whose tumors were MMR normal (hazard ratio, 1.37; 95% confidence interval, 1.00-1.86; P less than .05).

However, trends in disease-specific survival were similar, regardless of MMR type, the researchers wrote. Importantly, an exploratory analysis revealed a possible link between MMR status and response to adjuvant therapy. Specifically, women classified as having probable MMR mutations who received adjuvant therapy had substantially better progression-free survival, with a P-value that trended toward significant (HR, 0.24; 95% CI, 0.05-1.16; P = .07).

“No such effect was seen in the epigenetic defect group, and the differences in outcomes for patients with the two different classes of MMR defect are highly suggestive,” the researchers wrote. “Despite the large size of our study, our power to detect differences in survival is limited by the modest number of cases whose tumors were classified as probable mutation (99, 10% of cohort) and further by the fact that only 26 subjects received adjuvant therapy.”

Since many cancer centers regularly test tumor specimens for MMR defects and MLH1 methylation, “it should be possible to rapidly undertake retrospective studies to validate the findings we report here,” the researchers noted.

Dr. McMeekin reported having no financial disclosures. His coauthors reported ties to several companies, including Repros Therapeutics, Ethicon, Vitatex, Genentech, Janssen Oncology, Tesaro, AstraZeneca, and OvaGene Oncology.

Every 5-year increase in duration of oral contraceptive use was associated with about a 13% decrease in the risk of invasive ovarian cancers, and this protective effect persisted for all histologic subtypes except mucinous tumors, according to results of a meta-analysis.

“Oral contraceptives continue to be an important preventive factor for most types of ovarian cancer. Few other risk factors for ovarian cancer are modifiable, and those that are, such as smoking and obesity, did not show clear associations with serous carcinomas, the most common and fatal subtype,” Dr. Nicolas Wentzensen of the National Cancer Institute and his associates wrote June 20 in the Journal of Clinical Oncology.

©Thinkstock

Ovarian cancer is heterogeneous and its etiology poorly understood. Power limitations have prevented individual studies from parsing risk factors for distinct ovarian cancer histotypes, the researchers added. To solve this issue, they examined links between 14 different hormonal, reproductive, and lifestyle characteristics and histologic subtypes of tumors in the Ovarian Cancer Cohort Consortium.

Their analysis included 5,584 invasive ovarian cancers from more than 1.3 million women enrolled in 21 prospective studies (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2016.66.8178).

Patients who reported having ever used oral contraceptives were about 16% less likely to develop any type of invasive epithelial ovarian cancer, compared with those who had never used oral contraceptives (relative risk, 0.84; 95% confidence interval, 0.79-0.89). Associations were similar for high-grade serous, endometrioid, and clear cell histotypes, although OC use did not appear to protect against mucinous tumors, the researchers wrote.

Some of the strongest associations were for endometrioid and clear cell carcinomas, they noted. For example, the risk of endometrioid carcinoma fell by about 22% for every birth (RR per birth, 0.78; 95% CI, 0.74-0.83), and the risk of clear cell carcinoma fell by about 32% per birth (RR, 0.68; 95% CI, 0.61-0.76).

“Likewise, age at menopause, endometriosis, and tubal ligation were associated only with clear cell and endometrioid tumors,” the researchers wrote.

Smoking was tied to a higher risk of mucinous tumors (RR per 20 pack-years, 1.20; 95% CI, 1.04-1.39) but was associated with a lower risk of clear cell tumors (RR, 0.68; 95% CI, 0.53-0.89).

“The substantial heterogeneity of individual risk factor associations across ovarian cancer subtypes [suggests] that subtypes are indeed different diseases, and underscores the importance of evaluating risk factors and biomarkers by ovarian cancer subtypes,” the researchers concluded. “Due to weaker associations observed for high-grade serous carcinomas, prediction of the clinically most important subtype may perform worse than for other types, which underscores the importance of finding better risk factors for serous carcinomas.”

The consortium plans to search for more tumor predictors by analyzing circulating biomarkers and genetic data.

Dr. Wentzensen reported having no financial disclosures. Other researchers reported financial relationships with GlaxoSmithKline and Cepheid.

Every 5-year increase in duration of oral contraceptive use was associated with about a 13% decrease in the risk of invasive ovarian cancers, and this protective effect persisted for all histologic subtypes except mucinous tumors, according to results of a meta-analysis.

“Oral contraceptives continue to be an important preventive factor for most types of ovarian cancer. Few other risk factors for ovarian cancer are modifiable, and those that are, such as smoking and obesity, did not show clear associations with serous carcinomas, the most common and fatal subtype,” Dr. Nicolas Wentzensen of the National Cancer Institute and his associates wrote June 20 in the Journal of Clinical Oncology.

©Thinkstock

Ovarian cancer is heterogeneous and its etiology poorly understood. Power limitations have prevented individual studies from parsing risk factors for distinct ovarian cancer histotypes, the researchers added. To solve this issue, they examined links between 14 different hormonal, reproductive, and lifestyle characteristics and histologic subtypes of tumors in the Ovarian Cancer Cohort Consortium.

Their analysis included 5,584 invasive ovarian cancers from more than 1.3 million women enrolled in 21 prospective studies (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2016.66.8178).

Patients who reported having ever used oral contraceptives were about 16% less likely to develop any type of invasive epithelial ovarian cancer, compared with those who had never used oral contraceptives (relative risk, 0.84; 95% confidence interval, 0.79-0.89). Associations were similar for high-grade serous, endometrioid, and clear cell histotypes, although OC use did not appear to protect against mucinous tumors, the researchers wrote.

Some of the strongest associations were for endometrioid and clear cell carcinomas, they noted. For example, the risk of endometrioid carcinoma fell by about 22% for every birth (RR per birth, 0.78; 95% CI, 0.74-0.83), and the risk of clear cell carcinoma fell by about 32% per birth (RR, 0.68; 95% CI, 0.61-0.76).

“Likewise, age at menopause, endometriosis, and tubal ligation were associated only with clear cell and endometrioid tumors,” the researchers wrote.

Smoking was tied to a higher risk of mucinous tumors (RR per 20 pack-years, 1.20; 95% CI, 1.04-1.39) but was associated with a lower risk of clear cell tumors (RR, 0.68; 95% CI, 0.53-0.89).

“The substantial heterogeneity of individual risk factor associations across ovarian cancer subtypes [suggests] that subtypes are indeed different diseases, and underscores the importance of evaluating risk factors and biomarkers by ovarian cancer subtypes,” the researchers concluded. “Due to weaker associations observed for high-grade serous carcinomas, prediction of the clinically most important subtype may perform worse than for other types, which underscores the importance of finding better risk factors for serous carcinomas.”

The consortium plans to search for more tumor predictors by analyzing circulating biomarkers and genetic data.

Dr. Wentzensen reported having no financial disclosures. Other researchers reported financial relationships with GlaxoSmithKline and Cepheid.

Every 5-year increase in duration of oral contraceptive use was associated with about a 13% decrease in the risk of invasive ovarian cancers, and this protective effect persisted for all histologic subtypes except mucinous tumors, according to results of a meta-analysis.

“Oral contraceptives continue to be an important preventive factor for most types of ovarian cancer. Few other risk factors for ovarian cancer are modifiable, and those that are, such as smoking and obesity, did not show clear associations with serous carcinomas, the most common and fatal subtype,” Dr. Nicolas Wentzensen of the National Cancer Institute and his associates wrote June 20 in the Journal of Clinical Oncology.

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Ovarian cancer is heterogeneous and its etiology poorly understood. Power limitations have prevented individual studies from parsing risk factors for distinct ovarian cancer histotypes, the researchers added. To solve this issue, they examined links between 14 different hormonal, reproductive, and lifestyle characteristics and histologic subtypes of tumors in the Ovarian Cancer Cohort Consortium.

Their analysis included 5,584 invasive ovarian cancers from more than 1.3 million women enrolled in 21 prospective studies (J Clin Oncol. 2016 Jun. doi: 10.1200/JCO.2016.66.8178).

Patients who reported having ever used oral contraceptives were about 16% less likely to develop any type of invasive epithelial ovarian cancer, compared with those who had never used oral contraceptives (relative risk, 0.84; 95% confidence interval, 0.79-0.89). Associations were similar for high-grade serous, endometrioid, and clear cell histotypes, although OC use did not appear to protect against mucinous tumors, the researchers wrote.

Some of the strongest associations were for endometrioid and clear cell carcinomas, they noted. For example, the risk of endometrioid carcinoma fell by about 22% for every birth (RR per birth, 0.78; 95% CI, 0.74-0.83), and the risk of clear cell carcinoma fell by about 32% per birth (RR, 0.68; 95% CI, 0.61-0.76).

“Likewise, age at menopause, endometriosis, and tubal ligation were associated only with clear cell and endometrioid tumors,” the researchers wrote.

Smoking was tied to a higher risk of mucinous tumors (RR per 20 pack-years, 1.20; 95% CI, 1.04-1.39) but was associated with a lower risk of clear cell tumors (RR, 0.68; 95% CI, 0.53-0.89).

“The substantial heterogeneity of individual risk factor associations across ovarian cancer subtypes [suggests] that subtypes are indeed different diseases, and underscores the importance of evaluating risk factors and biomarkers by ovarian cancer subtypes,” the researchers concluded. “Due to weaker associations observed for high-grade serous carcinomas, prediction of the clinically most important subtype may perform worse than for other types, which underscores the importance of finding better risk factors for serous carcinomas.”

The consortium plans to search for more tumor predictors by analyzing circulating biomarkers and genetic data.

Dr. Wentzensen reported having no financial disclosures. Other researchers reported financial relationships with GlaxoSmithKline and Cepheid.

Individuals with newly diagnosed multiple myeloma who were ineligible for stem cell transplantation were 31% less likely to die or progress on continuous lenalidomide plus low-dose dexamethasone (Rd continuous) than were those on melphalan, prednisone, and thalidomide (MPT), according to an extended follow-up of patients from the FIRST trial.

In addition, Rd continuous was associated with a statistically significant 20% decrease in risk of death or disease progression, compared with MPT among patients older than 75 years, reported Dr. Cyrille Hulin of Bordeaux (France) Hospital University Center and associates. The finding “establishes continuous treatment with Rd until disease progression as a new standard of care for patients with newly diagnosed multiple myeloma who are ineligible for stem cell transplantation, regardless of age. With proper monitoring and dose adjustment, Rd continuous is an effective and tolerable treatment option for even the most elderly patients,” they wrote online June 20 in the Journal of Clinical Oncology.

FIRST (Frontline Investigation of Revlimid Plus Dexamethasone Versus Standard Thalidomide) was an international, randomized, phase III open-label study of patients with untreated symptomatic multiple myeloma enrolled between 2008 and 2011. Patients were randomly assigned to Rd continuous, 72 weeks/18 cycles of Rd (Rd18), or MPT. The primary endpoint was progression-free survival (PFS). In the original analysis, Rd continuous led to a 28% lower risk of progression or death, compared with MPT, for a statistically significant hazard ratio (HR) of 0.72. The current study involved longer follow-up, with an updated data cutoff that was 3 years after the end of recruitment, the researchers said (J Clin Oncol. 2016 Jun 20. doi: 10.1200/JCO.2016.66.7295).

The cohort included 1,623 patients, of whom 567 (35%) were older than 75 years. The intention-to-treat populations included 535 Rd continuous patients, 541 Rd18 patients, and 547 MPT patients. Survivors were followed for a median of 45.5 months. As in the earlier analysis of FIRST data, the PFS was longer with Rd continuous than with MPT. For the overall intention-to-treat group, the median PFS was 26 months with Rd continuous, and 21.9 months with MPT (HR, 0.69; 95% confidence interval, 0.59-0.80). Among patients aged 75 years and younger, the median PFS was 28.1 months and 22.4 months, respectively (HR, 0.64; 95% CI, 0.53-0.77). Among patients over age 75 years, the median PFS was 20.3 months and 19.8 months, respectively (HR, 0.80, 95% CI, 0.62-1.03). In addition, the 4-year PFS “was more than doubled with Rd continuous versus MPT, regardless of age,” the investigators said. In contrast, Rd18 and MPT led to a similar median PFS, regardless of age.

As in the prior FIRST analysis, MPT was more often linked to grade 3 and 4 neutropenia (40% and 47% of older and younger patients, respectively, versus about 28% of Rd continuous patients), while Rd more often led to grade 3 and 4 infections (about 30% of Rd continuous patients, about 22% of Rd18 patients, and 16%-20% of MPT patients).

A total of 40% of younger Rd patients remained at their starting lenalidomide dose at 72 weeks, while only 16% of MPT patients stayed at their starting thalidomide dose. Similarly, 30% of older Rd continuous patients remained on their starting dose at 72 weeks, compared with 19% of older MPT patients.

Older age was associated with International Staging System stage III disease, renal impairment, and more comorbidities, but not with high-risk cytogenetics (that is, del[17p] and t[4;14]). “Although chronologic age is not necessarily an indicator of frailty, FIRST trial results did show greater PFS and OS [overall survival] benefits with Rd continuous versus MPT therapy, regardless of age,” the researchers commented.

The study was funded by Intergroupe Francophone du Myélome and Celgene. Dr. Hulin disclosed honoraria from Celgene, Amgen, Bristol-Myers Squibb, and Novartis.

Individuals with newly diagnosed multiple myeloma who were ineligible for stem cell transplantation were 31% less likely to die or progress on continuous lenalidomide plus low-dose dexamethasone (Rd continuous) than were those on melphalan, prednisone, and thalidomide (MPT), according to an extended follow-up of patients from the FIRST trial.

In addition, Rd continuous was associated with a statistically significant 20% decrease in risk of death or disease progression, compared with MPT among patients older than 75 years, reported Dr. Cyrille Hulin of Bordeaux (France) Hospital University Center and associates. The finding “establishes continuous treatment with Rd until disease progression as a new standard of care for patients with newly diagnosed multiple myeloma who are ineligible for stem cell transplantation, regardless of age. With proper monitoring and dose adjustment, Rd continuous is an effective and tolerable treatment option for even the most elderly patients,” they wrote online June 20 in the Journal of Clinical Oncology.

FIRST (Frontline Investigation of Revlimid Plus Dexamethasone Versus Standard Thalidomide) was an international, randomized, phase III open-label study of patients with untreated symptomatic multiple myeloma enrolled between 2008 and 2011. Patients were randomly assigned to Rd continuous, 72 weeks/18 cycles of Rd (Rd18), or MPT. The primary endpoint was progression-free survival (PFS). In the original analysis, Rd continuous led to a 28% lower risk of progression or death, compared with MPT, for a statistically significant hazard ratio (HR) of 0.72. The current study involved longer follow-up, with an updated data cutoff that was 3 years after the end of recruitment, the researchers said (J Clin Oncol. 2016 Jun 20. doi: 10.1200/JCO.2016.66.7295).

The cohort included 1,623 patients, of whom 567 (35%) were older than 75 years. The intention-to-treat populations included 535 Rd continuous patients, 541 Rd18 patients, and 547 MPT patients. Survivors were followed for a median of 45.5 months. As in the earlier analysis of FIRST data, the PFS was longer with Rd continuous than with MPT. For the overall intention-to-treat group, the median PFS was 26 months with Rd continuous, and 21.9 months with MPT (HR, 0.69; 95% confidence interval, 0.59-0.80). Among patients aged 75 years and younger, the median PFS was 28.1 months and 22.4 months, respectively (HR, 0.64; 95% CI, 0.53-0.77). Among patients over age 75 years, the median PFS was 20.3 months and 19.8 months, respectively (HR, 0.80, 95% CI, 0.62-1.03). In addition, the 4-year PFS “was more than doubled with Rd continuous versus MPT, regardless of age,” the investigators said. In contrast, Rd18 and MPT led to a similar median PFS, regardless of age.

As in the prior FIRST analysis, MPT was more often linked to grade 3 and 4 neutropenia (40% and 47% of older and younger patients, respectively, versus about 28% of Rd continuous patients), while Rd more often led to grade 3 and 4 infections (about 30% of Rd continuous patients, about 22% of Rd18 patients, and 16%-20% of MPT patients).

A total of 40% of younger Rd patients remained at their starting lenalidomide dose at 72 weeks, while only 16% of MPT patients stayed at their starting thalidomide dose. Similarly, 30% of older Rd continuous patients remained on their starting dose at 72 weeks, compared with 19% of older MPT patients.

Older age was associated with International Staging System stage III disease, renal impairment, and more comorbidities, but not with high-risk cytogenetics (that is, del[17p] and t[4;14]). “Although chronologic age is not necessarily an indicator of frailty, FIRST trial results did show greater PFS and OS [overall survival] benefits with Rd continuous versus MPT therapy, regardless of age,” the researchers commented.

The study was funded by Intergroupe Francophone du Myélome and Celgene. Dr. Hulin disclosed honoraria from Celgene, Amgen, Bristol-Myers Squibb, and Novartis.

Individuals with newly diagnosed multiple myeloma who were ineligible for stem cell transplantation were 31% less likely to die or progress on continuous lenalidomide plus low-dose dexamethasone (Rd continuous) than were those on melphalan, prednisone, and thalidomide (MPT), according to an extended follow-up of patients from the FIRST trial.

In addition, Rd continuous was associated with a statistically significant 20% decrease in risk of death or disease progression, compared with MPT among patients older than 75 years, reported Dr. Cyrille Hulin of Bordeaux (France) Hospital University Center and associates. The finding “establishes continuous treatment with Rd until disease progression as a new standard of care for patients with newly diagnosed multiple myeloma who are ineligible for stem cell transplantation, regardless of age. With proper monitoring and dose adjustment, Rd continuous is an effective and tolerable treatment option for even the most elderly patients,” they wrote online June 20 in the Journal of Clinical Oncology.

FIRST (Frontline Investigation of Revlimid Plus Dexamethasone Versus Standard Thalidomide) was an international, randomized, phase III open-label study of patients with untreated symptomatic multiple myeloma enrolled between 2008 and 2011. Patients were randomly assigned to Rd continuous, 72 weeks/18 cycles of Rd (Rd18), or MPT. The primary endpoint was progression-free survival (PFS). In the original analysis, Rd continuous led to a 28% lower risk of progression or death, compared with MPT, for a statistically significant hazard ratio (HR) of 0.72. The current study involved longer follow-up, with an updated data cutoff that was 3 years after the end of recruitment, the researchers said (J Clin Oncol. 2016 Jun 20. doi: 10.1200/JCO.2016.66.7295).

The cohort included 1,623 patients, of whom 567 (35%) were older than 75 years. The intention-to-treat populations included 535 Rd continuous patients, 541 Rd18 patients, and 547 MPT patients. Survivors were followed for a median of 45.5 months. As in the earlier analysis of FIRST data, the PFS was longer with Rd continuous than with MPT. For the overall intention-to-treat group, the median PFS was 26 months with Rd continuous, and 21.9 months with MPT (HR, 0.69; 95% confidence interval, 0.59-0.80). Among patients aged 75 years and younger, the median PFS was 28.1 months and 22.4 months, respectively (HR, 0.64; 95% CI, 0.53-0.77). Among patients over age 75 years, the median PFS was 20.3 months and 19.8 months, respectively (HR, 0.80, 95% CI, 0.62-1.03). In addition, the 4-year PFS “was more than doubled with Rd continuous versus MPT, regardless of age,” the investigators said. In contrast, Rd18 and MPT led to a similar median PFS, regardless of age.

As in the prior FIRST analysis, MPT was more often linked to grade 3 and 4 neutropenia (40% and 47% of older and younger patients, respectively, versus about 28% of Rd continuous patients), while Rd more often led to grade 3 and 4 infections (about 30% of Rd continuous patients, about 22% of Rd18 patients, and 16%-20% of MPT patients).

A total of 40% of younger Rd patients remained at their starting lenalidomide dose at 72 weeks, while only 16% of MPT patients stayed at their starting thalidomide dose. Similarly, 30% of older Rd continuous patients remained on their starting dose at 72 weeks, compared with 19% of older MPT patients.

Older age was associated with International Staging System stage III disease, renal impairment, and more comorbidities, but not with high-risk cytogenetics (that is, del[17p] and t[4;14]). “Although chronologic age is not necessarily an indicator of frailty, FIRST trial results did show greater PFS and OS [overall survival] benefits with Rd continuous versus MPT therapy, regardless of age,” the researchers commented.

The study was funded by Intergroupe Francophone du Myélome and Celgene. Dr. Hulin disclosed honoraria from Celgene, Amgen, Bristol-Myers Squibb, and Novartis.