Lab mouse

New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).

Plek2 was previously shown to be involved in red blood cell production.

Now, researchers have found Plek2 is upregulated in patients with JAK2^V617F-positive MPNs.

And loss of Plek2 ameliorated JAK2^V617F-induced myeloproliferative phenotypes in a mouse model.

Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.

The researchers found that Plek2 was significantly upregulated in patients with JAK2^V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.

Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2^V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.

The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.

Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”

“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.

Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.

Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.

“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”

“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”

Lab mouse

New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).

Plek2 was previously shown to be involved in red blood cell production.

Now, researchers have found Plek2 is upregulated in patients with JAK2^V617F-positive MPNs.

And loss of Plek2 ameliorated JAK2^V617F-induced myeloproliferative phenotypes in a mouse model.

Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.

The researchers found that Plek2 was significantly upregulated in patients with JAK2^V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.

Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2^V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.

The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.

Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”

“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.

Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.

Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.

“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”

“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”

Lab mouse

New research suggests plecktrin-2 (Plek2) may be a therapeutic target for myeloproliferative neoplasms (MPNs).

Plek2 was previously shown to be involved in red blood cell production.

Now, researchers have found Plek2 is upregulated in patients with JAK2^V617F-positive MPNs.

And loss of Plek2 ameliorated JAK2^V617F-induced myeloproliferative phenotypes in a mouse model.

Peng Ji, MD, PhD, of Northwestern University in Chicago, Illinois, and his colleagues conducted this research and reported the results in The Journal of Clinical Investigation.

The researchers found that Plek2 was significantly upregulated in patients with JAK2^V617F-positive MPNs, including myelofibrosis, essential thrombocythemia, and polycythemia vera.

Plek2 was also upregulated in myeloid, lymphoid, and erythroid cells in a JAK2^V617F hematopoietic-specific knock-in mouse model that mimics the pathogenesis of MPNs.

The researchers assessed the effects of turning off Plek2 in this model and found that loss of Plek2 significantly reverted neutrophilia and thrombocytosis, partially reverted reticulocytosis, mildly reduced red blood cell count, significantly reduced megakaryocyte numbers and clusters, and reduced spleen size.

Loss of Plek2 also reduced red blood cell mass, which was the main contributing factor in the reversion of vascular occlusions, according to the researchers. The team detected “widespread vascular occlusions” in mice with Plek2, but mice without Plek2 had “relatively clear vasculature.”

“The risk of thrombosis was not completely cured because there are other factors aside from pleckstrin-2, but we saw a very dramatic amelioration in blood clotting,” Dr Ji said.

Finally, loss of Plek2 improved survival. All mice with Plek2 died at around 30 weeks, but more than 80% of the mice without Plek2 survived beyond 40 weeks.

Dr Ji and his colleagues hope to build upon these findings by developing a Plek2 inhibitor.

“We are looking for a molecule that can bind with pleckstrin-2 and block its functions,” Dr Ji said. “We’ve already screened compounds, and we have about 40 we are testing right now.”

“Mice with pleckstrin-2 deactivated experienced fewer side effects compared to mice without JAK2, so we believe the pleckstrin-2 inhibitor will generate fewer side effects as well.”

A DIETARY DIAGNOSIS

I’m a hospital CEO and came across an NP colleague’s issue of Clinician Reviews; your September editorial on aspartame (2017;27[9]:6-7) caught my eye. While mine is another “n = 1” experience with the effects of aspartame, it was life-changing.

About 10 years ago, my former wife’s seizures suddenly increased in frequency after a fairly lengthy period without them. The problem was severe enough that she was faced with losing her ability to drive a car.

I had a good business relationship with the Massachusetts General Hospital and sought help from a prominent neurologist there. He asked us to keep a dietary journal before the appointment.

Though he ordered routine diagnostic tests, the journal told him all he needed to know: He told her to eliminate aspartame from her diet. It felt like a miracle when the seizures disappeared—no longer did I need to maintain bumpers on every sharp edge in the house!

Since this experience, I read every article that I can about this chemical additive and was interested to learn of your experiences.

Doug Jones
Ellsworth, ME

THE SCIENCE IS JUNK

I had to write because I can’t believe they allowed you to publish such a ridiculous article based on junk science. Anecdotal reports have no place in medicine. Aspartame is one of the most studied food items around. Many of these claims about the alleged danger of aspartame have been debunked by real scientists.

I am very disappointed.

Darlene Elliott, MSN, RN, CNP
Albuquerque, NM

STOP IGNORING THE BODY OF KNOWLEDGE

Thank you for addressing an issue that I believe to be of great importance. There is a huge body of knowledge that the medical community is ignoring regarding the correlation between diet and health in general, in particular the diabetes epidemic. As NPs, we are in a great position to lead.

I encourage you to read Jason Fung’s book, The Obesity Code. The entire book is eye popping, but chapter 15 (“The Diet Soda Delusion”) is particularly pertinent. He has the most thorough understanding of carbohydrate metabolism of all the authors I have read. However, Gary Taubes and Eric Westman have also published valuable resources; their books have changed my life, and I believe their knowledge could apply to many of our patients. If doctors will not embrace science, perhaps NPs will.

Martha DelGiudice, CNM
Smithtown, NY

MAYBE IT'S US …

Every time the “fasten seat belt” sign comes on, the ride gets very bumpy—so from now on, I’m going to ignore it. Aspartame “tricks our brain,” does it? What about agency? Or are we just passive leaves in the air blown about by gusts of aspartame?

Robert Pearlman, PA
Providence, RI

FAST TRACK FROM SWEET TO SOUR

Thank you for shedding light on the dangers of aspartame! My personal experience with it has not been good: One night, after drinking a large quantity of artificially sweetened powdered iced tea, I began to feel numb and experienced strange nerve sensations. I quickly learned that it is a migraine trigger for me. I now avoid aspartame and all other artificial sweeteners.

As a clinical dietitian (and NP), I’ve realized that fake food just doesn’t cut it for the body. Another issue in the dietary realm is that of folic acid. Yes, fortification has done wonders for preventing neural tube defects. But did you know that the folic acid put in our grains is a chemical that our bodies have to methylate to folinic acid, and that more than half of us do not do that well? This means excess synthetic folic acid is floating around in our bodies and brains, attributing to seizures, ADD, ADHD, migraines, miscarriages, etc.

I try to avoid eating foods with added folic acid. Talk about difficult! It means eating a lot of organic grains, whole grains, and natural vitamins with natural methylfolate to prevent anemia. Our bodies are designed to eat natural foods; the more processed something is, the more likely it is to be harmful to us.

Caroline Conneen, C-FNP, RD, IBCLC
Fredericksburg, VA

FAKE FOOD, NOT OUR FRIEND

My husband was habitually drinking flavored seltzer sweetened with aspartame when he became anxious, irritable, and developed insomnia. As soon as he stopped consuming it, the adverse effects dissipated. Since then, he has been astute about reading labels, and we do not support the use of any artificial sweeteners.

I believe aspartame should be taken off the market. The Internet is full of articles that report adverse effects from it. It seems more people are trying to avoid it. As an FNP and PMHNP, I educate my clients about aspartame and how it can exacerbate preexisting problems and contribute to insomnia, mood disorders, and panic/anxiety disorders.

I appreciate your scientific information about aspartame. We need to talk more about this chemical food additive; it is not our friend.

SUCRALOSE, ASPARTAME … ARE THE EFFECTS ONE AND THE SAME?

I have had negative thoughts concerning artificial sweeteners, including sucralose, which seems to be commonly used these days. I do not like the way I feel after ingesting these substances; it’s hard to describe—I just don’t feel right. I wonder if one answer lies in genomics and an individual’s inability to metabolize it? And to think of the byproducts you describe. Thank you for bringing this topic to light.

Anna Simon, CRNP
Allentown, PA

A DIETARY DIAGNOSIS

I’m a hospital CEO and came across an NP colleague’s issue of Clinician Reviews; your September editorial on aspartame (2017;27[9]:6-7) caught my eye. While mine is another “n = 1” experience with the effects of aspartame, it was life-changing.

About 10 years ago, my former wife’s seizures suddenly increased in frequency after a fairly lengthy period without them. The problem was severe enough that she was faced with losing her ability to drive a car.

I had a good business relationship with the Massachusetts General Hospital and sought help from a prominent neurologist there. He asked us to keep a dietary journal before the appointment.

Though he ordered routine diagnostic tests, the journal told him all he needed to know: He told her to eliminate aspartame from her diet. It felt like a miracle when the seizures disappeared—no longer did I need to maintain bumpers on every sharp edge in the house!

Since this experience, I read every article that I can about this chemical additive and was interested to learn of your experiences.

Doug Jones
Ellsworth, ME

THE SCIENCE IS JUNK

I had to write because I can’t believe they allowed you to publish such a ridiculous article based on junk science. Anecdotal reports have no place in medicine. Aspartame is one of the most studied food items around. Many of these claims about the alleged danger of aspartame have been debunked by real scientists.

I am very disappointed.

Darlene Elliott, MSN, RN, CNP
Albuquerque, NM

STOP IGNORING THE BODY OF KNOWLEDGE

Thank you for addressing an issue that I believe to be of great importance. There is a huge body of knowledge that the medical community is ignoring regarding the correlation between diet and health in general, in particular the diabetes epidemic. As NPs, we are in a great position to lead.

I encourage you to read Jason Fung’s book, The Obesity Code. The entire book is eye popping, but chapter 15 (“The Diet Soda Delusion”) is particularly pertinent. He has the most thorough understanding of carbohydrate metabolism of all the authors I have read. However, Gary Taubes and Eric Westman have also published valuable resources; their books have changed my life, and I believe their knowledge could apply to many of our patients. If doctors will not embrace science, perhaps NPs will.

Martha DelGiudice, CNM
Smithtown, NY

MAYBE IT'S US …

Every time the “fasten seat belt” sign comes on, the ride gets very bumpy—so from now on, I’m going to ignore it. Aspartame “tricks our brain,” does it? What about agency? Or are we just passive leaves in the air blown about by gusts of aspartame?

Robert Pearlman, PA
Providence, RI

FAST TRACK FROM SWEET TO SOUR

Thank you for shedding light on the dangers of aspartame! My personal experience with it has not been good: One night, after drinking a large quantity of artificially sweetened powdered iced tea, I began to feel numb and experienced strange nerve sensations. I quickly learned that it is a migraine trigger for me. I now avoid aspartame and all other artificial sweeteners.

As a clinical dietitian (and NP), I’ve realized that fake food just doesn’t cut it for the body. Another issue in the dietary realm is that of folic acid. Yes, fortification has done wonders for preventing neural tube defects. But did you know that the folic acid put in our grains is a chemical that our bodies have to methylate to folinic acid, and that more than half of us do not do that well? This means excess synthetic folic acid is floating around in our bodies and brains, attributing to seizures, ADD, ADHD, migraines, miscarriages, etc.

I try to avoid eating foods with added folic acid. Talk about difficult! It means eating a lot of organic grains, whole grains, and natural vitamins with natural methylfolate to prevent anemia. Our bodies are designed to eat natural foods; the more processed something is, the more likely it is to be harmful to us.

Caroline Conneen, C-FNP, RD, IBCLC
Fredericksburg, VA

FAKE FOOD, NOT OUR FRIEND

My husband was habitually drinking flavored seltzer sweetened with aspartame when he became anxious, irritable, and developed insomnia. As soon as he stopped consuming it, the adverse effects dissipated. Since then, he has been astute about reading labels, and we do not support the use of any artificial sweeteners.

I believe aspartame should be taken off the market. The Internet is full of articles that report adverse effects from it. It seems more people are trying to avoid it. As an FNP and PMHNP, I educate my clients about aspartame and how it can exacerbate preexisting problems and contribute to insomnia, mood disorders, and panic/anxiety disorders.

I appreciate your scientific information about aspartame. We need to talk more about this chemical food additive; it is not our friend.

SUCRALOSE, ASPARTAME … ARE THE EFFECTS ONE AND THE SAME?

I have had negative thoughts concerning artificial sweeteners, including sucralose, which seems to be commonly used these days. I do not like the way I feel after ingesting these substances; it’s hard to describe—I just don’t feel right. I wonder if one answer lies in genomics and an individual’s inability to metabolize it? And to think of the byproducts you describe. Thank you for bringing this topic to light.

Anna Simon, CRNP
Allentown, PA

A DIETARY DIAGNOSIS

I’m a hospital CEO and came across an NP colleague’s issue of Clinician Reviews; your September editorial on aspartame (2017;27[9]:6-7) caught my eye. While mine is another “n = 1” experience with the effects of aspartame, it was life-changing.

About 10 years ago, my former wife’s seizures suddenly increased in frequency after a fairly lengthy period without them. The problem was severe enough that she was faced with losing her ability to drive a car.

I had a good business relationship with the Massachusetts General Hospital and sought help from a prominent neurologist there. He asked us to keep a dietary journal before the appointment.

Though he ordered routine diagnostic tests, the journal told him all he needed to know: He told her to eliminate aspartame from her diet. It felt like a miracle when the seizures disappeared—no longer did I need to maintain bumpers on every sharp edge in the house!

Since this experience, I read every article that I can about this chemical additive and was interested to learn of your experiences.

Doug Jones
Ellsworth, ME

THE SCIENCE IS JUNK

I had to write because I can’t believe they allowed you to publish such a ridiculous article based on junk science. Anecdotal reports have no place in medicine. Aspartame is one of the most studied food items around. Many of these claims about the alleged danger of aspartame have been debunked by real scientists.

I am very disappointed.

Darlene Elliott, MSN, RN, CNP
Albuquerque, NM

STOP IGNORING THE BODY OF KNOWLEDGE

Thank you for addressing an issue that I believe to be of great importance. There is a huge body of knowledge that the medical community is ignoring regarding the correlation between diet and health in general, in particular the diabetes epidemic. As NPs, we are in a great position to lead.

I encourage you to read Jason Fung’s book, The Obesity Code. The entire book is eye popping, but chapter 15 (“The Diet Soda Delusion”) is particularly pertinent. He has the most thorough understanding of carbohydrate metabolism of all the authors I have read. However, Gary Taubes and Eric Westman have also published valuable resources; their books have changed my life, and I believe their knowledge could apply to many of our patients. If doctors will not embrace science, perhaps NPs will.

Martha DelGiudice, CNM
Smithtown, NY

MAYBE IT'S US …

Every time the “fasten seat belt” sign comes on, the ride gets very bumpy—so from now on, I’m going to ignore it. Aspartame “tricks our brain,” does it? What about agency? Or are we just passive leaves in the air blown about by gusts of aspartame?

Robert Pearlman, PA
Providence, RI

FAST TRACK FROM SWEET TO SOUR

Thank you for shedding light on the dangers of aspartame! My personal experience with it has not been good: One night, after drinking a large quantity of artificially sweetened powdered iced tea, I began to feel numb and experienced strange nerve sensations. I quickly learned that it is a migraine trigger for me. I now avoid aspartame and all other artificial sweeteners.

As a clinical dietitian (and NP), I’ve realized that fake food just doesn’t cut it for the body. Another issue in the dietary realm is that of folic acid. Yes, fortification has done wonders for preventing neural tube defects. But did you know that the folic acid put in our grains is a chemical that our bodies have to methylate to folinic acid, and that more than half of us do not do that well? This means excess synthetic folic acid is floating around in our bodies and brains, attributing to seizures, ADD, ADHD, migraines, miscarriages, etc.

I try to avoid eating foods with added folic acid. Talk about difficult! It means eating a lot of organic grains, whole grains, and natural vitamins with natural methylfolate to prevent anemia. Our bodies are designed to eat natural foods; the more processed something is, the more likely it is to be harmful to us.

Caroline Conneen, C-FNP, RD, IBCLC
Fredericksburg, VA

FAKE FOOD, NOT OUR FRIEND

My husband was habitually drinking flavored seltzer sweetened with aspartame when he became anxious, irritable, and developed insomnia. As soon as he stopped consuming it, the adverse effects dissipated. Since then, he has been astute about reading labels, and we do not support the use of any artificial sweeteners.

I believe aspartame should be taken off the market. The Internet is full of articles that report adverse effects from it. It seems more people are trying to avoid it. As an FNP and PMHNP, I educate my clients about aspartame and how it can exacerbate preexisting problems and contribute to insomnia, mood disorders, and panic/anxiety disorders.

I appreciate your scientific information about aspartame. We need to talk more about this chemical food additive; it is not our friend.

SUCRALOSE, ASPARTAME … ARE THE EFFECTS ONE AND THE SAME?

I have had negative thoughts concerning artificial sweeteners, including sucralose, which seems to be commonly used these days. I do not like the way I feel after ingesting these substances; it’s hard to describe—I just don’t feel right. I wonder if one answer lies in genomics and an individual’s inability to metabolize it? And to think of the byproducts you describe. Thank you for bringing this topic to light.

Anna Simon, CRNP
Allentown, PA

WASHINGTON – In patients with epilepsy, treatment of obstructive sleep apnea with continuous positive airway pressure may lead to substantial and sustained reductions in seizure activity, according to data presented at the annual meeting of the American Epilepsy Society.

The reduction in seizure activity with continuous positive airway pressure (cPAP) in patients with epilepsy contributes to other evidence that poor sleep quality is an important but preventable risk factor for seizures, according to Thapanee Somboon, MD, a research fellow at the Sleep Disorders Center at the Cleveland Clinic in Ohio.

Ted Bosworth/Frontline Medical News

Dr. Somboon reported no financial relationships relevant to the study.

WASHINGTON – In patients with epilepsy, treatment of obstructive sleep apnea with continuous positive airway pressure may lead to substantial and sustained reductions in seizure activity, according to data presented at the annual meeting of the American Epilepsy Society.

The reduction in seizure activity with continuous positive airway pressure (cPAP) in patients with epilepsy contributes to other evidence that poor sleep quality is an important but preventable risk factor for seizures, according to Thapanee Somboon, MD, a research fellow at the Sleep Disorders Center at the Cleveland Clinic in Ohio.

Ted Bosworth/Frontline Medical News

Dr. Somboon reported no financial relationships relevant to the study.

WASHINGTON – In patients with epilepsy, treatment of obstructive sleep apnea with continuous positive airway pressure may lead to substantial and sustained reductions in seizure activity, according to data presented at the annual meeting of the American Epilepsy Society.

The reduction in seizure activity with continuous positive airway pressure (cPAP) in patients with epilepsy contributes to other evidence that poor sleep quality is an important but preventable risk factor for seizures, according to Thapanee Somboon, MD, a research fellow at the Sleep Disorders Center at the Cleveland Clinic in Ohio.

Ted Bosworth/Frontline Medical News

Dr. Somboon reported no financial relationships relevant to the study.

Intense monitoring of urine output could be a useful tool in detecting acute kidney injury (AKI), according to a study conducted at the University of Pittsburgh.

Kui Jin, MD, of the University of Pittsburgh and his associates found that, after adjustment for baseline characteristics, intensive monitoring of urine output (UO) was associated with higher rates of AKI, with an odds ratio of 1.22. Intensive UO monitoring also was strongly associated with improved 30-day survival among patients developing AKI.

shironosov/Thinkstock

None of the authors had financial disclosures to report. Partial funding was provided by a research grant from C.R. Bard.

[email protected]

Intense monitoring of urine output could be a useful tool in detecting acute kidney injury (AKI), according to a study conducted at the University of Pittsburgh.

Kui Jin, MD, of the University of Pittsburgh and his associates found that, after adjustment for baseline characteristics, intensive monitoring of urine output (UO) was associated with higher rates of AKI, with an odds ratio of 1.22. Intensive UO monitoring also was strongly associated with improved 30-day survival among patients developing AKI.

shironosov/Thinkstock

None of the authors had financial disclosures to report. Partial funding was provided by a research grant from C.R. Bard.

[email protected]

Intense monitoring of urine output could be a useful tool in detecting acute kidney injury (AKI), according to a study conducted at the University of Pittsburgh.

Kui Jin, MD, of the University of Pittsburgh and his associates found that, after adjustment for baseline characteristics, intensive monitoring of urine output (UO) was associated with higher rates of AKI, with an odds ratio of 1.22. Intensive UO monitoring also was strongly associated with improved 30-day survival among patients developing AKI.

shironosov/Thinkstock

None of the authors had financial disclosures to report. Partial funding was provided by a research grant from C.R. Bard.

[email protected]

SAN ANTONIO – An easy-to-use risk stratification tool accurately predicted which pregnancies of unknown location were ectopic pregnancies by using a model validated by retrospective chart review.

Reeva Makhijani, MD, and her colleagues built the tool using a composite of risk factors to create a “generalized additive model,” or GAM, in combination with beta HCG levels. They presented the results during a poster session at the annual meeting of the American Society for Reproductive Medicine.

The model showed that a prior history of ectopic pregnancy (EP) (P = .0045), a history of pelvic surgery (P = .397), and a presentation of vaginal bleeding (P = .0003) all significantly increased the risk of EP.

Another statistical measure, the area under the receiver operating curve (AUC), helps estimate the likelihood of EP according to beta-HCG levels. When the initial beta-HCG was considered together with the ratio of the initial beta HCG to the presenting beta-HCG, the AUC was 0.889. For the initial beta-HCG level alone, the AUC was 0.793, while for the ratio alone, the AUC was 0.88. Higher AUC figures indicate more predictive power.

Dr. Makhijani, an ob.gyn. resident physician at Brown University, Providence, R.I., and her colleagues have built a prototype of a computer application that calculates risk of EP when the significant risk factors and lab values are entered.

After reviewing the electronic medical records of 800 patients who had pregnancies of unknown location (PUL), in the final analysis Dr. Makhijani and her coauthors included 398 patients whose medical histories allowed assessment of risk factors and whose record included at least two beta-HCG values taken 36-72 hours apart. The investigators also excluded patients with molar pregnancies, ruptured EPs, or who had undergone surgery before a second beta-HCG was obtained.

Of the 398 patients, 40 (10%) were eventually found to have EP, while 168 (42%) had an intrauterine pregnancy, and 190 (48%) were diagnosed with spontaneous abortion.

The patients were about 27 years old on average, and just over half (n = 224) were parous. Vaginal bleeding was a presenting sign in 233 patients, and 284 had abdominal pain. Of those with EP, 34 of 40 had vaginal bleeding, and 25 of 40 had abdominal pain.

In addition to the three factors found to have significant association with EP, the investigators initially considered a number of other patient characteristics, including age, parity, and presentation with abdominal pain. Additional risk factors examined included history of infertility, pelvic inflammatory disease, sexually transmitted disease, intrauterine device placement, and diethylstilbestrol (DES) exposure. None of these were significantly associated with risk of EP.

“Our model can be translated into an easy-to-use risk stratification tool that can accurately predict the risk of EP,” said Dr. Makhijani and her coauthors. “This tool could potentially be used by clinicians and ob.gyn. residencies nationally as [pregnancies of unknown location] are a very common management scenario.”

Dr. Makhijani reported having no disclosures and no outside sources of funding.

[email protected]

On Twitter @karioakes

SAN ANTONIO – An easy-to-use risk stratification tool accurately predicted which pregnancies of unknown location were ectopic pregnancies by using a model validated by retrospective chart review.

Reeva Makhijani, MD, and her colleagues built the tool using a composite of risk factors to create a “generalized additive model,” or GAM, in combination with beta HCG levels. They presented the results during a poster session at the annual meeting of the American Society for Reproductive Medicine.

The model showed that a prior history of ectopic pregnancy (EP) (P = .0045), a history of pelvic surgery (P = .397), and a presentation of vaginal bleeding (P = .0003) all significantly increased the risk of EP.

Another statistical measure, the area under the receiver operating curve (AUC), helps estimate the likelihood of EP according to beta-HCG levels. When the initial beta-HCG was considered together with the ratio of the initial beta HCG to the presenting beta-HCG, the AUC was 0.889. For the initial beta-HCG level alone, the AUC was 0.793, while for the ratio alone, the AUC was 0.88. Higher AUC figures indicate more predictive power.

Dr. Makhijani, an ob.gyn. resident physician at Brown University, Providence, R.I., and her colleagues have built a prototype of a computer application that calculates risk of EP when the significant risk factors and lab values are entered.

After reviewing the electronic medical records of 800 patients who had pregnancies of unknown location (PUL), in the final analysis Dr. Makhijani and her coauthors included 398 patients whose medical histories allowed assessment of risk factors and whose record included at least two beta-HCG values taken 36-72 hours apart. The investigators also excluded patients with molar pregnancies, ruptured EPs, or who had undergone surgery before a second beta-HCG was obtained.

Of the 398 patients, 40 (10%) were eventually found to have EP, while 168 (42%) had an intrauterine pregnancy, and 190 (48%) were diagnosed with spontaneous abortion.

The patients were about 27 years old on average, and just over half (n = 224) were parous. Vaginal bleeding was a presenting sign in 233 patients, and 284 had abdominal pain. Of those with EP, 34 of 40 had vaginal bleeding, and 25 of 40 had abdominal pain.

In addition to the three factors found to have significant association with EP, the investigators initially considered a number of other patient characteristics, including age, parity, and presentation with abdominal pain. Additional risk factors examined included history of infertility, pelvic inflammatory disease, sexually transmitted disease, intrauterine device placement, and diethylstilbestrol (DES) exposure. None of these were significantly associated with risk of EP.

“Our model can be translated into an easy-to-use risk stratification tool that can accurately predict the risk of EP,” said Dr. Makhijani and her coauthors. “This tool could potentially be used by clinicians and ob.gyn. residencies nationally as [pregnancies of unknown location] are a very common management scenario.”

Dr. Makhijani reported having no disclosures and no outside sources of funding.

[email protected]

On Twitter @karioakes

SAN ANTONIO – An easy-to-use risk stratification tool accurately predicted which pregnancies of unknown location were ectopic pregnancies by using a model validated by retrospective chart review.

Reeva Makhijani, MD, and her colleagues built the tool using a composite of risk factors to create a “generalized additive model,” or GAM, in combination with beta HCG levels. They presented the results during a poster session at the annual meeting of the American Society for Reproductive Medicine.

The model showed that a prior history of ectopic pregnancy (EP) (P = .0045), a history of pelvic surgery (P = .397), and a presentation of vaginal bleeding (P = .0003) all significantly increased the risk of EP.

Another statistical measure, the area under the receiver operating curve (AUC), helps estimate the likelihood of EP according to beta-HCG levels. When the initial beta-HCG was considered together with the ratio of the initial beta HCG to the presenting beta-HCG, the AUC was 0.889. For the initial beta-HCG level alone, the AUC was 0.793, while for the ratio alone, the AUC was 0.88. Higher AUC figures indicate more predictive power.

Dr. Makhijani, an ob.gyn. resident physician at Brown University, Providence, R.I., and her colleagues have built a prototype of a computer application that calculates risk of EP when the significant risk factors and lab values are entered.

After reviewing the electronic medical records of 800 patients who had pregnancies of unknown location (PUL), in the final analysis Dr. Makhijani and her coauthors included 398 patients whose medical histories allowed assessment of risk factors and whose record included at least two beta-HCG values taken 36-72 hours apart. The investigators also excluded patients with molar pregnancies, ruptured EPs, or who had undergone surgery before a second beta-HCG was obtained.

Of the 398 patients, 40 (10%) were eventually found to have EP, while 168 (42%) had an intrauterine pregnancy, and 190 (48%) were diagnosed with spontaneous abortion.

The patients were about 27 years old on average, and just over half (n = 224) were parous. Vaginal bleeding was a presenting sign in 233 patients, and 284 had abdominal pain. Of those with EP, 34 of 40 had vaginal bleeding, and 25 of 40 had abdominal pain.

In addition to the three factors found to have significant association with EP, the investigators initially considered a number of other patient characteristics, including age, parity, and presentation with abdominal pain. Additional risk factors examined included history of infertility, pelvic inflammatory disease, sexually transmitted disease, intrauterine device placement, and diethylstilbestrol (DES) exposure. None of these were significantly associated with risk of EP.

“Our model can be translated into an easy-to-use risk stratification tool that can accurately predict the risk of EP,” said Dr. Makhijani and her coauthors. “This tool could potentially be used by clinicians and ob.gyn. residencies nationally as [pregnancies of unknown location] are a very common management scenario.”

Dr. Makhijani reported having no disclosures and no outside sources of funding.

[email protected]

On Twitter @karioakes

Research on pregnancy is now being crowdsourced, with pregnant women being asked in a new federal research project to “tell researchers and health care providers what pregnancy is really like.”

The project, PregSource, was launched in November by the National Institute of Child Health and Human Development (NICHD). Women who join PregSource (https://pregsource.nih.gov) are asked to chart changes to their weight, sleep, mood, morning sickness, and physical activity and to answer monthly online surveys about their pregnancy experiences, symptoms, and complications. It is hoped that resulting de-identified data will help inform future studies and improve maternal care, NICHD officials said.

digitalskillet/Thinkstock

“We spend a lot of time talking about the complications of pregnancy, but we don’t know a whole lot about the baseline experiences. . .the experiential trends of pregnancy” such as how many women experience morning sickness and for how long, and how pregnancy affects sleep patterns, she said.

By crowdsourcing to pregnant women themselves – by asking them to voluntarily offer data and make observations, “we’re researching on a large scale and doing so relatively cost effectively,” said Dr. Signore, an ob.gyn. “Women who are interested in contributing to science can [do so] on their own terms. They can visit PregSource on their own time and enter as much data as they want.”

Hal E. Lawrence III, MD, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists, called the project “groundbreaking” and said that NICHD should have “no problem” meeting its initial target of 100,000 pregnant women. “This is different from the other pregnancy apps,” he said. “This is more of a reporting and an informative [site], which the others aren’t.”

ACOG is one of about a dozen partnering organizations – along with the American Academy of Pediatrics and the American College of Nurse-Midwives – that have worked with NICHD on shaping the project and contributing content for a resource library that PregSource participants will have access to.

The project is currently in a “soft-launch phase,” Dr. Signore said, and will step up its outreach to women and providers in January.

Along with the current series of “trackers” and monthly questionnaires (in addition to questionnaires about prepregnancy health), women who indicate that they have physical disabilities or certain complications or conditions such as diabetes will be asked to participate in additional information-gathering modules. And once the project has amassed enough data, women will be able to compare specific experiences with those of other participants.

“A woman who’s 5 months’ pregnant and completes questions on nausea and vomiting, say, can click a button and see how everyone else who’s been in PregSource at this time has answered that question,” Dr. Signore said. “Or a woman who indicates she’s having a lot of heartburn at 27 weeks can learn about how many other women are having heartburn. We think this will be valuable for women, because [they’re] always wondering, ‘Is my experience unique?’ ”

NICHD officials said they hope women will share with their ob.gyns. or other providers the charts from their PregSource trackers, such as those plotting the individual’s weight gain against Institute of Medicine-recommended weight gain ranges. “We like to think that PregSource will promote conversations and shared decision making. . .and hopefully that it will improve that individual woman’s outcomes,” Dr. Signore said.

Indeed, said Uma M. Reddy, MD, MPH, project scientist for the NICHD’s Maternal-Fetal Medicine Units (MFMU) Network, women who use PregSource’s trackers should be “more in tune with their pregnancies” and with staying healthy. She and other experts touted PregSource at the recent biennial meeting of the Diabetes in Pregnancy Study Group.

The NICHD also plans to gently nudge women toward any relevant clinical studies underway in their locales “by simply notifying the women and making the information available to them,” Dr. Signore said. In addition, the project will invite women to track their experiences for several years after childbirth so more data can be generated on associations between pregnancy and child and maternal health. “Just as with the whole project, we’re trying to take into account the benefit-burden ratio and hope that women will continue to see value,” she said.

The NICHD-sponsored project will not sell or share any personal information to a third party, and participants will not receive any ads or product announcements. Data from the project – all of it de-identified – will be shared with approved researchers for their own analyses.

“We see it being already equipped to answer [existing] questions and to probe relationships” between pregnancy characteristics and complications, for instance, Dr. Signore said. “But it also could be a hypothesis-generating resource.”

A Spanish version will come “once we know we’ve optimized functionality and syntax,” she said. And overall, the NICHD is ready for growth, both in numbers of participants and in content.

ACOG is rooting for its success, Dr. Lawrence said. “We’ll have to wait and see how the results help us, but I’ll tell you one thing, having no data will never help us.”

Research on pregnancy is now being crowdsourced, with pregnant women being asked in a new federal research project to “tell researchers and health care providers what pregnancy is really like.”

The project, PregSource, was launched in November by the National Institute of Child Health and Human Development (NICHD). Women who join PregSource (https://pregsource.nih.gov) are asked to chart changes to their weight, sleep, mood, morning sickness, and physical activity and to answer monthly online surveys about their pregnancy experiences, symptoms, and complications. It is hoped that resulting de-identified data will help inform future studies and improve maternal care, NICHD officials said.

digitalskillet/Thinkstock

“We spend a lot of time talking about the complications of pregnancy, but we don’t know a whole lot about the baseline experiences. . .the experiential trends of pregnancy” such as how many women experience morning sickness and for how long, and how pregnancy affects sleep patterns, she said.

By crowdsourcing to pregnant women themselves – by asking them to voluntarily offer data and make observations, “we’re researching on a large scale and doing so relatively cost effectively,” said Dr. Signore, an ob.gyn. “Women who are interested in contributing to science can [do so] on their own terms. They can visit PregSource on their own time and enter as much data as they want.”

Hal E. Lawrence III, MD, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists, called the project “groundbreaking” and said that NICHD should have “no problem” meeting its initial target of 100,000 pregnant women. “This is different from the other pregnancy apps,” he said. “This is more of a reporting and an informative [site], which the others aren’t.”

ACOG is one of about a dozen partnering organizations – along with the American Academy of Pediatrics and the American College of Nurse-Midwives – that have worked with NICHD on shaping the project and contributing content for a resource library that PregSource participants will have access to.

The project is currently in a “soft-launch phase,” Dr. Signore said, and will step up its outreach to women and providers in January.

Along with the current series of “trackers” and monthly questionnaires (in addition to questionnaires about prepregnancy health), women who indicate that they have physical disabilities or certain complications or conditions such as diabetes will be asked to participate in additional information-gathering modules. And once the project has amassed enough data, women will be able to compare specific experiences with those of other participants.

“A woman who’s 5 months’ pregnant and completes questions on nausea and vomiting, say, can click a button and see how everyone else who’s been in PregSource at this time has answered that question,” Dr. Signore said. “Or a woman who indicates she’s having a lot of heartburn at 27 weeks can learn about how many other women are having heartburn. We think this will be valuable for women, because [they’re] always wondering, ‘Is my experience unique?’ ”

NICHD officials said they hope women will share with their ob.gyns. or other providers the charts from their PregSource trackers, such as those plotting the individual’s weight gain against Institute of Medicine-recommended weight gain ranges. “We like to think that PregSource will promote conversations and shared decision making. . .and hopefully that it will improve that individual woman’s outcomes,” Dr. Signore said.

Indeed, said Uma M. Reddy, MD, MPH, project scientist for the NICHD’s Maternal-Fetal Medicine Units (MFMU) Network, women who use PregSource’s trackers should be “more in tune with their pregnancies” and with staying healthy. She and other experts touted PregSource at the recent biennial meeting of the Diabetes in Pregnancy Study Group.

The NICHD also plans to gently nudge women toward any relevant clinical studies underway in their locales “by simply notifying the women and making the information available to them,” Dr. Signore said. In addition, the project will invite women to track their experiences for several years after childbirth so more data can be generated on associations between pregnancy and child and maternal health. “Just as with the whole project, we’re trying to take into account the benefit-burden ratio and hope that women will continue to see value,” she said.

The NICHD-sponsored project will not sell or share any personal information to a third party, and participants will not receive any ads or product announcements. Data from the project – all of it de-identified – will be shared with approved researchers for their own analyses.

“We see it being already equipped to answer [existing] questions and to probe relationships” between pregnancy characteristics and complications, for instance, Dr. Signore said. “But it also could be a hypothesis-generating resource.”

A Spanish version will come “once we know we’ve optimized functionality and syntax,” she said. And overall, the NICHD is ready for growth, both in numbers of participants and in content.

ACOG is rooting for its success, Dr. Lawrence said. “We’ll have to wait and see how the results help us, but I’ll tell you one thing, having no data will never help us.”

Research on pregnancy is now being crowdsourced, with pregnant women being asked in a new federal research project to “tell researchers and health care providers what pregnancy is really like.”

The project, PregSource, was launched in November by the National Institute of Child Health and Human Development (NICHD). Women who join PregSource (https://pregsource.nih.gov) are asked to chart changes to their weight, sleep, mood, morning sickness, and physical activity and to answer monthly online surveys about their pregnancy experiences, symptoms, and complications. It is hoped that resulting de-identified data will help inform future studies and improve maternal care, NICHD officials said.

digitalskillet/Thinkstock

“We spend a lot of time talking about the complications of pregnancy, but we don’t know a whole lot about the baseline experiences. . .the experiential trends of pregnancy” such as how many women experience morning sickness and for how long, and how pregnancy affects sleep patterns, she said.

By crowdsourcing to pregnant women themselves – by asking them to voluntarily offer data and make observations, “we’re researching on a large scale and doing so relatively cost effectively,” said Dr. Signore, an ob.gyn. “Women who are interested in contributing to science can [do so] on their own terms. They can visit PregSource on their own time and enter as much data as they want.”

Hal E. Lawrence III, MD, executive vice president and chief executive officer of the American College of Obstetricians and Gynecologists, called the project “groundbreaking” and said that NICHD should have “no problem” meeting its initial target of 100,000 pregnant women. “This is different from the other pregnancy apps,” he said. “This is more of a reporting and an informative [site], which the others aren’t.”

ACOG is one of about a dozen partnering organizations – along with the American Academy of Pediatrics and the American College of Nurse-Midwives – that have worked with NICHD on shaping the project and contributing content for a resource library that PregSource participants will have access to.

The project is currently in a “soft-launch phase,” Dr. Signore said, and will step up its outreach to women and providers in January.

Along with the current series of “trackers” and monthly questionnaires (in addition to questionnaires about prepregnancy health), women who indicate that they have physical disabilities or certain complications or conditions such as diabetes will be asked to participate in additional information-gathering modules. And once the project has amassed enough data, women will be able to compare specific experiences with those of other participants.

“A woman who’s 5 months’ pregnant and completes questions on nausea and vomiting, say, can click a button and see how everyone else who’s been in PregSource at this time has answered that question,” Dr. Signore said. “Or a woman who indicates she’s having a lot of heartburn at 27 weeks can learn about how many other women are having heartburn. We think this will be valuable for women, because [they’re] always wondering, ‘Is my experience unique?’ ”

NICHD officials said they hope women will share with their ob.gyns. or other providers the charts from their PregSource trackers, such as those plotting the individual’s weight gain against Institute of Medicine-recommended weight gain ranges. “We like to think that PregSource will promote conversations and shared decision making. . .and hopefully that it will improve that individual woman’s outcomes,” Dr. Signore said.

Indeed, said Uma M. Reddy, MD, MPH, project scientist for the NICHD’s Maternal-Fetal Medicine Units (MFMU) Network, women who use PregSource’s trackers should be “more in tune with their pregnancies” and with staying healthy. She and other experts touted PregSource at the recent biennial meeting of the Diabetes in Pregnancy Study Group.

The NICHD also plans to gently nudge women toward any relevant clinical studies underway in their locales “by simply notifying the women and making the information available to them,” Dr. Signore said. In addition, the project will invite women to track their experiences for several years after childbirth so more data can be generated on associations between pregnancy and child and maternal health. “Just as with the whole project, we’re trying to take into account the benefit-burden ratio and hope that women will continue to see value,” she said.

The NICHD-sponsored project will not sell or share any personal information to a third party, and participants will not receive any ads or product announcements. Data from the project – all of it de-identified – will be shared with approved researchers for their own analyses.

“We see it being already equipped to answer [existing] questions and to probe relationships” between pregnancy characteristics and complications, for instance, Dr. Signore said. “But it also could be a hypothesis-generating resource.”

A Spanish version will come “once we know we’ve optimized functionality and syntax,” she said. And overall, the NICHD is ready for growth, both in numbers of participants and in content.

ACOG is rooting for its success, Dr. Lawrence said. “We’ll have to wait and see how the results help us, but I’ll tell you one thing, having no data will never help us.”

NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.

Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.

Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.

In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).

During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.

Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.

Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.

“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.

In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.

A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.

In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).

“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.

The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.

“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.

Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.

[email protected]

NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.

Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.

Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.

In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).

During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.

Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.

Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.

“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.

In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.

A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.

In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).

“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.

The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.

“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.

Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.

[email protected]

NATIONAL HARBOR, MD. – Combination treatment with the first-in-class glutaminase inhibitor CB-839 and nivolumab is well-tolerated and shows clinical activity in patients with advanced melanoma, renal cell carcinoma, or non-small cell lung cancer, including anti-PD-1/PD-L1 refractory patients, according to initial results from a phase 1/2 study.

Responses in melanoma patients who were progressing on nivolumab at study entry and who were refractory to multiple prior immunotherapy regimens are particularly notable, as they highlight the potential for CB-839, when added to nivolumab (Opdivo), to help overcome resistance to anti-PD-L1 therapy, Funda Meric‐Bernstam, MD, reported at the annual meeting of the Society for Immunotherapy of Cancer.

CB‐839 is highly selective and targets tumor glutamine metabolism, said Dr. Meric-Bernstam of the University of Texas MD Anderson Cancer Center, Houston.

Competition between tumor cells and immune cells for nutrients such as glutamine in the tumor microenvironment can create a metabolic checkpoint that induces local immune suppression. CB‐839 inhibits tumor glutamine consumption, thereby increasing glutamine availability to support T‐cell activity, she explained, noting that in preclinical models, CB‐839 increased intra‐tumoral glutamine and enhanced antitumor activity of PD‐1/PD‐L1 inhibitors.

In the phase 1 dose escalation study, she and her colleagues evaluated the safety and efficacy of CB-839 in combination with the PD‐1 inhibitor nivolumab in patients with melanoma, non-small cell lung cancer (NSCLC), or renal cell carcinoma (RCC). Phase 2 expansion cohorts include a melanoma rescue cohort of patients progressing on anti-PD-L1 therapy at study entry (22 patients), an NSCLC and RCC rescue cohort of patients who were progressing on anti-PD-L1 therapy at study entry or who had stable disease for 6 months or longer without a response (11 NSCLC and 11 RCC), an RCC cohort of patients with prior immunotherapy exposure and no response (10 patients), and an RCC cohort of patents who had no prior immunotherapy exposure (28 patients).

During dose escalation, patients received oral CB‐839 at 600 mg or 800 mg twice daily in combination with standard‐dose nivolumab. In the ongoing phase 2 expansion study, which continues to enroll, patients are receiving 800 mg of CB-839 twice daily with standard‐dose nivolumab, Dr. Meric-Bernstam said.

Patients in each of the cohorts were high risk and/or had intermediate or poor prognostic status at study entry. For example, 50% of patients in the melanoma rescue cohort had liver metastases, 77% had other visceral metastases, and 18% had brain metastases, and the majority of patients in the lung cancer/RCC cohort had visceral metastases. Most had progressive disease as their best response on their last line of immunotherapy.

Of 16 response-evaluable melanoma patients, 1 experienced a complete response, 2 had partial responses, and 4 had stable disease.

“So overall in this patient population that was progressing on a PD-1/PD-L1 inhibitor at enrollment, 19% had an objective response. The disease control rate in this group was 44%,” she said.

In evaluable patients in the lung cancer rescue cohort (6 patients), RCC rescue cohort (8 patients), and RCC prior exposure cohort (7 patients), disease control rates ranged from 57% to 75%, and in the immunotherapy-naive RCC cohort (19 patients), the partial response rate was 21%, and 53% had stable disease, so the overall disease control rate was 74%. Half of the patients in that group remain on study, she noted.

A closer look at the melanoma rescue cohort showed dramatic and rapid responses in two patients who each achieved a partial response in about 8 weeks with response durations of 3.7 months and 5.4 months, respectively. Additionally, pre-treatment biopsies in this cohort showed an elevated T-cell inflamed signature associated with clinical benefit from the addition of CB-839, and in one patient who had both a pretreatment and on-treatment biopsy that was evaluable, the latter showed an increase in T-cell inflamed signature and T-cell effector genes.

In all cohorts, the combination therapy was generally well tolerated. A maximum tolerated dose was not reached. Dose-limiting toxicity – a grade 3 alanine aminotransferase (ALT) increase – occurred in one patient on the 800-mg dose. The most common grade 3 or greater adverse events were fatigue, nausea, photophobia, rash, and elevated ALT, she said, noting that two patients discontinued for treatment-related adverse events (one for a grade 3 rash and one for grade 2 pneumonitis).

“Overall there appeared to be no apparent increase in immune-related adverse events, either in rate or severity, compared with [nivolumab] monotherapy,” she said.

The combination of CB-839 and nivolumab was well tolerated, and in some patients – as seen in the melanoma cohort – adding CB-839 to checkpoint blockade can overcome checkpoint blockade resistance, Dr. Meric-Bernstam concluded, noting that the disease control rates seen in the majority of lung cancer and RCC patients who were progressing on checkpoint blockade is encouraging, as is the objective response rate seen thus far in the RCC therapy-naive patients, and the stable and deep responses seen in the melanoma rescue cohort.

“Based on our encouraging signal in the melanoma rescue cohort, this [cohort] has been expanded,” she said.

Calithera Biosciences sponsored the study. Bristol-Myers Squibb provided nivolumab for the study. Dr. Meric-Bernstam has received grant or research support from Calithera Biosciences and many other companies. She also reported being a paid consultant for several companies and serving on an advisory committee or review panel, or as a board member for multiple companies.

[email protected]

Pancreatic tumor involvement with the superior mesenteric vein/portal vein (SMV/PV) is common and requires exploration and resection, which has now become an integral part of routine surgical treatment. The short-term outcome of SMV/PV reconstruction with interposed cold-stored cadaveric venous allografts was found to be comparable to that of reconstruction with primary end-to-end anastomosis, according to the results of a study performed by Dyre Kleive, MD, and his colleagues.

In order to assess the optimal method of reconstructing the portal vein during pancreatic surgery, Dr. Kleive and his colleagues performed a retrospective review of all patients undergoing pancreatic surgery with venous resection and reconstruction at a single center between January 2006 and December 2015.

A total of 857 patients underwent open pancreatic surgery during the study period, of whom 171 (20%) had vascular resection and reconstruction. The study population comprised 42 patients treated with cold-stored interposition cadaveric allografts for reconstruction and 71 patients who had primary end-to-end anastomosis instead. Patients with other forms of reconstruction were excluded, according to an online report in the Journal of Vascular Surgery: Venous and Lymphatic Disorders (2017. doi: 10.1016/j.jvsv.2017.09.003).

Early failure at the reconstruction site was defined as the presence of thrombosis or no flow or low flow within the first 30 days after surgery.

Patients in the allograft group had statistically significantly longer mean operative times, more intraoperative bleeding, more frequent use of neoadjuvant therapy, and a longer length of tumor-vein involvement than the anastomosis group.

However, there was no statistically significant difference in the number of patients with major complications (42.9% for allografts vs. 36.6% for anastomosis) or early failure at the reconstruction site (9.5% for allografts vs. 8.5% for anastomosis) between the two groups, Dr Kleive and his colleagues reported.

The proportion of patients with grade C stenosis at last available imaging scan was significantly higher in the allograft group (26/42 [61.9%] vs. 13 of 66 [19.7%] for the anastomosis group; P less than .01). A subgroup analysis of 10 patients in the allograft group showed the presence of donor-specific antibodies in all patients. This could indicate that graft rejection was a contributing factor to the statistically higher development of severe stenosis in allograft vs. anastomosis patients, the authors suggested.

“This study shows that the short-term outcome of SMV/PV reconstruction with interposed cold-stored cadaveric venous allografts is comparable to that of reconstruction with primary end-to-end anastomosis,” the researchers concluded.

Dr. Kleive and his colleagues reported that they had no conflicts of interest.

[email protected]

Pancreatic tumor involvement with the superior mesenteric vein/portal vein (SMV/PV) is common and requires exploration and resection, which has now become an integral part of routine surgical treatment. The short-term outcome of SMV/PV reconstruction with interposed cold-stored cadaveric venous allografts was found to be comparable to that of reconstruction with primary end-to-end anastomosis, according to the results of a study performed by Dyre Kleive, MD, and his colleagues.

In order to assess the optimal method of reconstructing the portal vein during pancreatic surgery, Dr. Kleive and his colleagues performed a retrospective review of all patients undergoing pancreatic surgery with venous resection and reconstruction at a single center between January 2006 and December 2015.

A total of 857 patients underwent open pancreatic surgery during the study period, of whom 171 (20%) had vascular resection and reconstruction. The study population comprised 42 patients treated with cold-stored interposition cadaveric allografts for reconstruction and 71 patients who had primary end-to-end anastomosis instead. Patients with other forms of reconstruction were excluded, according to an online report in the Journal of Vascular Surgery: Venous and Lymphatic Disorders (2017. doi: 10.1016/j.jvsv.2017.09.003).

Early failure at the reconstruction site was defined as the presence of thrombosis or no flow or low flow within the first 30 days after surgery.

Patients in the allograft group had statistically significantly longer mean operative times, more intraoperative bleeding, more frequent use of neoadjuvant therapy, and a longer length of tumor-vein involvement than the anastomosis group.

However, there was no statistically significant difference in the number of patients with major complications (42.9% for allografts vs. 36.6% for anastomosis) or early failure at the reconstruction site (9.5% for allografts vs. 8.5% for anastomosis) between the two groups, Dr Kleive and his colleagues reported.

The proportion of patients with grade C stenosis at last available imaging scan was significantly higher in the allograft group (26/42 [61.9%] vs. 13 of 66 [19.7%] for the anastomosis group; P less than .01). A subgroup analysis of 10 patients in the allograft group showed the presence of donor-specific antibodies in all patients. This could indicate that graft rejection was a contributing factor to the statistically higher development of severe stenosis in allograft vs. anastomosis patients, the authors suggested.

“This study shows that the short-term outcome of SMV/PV reconstruction with interposed cold-stored cadaveric venous allografts is comparable to that of reconstruction with primary end-to-end anastomosis,” the researchers concluded.

Dr. Kleive and his colleagues reported that they had no conflicts of interest.

[email protected]

Pancreatic tumor involvement with the superior mesenteric vein/portal vein (SMV/PV) is common and requires exploration and resection, which has now become an integral part of routine surgical treatment. The short-term outcome of SMV/PV reconstruction with interposed cold-stored cadaveric venous allografts was found to be comparable to that of reconstruction with primary end-to-end anastomosis, according to the results of a study performed by Dyre Kleive, MD, and his colleagues.

In order to assess the optimal method of reconstructing the portal vein during pancreatic surgery, Dr. Kleive and his colleagues performed a retrospective review of all patients undergoing pancreatic surgery with venous resection and reconstruction at a single center between January 2006 and December 2015.

A total of 857 patients underwent open pancreatic surgery during the study period, of whom 171 (20%) had vascular resection and reconstruction. The study population comprised 42 patients treated with cold-stored interposition cadaveric allografts for reconstruction and 71 patients who had primary end-to-end anastomosis instead. Patients with other forms of reconstruction were excluded, according to an online report in the Journal of Vascular Surgery: Venous and Lymphatic Disorders (2017. doi: 10.1016/j.jvsv.2017.09.003).

Early failure at the reconstruction site was defined as the presence of thrombosis or no flow or low flow within the first 30 days after surgery.

Patients in the allograft group had statistically significantly longer mean operative times, more intraoperative bleeding, more frequent use of neoadjuvant therapy, and a longer length of tumor-vein involvement than the anastomosis group.

However, there was no statistically significant difference in the number of patients with major complications (42.9% for allografts vs. 36.6% for anastomosis) or early failure at the reconstruction site (9.5% for allografts vs. 8.5% for anastomosis) between the two groups, Dr Kleive and his colleagues reported.

The proportion of patients with grade C stenosis at last available imaging scan was significantly higher in the allograft group (26/42 [61.9%] vs. 13 of 66 [19.7%] for the anastomosis group; P less than .01). A subgroup analysis of 10 patients in the allograft group showed the presence of donor-specific antibodies in all patients. This could indicate that graft rejection was a contributing factor to the statistically higher development of severe stenosis in allograft vs. anastomosis patients, the authors suggested.

“This study shows that the short-term outcome of SMV/PV reconstruction with interposed cold-stored cadaveric venous allografts is comparable to that of reconstruction with primary end-to-end anastomosis,” the researchers concluded.

Dr. Kleive and his colleagues reported that they had no conflicts of interest.

[email protected]

DENVER – Percutaneous coronary intervention using a contemporary drug-eluting stent on a shortened regimen of dual antiplatelet therapy proved significantly more effective and equally safe as a bare metal stent in elderly patients in the randomized, multicenter SENIOR trial.

“I think BMS [bare metal stents] should no longer be used as a strategy to reduce DAPT [dual antiplatelet therapy] duration in the elderly,” Olivier Varenne, MD, concluded in presenting the SENIOR findings at the Transcatheter Cardiovascular Therapeutics annual educational meeting.

[email protected]

DENVER – Percutaneous coronary intervention using a contemporary drug-eluting stent on a shortened regimen of dual antiplatelet therapy proved significantly more effective and equally safe as a bare metal stent in elderly patients in the randomized, multicenter SENIOR trial.

“I think BMS [bare metal stents] should no longer be used as a strategy to reduce DAPT [dual antiplatelet therapy] duration in the elderly,” Olivier Varenne, MD, concluded in presenting the SENIOR findings at the Transcatheter Cardiovascular Therapeutics annual educational meeting.

[email protected]

DENVER – Percutaneous coronary intervention using a contemporary drug-eluting stent on a shortened regimen of dual antiplatelet therapy proved significantly more effective and equally safe as a bare metal stent in elderly patients in the randomized, multicenter SENIOR trial.

“I think BMS [bare metal stents] should no longer be used as a strategy to reduce DAPT [dual antiplatelet therapy] duration in the elderly,” Olivier Varenne, MD, concluded in presenting the SENIOR findings at the Transcatheter Cardiovascular Therapeutics annual educational meeting.

[email protected]

The Food and Drug Administration has approved an extended-release, subcutaneous injection formulation of buprenorphine for use in treating moderate to severe opioid use disorder (OUD), the manufacturer of the drug announced Nov. 30.

The new product, called Sublocade, is a monthly injection intended for use in patients who have already begun treatment of OUD with transmucosal buprenorphine products, followed by a dose adjustment for a minimum of 7 days. Sublocade contains the partial mu-opioid agonist buprenorphine. By administering a consistent level of buprenorphine into the body, it ensures that levels of buprenorphine are delivered to the mu-opioid receptors, diminishing the effects of opioids, including the euphoric sensations associated with opioid use. During the clinical trial program, buprenorphine plasma concentrations of 2-3 ng/mL were found to bind to greater than 70% of mu-opioid receptors.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

The Food and Drug Administration has approved an extended-release, subcutaneous injection formulation of buprenorphine for use in treating moderate to severe opioid use disorder (OUD), the manufacturer of the drug announced Nov. 30.

The new product, called Sublocade, is a monthly injection intended for use in patients who have already begun treatment of OUD with transmucosal buprenorphine products, followed by a dose adjustment for a minimum of 7 days. Sublocade contains the partial mu-opioid agonist buprenorphine. By administering a consistent level of buprenorphine into the body, it ensures that levels of buprenorphine are delivered to the mu-opioid receptors, diminishing the effects of opioids, including the euphoric sensations associated with opioid use. During the clinical trial program, buprenorphine plasma concentrations of 2-3 ng/mL were found to bind to greater than 70% of mu-opioid receptors.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]

The Food and Drug Administration has approved an extended-release, subcutaneous injection formulation of buprenorphine for use in treating moderate to severe opioid use disorder (OUD), the manufacturer of the drug announced Nov. 30.

The new product, called Sublocade, is a monthly injection intended for use in patients who have already begun treatment of OUD with transmucosal buprenorphine products, followed by a dose adjustment for a minimum of 7 days. Sublocade contains the partial mu-opioid agonist buprenorphine. By administering a consistent level of buprenorphine into the body, it ensures that levels of buprenorphine are delivered to the mu-opioid receptors, diminishing the effects of opioids, including the euphoric sensations associated with opioid use. During the clinical trial program, buprenorphine plasma concentrations of 2-3 ng/mL were found to bind to greater than 70% of mu-opioid receptors.

Wikimedia Commons/FitzColinGerald/Creative Commons License

[email protected]